who consolidated guidelines on tuberculosis · 2020. 6. 24. · who consolidated guidelines on...

WHO consolidated guidelines ontuberculosis

Module 4: Treatment

Online annexes

Drug-resistant tuberculosis treatment

WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment. Online annexes

ISBN 978-92-4-000706-2 (electronic version)

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WHO consolidated guidelines ontuberculosis

Drug-resistant tuberculosis treatment

Module 4: Treatment

Online annexes

Contents

Abbreviations and acronyms 3

Annex 1: Methods and expert panels 5

Annex 2: Declarations of interest 31

Annex 3: GRADE evidence summary tables 44

Annex 4: GRADE evidence-to-decision tables 64

Annex 5: Summaries of unpublished data 121

Annex 6: Statistical analysis plans 129

Abbreviations and acronyms 3

Abbreviations and acronyms

ACSM advocacy, communication and social mobilizationACTG AIDS Clinical Trials Group

ATS American Thoracic Society

CDC United States Centers for Disease Control and Prevention

DALY disability-adjusted life year

DoI declaration of interest

DR-TB drug-resistant tuberculosis

DSMB Data and Safety Monitoring Board

DST drug-susceptibility testing

EFPIA European Federation of Pharmaceutical Industries and Associations

ERG Evidence Review Group

EtD evidence-to-decision (framework)

EU European Union

FDC fixed-dose combination

FIND Foundation for Innovative New Diagnostics

FTE full-time equivalent

GDG Guideline Development Group

GRADE Grading of Recommendations Assessment, Development and Evaluation

GRC WHO Guideline Review Committee

GSK Glaxo SmithKline

HALT Hepatitis and Latent TB infection

HIV human immunodeficiency virus

Hr-TB isoniazid (H)-resistant tuberculosis

IDSA United States Infectious Diseases Society of America

IPD individual patient data

KNCV KNCV Tuberculosis Foundation

LAM lipoarabinomannan assay

LSHTM London School of Hygiene & Tropical Medicine

LTBI latent tuberculosis infectionMDR-TB multidrug-resistant tuberculosis

WHO consolidated guidelines on tuberculosis: Online annexes4

MDR/RR-TB multidrug- or rifampicin-resistant tuberculosisMSF Médecins Sans FrontièresNIAID United States National Institutes of Allergy and Infectious DiseaseNIH United States National Institutes of HealthOpti-Q Efficacy and safety of levofloxacin for the treatment of MDR-TB (study)PICO population, intervention, comparator and outcomesPMDT programmatic management of drug-resistant TBPK/PD pharmacokinetics/pharmacodynamicsTB-PRACTECAL Pragmatic clinical trial for more effective, concise and less toxic MDR-TB treatment

regimen(s)RCT randomized controlled trialRECRU Respiratory Epidemiology and Clinical Trials Unit (McGill University)RR-TB rifampicin-resistant TBSAE serious adverse eventSIAPS Systems for Improved Access to Pharmaceuticals and ServicesSTREAM Evaluation of a standardised treatment regimen of anti-tuberculosis drugs for

patients with MDR-TB (trial)TAG Treatment Action GroupTB tuberculosisTBTC Tuberculosis Trials ConsortiumUNION International Union Against Tuberculosis and Lung DiseaseUNITAID Global investment initiative for TB, HIV, malaria and Hepatitis CUSAID United States Agency for International DevelopmentWHO World Health OrganizationWHO/GTB World Health Organization Global TB ProgrammeXDR-TB extensively drug-resistant tuberculosis


Annex 1: Methods and expert panels

A1 MethodsSince 2007, the guideline development process within the World Health Organization (WHO) has been overseen by the WHO Guidelines Review Committee (GRC), which follows internationally recognized standards such as the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach, to support to a structured and transparent methodology for policy-making. The policy recommendations presented here were developed following the standards and updated procedures described in the WHO handbook for guideline development.1

Initially, a WHO Guideline Steering Group was established to determine specific areas requiring up-to-date evidence, and to bring together experts to synthesize and independently review new evidence and develop recommendations (see Annex 2 and Annex 4). Also, an external review group was assembled to review the updated recommendations based on the input of the Guideline Development Group (GDG; see Annex 4). The GDG comprised researchers, epidemiologists, end-users (clinicians and national tuberculosis [TB] control programme officers), community representatives and experts in evidence synthesis. In compliance with the procedures and practices established by the GRC, declarations of interest (DOI) were managed according to the WHO Conflict of Interest Policy, including review of curricula vitae and critical evaluation of DOI. Additionally, contingent to the assessment of competing interests, the full list of members of the GDG and their biographies were published on the WHO website on 30 September 2019. This was followed by a public notice and comment period, during which WHO allowed members of the public to provide comments pertinent to any interests that might have gone unnoticed or unreported during earlier assessments.

During the face-to-face GDG meeting held in Geneva, Switzerland on 12–14 November 2019, the members of the GDG reached decisions through a process of discussion and consensus. Where consensus could not be reached through discussion, the GDG voted on decisions – these decisions were noted in GRADEpro and were made based on the vote of the majority.

A1.1 Preparation for evidence assessment The GRADE approach was used to rate the certainty in the estimate of effect (quality of evidence) as high, moderate, low or very low, and to determine the strength of the recommendations (as strong or conditional). A scoping proposal was submitted and approved by the WHO GRC in September 2019. Details about the preparatory work ahead of the update were released to the public through a public comment that focused on the following: the rationale for providing up-to-date guidance, including the scope of the updates; prioritization and formulation of key questions; and the list, affiliations and constituencies of potential members of the GDG undergoing conflict of interest assessments, as per the policies of the WHO Office of Compliance, Risk Management and Ethics policies.

1 WHO handbook for guideline development – 2nd edition Geneva, Switzerland World Health Organization; 2014 (https://apps.who.int/iris/handle/10665/145714, accessed 20 March 2020).


In preparation for the GDG meeting, four webinars were held with the group to finalize the scoping and PICO (patients, intervention, comparator and outcomes) questions, score outcomes of interest and discuss preliminary data analysis results. The PICO questions – inclusive of subpopulations, treatment regimen composition and duration, and outcomes – were agreed on by members of the GDG. The questions were framed to capture the effect of novel treatment regimens for specific populations and the value (in terms of effectiveness and safety) of adding, prolonging and combining specific anti-TB agents (see Box A1).

Î In MDR/RR-TB patients, does an all-oral treatment regimen lasting <12 months safely improve outcomes when compared with other regimens conforming to current WHO guidelines?

Î In XDR-TB patients or patients who are treatment intolerant or with non-responsive MDR-TB, does a treatment regimen lasting 6–9 months composed of bedaquiline, pretomanid and linezolid safely improve outcomes when compared with other regimens conforming to current WHO guidelines?

Î In MDR/RR-TB patients, does treatment with bedaquiline for more than six months safely improve outcomes when compared with treatment up to six months as part of regimens otherwise conforming to current WHO guidelines?

Î In MDR/RR-TB patients, does concurrent use of bedaquiline and delamanid safely improve outcomes when compared with other treatment regimen options otherwise conforming to current WHO guidelines?

MDR/RR-TB: multidrug-resistant or rifampicin-resistant tuberculosis; MDR-TB: multidrug-resistant tuberculosis; PICO: patients, intervention, comparator and outcomes; XDR-TB: extensively drug-resistant tuberculosis; WHO: World Health Organization.

Box A1. PICO questions

The PICO questions looked at the following eight distinct outcomes: successful completion of treatment; bacteriological cure by end of treatment; adherence to treatment (or treatment interruption by non-adherence); treatment failure or relapse; death during treatment; adverse reactions caused by anti-TB medicines; acquisition (amplification) of drug resistance; and sustained bacteriological cure at least 6 months after successful treatment.

Members of the GDG were invited to score the outcomes as “critical”, “important” or “not important” for making recommendations on the use of specific regimens under evaluation. The scores are shown in Table A1.


Table A1. Scoring of outcomes considered relevant by the GDG for the evidence review

Outcomes (as outlined in scoping proposal) Rating

Survival (or death) 8.33

Relapse-free cure 8.22

Bacteriological cure by end of treatment 8.19

Successful completion of treatment (or lack of successful completion) 7.96

Treatment failure or relapse 7.93

Adherence to treatment (or treatment interruption due to non-adherence) 7.48

Acquisition (amplification) of drug resistance 7.33

Adverse events from anti-TB medicines 7.19

GDG: Guidelines Development Group; TB: tuberculosis.

Note: Relative importance was rated on an incremental scale, as follows: 1–3 points: not important for making recommendations; 4–6 points: important but not critical for making recommendations; and 7–9 points: critical for making recommendations on the evaluated interventions.

A1.2 Evidence gathering and analysis The evidence to inform the update and development of recommendations resulted from a cooperative effort between WHO, national TB programmes (NTPs) and partner organizations, and close collaboration a with not-for-profit product development partnership (TB Alliance). For this particular update, the following data sources were used:

• Programmatic data of multidrug- or rifampicin-resistant TB (MDR/RR-TB) patients from South Africa treated with all-oral bedaquiline-containing shorter regimens, provided by the National TB Control and Management Cluster of the Department of Health of the Republic of South Africa.

• Data from a single-arm study [Nix-TB] containing records on patients receiving a novel all-oral regimen consisting of bedaquiline, pretomanid and linezolid, provided by the TB Alliance.

• Data for patients with MDR/RR-TB and extensively drug-resistant TB (XDR-TB) from 17 epidemiologically diverse countries treated with bedaquiline or delamanid-containing regimens, from the observational study of the EndTB project provided by the EndTB Consortium (Partners in Health, Médecins Sans Frontières, Interactive Research & Development and Unitaid).

• Data from a cohort study that included records of women treated during pregnancy for MDR/RR-TB using bedaquiline-containing regimens, provided by the South African Medical Research Council.

• Data resulting from a public call for records on patients from India, Republic of Belarus and Uzbekistan, treated according to WHO-recommended regimens.

Only individual patient data (IPD) was used for purposes of this update. Comparator data was assembled as part of an IPD database containing records of more than 13 000 patients with MDR/RR-TB, from 53 individual datasets from 40 countries. Sample sizes varied according to the availability of IPD for each analysable outcome. Analysable sample sizes are presented in Annex 4.

The methods used to minimize bias and confounding, and to make the intervention and comparator groups as similar as possible were exact matching (HIV coinfection or antiretroviral therapy [ART] use, TB treatment history and total number of drugs the strain was resistant to) and propensity score-based matching (on age, sex, and baseline sputum acid-fast bacilli [AFB] smear result). This process was conducted with replacement using a caliper distance of 0.02 during the propensity score-based matching, to estimate the adjusted odds ratios (aORs) of outcomes and their 95% confidence intervals


(CI). In addition, the distribution of the matched covariates within the intervention and comparator groups was further examined to assess the fidelity of the matching process.

The decision process that informs and leads to the making of any recommendations goes beyond the understanding of the magnitude of the desirable and undesirable effects resulting from the implementation of a particular intervention, and beyond the certainty of the evidence assessed. It also takes into account how people who are directly affected value a given intervention in terms of the main outcomes, resource implications, cost–effectiveness, impact on equity, feasibility and acceptability. For this update, the magnitude of the desirable and undesirable effects of the interventions was evaluated through the analysis methods already described. Other critical factors that could help to inform the judgements of the GDG for making an evidence-informed assessment were considered. The evidence reviews on cost–effectiveness, values, preferences and acceptability described below were commissioned to help inform the decision-making process and the conclusions drawn on the interventions under evaluation.

Evidence on cost–effectiveness

Costs could be affected, for example, through changes in duration of a regimen, use or replacement of newer agents, health care delivery costs, duration of follow-up visits and safety monitoring (and type of monitoring required; e.g. electrocardiography and audiometry). Therefore, a decision analytic model, together with estimates of the efficacy and safety differences between regimens, was used to help inform any considerations for the implementation of these recommendations. The model aimed to assess the cost of changes to recommended regimens for drug-resistant TB; estimate cost–effectiveness; and identify parameters and set specific characteristics that could influence cost or cost–effectiveness, focusing2 on the use of an all-oral bedaquiline-containing shorter regimen of 9–12 months’ duration, and on the use of bedaquiline for longer than 6 months and its concurrent use with delamanid. The modelling approach used projections from existing models, incorporated into certain individual parameter estimates (e.g. transmission models for secondary cases prevented by more effective treatment, and Markov cost–effectiveness models for total costs of MDR-TB cases). Costs were evaluated from a health system perspective (see Annex 4).

In addition, an economic evaluation was carried out to estimate the cost–effectiveness of a new regimen containing bedaquiline, pretomanid, and linezolid (BPaL), compared with the standard of care for patients who have XDR-TB, or have failed or are intolerant to their MDR-TB treatments, in three epidemiological settings at a given price. A Markov model was developed to follow a cohort of the intended population for the BPaL regimen. This provided the advantage of modelling both disease and treatment processes, where timing of events was important. Clinical data from the Nix-TB study were used to inform clinical efficacy of the intervention, and costing estimates were obtained through data available in the Global Health Costing Consortium database and from Value-TB (a multicounty TB costing study funded by the Bill & Melinda Gates Foundation).

Evidence on values and preferences

A qualitative study was undertaken to provide better understanding of the values and preferences for treatment, and perspectives on treatment acceptability, feasibility and equity. Although the goal was to gather evidence representing all individuals who would either use or be affected by the recommendations on each intervention – including policy-makers, health professionals, patients and other key stakeholders – this qualitative study was only able to capture data on patient representatives and MDR/RR-TB survivors. The methodology used to capture relevant data focused on in-depth interviews with stakeholders from high TB burden countries in Asia, Africa, Eastern Europe and South America. Fig. A1 provides an overview of the qualitative themes that reflect the values, preferences and perspectives regarding acceptability, feasibility and equity of the treatment of drug-resistant TB.

2 A separate evaluation of the BPaL regimen for the treatment of patients who have XDR-TB, or have failed or are intolerant to their MDR-TB treatments, was commissioned by the manufacturer and presented to the GDG.


Fig. A1. Overview of the main qualitative themes

Values & Preferences

Equity

Acceptability

Feasibility

• Minimal life disruption• Full recovery• Independence• Informed choice

• Treatment access• Social and

economic burden

• Prompt effective treament

• Risk-priority balance• Community/

social ties

• Community-based treatment

• Rigorous monitoring• Individualized

treatment

A1.3 Certainty of evidence and strength of recommendationsIn assessing the quality of evidence, several factors can increase or decrease the quality of evidence. The highest quality rating is usually assigned to evidence gathered from randomized, controlled trials (RCTs), whereas evidence from observational studies, including programmatic data, is usually assigned a value of low or very low quality. The higher the quality of evidence, the more likely it is that a strong recommendation can be made (Table A2). The criteria used by the GDG to determine the quality of available evidence are summarized in Annex 4. The certainty in the estimates of effect (quality of evidence) was assessed and rated either down or up on the basis of risk of bias, inconsistency or heterogeneity, indirectness, imprecision and other considerations.

Table A2. Certainty of evidence and strength of recommendations

Certainty in the evidence Definition

High ( ) Further research is very unlikely to change our confidence in the estimate of effect.

Moderate ( ) Further research is likely to have an important impact on our confidence in the effect and may change the estimate.

Low ( ) Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Very low ( ) Any estimate of effect is very uncertain.

Through the GRADE system, the strength of a recommendation is classified as “strong” or “conditional”. The strength of a recommendation is determined by the balance between desirable and undesirable effects, values and preferences, resource use, equity considerations, acceptability and feasibility to implement the intervention. For strong recommendations, the GDG is confident that the desirable


effects of adherence to the recommendation outweigh the undesirable effects. For conditional recommendations, the GDG considers that the desirable effects probably outweigh the undesirable effects. The strength of a recommendation has implications for the individuals affected by these guidelines (Table A3).

Table A3. Perspective taken, and description of strength and conditionality of recommendations

Perspective Strong recommendation Conditional recommendation

From patients Most individuals in this situation would want the recommended course of action and only a small proportion would not. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences.

The majority of individuals in this situation would want the suggested course of action, but many would not.

From clinicians Most individuals should receive the intervention. Adherence to this recommendation according to the guidelines could be used as a quality criterion or performance indicator.

Recognize that different choices will be appropriate for individual patients, and that patients must be helped to arrive at a management decision consistent with their values and preferences. Decision aids may be useful in helping individuals to make decisions consistent with their values and preferences.

From policy-makers

The recommendation can be adopted as policy in most situations.

Policy-making will require substantial debate and involvement of various stakeholders.

A1.4 Assessment of the quality of the evidenceThe WHO guideline development process uses specific criteria to assess the characteristics of a body of evidence, such as within-study bias (methodological quality), consistency, precision, and directness or applicability of the evidence. The evidence reviewed at the November 2019 GDG meeting was primarily programmatic data or data from cohort studies, although one dataset was from an RCT. These data were assessed as having low or very low certainty, based on an assessment of the criteria described above. The low or very low certainty of the evidence reinforced the need for additional high-quality evidence (from carefully executed research studies, including RCTs) to inform policy-making. To ensure proper assessment of the quality of the evidence, quality assurance procedures were performed by the Research Institute of the McGill University Health Centre, assisted by a GRADE methodologist.

Analysis of IPD data from studies or programmatic cohorts described in Section A1.1 was used to inform the development of specific recommendations. The IPD-based analyses help to reduce between-study heterogeneity; they also allow the examination of patient-level characteristics, harmonization of outcomes and exploration of variability in effectiveness. Although double-adjustment in propensity score matching analyses was carried out to remove the effects of confounding, there was still potential for bias in the effect estimates to have occurred through residual or unmeasured


confounding. Residual confounding could also have arisen from unknown factors, associated with both the exposure and the outcome, for which data were not collected.

A1.5 Publication, implementation, evaluation and expiry These guidelines were prepared in accordance with the requirements of the GDG.3 They will be published on the WHO website and made freely available to download, as part of a comprehensive set of WHO consolidated guidelines on TB. They will also be communicated widely at international and regional conferences, and at meetings of programme managers in all regions. In 2020, WHO will also release an operational guide with more practical details, to support programmatic implementation of the revised recommendations. National programmes will be supported by WHO and technical and funding partners, to prepare a national plan for the programmatic management of drug-resistant TB. Implementers should create a conducive policy and programmatic environment – including national and local policies, and standard operating procedures – to facilitate implementation of the recommendations in these guidelines. This should include promoting universal health coverage and offering public financing for management of drug-resistant TB. Furthermore, dedicated resources should be allocated, including for staff development and service delivery in the community. It is important to train frontline health care staff and students in critical areas such as diagnosis, designing a regimen, patient support, monitoring response to treatment and management of adverse reactions. National programmes should ensure meaningful engagement with affected populations, their communities, the private sector, other relevant health programmes and ministries in both planning and implementing the recommendations. The uptake of these WHO recommendations will be monitored in the annual data collection of WHO Global TB Data Monitoring. WHO will update the guidelines 5 years after their publication, or earlier if new evidence becomes available that necessitates a revision.

3 WHO handbook for guideline development – 2nd edition Geneva, Switzerland World Health Organization; 2014 (https://apps.who.int/iris/handle/10665/145714, accessed 20 March 2020).

https://apps.who.int/iris/handle/10665/145714

https://apps.who.int/iris/handle/10665/145714


A2 Expert panelsThis section lists the participants at GDG meetings for various updates of the drug-resistant TB treatment guidelines.

A2.1 WHO treatment guidelines for drug-resistant TB treatment guidelines, 2020 update

GDG members

1. Holger SCHÜNEMANN (Chair)GRADE methodologistCochrane Canada & McMaster UniversityHamilton, ONCanada

2. Rafael LANIADO-LABORIN (Co-Chair)Clinician; National TB programme; end-userNational TB ProgrammeTijuanaMexico

3. Susan ABDEL RAHMANChildren’s Mercy HospitalKansas City, MOUnited States of America

4. Erlina BURHANClinician; end-userDepartment of Respiratory and Pulmonology, Persahabatan HospitalJakartaIndonesia

5. Daniela CIRILLOLaboratory specialistSan Raffaele Supranational TB Reference LaboratoryMilanItaly

6. Charles DALEYPulmonologist; MDR-TB expertNational Jewish HealthDenver, COUnited States of America

7. Geraint (Gerry) Rhys DAVIESTrials expert; PharmacologistUniversity of LiverpoolLiverpoolUnited Kingdom of Great Britain and Northern Ireland

8. Fernanda DOCKHORN COSTA JOHANSENNational TB programme; end-user; ClinicianMinistry of Health MDR-TB referral centreBrasiliaBrazil

9. Kelly DOOLEYClinical pharmacologist; ResearcherJohns Hopkins University School of MedicineBaltimore, MDUnited States of America

10. Bernard FOURIEClinical trials expertUniversity of PretoriaPretoriaSouth Africa

11. Agnes GEBHARDTechnical agency; end-user; ClinicianKNCV Tuberculosis FoundationThe HagueNetherlands

12. Elmira GURBANOVArGLC; Clinician; end-userLung Clinic, University of TartuTartuEstonia

13. Muhammad Amir KHANCivil society representatitveAssociation for Social DevelopmentIslamabadPakistan

14. Yuhong LIUClinician; end-userNational Clinical Center on Tuberculosis, China CDC, Beijing Chest HospitalBeijingChina (People’s Republic of )


15. Marian LOVEDAYSpecialist Scientist; maternal health medicineSouth African Medical Research CouncilCape TownSouth Africa

16. Barend (Ben) MARAISPaediatricianThe University of Sydney School of MedicineSydneyAustralia

17. Iqbal MASTERClinician; MDR-TB physician; end-userKing George V Hospital, Kwazulu NatalDurbanSouth Africa

18. Alberto MENDOZAClinician; end-userNational TB ProgrammeLimaPeru

19. Beatrice MUTAYOBAProgramme Manager; end-userNational TB and Leprosy ProgrammeDar Es SalaamUnited Republic of Tanzania

20. Payam NAHIDClinician; Clinical trials expertUniversity of California SF & American Thoracic Society ATSSan Francisco, CAUnited States of America

21. Mahshid NASEHIProgramme Manager; end-userNational TB and Leprosy Control ProgrammesTehranIran (Islamic Republic of )

22. Viet Nhung NGUYENNational TB programme; end-userNational TB Control Programme, Ministry of HealthHanoiViet Nam

23. Alberto PIUBELLOClinician; MDR-TB physician; end-userInternational Union Against Tuberculosis and Lung DiseaseNiameyNiger

24. Maria RODRIGUEZClinician; National TB programme; end-userMinistry of Health MDR-TB referral centreSanto DomingoDominican Republic

25. Rohit SARINTechnical agency end-userNational Institute of TB & Respiratory Diseases NITRDNew DelhiIndia

26. Ingrid SCHOEMANFormer MDR-TB patientTB PROOFPretoriaSouth Africa

27. Alena SKRAHINANational TB programme; MDR-TB physician; end-userRepublican Research and Practical Centre for Pulmonology and TuberculosisMinskBelarus

28. Carrie TUDORNursing specialist; Technical agency; end-userInternational Council of NursesDurbanSouth Africa

29. Debrah VAMBENational TB programme; end-userNational TB Control ProgramMbabaneEswatini

30. Andrew VERNONTrials expert; Technical agency end-userUS Centers for Disease Control and PreventionAtlanta, GAUnited States of America


Evidence reviewers

31. Jonathon CAMPBELLEpidemiologist; health economist.McGill University’s Faculty of MedicineMontreal, QCCanada

32. Amrita DAFTARYBehavioural health scientistDahdaleh Institute for Global Health Research, York UniversityToronto, ONCanada

33. Gabriela GOMEZHonorary Associate ProfessorLondon School of Hygiene and Tropical MedicineLondonUnited Kingdom of Great Britain and Northern Ireland

34. Emily KENDALLInfectious diseases dynamics; mechanistic modelingJohns Hopkins Bloomberg School of Public HealthBaltimore, MDUnited States of America

35. Richard MENZIESLead - Evidence reviewerMcGill University’s Faculty of MedicineMontreal, QCCanada

36. Rada SAVICAssociate ProfessorDepartment of Bioengineering and Therapeutic Sciences, Division of Pulmonary and Critical Care Medicine, Schools of Pharmacy and Medicine, University of California San FranciscoSan Francisco, CAUnited States of America

37. Nick WINTERSResearch AssistantMcGill University’s Faculty of MedicineMontreal, QCCanada

Observers

38. Draurio BARREIRA CRAVO NETOTechnical manager, TBUnitaidGenevaSwitzerland

39. Dan EVERITTVice President and Senior Medical Officer, Principal Investigator Nix-TBTB AllianceNew York, NYUnited States of America

40. Abdul GHAFOORNational TB ProgrammeIslamabadPakistan

41. Christopher GILPINMigration Health DivisionInternational Organization for MigrationGenevaSwitzerland

42. Anisa HAJIZADEHMcMaster UniversityHamilton, ONCanada

43. Brian KAISERTechnical OfficerStop TB Partnership’s Global Drug FacilityGenevaSwitzerland

44. Blessina KUMARCEOGlobal Coalition of TB ActivistsNew DelhiIndia

45. Tamara LOTFIResearch AssociateFaculty of Medicine, American University of BeirutBeirutLebanon

46. YaDiul MUKADITechnical AdvisorUnited States Agency for International DevelopmentWashington, DCUnited States of America


47. Norbert NDJEKADirector, Drug-Resistant TB, TB & HIVDepartment of HealthPretoriaSouth Africa

48. Eugene SUNHead of R&DTB AllianceNew York, NYUnited States of America

49. Kitty VAN WEEZENBEEKExecutive DirectorKNCV TB FoundationThe HagueNetherlands

50. Francis VARAINEProject Lead, EndTB ProjectMédecins Sans FrontièresParisFrance

51. Mohammed YASSINSenior Disease Advisor, TBThe Global Fund to Fight AIDS, Tuberculosis and MalariaGenevaSwitzerland

WHO Regional Offices

52. Askar YEDILBAYEVRegional TB adviser EUROWHO/EUROCopenhagenDenmark

53. Mohammed AKHTARRegional TB adviser EMROWHO/EMROCairoEgypt

54. Vineet BHATIArepresenting Regional TB adviser SEAROWHO/SEARONew DelhiIndia

WHO headquarters

55. Tereza KASAEVA, Director, GTB

56. John GROVE, Director, QNS

57. Medea GEGIA,Technical Officer, GTB/TSC

58. Lice GONZÁLEZ-ANGULO, Technical Officer, GTB/LDR

59. Malgorzata GRZEMSKA, Coordinator, GTB/TSC

60. Alexei KOROBITSYN,Technical Officer, GTB/LDR

61. Corinne MERLE, Scientist, IIR

62. Fuad MIRZAYEV, Medical Officer, GTB/LDR

63. Lorenzo MOJA, Technical Officer, IAU

64. Deusdedit MUBANGIZI, Coordinator, PQ

65. Linh Nhat NGUYEN, Technical Officer, GTB/TSC

66. Susan NORRIS, GRC Secretariat

67. Andreas REIS, Senior Ethics Officer, REK

68. Kerri VINEY, Scientist, GTB/LDR

69. Marco VITORIA, Medical Officer, TAC

70. Karin WEYER, Coordinator, GTB/LDR

71. Matteo ZIGNOL, Coordinator, THC/RTE

A2.2 WHO treatment guidelines for rifampicin- and multidrug-resistant tuberculosis, 2018 update

GDG members

1. Holger SCHÜNEMANN (Chair)Cochrane Canada & McMaster UniversityCanada(GRADE methodologist)

2. Susan ABDEL RAHMANChildren’s Mercy Hospital, KansasUnited States of America(Clinician; Pharmacologist (paediatrics))


3. Sarabjit S CHADHAThe UNION / Regional Green Light CommitteeIndia(Technical agency end-user)

4. Daniela CIRILLOSan Raffaele Supranational TB Reference LaboratoryItaly(Laboratory specialist)

5. Geraint (Gerry) Rhys DAVIESUniversity of LiverpoolUnited Kingdom of Great Britain and Northern Ireland(Trials expert; Pharmacologist)

6. Fernanda DOCKHORN COSTA JOHANSENMinistry of Health (MDR-TB referral centre)Brazil(National TB programme end-user; Clinician)

7. Bernard FOURIEUniversity of PretoriaSouth Africa(Clinical trials expert)

8. Edwin HERRERA-FLORESHospital Nacional (MDR-TB referral centre), Arzobispo Loayza, LimaPeru(Clinician)

9. Ayuko HIRAIMédecins Sans FrontièresPapua New Guinea(Technical agency end-user; Clinician)

10. Alexander KAYBaylor Global TB Program, MbabaneEswatini(Paediatrician)

11. Rafael LANIADO-LABORINNational TB Programme / Regional Green Light CommitteeMexico(Clinician; National TB programme end-user)

12. Eden MARIANOSLB Group of TB ActivistsPhilippines(Past MDR-TB patient)

13. Lawrence MBUAGBAWMcMaster UniversityCanada(Epidemiologist; Biostatistician)

14. Payam NAHIDUniversity of California SF & American Thoracic Society (ATS)United States of America(Clinician; Clinical trials expert)

15. Austin Arinze OBIEFUNAAfro Global AllianceGhana(Civil society)

16. Cristina POPAMarius Nasta TB institute (MDR-TB referral centre), BucharestRomania(Clinician)

17. Wipa REECHAIPICHITKULUniversity of Khon Kaen (MDR-TB referral centre)Thailand(Clinician)

18. Maria RODRIGUEZMinistry of Health (MDR-TB referral centre)Dominican Republic(Clinician; National TB programme end-user)

19. Adman Skirry SHABANGUNational TB Control Programme, Ministry of HealthEswatini(National TB programme end-user)

20. Sabira TAHSEENNational Reference Laboratory, IslamabadPakistan(Laboratory specialist)

21. Carrie TUDORInternational Council of NursingUnited States of America(Nursing specialist; Technical agency end-user)

22. Zarir UDWADIAHinduja Hospital (MDR-TB referral centre), Breach Candy Hospital and Parsee General Hospitals, Mumbai,India(Clinician)


23. Andrew VERNONUS-CDCUnited States of America(Trials expert; Technical agency end-user)

Evidence Reviewers (Observers)

24. Syed ABIDIMcGill University, MontréalCanada

25. Faiz A KHANMcGill University, MontréalCanada

26. Jonathon CAMPBELLMcGill University, MontréalCanada

27. Zhiyi LANMcGill University, MontréalCanada

28. Dick MENZIESMcGill University, MontréalCanada

Technical resource persons (observers)

29. Charles DALEYNational Jewish Health (MDR-TB referral centre), DenverUnited States of America(Clinician; Chair of the Global Drug-Resistant TB Initiative)

30. Kelly DOOLEYJohns Hopkins University, BaltimoreUnited States of America(Clinical trials expert; Clinician; Pharmacologist)

31. Gregory KEARNSArkansas Children’s Hospital Research InstituteUnited States of America(Pharmacologist (paediatrics))

32. Anneke HESSELING (remote participation)Stellenbosch University, Cape TownSouth Africa(Paediatrician; Clinical trials expert)

33. Gary MAARTENSUniversity of Cape TownSouth Africa(Clinician; TB/HIV specialist; Pharmacologist)

34. Norbert NDJEKADepartment of Health, PretoriaSouth Africa(National TB programme end-user; Clinician)

35. Michael L. RICHPartners in Health, BostonUnited States of America(Technical agency end-user; Clinician)

36. H Simon SCHAAF (remote participation)Stellenbosch University, Cape TownSouth Africa(Paediatrician; Clinical trials expert)

37. Valérie SCHWOEBELThe UNIONFrance(Technical agency end-user)

38. Shenjie TANGBeijing Chest Hospital (MDR-TB referral centre), BeijingChina(Clinician)

39. Ye TUNNational Expert DR-TB Committee & Thingungyun San Pya General Hospital (MDR-TB referral centre) / University of Medicine (2), YangonMyanmar(Clinician)

40. Kitty VAN WEEZENBEEKKNCV TB Foundation, The HagueNetherlands(Technical agency end-user)

41. Francis VARAINEMSF France, ParisFrance(Technical agency end-user)

42. Irina VASILYEVANational Medical Research Centre of TB and Infectious Disease, MoscowRussian Federation(National TB programme end-user; Clinician)


43. Kerri VINEYMeeting RapporteurSweden(WHO consultant)

Trial investigators (observers; joining via webinar)

44. Lawrence GEITEROtsukaUnited States of America

45. Chrispin KAMBILIJohnson & JohnsonUnited States of America

46. Carole MITNICKPartners in Health, BostonUnited States of America

47. Andrew NUNNMedical Research CouncilUnited Kingdom of Great Britain and Northern Ireland

Other observers

48. Draurio BARREIRA CRAVO NETOUNITAID, GenevaSwitzerland

49. Edward M COXUS Food and Drugs Administration, Washington DCUnited States of America

50. Jennifer FURINSentinel ProjectUnited States of America

51. Brian KAISERGlobal Drug Facility, Stop TB Partnership, GenevaSwitzerland

52. Lindsay McKennaTreatment Action GroupUnited States of America

53. YaDiul MUKADIUSAID, WashingtonUnited States of America

54. Eric PELFRENEEuropean Medicines Agency, LondonUnited Kingdom of Great Britain and Northern Ireland

55. Anna SCARDIGLIGlobal Fund to Fight AIDS, TB and Malaria, GenevaSwitzerland

WHO headquarters

Deputy Director General for ProgrammesSoumya SWAMINATHAN

Global TB Programme Tereza KASAEVA, DirectorNicola COCCODennis FALZONGiuliano GARGIONIMedea GEGIAChristopher GILPINLicé GONZALEZ-ANGULOMalgosia GRZEMSKAErnesto JARAMILLOAlexei KOROBITSYNFuad MIRZAYEV Kefas SAMSONKarin WEYERMatteo ZIGNOL

Guideline Review CommitteeSusan NORRIS

Tropical Disease ResearchPiero OLLIAROCorinne MERLE

HIV DepartmentSatvinder SINGH

Essential Medicines ProgrammeLorenzo MOJA

Research, Ethics and Knowledge ManagementAndreas Alois REIS

WHO Regional Offices

Ogtay GOZALOV (EUR)Vineet BHATIA (SEAR)


A2.3 WHO treatment guidelines for isoniazid-resistant tuberculosis, 2018 update

GDG members

1. Farhana AMANULLAHConsultant PaediatricianDirector Paediatric TB ProgramThe Indus Hospital, Korangi Crossing,KarachiPAKISTAN

2. Tsira CHAKHAIA (via webinar)ACSM Advisor, Civil Society GeorgiaUSAID Georgia TB Prevention ProjectUniversity Research Co., LLCTbilisiGEORGIA

3. Daniela Maria CIRILLOHeadEmerging Bacterial Pathogens UnitFondazione Centro San RaffaeleMilanoITALY

4. Kelly DOOLEY (Co-chair)Associate Professor of MedicinePharmacology & Molecular ScienceDivisions of Clinical Pharmacology &Infectious DiseasesJohns Hopkins University Baltimore, MDUNITED STATES

5. Luis Gustavo DO VALLE BASTOSCapacity Building Team LeaderStop TB Partnership’s Global DrugFacility (GDF)SWITZERLAND

6. Philipp DU CROSResearch AdvisorMédecins Sans FrontièresLondonUNITED KINGDOM

7. Raquel DUARTETB consultantNational HIV/AIDS/TB ProgrammeMedical School, Porto UniversityInstitute of Public Health, Porto UniversityPortoPORTUGAL

8. Christopher KUABANDean, Faculty of Health SciencesUniversity of Bamenda, CameroonBamenda, North West RegionCAMEROON

9. Rafael LANIADO-LABORINHead, TB Clinic, HospitalGeneral de TijuanaInstituto Estatal de Salud de Baja CaliforniaTijuanaMEXICO

10. Gary MAARTENSFaculty of Health SciencesDivision of Clinical PharmacologyDepartment of MedicineUniversity of Cape TownCape Town SOUTH AFRICA

11. Andrei MARYANDYSHEVHead of Phthisiopulmonary DepartmentNorthern State Medical UniversityTroitsky 51, 163061 - ArkhangelskRUSSIAN FEDERATION

12. Ignacio MONEDERO-RECUEROMDR-TB and TB-HIV ConsultantInternational Union of TB and LungDisease (The Union)ParisFRANCE

13. Maria Imelda Josefa QUELAPIOSenior ConsultantKNCV TB FoundationThe HagueNETHERLANDS

14. Wipa REECHAIPITKULProfessorDepartment of MedicineFaculty of MedicineKhon Kaen UniversityKhon Kaen THAILAND


15. Michael RICHGlobal Health PhysicianPartners in HealthHarvard Medical SchoolBoston, MAUNITED STATES

16. Nancy SANTESSO (Co-chair)Assistant ProfessorDepartment of Health Research Methods,Evidence, and ImpactMcMaster UniversityHamiltonCANADA

17. Rada SAVIC Associate ProfessorDepartment of Bioengineering andTherapeutic SciencesDivision of Pulmonary and CriticalCare MedicineSchools of Pharmacy and MedicineUniversity of California San FranciscoSan Francisco, CAUNITED STATES

18. Welile SIKHONDZENational Tuberculosis Control Programme Advisor and Research CoordinatorMbabaneSWAZILAND

19. Armand VAN DEUNBacteriology ConsultantDepartment of Biomedical SciencesMycobacteriology UnitPrince Leopold Institute of TropicalMedicineAntwerpenBELGIUM

Observers

20. Giovanni Battista MIGLIORIDirector, WHO Collaborating Centre forTB and Lung DiseasesFondazione S. Maugeri, Care andResearch InstituteTradate ITALY

21. Ya Diul MUKADIMedical OfficerTuberculosis Division/InfectiousDisease OfficeGlobal Health BureauWashington, DC UNITED STATES

22. Payam NAHIDProfessor of MedicineDivision of Pulmonary and Critical CareMedicineUniversity of CaliforniaSan Francisco General HospitalSan Francisco CAUNITED STATES

23. Timothy RODWELLFoundation for Innovative NewDiagnostics (FIND)GenevaSWITZERLAND

24. Mohammed YASSINSenior AdvisorThe Global FundGenevaSWITZERLAND

Evidence Reviewers

25. Dick MENZIESDirector, Respiratory DivisionMUHC and McGill University,Room K1.24Montréal Chest InstituteMontréal, PQCANADA

26. Federica FREGONESEMcGill University Health CentreMontréal, Quebec,CANADA

WHO headquarters Secretariat

27. WEYER, Karin, Coordinator,HQ/HTM/GTB/LDR

28. FALZON, Dennis, Medical Officer,HQ/HTM/GTB/LDR

29. GAO Xu, Intern, HQ/HTM/GTB/RTE

30. van GEMERT, Wayne, TechnicalOfficer, HQ/HTM/GTB/LDR


31. GILPIN, Christopher, Scientist,HQ/HTM/GTB/LDR

32. GONZÁLEZ-ANGULO, Lice Y., Technical Officer, HQ/HTM/GTB/RTE

33. JARAMILLO, Ernesto, MedicalOfficer, HQ/HTM/GTB/LDR

34. KOROBITSYN, Alexei, TechnicalOfficer, HQ/HTM/GTB/LDR

35. MIRYAZEV, Fuad, Medical Officer, HQ/HTM/GTB/LDR

36. OLLIARO, Piero, Unit Leader, Intervention Research, HQ/HTM/TDR/IIR

37. ZIGNOL, Matteo, Scientist, HQ/HTM/GTB/TM

A2.4 WHO guidelines for the treatment of drug-susceptible tuberculosis and patient care, 2017 update

GDG members

1. Si Thu AUNGDeputy Director (TB) and National TB Programme ManagerDepartment of Public Health Ministry of HealthNay Pyi Taw, Myanmar(Unable to attend the meeting)

2. Frank BONSUNational TB Programme Manager Ministry of HealthAccra, Ghana

3. Jeremiah Muhwa CHAKAYAClinicianNational TB Programme Manager KEMRI,Nairobi, Kenya

4. Lucy CHESIRETB ACTION Group Nairobi, Kenya

5. Daniela CIRILLOHead of Emerging Bacterial Pathogens Unit WHO Collaborating Centre and TB Supranational Reference LaboratorySan Raffaele Scientific Institute Milano, Italy

6. Poonam DHAVANMigration Health Programme Coordinator International Organization for Migration Geneva, Switzerland(Unable to attend the meeting)

7. Kelly DOOLEYAssociate Professor of Medicine, Pharmacology & Molecular Sciences Divisions of Clinical Pharmacology & Infectious Diseases

Center for Tuberculosis Research Faculty Leader, Janeway Firm of theOsler Residency ProgramJohns Hopkins University School of Medicine Baltimore, MD, United States of America

8. Kathy FIEKERTSenior TB ConsultantKNCV Tuberculosis FoundationThe Hague, Netherlands

9. Paula FUJIWARAScientific DirectorInternational Union Against Tuberculosis and Lung Disease (The Union) Paris, France

10. Mike FRICKTB/HIV Project Treatment Action Group New York, NY, United States of America

11. Andrei MARYANDYSHEVHead of Phthisiopulmonary Department Arkhangelsk, Russian Federation

12. Nguyen Viet NHUNGDirector of National Lung Hospital Vietnam National TB ProgrammeHanoi, Viet Nam

13. Ejaz QADEERMinistry of Health Islamabad, Pakistan


14. Abdul Hamid SALIMAdvisor to National TB Programme Bangladesh onGlobal Fund and MDR-TBTB Gate, Leprosy Hospital Compound, MohakhaliDhaka, Bangladesh

15. Simon SCHAAFPaediatricianPaediatrics and Child Health Faculty of Medicine and Health SciencesUniversity of Stellenbosch Stellenbosch, South Africa

16. Holger SCHÜNEMANN (Chair)MethodologistMcMaster UniversityHamilton, Canada

17. Pedro Guillermo SUAREZManagement Sciences for Health Arlington, VA, United States of America(Unable to attend the meeting)

18. Carrie TUDORTB Project Director International Council of NursesDurban, South Africa

19. Justin Wong Yun YAWHead, Disease Control Division Ministry of HealthJalan Menteri Besar Brunei

Evidence reviewers

20. Narges ALIPANAHPhysicianSanta Clara Valley Medical Center San Jose, CA, United States of America

21. Lelia CHAISSONEpidemiologistInfectious Disease Epidemiology Department of EpidemiologyJohns Hopkins Bloomberg School of Public Health Baltimore, MD, United States of America

22. Jennifer HOWoolcock Institute of Medical Research University of Sydney AustraliaJames JOHNSTONEvaluation Lead, TB Services British Columbia Centre for Disease Control VancouverBritish Columbia, Canada

23. Dick MENZIESRECRU/ Montreal Chest Institute MontrealQuebec, Canada

24. Payam NAHIDProfessorUniversity of California San FranciscoSan Francisco, CA, United States of America

Observers

25. Amy BLOOMSenior Technical Advisor Bureau of Global HealthUS Agency for International Development Washington, D.C., United States of America

26. Janet GINNARDUNITAIDGeneva, Switzerland

Members of the External Review Group (area of expertise shown in parentheses for non-WHO staff)

27. Mohammed AZIZ WHO Regional Office for the Eastern Mediterranean

28. Masoud DARA WHO Regional Office for Europe

29. Riitta DLODLO International Union Against Tuberculosis and Lung Disease (Technical agency/programme implementation)France

30. Celine GARFIN Ministry of Health (National programme/end-user)Philippines

31. Mirtha del GRANADO WHO Regional Office for the Americas


32. Daniel KIBUGA WHO Regional Office for Africa

33. Hyder KHURSHID WHO Regional Office for South- East Asia

34. Vaira LEIMANE Riga East University Hospital,Centre of Tuberculosis and Lung Diseases(Clinician/end-user)Latvia

35. Nobuyuki NISHIKIORI WHO Regional Office for the Western Pacific

36. Lee REICHMAN Rutgers New Jersey Medical School(Clinician/end-user)United States of America

37. Rohit SARIN National Institute of TB & Respiratory Diseases, Ministry of Health(National programme/end-user)India

38. Dalene VON DELFT TB Proof (Patient representative)South Africa

39. Fraser WARES Royal Dutch Tuberculosis Foundation (KNCV)(Technical agency/programme implementation)The Netherlands

WHO headquarters Secretariat

40. Annabel BADDELEY, GTB/THC

41. Dennis FALZON, GTB/LDR

42. Giuliano GARGIONI, GTB/TSC

43. Nebiat GEBRESSELASSIE, GTB/RTE

44. Haileyesus GETAHUN, GTB/THC

45. Lice Y. GONZÁLEZ-ANGULO, GTB/RTE

46. Malgorzata GRZEMSKA, GTB/TSC

47. Elizabeth HARAUSZ (GTB/TSC Consultant)

48. Ernesto JARAMILLO, GTB/LDR

49. Avinash KANCHAR, GTB/THC

50. Soleil LABELLE, GTB/TSC

51. Christian LIENHARDT, GTB/RTE

52. Knut LÖNNROTH, GTB/PSI

53. Fuad MIRZAYEV, GTB/LDR

54. Linh NGUYEN, GTB/TSC

55. Marco VITORIA, HIV/TAC

56. Diana WEIL, GTB/PSI

57. Karin WEYER, GTB/LDR

58. Matteo ZIGNOL, GTB/TME

A2.5 WHO treatment guidelines for drug-resistant TB, 2016 update

GDG members

1. Farhana AMANULLAHAssociate DirectorPediatric TB ProgramIndus HospitalKarachiPakistan

2. Tsira CHAKHAIAACSM Advisor, Civil SocietyUniversity Research Co., LLCTbilisiGeorgia

3. Daniela Maria CIRILLOHeadEmerging Bacterial Pathogens UnitSan Raffaele del Monte Tabor Foundation (hSR)San Raffaele Scientific InstituteMilanoItaly


4. Charles L DALEY (Co-Chair)ChiefDivision of Mycobacterial and RespiratoryInfectionsNational Jewish HealthDenver, COUSA

5. Luis Gustavo DO VALLE BASTOSSenior Technical AdvisorCenter for Pharmaceutical ManagementManagement Sciences for HealthArlington, VAUSA

6. Kelly DOOLEYAssociate Professor of MedicinePharmacology & Molecular Science Divisions ofClinical Pharmacology & Infectious DiseasesJohns Hopkins University School of MedicineCenter for Tuberculosis ResearchBaltimore, MDUSA

7. Carlos A TORRES-DUQUEDirectorTuberculosis DepartmentLatin American Thoracic SocietyBogotáColombia

8. Michel GASANAManagerNational TB & Other RespiratoryCommunicable Diseases DivisionMinistry of HealthKigaliRwanda

9. Agnes GEBHARDSenior ConsultantTeam Leader of ACCESS TeamTechnical DivisionKNCV Tuberculosis FoundationThe HagueNetherlands

10. Armen HAYRAPETYANDirectorNational TB Control CentreMinistry of HealthAbovyan cityArmenia

11. Antonia KWIECIENSenior Technical AdvisorSystems for Improved Access toPharmaceuticals and Services Program (SIAPS)Management Sciences for Health (MSH)Arlington, VAUSA

12. José A CAMINERO LUNACoordinatorMDR-TB Unit, International Union AgainstTuberculosis & Lung Disease (UNION)General Hospital of Gran Canaria “Dr. Negrin”Las Palmas de Gran CanariaSpain

13. Sundari MASEMedical Team LeadField Services and Evaluation Branch Division of Tuberculosis Elimination National Center for HIV, Hepatitis, STD and TB PreventionCenters for Disease Control and PreventionAtlanta, GAUSA

14. Lindsay MCKENNATB/HIV Project OfficerTreatment Action GroupNew York, NYUSA

15. Nguyen Viet NhungDirectorNational Tuberculosis Control ProgrammeHanoiViet Nam

16. Maria RODRIGUEZCoordinatorMDR-TB National Technical UnitMinistry of HealthSanto DomingoDominican Republic

17. Holger SCHÜNEMANN (Chair)Chair and ProfessorDepartments of Clinical Epidemiology &Biostatistics and of MedicineMcMaster UniversityHamilton, ONCanada


18. James SEDDONClinical LecturerDepartment of PaediatricsImperial CollegeLondonUnited Kingdom

19. Thomas SHINNICKAssociate DirectorGlobal Laboratory Activities MycobacteriologyLaboratory Branch, Division of TuberculosisElimination Centers for Disease Control andPreventionAtlanta, GAUSA

20. Alena SKRAHINAScientific DirectorRepublican Scientific & Practical Centre forPulmonology & TuberculosisBelarus Research Institute of Pulmonology and TuberculosisMinskBelarus

Observers (at the GDG meeting in Geneva in November 2015)

21. J Peter CEGIELSKITeam LeaderMDR TB International Programs and Research Branch, Division of Tuberculosis EliminationCenters for Disease Control & PreventionAtlanta, GAUSA

22. Janet Kristen GINNARDTechnical Officer Strategy & ResultsUNITAIDGenevaSwitzerland

23. Giovanni BATTISTA MIGLIORIDirectorWHO Collaborating Centre for Tuberculosisand Lung DiseasesFondazione Salvatore MaugeriTradate, VAItaly

24. Payam NAHIDProfessor of MedicineUniversity of California, San FranciscoSan Francisco General Hospital Division ofPulmonary and Critical Care MedicineSan Francisco, CAUSA

25. Nobuyuki NISHIKIORIRegional Adviser, TBWHO Western Pacific Regional OfficeManilaThe Philippines

26. Thomas W PIGGOTTResident PhysicianMcMaster UniversityHamilton ONCanada

27. Anna SCARDIGLIDisease Advisor, TuberculosisTechnical Advice and PartnershipThe Global Fund to Fight AIDS, Tuberculosisand MalariaGenevaSwitzerland

28. Barbara SEAWORTHProfessor of MedicineDirector Heartland National TB CenterUniversity of Texas Health Science Center, TylerSan Antonio, TXUSA

29. Mohammed YASSINTechnical Advisor, TuberculosisThe Global Fund to Fight AIDS, Tuberculosisand MalariaGenevaSwitzerland

30. Ya Diul MUKADISenior TB Technical AdvisorInfectious Disease Division, Global HealthBureauUS Agency for International Development(USAID)Washington, DCUSA


Resource persons

31. Philipp DU CROSTB AdvisorMédecins sans Frontières (MSF)LondonUnited Kingdom

32. Michael L RICHMedical OfficerPartners in HealthHarvard Medical SchoolBoston, MAUSA

33. Abdul Hamid SALIMAdvisor, NTP BangladeshTB Gate, Leprosy hospital CompoundMohakhaliDhakaBangladesh

34. Valérie SCHWOEBELMedical OfficerInternational Union Against Tuberculosis &Lung Disease (UNION)ParisFrance

35. Francis VARAINEInternational Medical CoordinatorMédecins sans Frontières (MSF)ParisFrance

36. Askar B. YEDILBAYEVMedical OfficerPartners in HealthBoston, MAUSA

External Review Group

37. Chen-Yuan CHIANGInternational Union Against Tuberculosis and Lung Disease (UNION)ParisFrance

38. Celine GARFINInfectious Diseases for Prevention and Control DivisionDisease Prevention and Control BureauDepartment of HealthManilaThe Philippines

39. Michael KIMERLINGKNCV Tuberculosis FoundationThe HagueNetherlands

40. Vaira LEIMANENational TB ProgrammeMinistry of HealthRigaLatvia

41. Guy MARKSInternational Union Against Tuberculosis and Lung Disease (UNION)ParisFrance

42. Gao MENGQIUBeijing Chest HospitalCapital Medical University, Beijing Tuberculosis and Thoracic Tumor Research InstituteBeijingChina

43. Norbert NDJEKADrug Resistant TB, TB & HIVDepartment of HealthPretoriaSouth Africa

44. Ejaz QADEERNational TB ProgrammeMinistry of HealthIslamabadPakistan

45. Lee REICHMANRutgers UniversityNew Jersey, NJUSA

46. Rohit SARINLRS Institute of TB and Respiratory DiseasesDelhiIndia

47. Irina VASILYEVACentral Tuberculosis Research Institute (CTRI)MoscowRussian Federation

48. Dalene VON DELFTTB ProofSouth Africa


Evidence Reviewers

49. Mayara LISBOA SOARES DE BASTOSMcGill UniversityMontreal, QcCanada

50. Gregory J FOX*University of SydneySpit Junction, NSWAustralia

51. Rebecca HARRISLondon School of Hygiene and TropicalMedicineLondonUnited Kingdom

52. Anneke HESSELINGPaediatric TB Research ProgrammeDesmond Tutu TB Centre Department ofPaediatrics and Child HealthFaculty of Medicine and Health SciencesStellenbosch UniversityCape TownSouth Africa

53. Faiz KHANFaculty of Medicine, McGill UniversityMontreal Chest InstituteMcGill University Health CentreMontreal, QcCanada

54. Mishal KHANLondon School of Hygiene and TropicalMedicineLondonUnited Kingdom

55. Dick MENZIESMontreal Chest InstituteMcGill University Health CentreMontreal, QcCanada

WHO Guideline Steering Committee

56. Dennis FALZON, LDR/GTB

57. Nathan FORD, TAC/HIV

58. Giuliano GARGIONI, TSC/GTB

59. Haileyesus GETAHUN, THC/GTB

60. Malgorzata GRZEMSKA, TSC/GTB

61. Ernesto JARAMILLO, LDR/GTB

62. Avinash KANCHAR, THC/GTB

63. Soleil LABELLE, TSC/GTB

64. Christian LIENHARDT, PSI/GTB

65. Knut LÖNNROTH, PSI/GTB

66. Alberto MATTEELLI, THC/GTB

67. Fuad MIRZAYEV, LDR/GTB

68. Linh Nhat NGUYEN, LDR/GTB

69. Marco Antonio VITORIA, TAC/HIV

70. Fraser WARES, LDR/GTB

71. Diana WEIL, PSI/GTB

72. Karin WEYER, LDR/GTB

73. Matteo ZIGNOL, TME/GTB

WHO Consultant

74. Elizabeth HARAUSZ

A2.6 WHO guidelines for the programmatic management of drug-resistant tuberculosis, 2011 update

GDG members (area of expertise shown in parentheses)

1. Jaime BAYONASocios En Salud Sucursal(Programme management, public health)Peru

2. José A. CAMINEROUniversity General Hospital of Gran Canaria, Spain and The UNION(Clinical practice)Paris, France

* Affiliated with McGill University for the evidence reviews done for these guidelines


3. Charles L. DALEYNational Jewish Health, (clinical practice)United States of America

4. Agnes GEBHARDKNCVTuberculosis Foundation(Programme management)Netherlands

5. Myriam HENKENS, Médecins Sans Frontières(Programme management)France

6. Timothy H. HOLTZHIV/STD Research Program, United States Centers for Disease Control and Prevention–CDC, Asia Regional Office(Epidemiology, surveillance, programme evaluation)Thailand

7. Joël KERAVECManagement Sciences for Health(Drug management)Brazil

8. Salmaan KESHAVJEEHarvard Medical School(Programme management, public health)United States of America

9. Aamir J. KHANIndus Hospital TB Program(Epidemiology, programme management) Pakistan

10. Vaira LEIMANEState Infectology CenterClinic of Tuberculosis and Lung Diseases(Programme management, clinical practice)Latvia

11. Andrei MARYANDYSHEVNorthern State Medical UniversityArchangelsk(Clinical practice)Russian Federation

12. Carole D. MITNICKHarvard Medical School(Epidemiology, programme support)United States of America

13. Gloria NWAGBONIWEAlliance for Hope, (Civil society)Nigeria

14. Domingo PALMEROPulmonology DivisionHospital Muñiz,(Clinical practice)Argentina

15. Ma. Imelda QUELAPIOTropical Disease Foundation, (Programme management)Philippines

16. Michael L. RICHPartners In Health(Clinical practice)United States of America

17. Sarah ROYCEPATH(Surveillance, public health)United States of America

18. Sabine RÜSCH-GERDESNational Reference Centre for Mycobacteria, (Laboratory specialist)Germany

19. Archil SALAKAIAManagement Sciences for Health, (Programme management)United States of America

20. Rohit SARINLRS Institute of TB and Allied Diseases, (Clinical practice)India

21. Holger SCHÜNEMANNMcMaster University(Chairman of the Guideline Development Group; epidemiology, guideline methodology)Canada

22. Elena SKACHKOVAFederal Centre of TB Monitoring, (Surveillance)Russian Federation

23. Francis VARAINEMédecins Sans Frontières(Clinical and programme management)France


WHO headquarters, Geneva, Switzerland

TB Department

24. Léopold BLANC

25. Dennis FALZON

26. Christopher FITZPATRICK

27. Katherine FLOYD

28. Haileyesus GETAHUN

29. Malgorzata GRZEMSKA

30. Christian GUNNEBERG

31. Ernesto JARAMILLO

32. Christian LIENHARDT

33. Fuad MIRZAYEV

34. Paul NUNN

35. Mario C. RAVIGLIONE

36. Delphine SCULIER

37. Fraser WARES

38. Karin WEYER

39. Matteo ZIGNOL

HIV Department

40. Chris DUNCOMBE

41. Marco Antonio DE AVILA VITORIA

External Review Group (area of expertise shown in parentheses for non-WHO staff)

42. Samiha BAGHDADIWHO Regional Office for the Eastern MediterraneanEgypt

43. Mercedes BECERRAHarvard Medical School(Academia)United States of America

44. Vineet BHATIAWHO Regional Office for South-East AsiaIndia

45. Masoud DARAWHO Regional Office for EuropeDenmark

46. Mirtha DEL GRANADOWHO Regional Office for the AmericasUnited States of America

47. Reuben GRANICHWHO HIV DepartmentSwitzerland

48. Lindiwe MVUSIDepartment of Health(Programme management)South Africa

49. Nani NAIRWHO Regional Office for South- East AsiaIndia

50. Norbert NDJEKADepartment of Health(Programme management, clinical practice)South Africa

51. Wilfred A.C. NKHOMAWHO Regional Office for Africa, Zimbabwe

52. Katsunori OSUGAWHO Regional Office for the Western PacificPhilippines

53. Hendrik Simon SCHAAFDepartment of Paediatrics and Child Health, Stellenbosch University and Tygerberg Children’s Hospital(Clinical practice, paediatric MDR-TB, surveillance)South Africa

54. Catharina VAN WEEZENBEEKWHO Regional Office for the Western Pacific, Philippines

55. Irina VASILYEVACentral TB Research Institute of RAMS(Research, clinical practice)Russian Federation

56. Wang Xie XIUTianjin Centers for Disease Control and Prevention(Surveillance)China

57. Richard ZALESKISWHO Regional Office for EuropeDenmark


Evidence review teams

58. Chunling LUHarvard Medical SchoolUnited States of America

59. Carole D. MITNICKHarvard Medical School United States of America

60. Richard A. WHITEHarvard Medical SchoolUnited States of America

61. Gail KENNEDYUniversity of California (San Francisco)United States of America

62. George RUTHERFORDUniversity of California (San Francisco)United States of America

63. Karen STEINGARTUniversity of California (San Francisco)United States of America

64. Matthew ARENTZUniversity of WashingtonUnited States of America

65. David HORNEUniversity of WashingtonUnited States of America

66. Patricia PAVLINACUniversity of WashingtonUnited States of America

67. Judd L. WALSONUniversity of WashingtonUnited States of America

68. Melissa BAUERMcGill UniversityCanada

69. Richard (Dick) MENZIESMcGill UniversityCanada

70. Olivia OXLADEMcGill UniversityCanada

71. Patricia WHYTEGriffith University Queensland(Guideline development)Australia


Annex 2: Declarations of interest

A2.1 WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2020In conformity with WHO guidelines for declaration of interests for WHO experts issued by the WHO Office for Compliance and Risk Management and Ethics, members of the Guideline Development Group, External Review Group and evidence reviewers were requested to submit completed WHO Declaration of Interest forms (DOIs) and declare in writing any competing interest (whether academic, financial or other) which could be deemed as conflicting with their role in the development of this guideline. In order to ensure the neutrality and independence of experts, an assessment of the DOI forms, curricula vitae, research interests and activities was conducted by the WHO Guideline Steering Committee. For cases in which potential conflicts were identified, the WHO Office for Compliance and Risk Management and Ethics was consulted for further clarification and advice as to how to manage competing interests. If any declared interests were judged significant, individuals were not included as members of the Guideline Development Group.

As per WHO rules, the objectives of the guideline development process and the composition of the GDG, including member biographies, were made public ahead of the meeting (https://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/drug-resistant-tb-gdg/en/). This public notice was conducted to allow the public to provide comments pertinent to any competing interests that may have gone unnoticed or not reported during earlier assessments.

Guideline Development Group The following Guideline Development Group members declared no conflicts of interest: Holger Schünemann (Chair); Rafael Laniado-Laborin (Co-Chair); Erlina Burhan; Fernanda Dockhorn Costa Johansen; Bernard Fourie; Elmira Gurbanova; Muhammad Amir Khan; Marian Loveday; Mahshid Nasehi; Ben Marais; Beatrice Mutayoba; Maria Rodríguez; Debrah Vambe; and Nguyen Viet Nhung. One member of the Guideline Development Group submitted additional information, which required no further action as this did not result in any conflict.

• Ingrid Schoeman: As an XDR-TB survivor, she went through the side-effects of being on treatment for 2 years. She works at TB Proof, and advocacy organisation which is often invited to attend key stakeholder meetings where they share the experiences of DR-TB survivors and advocated for high-quality TB care. She has been employed by TB Proof since 2017. She is certain that better evidence-based guidelines for treating DR-TB would benefit her colleagues, friends and local communities.

Six members of the Guideline Development Group declared interests that were judged non-significant and were believed not to affect the independence and impartiality of the experts during the guideline development process. Therefore, no restrictions to their participation applied:

• Charles Daley: Participation in the Data Monitoring Committee (DMC) for delamanid. A total of 5000 USD by Otsuka Pharmaceutical for services rendered in 2016 as the Chairman of the Committee. Participation in the DMC for pediatric trials of delamanid (Role Member). A total of 4000 USD by Otsuka Pharmaceutical for current services as a member of the Committee.

https://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/drug-resistant-tb-gdg/en/

https://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/drug-resistant-tb-gdg/en/


• Gerry Davies: Participation in the PreDiCT-TB consortium, a public-private partnership funded by the European Union Innovative Medicines Initiative and the European Federation of Pharmaceutical Industries and Associations (EFPIA). Role as academic coordinator (2012–2017) led to engagement with industrial partners in pre-competitive areas of research into TB drug development. All of these activities were fully supported by public funding from the European Union. No financial support was received from EFPIA. Current collaborator on pharmacokinetic sub-studies deriving from the STREAM Stage 1 trial. Funding support will be provided through research institution [University of Liverpool] to support analysis of pharmacokinetic samples and data later in late 2019/early 2020. This works focuses on evaluating clofazimine and fluoroquinolones. Academic co-supervisor of PhD candidate who is currently involved in the TB-PRACTECAL trial (chief investigator) at the London School of Hygiene and Tropical Medicine. Funding support will be provided through research institution [University of Liverpool] from Médecins Sans Frontières to support analysis of pharmacokinetic samples in early 2020. This work will involve bedaquiline, pretomanid, clofazimine, linezolid and moxifloxacin.

• Yuhong Liu: China’s New Drug Introduction and Protection Program (NDIP) was supported by the Bill & Melinda Gates Foundation (BMGF) and Janssen Pharmaceutica. Bedaquiline was provided by Janssen Pharmaceutica through the global donation project (4000 patients) . BMGF and Janssen Pharmaceutica also project support to doctors’ training, project activity implementation, quality control, etc. A total of 500 000 USD were provided for project implementation by BMGF including training, data collection, project supervision, between 2016–2020. Financial interests (resulting from funding source) that could directly affect, or could appear to affect, the professional judgment of the expert were not identified.

• Iqbal Master: Non-monetary support provided by Janssen Pharmaceutica to attend the 2016 International Lung conference in Liverpool. Only flights and accommodation were sponsored. No direct or indirect payments were made. As a manger in the MDR unit, I provide a link for the implementation of research studies, including STREAM 1 and the Nix-TB trial from 2013 onwards. I received no monetary support or remuneration for involvement in these studies. My involvement was purely from an altruistic wish to facilitate research in order to improve treatment regimens and outcomes in MDR patients in general. As a Government official, working in at a public health hospital, participation in the roll-out of bedaquiline and delamanid through a Clinical access programme, launched by the National TB programme. Member of the Provincial and National MDR-TB Advisory Committee of South Africa which makes recommendations and advises Government sites on clinical management.

• Payam Nahid: Federal CDC contract to support clinical trial units in San Francisco and Hanoi, Vietnam United States Centers for Disease Control and Prevention University of California, San Francisco Federal contract to support clinical trial units in San Francisco and Hanoi, Vietnam. Participation as a member of the DSMB for an MDR-TB clinical trial, TB-PRACTECAL. All DSMB related materials are obviously kept confidential. Discussions are underway with Médecins Sans Frontières (MSF) for future potential participation of Vietnam clinical trial units in Hanoi and HCMC in EndTB MDR -TB clinical trials. No contracts or agreements have been offered, signed or formalized. If agreements are formalized, enrolments into the EndTB trials would be anticipated to begin in 2020.

• Carrie Tudor: Grant from Eli Lilly Foundation – Lilly MDR-TB Partnership for TB Project managed by the International Council of Nurses. Award of approximately USD 1 000 000 from 2013–2019.

The below-mentioned members of the Guideline Development Group declared interests which were judged to be significant and which required further discussion and assessment by the WHO Office for Compliance and Risk Management and Ethics to outline a management plan:

• Susan Abdel-Rahman: (Significant) Research Support from the Thrasher Foundation for an amount of 197 000 USD. Funding ended on 30 October 2017. The Thrasher Research Fund provides grants for paediatric medical research. The Fund is currently supporting over 150 projects, including but not limited to research on childhood blindness, nutritional deficiencies, brain injuries, diabetes, asthma, cancer, genetic diseases and a number of infections including HIV, malaria, TB, schistosomiasis, cytomegalovirus and otitis media. Employment & Consultancies: WHO Agreement


for performance of work to conduct a summary review of preclinical and EBA data on pretomanid use. Financial interests (resulting from research support) that could directly affect, or could appear to affect, the professional judgment of the expert were not identified. Financial interest resulting from WHO Agreement for performance of work may be perceived to compromise the expert’s objectivity or independent professional judgment in the discharge of GDG duties and responsibilities led to partial exclusion from decision-making and voting limited to BPaL regimen.

• Daniela Cirillo: Research grant to measure minimum inhibitory concentrations (MIC) for bedaquiline. Work sponsored through the Ospedale San Raffaele by Janssen Therapeutics. The amount granted was 50 000 USD in 2018. Research grant to study MIC distributions for new TB drugs. Work sponsored through the Ospedale San Raffaele by the TB Alliance. The amount granted was 30 000 USD in 2018. Payment for MIC work for new TB drugs was done through Ospedale San Raffaele and not direct to the individual. Although these interests are tangentially related to the subject of the current guideline development meeting (i.e. diagnostics), a significant conflict of interest was identified for participation in the decision-making process and voting related to funding from the TB Alliance, leading to partial exclusion from decision-making and voting limited to BPaL regimen.

• Kelly Dooley: Participation as PI of the “Assessing Pretomanid for TB (APT)” trial, assessing pretomanid for treatment of drug-sensitive TB. Support and funding is from the U.S. FDA. Drug donation from TB Alliance (pretomanid) and Pfizer (rifabutin). No salary support. Participation as investigator on trials sponsored by the NIH, FDA, the U.S. CDC or UNITAID, assessing: Use of rifapentine for TB infection in pregnant women, young children, patients with HIV co-infection; use of rifapentine for treatment shortening in patients with pulmonary TB (rifapentine donated by Sanofi); use of high-dose rifampin and levofloxacin for pediatric TB meningitis (NIH funded); use of high-dose isoniazid for MDR-TB (NIH funded, ACTG A5312); delamanid for MDR-TB in children with HIV infection (NIH funded, IMPAACT 2005; drug donation by Otsuka); bedaquiline for children with MDR-TB and HIV infection (NIH Funded, IMPAACT 1108); meropenem/amox/clav for drug-sensitive- and MDR-TB (FDA funded). No salary support. Protocol Co-Chair ACTG study A5343 assessing use of delamanid and bedaquiline among patients with MDR-TB. Drug donation by Otsuka, Janssen and ViiV Healthcare. Support and funding for this trial are provided by the U.S. NIH, Division of AIDS (DAIDS); no salary support. Involvement in the DELamanId BEdaquiline for ResistAnt TubErculosis study (A53439) led to partial exclusion limited to discussions and voting processes related to the combined use of bedaquiline and delamanid.

• Agnes Gebhard: Research grant provided to KNCV by the TB Alliance to conduct a situational analysis in 3 countries (Indonesia, Kyrgyzstan, Nigeria) to understand the current infrastructure, resources, and practices for management of all forms of TB, and potential hurdles for integrating regimens (BPaL, BPaMZ, separately and together as a comprehensive solution to TB treatment). Research grant provided by the TB Alliance (305 000 USD – Between 2018 and 2019) to develop a country roadmap for introduction of new regimens. Four countries were chosen as examples (Kazakhstan, Kyrgyzstan, Uzbekistan and Indonesia). These roadmaps are flexible for use with any new (DR) TB regimen. Public support for the approval of Pretomanid in combination with bedaquiline and linezolid submitted to the U.S. FDA Antimicrobial Drugs Advisory Committee in response to a request for comments. The letter is in the public domain (https://www.regulations.gov/docketBrowser?rpp=25&so=DESC&sb=commentDueDate&po=0&dct=PS&D=FDA-2019-N-1317). Financial interest (Institutional) resulting from research grants provided by the TB Alliance led to partial exclusion from decision-making and voting limited to BPaL regimen.

• Alberto Piubello: Involvement in the Union-sponsored study “Treatment Regimen of Anti-tuberculosis Drugs for Patients With Multi-Drug-Resistant TB (STREAM), Stage 2” led to partial exclusion from decision-making and voting limited to the all-oral bedaquiline-containing shorter regimen.

• Alena Skrahina: Principal Investigator in the Pragmatic Clinical Trial for a More Effective Concise and Less Toxic MDR-TB Treatment Regimen(s) (TB-PRACTECAL) led to partial led to partial exclusion from decision-making and voting limited to BPaL regimen.

https://www.regulations.gov/docketBrowser?rpp=25&so=DESC&sb=commentDueDate&po=0&dct=PS&D=FDA-2019-N-1317

https://www.regulations.gov/docketBrowser?rpp=25&so=DESC&sb=commentDueDate&po=0&dct=PS&D=FDA-2019-N-1317


• Andrew Vernon: Work in the Division of TB Elimination at CDC which involved collaboration with NIH and Sanofi on the conduct of a multinational phase 3 trial of TB treatment using daily rifapentine. Sanofi provided medications for the trial, and has supported costs of PK testing. Total contribution to CDC Foundation was ~$3million (from 2007–17). No payment was received through these funds. Moreover, these funds were only a small proportion of overall trial costs, the vast majority of which were borne by CDC as the trial sponsor. In his capacity as a TB researcher and clinician at CDC, Andrew participated in meetings, both internal and external, concerned with the development of guidelines for the treatment of active TB and of LTBI in the United States. Role of the U.S. CDC as temporary voting members within the U.S. FDA’s Antimicrobial Drugs Advisory Committee Meeting. The latter interest led to partial exclusion from decision-making and voting limited to BPaL regimen.

External Review GroupThe following External Review Group members declared no conflicts of interest: Heather ALEXANDER, Sarabjit Singh CHADHA, Lisa CHEN, Edwin H HERRERA-FLORES, Anna Marie Celina GARFIN, Mathilde JACHYM, Giovanni Battista MIGLIORI, Thato MOSIDI, Welile SIKHONDZE, Bhabana SHRESTHA, Ivan SOLOVIC, Carlos TORRES, Zarir UDWADIA.

The following ERG member declared interests that were judged not to be in conflict with the objectives of the guidelines:

• Amanullah FARHANA: Declared that she has been employed and undertaken consultancy work for WHO and that she has had research activities funded by WHO and the Global Fund.

• Guy MARKS: Is the President of The Union (IUATLD), which undertakes projects and work in the field of MDR-TB. He is an investigator on the VQUIN trial, an investigated-initiated, publicly funded study on preventive therapy for contacts of patients with MDR-TB.

• Andrei MARYANDYSHEV: Declared research undertaken on MDR/RR-TB. The new TB drugs were investigated in the clinical trials in the hospital where Dr Maryandyshev works, i.e. Arkhangelsk clinical antituberculosis dispensary, Russian Federation where he was a main investigator. He participated in the clinical trials of new TB drugs: TMC207-TiDP13-C209 and TMC207TBC3001 phase II-III from 1.02.2012 to 3.10.2016; “An international, multicenter, prospective, randomized, double-blind, controlled study evaluating the efficacy and tolerability of a chemotherapy regimen including SQ 109 in pulmonary tuberculosis patients with multiple drug-resistant M. tuberculosis (phase IIc-III) from 19.08.2014 to 13.07.2016; PBTZ169-A15-C2b-1 “An international multicenter, double-blind, placebo-controlled, randomized trial to evaluate the efficacy, safety, and pharmacokinetics of PBTZ169 when used in combination therapy for patients with respiratory tuberculosis with bacterial excretion and drug resistance, phase IIb-III” from 13.12.2016 to 29.05.2017; Compassionate use of Delamanid (OPC-6768) for patients MDR TB, 6.12.2016 his hospital has received Delamanid for 5 patients from Otsuka company.

• Lawrence MBUAGBAW: Undertook a biostatistical consultation to support FDA reporting requirements for the use of bedaquiline, for Janssen Pharmaceuticals for which he received payment.

• Anuj K BHATNAGAR: Is the Co-Principal investigator for the STREAM 2 trial (Medical Research Council Clinical Trials Unit, London), for the Rajan Babu Institute of Pulmonary Medicine and Tuberculosis (RBIPMT) site, Delhi in India. The trial was initiated in this site in March 2019. The monetary aspects of the trial are being looked after by Vital Strategies as an affiliate of IUATLD for refurbishment of the ward, equipment, hiring of staff, upgrading laboratory facilities, access to all laboratory tests and patient support including monetary compensation. No money has been transferred to the institute for this trial. In addition, the National Institute for Research in Tuberculosis, Chennai (NIRT), an organization of the Indian Council of Medical Research (ICMR), Ministry of Health and Family Welfare, Government of India has initiated a Phase 3 trial – called BEAT TB, to study the efficacy and tolerability of a combination of newer drugs for shortening the treatment for pre-XDR and XDR-TB in 5 sites of India. At the RBIPMT site, of which Dr Bhatnagar is the Principal Investigator for this trial, they have just completed a site initiation visit and recruitment of personnel.


The first instalment of the grant for the initiation of this trial by NIRT Chennai has been given for recruitment of staff, equipment, laboratory reagents and patient and DOT provider support.

Evidence reviewers:The following experts who conducted the evidence for to inform the revision of the recommendations declared the below interests, which require no action beyond reporting for transparency purposes.

• Amrita Daftary: Columbia University Consultancy (2016–2021) – This is an ongoing consultancy to provide qualitative expertise to the design and evaluation of an adherence intervention in people with XDRTB-HIV in KwaZulu Natal, South Africa. Commissioned qualitative research for current GDG meeting. IC-IMPACTS funded grant (2015 – 2018) – study has been completed at McGill University; this was an intervention to engage pharmacy providers in Patna, India, to screen and refer TB symptomatic persons for a chest x-ray and doctor for timely TB detection. BMGF funded grant (2017–2020) – This study is held at McGill University where she was based until June 2019; this is an observational study using standardized patients to assess quality of clinical care for TB diagnosis in Cape Town and Durban, South Africa. NIH funded grant (2018 – 2020) – study is based at CAPRISA and Columbia University; this is an intervention to reduce XDRTB-HIV stigma in coinfected patients in KwaZulu Natal, South Africa.

• David Dowdy: Research grant Bill and Melinda Gates Foundation Grant to Institution (not owned by me) approx $300,000 current year interest, approximately $50,000. Travel to meetings Bill and Melinda Gates Foundation Travel paid for me to attend, approx. $10,000.

• Gabriela Gomez: Consultant providing modelling results for an investment case on a universal drug regimen for TB. Direct funding granted through BMGF for an amount of USD 40000. Funding concluded in 2018. Managed research grant to LSHTM for an economic evaluation of TB-PRACTECAL. Funding provided through MSF to research unit. Approximately £ 150 000. Her involvement stopped August 2019, although the project continues. In addition, a second grant from TB Alliance was granted to conduct an economic evaluation of the BPaL regimen. Approximately £ 60 000. Since 12 August 2019, she has been employed by Sanofi Pasteur. She is the lead for Europe in Vaccine Epidemiology and Modelling. There is no TB vaccine in the commercial pipeline of Sanofi Pasteur to her knowledge currently. She was not representing Sanofi Pasteur at this meeting, but only presenting work done as part of her previous position as Associate Professor at LSHTM.

• Richard Menzies: Commissioned WHO evidence reviews (2016-current) to identify, assess and synthesize the evidence for the development of guidelines for treatment of MDR-TB.

• Rada Savic: She received research funding from NIH, UNITAID and BMGF. Research funding to her institution (UCSF) where she is a principal investigator. She serves on Scientific Advisory Committee for TB Alliance, but receives no income for that role. She is a member of Core Science Group for NIH clinical trial network (ACTG) and for CDC clinical trial consortia (TBTC).

A2.2 WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2018Guideline Development Group The scope of the guidelines update and the composition of the Guidelines Development Group (GDG), including the biographies of the members, were made public for comment ahead of the meeting, in line with WHO requirements (https://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/gdg-meeting-mdr-rr-tb-treatment-2018-update/en/). All GDG members completed the WHO Declaration of interest (DoI) form and agreed to the confidentiality undertaking. The WHO Guideline Steering Committee reviewed the completed forms.

The following GDG members declared no interests conflicting with the objectives of the guidelines: Eden ABADIANO MARIANO, Sarabjit S CHADHA, Fernanda DOCKHORN COSTA JOHANSEN, Edwin


HERRERA-FLORES, Ayuko HIRAI, Alexander KAY, Rafael LANIADO-LABORIN, Lawrence MBUAGBAW, Austin Arinze OBIEFUNA, Cristina POPA, Wipa REECHAIPICHITKUL, Maria RODRIGUEZ, Holger SCHÜNEMANN, Adman Skirry SHABANGU and Sabira TAHSEEN.

The following GDG members declared interests that were judged not to be in conflict with the objectives of the guidelines:

Susan ABDEL-RAHMAN declared that a research grant (US$ 196 356) was received by her institution from the Thrasher Foundation in September 2017 for her role as Principal Investigator to study whether second-line TB medicines can be accurately quantified from dried blood spots (funding ongoing). Daniela CIRILLO declared that a grant (US$ 26 000) was provided to her research unit by the Foundation for Innovative New Diagnostics (FIND) to evaluate new TB diagnostics (funding ongoing). In 2014, she received funding from Janssen (US$ 10 000) and Otsuka (US$ 25 000) for work on drug-susceptibility testing (DST) of new drugs. In 2014, Janssen Italy funded her participation in an expert working group on the use of bedaquiline in Italy (US$ 1000). Geraint (Gerry) Rhys DAVIES declared that he was until November 2017 the academic coordinator of the PreDiCT-TB consortium, a public–private partnership funded by the European Union Innovative Medicines Initiative and the European Federation of Pharmaceutical Industries and Associations (EFPIA). Although this role involved engagement with industrial partners (GSK, Sanofi, Janssen) in pre-competitive areas of research into TB drug development, these activities were fully supported by public funding from the European Union (EU) and neither he nor his research institution have received any funding from EFPIA or from the individual industrial partners. He has been asked and intends to provide advice to the STREAM study team on possible PK studies, which may be carried out in future using existing or further prospectively collected samples (no payment or research support has been offered for this activity). In 2017, he was paid fees by WHO for expert consultancies (US$ 5000). He is a member of a steering group convened by Critical Path to TB Regimens to advise on development of the lipoarabinomannan (LAM) biomarker developed by Otsuka in the context of adaptive clinical trials (receives no payment for this activity). Bernard FOURIE declares receiving US$ 16 000 per year (ongoing) to act as a non-executive director and member of the Board of the National Bioproducts Institute in South Africa, which is exclusively involved in the production and marketing of blood- and plasma-derived products. Payam NAHID declares an ongoing Federal US Centers for Disease Control and Prevention (CDC) contract to the University of California San Francisco to support clinical trial units in San Francisco and Viet Nam (total amount not specified). Carrie TUDOR declares that her employer receives funding from the Eli Lilly Foundation (~US$ 1000 000 for 2013–2017; ongoing at US$ 243 000 in 2018) to run the International Council of Nurses’ TB/MDR-TB project. The project focuses on building the capacity of nurses and allied professionals on TB and DR-TB care through training and currently operates in China, Eswatini, Ethiopia, Lesotho, Malawi, the Russian Federation, Uganda and Zambia. She also received US$ 20 000 from the KwaZulu Natal Research Institute for TB & HIV (South Africa) and Fogarty/NIH (US) for her dissertation and postdoctoral research on TB until 2014. Zarir UDWADIA declares that he has supported about 40 patients to access bedaquiline and three patients to access delamanid through the compassionate use programmes of Janssen and Otsuka, respectively. He declares that he did not charge fees to the patients involved and there were no financial transactions with the manufacturers. Andrew VERNON declares that he heads a clinical research group at US CDC (Tuberculosis Trials Consortium [TBTC]) doing TB trials. TBTC often collaborates with pharmaceutical companies, which may provide modest support, e.g. drug supplies, funding for PK sub-studies. Sanofi Aventis awarded ~US$ 2.8 million in six unrestricted grants to CDC Foundation in 2007–2015 to facilitate or support TBTC work on rifapentine (e.g. PK studies, staff contracts, travel for invited speakers, preparation of data to support regulatory filings). These funds have not otherwise benefited the research group. TBTC has studies under way with rifapentine (TBTC Study 31) and levofloxacin (Opti-Q, TBTC Study 32). He declares that his branch has supported studies of drug-susceptible TB that have included moxifloxacin (TBTC Study 27, Study 28 and Study 31). His branch has also supported enrolment at two of the three sites involved in the Opti-Q Study. This study evaluates different doses of levofloxacin in the treatment of DR-TB and has no comparator arm. There is no involvement with drug procurement. The principal investigator and management of the study, including data handling, analysis and drug


procurement, are at Boston University. The Opti-Q outcomes are not yet known and the final analysis has yet to start. The majority of the study was funded by the US NIH (National Institutes of Allergy and Infectious Diseases [NIAID]).

The following GDG member declared an interest that was judged to conflict with the objectives of the guidelines (funding for new medicines for use in MDR-TB regimens). He therefore withdrew from the GDG panel and participated as a technical resource. Gary MAARTENS declared that his laboratory will receive US$ 2 184 608 from the US NIH (NIAID) to undertake drug assays for a trial on the safety, tolerability and PK of bedaquiline and delamanid, alone and in combination, among patients on MDR-TB treatment (AIDS Clinical Trials Group study A5343). He will receive no salary support.

External Review Group (ERG)The following ERG members declared no interest conflicting with the objectives of the guidelines: Essam ELMOGHAZI, Mildred FERNANDO-PANCHO, Anna Marie Celina GARFIN, Barend (Ben) MARAIS, Andrei MARYANDYSHEV, Alberto MATTEELLI, Giovanni Battista MIGLIORI, Nguyen Viet NHUNG, Rohit SARIN, Welile SIKHONDZE, Ivan SOLOVIC, Pedro SUAREZ and Carlos TORRES.

The following ERG member declared interests that were judged not to be in conflict with the objectives of the guidelines:

Thato MOSIDI declares that she represents people affected by and living with TB on the Global Fund Country Coordinating Mechanism in South Africa. She is also an active member of TB Proof, a not-for-profit organization that advocates for patient access to TB medicines.

The following evidence reviewers were from McGill University, Montréal, Canada – Syed ABIDI, Jonathon CAMPBELL, Zhiyi LAN and Dick MENZIES. They declared no interest conflicting with the objectives of the guidelines.

The following evidence reviewer declared interests that were judged not to be in conflict with the objectives of the guidelines: Faiz Ahmad KHAN declared payment by WHO to collect data and carry out a meta-analysis on the shorter MDR-TB regimens for the 2016 guidelines (CAD$ 4080) and travel fees to present these findings at a GDG meeting in 2015. He also declares undertaking an update of the same analysis in 2016–2018 for the ATS guidelines for which he receives no remuneration.

A2.3 WHO treatment guidelines for isoniazid-resistant tuberculosis, 2018In conformity with the WHO guidelines for declarations of interest1 for WHO experts issued by the WHO Compliance, Risk Management and Ethics Office, members of the Guideline Development Group (GDG), Evidence Review Group (ERG) and evidence reviewers were requested to submit completed WHO Declaration of Interest forms (DoIs) and declare in writing any competing interest (whether academic, financial or other) that could be deemed as conflicting with their role in the development of this guideline. In order to ensure the neutrality and independence of experts, an assessment of the DoI forms, curricula vitae, research interests and activities was conducted by the WHO Guideline Steering Committee. For cases in which potential conflicts were identified, the WHO Compliance, Risk Management and Ethics Office was consulted for further clarification and advice as to how to manage competing interests. If any declared interests were judged significant, individuals were not included in the GDG.

ERG members were also requested to declare interests and these were also assessed for potential conflict. As per WHO rules, the objectives of the guideline development process and the composition of the GDG, including member biographies, were made public 4 weeks ahead of the meeting (https://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/gdg-meeting-izoniazid-resistant-tb/en/).

https://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/gdg-meeting-izoniazid-resistant-tb/en/

https://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/gdg-meeting-izoniazid-resistant-tb/en/


This public notice was conducted to allow the public to provide comments pertinent to any competing interests that may have gone unnoticed or not reported during earlier assessments.

Guideline Development GroupThe following GDG members declared no interests: Daniela CIRILLO, Kelly DOOLEY (Co-Chair), Gustavo DO VALLE BASTOS, Raquel DUARTE, Christopher KUABAN, Rafael LANIADO-LABORIN, Gary MAARTENS, Andrei MARYANDYSHEV, Ignacio MONEDERO-RECUERO, Maria Imelda Josefa QUELAPIO, Wipa REECHAIPICHITKUL, Nancy SANTESSO (Co-Chair), Welile SIKHONDZE and Armand VAN DEUN.

Five GDG members declared interests that were judged non-significant and not affecting the neutrality of the guideline development process. Therefore, no restrictions to their participation applied:

Farhana AMANULLAH: (1b) paediatric expert for WHO TB monitoring mission in Indonesia (value US$ 600/day, 14–27 January 2017); (2a) paediatric TB expert for Harvard Medical School Global Health Delivery grant (20% full-time equivalent [FTE]; June 2016–June 2018); (2b) paediatric TB expert for Global Fund grant (20% FTE; June 2016–December 2017).

Tsira CHAKHAIA: (1b) Research coordinator for TB Alliance NC-006 clinical trial (2016); community engagement project coordinator for TB Alliance (current); research coordinator for NiX-TB (from May 2017).

Philipp DU CROS: (2a) Member of the protocol writing committee and steering committee of the TB-PRACTECAL Clinical Trial, which has received a grant of €6.8 million from the Dutch Postcode Lottery to Médecins Sans Frontières, Operational Centre Amsterdam (currently active).

Michael RICH: (1a) employed by Partners in Health to work on clinical care guidelines and in the programmatic management of DR-TB; (1a) WHO consultancies on treatment of drug-resistant TB to national TB programmes; (2a) conduct research and develop regimens for drug-resistant tuberculosis (DR-TB) as a recipient of the UNITAID’s Expand new drug markets for TB [EndTB] grant (all active during the development of the present recommendations).

Rada SAVIC: (1b) Member of the panel of the WHO Meeting on Target Regimen Profiles (value US$ 2500); grant reviewer for European and Developing Countries Clinical Trials Partnership (value US$ 1000); (2a) principal investigator or co-principal investigator of research grants by United States National Institutes of Health (NIH) and Gates Foundation on improving TB treatment options (all currently active).

External Review GroupThe following ERG members declared no interests related to the objectives of this meeting: Essam ELMOGHAZI, James JOHNSTON, Enos MASINI, Rohit SARIN, Kitty VAN WEEZENBEEK, Irina VASILYEVA and Piret VIIKLEPP.

The below-mentioned ERG members declared interests that were judged not to be significant to the topic of the guideline. Some of the ERG members were involved in clinical trials not related to the treatment of Hr-TB and therefore no restrictions applied to their participation as expert reviewers.

Charles L. DALEY: (1b) Chair and member of data monitoring committees for delamanid studies (US$ 45 000 provided by Otsuka Pharmaceutical over 8 years; ongoing); Chair of data monitoring committee for clofazimine studies (US$ 2500 provided by Novartis; finished in 2016).

Ingrid OXLEY: (5b) at the Union Conference 2015 in Cape Town, TB Proof campaigns advocated for treatment of latent TB infection (LTBI) among health care workers. She is a health care worker and has had two episodes of TB. Many members of TB Proof who are health care workers may have benefited


from the WHO guidelines for the treatment of LTBI or received funding for LTBI treatment. This was not the focus of the current guideline.

Simon SCHAAF: (2a) research support to employer for pharmacokinetics work on second-line TB medicines in children from the NIH and Otsuka Pharmaceutical (approximately ZAR 5 million/year). NIH grant ceased in 2015; Otsuka Pharmaceutical grant is still active.

Helen STAGG: (1b) grant to employer for consultancy work on MDR-TB clinical pathways in eastern Europe (Otsuka Pharmaceutical: £59 925; 2013–2015); (2a) grant to employer for Hepatitis and Latent TB Infection (HALT) study (Department of Health of the United Kingdom; National Institute for Health Research, United Kingdom; £86 000 for HALT study (2014); £315 265 for fellowship, salary, research costs; 2015–2017); (2b) non-monetary support for HALT study (Sanofi provides free rifapentine to the research study participants; 2014–2017); (6d) received International Trainee Scholarship Award (US$ 1000 value) at the American Thoracic Society (ATS) conference 2016 where she presented the results of a review she conducted (1).

Carlos A. TORRES-DUQUE: (5a) & (5b) as member of the National Advisory Committee for Tuberculosis (Ministry of Health of Colombia) participates in the updates of national TB treatment guidelines. His expert opinion is based upon evidence and local/international experience and does not generate any profits for him.

Evidence reviewersThe independent experts who undertook the systematic reviews of evidence for this revision declared no interests related to the topic of the policy guideline objectives.

This information is included in the Declaration of interest section in the WHO treatment guidelines for isoniazid-resistant tuberculosis, pages ix–xi, available at: https://apps.who.int/iris/bitstream/handle/10665/260494/9789241550079-eng.pdf

A2.4 WHO guidelines for the treatment of drug-susceptible tuberculosis and patient care, 2017 updateThe scope for the update of the Guidelines for treatment of drug-susceptible tuberculosis and patient care and the composition of the Guideline Development Group (GDG), as well as the External Review Group, were established in line with WHO’s policy on conflict of interest. All contributors completed a WHO Declaration of Interest form. All stated declarations of interest were evaluated by three members of the steering group for the existence of any possible financial or intellectual conflict of interest. In some cases there was possible conflict of interest justifying the exclusion from membership of the GDG, and the Director of the WHO Global TB Programme, the WHO Guideline Review Committee and the WHO Legal Office were consulted on this and a decision was made. Diversity and broad representation in the GDG were sought in an effort to address and overcome any potential intellectual conflicts of interest. The GDG was composed of representatives of technical partners and academia, a GRADE methodologist, national TB programme managers from different WHO regions, representatives of civil society organizations, experts from WHO collaborating centres, professional organizations and a representative from the International Organization for Migration (see web Annex 1). The biographies of the GDG members were made public ahead of the meeting, and the WHO Guidelines Steering Committee, which was formed in preparation for the update of the guidelines, reviewed the completed forms at the beginning of the meeting with everyone present.

https://apps.who.int/iris/bitstream/handle/10665/260494/9789241550079-eng.pdf

https://apps.who.int/iris/bitstream/handle/10665/260494/9789241550079-eng.pdf


Guideline Development GroupThe following members declared no interests: Si Thu AUNG; Frank BONSU; Jeremiah CHAKAYA; Lucy CHESIRE; Daniela CIRILLO; Poonam DHAVAN; Kathy FIEKERT; Andrei MARYANDYSHEV; Nguyen Viet NHUNG; Ejaz QADEER; Abdul Hamid SALIM; Holger SCHÜNEMANN; Pedro SUAREZ; Justin Wong Yun YAW.

The following GDG members declared interests that were judged not to be in conflict with the policy of WHO, or the objectives of the meeting:

Kelly DOOLEY declared that she did not receive any salary support from drug companies for her work in the following roles and activities: Co-chair of the AIDS Clinical Trials Group (ACTG) study assessing bedaquiline and delamanid for MDR-TB; principal investigator, assessing pretomanid for tuberculosis trial, assessing pretomanid (PA-824, investigational drug) for treatment of drug-sensitive TB; investigator on trials assessing rifapentine for pregnant women with latent TB infection, rifapentine for treatment shortening in patients with pulmonary TB, high-dose rifampicin and levofloxacin for paediatric TB meningitis, high-dose isoniazid for MDR-TB, and delamanid for MDR-TB in children with and without HIV. Mike FRICK declared that his organization received non-commercial support (1) to track investment made in TB research and development; (2) to host a symposium at the UNION meeting; (3) advocate for increased funding for TB research and development, research and access to evidence-based interventions; and (4) management of community research advisors group. Simon SCHAAF declared receiving grants for pharmacokinetic drug studies in children of second-line drugs and for studying preventive therapy in MDR-TB. Carrie TUDOR declared that her organization receives funding from Eli Lilly Foundation for activities related to TB and MDR-TB projects.

External Review GroupThe following External Review Group members declared no interest related to the objectives of this meeting: Riitta DLODLO, Celine GARFIN, Lee REICHMAN, Vaira LEIMANE, Rohit SARIN, Dalene VON DELFT and Fraser WARES. The following WHO staff from the regional offices reviewed the final draft of the guideline document: Masoud DARA (Europe), Mirtha DEL GRANADO (Americas), Daniel KIBUGA (Africa), Hyder KHURSHID (South-East Asia), Mohamed AZIZ (Eastern Mediterranean), and Nobuyuki NISHIKIORI (Western Pacific).

Evidence ReviewersThe researchers who undertook the systematic reviews of evidence for this revision were the following:

Narges ALIPANAH, Cecily MILLER, Payam NAHID (team leader for PICO 1, 2 & 7–10), University of California, San Francisco, United States of America; and Lelia CHAISSON, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America.

Richard MENZIES, McGill University, Montreal, Canada (team leader for PICO 3, 4 & 6); and James JOHNSTON, University of British Columbia, Vancouver, Canada.

Gregory FOX (team leader for PICO 11) and Jennifer HO, University of Sydney, Sydney, Australia.

The evidence reviewers did not participate in the formulation of the policy recommendations.

The following reviewers declared no interest related to the objectives of and their attendance at the meeting: Narges ALIPANAH, Jennifer HO and James JOHNSTON. The following reviewer declared interests that were judged not to be in conflict with the policy of WHO, or the objectives of the meeting: Payam NAHID declared that his research unit received support from the United States Centers for Disease Control and Prevention through a federal contract to support clinical trial units in San Francisco, USA, and in Hanoi, Viet Nam.


This information is included in the Declaration and management of conflict of interest section in the Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update, pages 6–7, available at: https://apps.who.int/iris/bitstream/handle/10665/255052/9789241550000-eng.pdf

A2.5 WHO treatment guidelines for drug-resistant tuberculosis, 2016 updateGuideline Development GroupThe scope of the guidelines update, and the composition of the GDG, including their biographies, were made public for comment ahead of the meeting in line with WHO’s conflict of interest policy. All GDG members completed the WHO Declaration of Interest forms. The WHO Guideline Steering Committee, in preparation for the update of the guidelines and the GDG meeting, reviewed the completed forms. The following GDG members declared no conflicting interests: Luis Gustavo do

Valle BASTOS, José A CAMINERO, Tsira CHAKHAIA, Michel GASANA, Armen HAYRAPETYAN, Antonia KWIECIEN, Sundari MASE, Nguyen Viet NHUNG, Maria RODRIGUEZ, Holger SCHÜNEMANN, James SEDDON and Alena SKRAHINA.

The following GDG members declared interests that were judged not to be in conflict with the objectives of the meeting: Farhana AMANULLAH declared having received funding for consultancies (US$ 500/ day) and travel from WHO; and grants from the Global Fund and TB-REACH to cover her salary (10% full-time equivalent).

Daniela CIRILLO declared having received funding from FIND to conduct evaluation of drug-susceptibility testing (DST) for new drugs (US$ 16 000), and from Otsuka to evaluate DST for delamanid (US$ 25 000). She also declared being the head of a supranational TB reference laboratory in Italy involved in country capacity-building in DST technologies for second-line drugs and new diagnostics for drug-resistant TB; and being a member of the Italian national committee for the use of bedaquiline. Charles L. DALEY declared having received funding from Otsuka to serve as chair of the data monitoring committee for trials of delamanid (US$ 47 000 over 7 years–current). Kelly DOOLEY declared having received funding to provide expert advice on a trial design for TB/HI (US$ 2000/year paid to the university/ employer); she also declared the following activities and roles: co-chair AIDS Clinical Trials Group (ACTG) study assessing bedaquiline and delamanid; principal investigator for adjuvant paclitaxel and trastuzumab (APT) trial assessing pretomanid (PA-824); and investigator in trials assessing high-dose isoniazid for MDR-TB, rifapentine for pregnant women and children with latent TB infection (LTBI), high- dose rifampicin and levofloxacin for paediatric TB meningitis, as well as bedaquiline and delamanid for children with MDR-TB and HIV infection.

Agnes GEBHARD declared that she works for the KNCV TB Foundation, which has two projects funded by the Eli Lilly and Company Foundation: (i) engaging the private sector in diagnosis and treatment of TB and MDR-TB with quality-assured second-line TB drugs, and (ii) the roll-out of QuanTB (a drug forecasting tool) in countries not supported by the Systems for Improved Access to Pharmaceuticals and Services (SIAPS) implemented by Management Sciences for Health. In addition, she declared that the KNCV TB Foundation has a collaborative project with Cepheid in two countries (Nigeria, Viet Nam), with KCNV providing services for the installation and initial training on the use of GeneXpert machines. Carlos TORRES-DUQUE declared having received honoraria from Janssen Pharmaceuticals for presentations on TB prevention and WHO policy on bedaquiline at a Latin American Meeting on MDR-TB held in 2014 (US$ 2000). Tom SHINNICK declared being an employee of the United States Centers for Disease Control and Prevention (CDC). CDC supports his travel and research related to his work on laboratory services needed for TB control. He declared having often represented CDC’s position on laboratory services needed for TB diagnosis, treatment and control. As part of his official duties for CDC, he served on the Data and Safety Monitoring Board (DSMB) organized by Otsuka


for the clinical trial of delamanid. He did not receive any remuneration for serving on the DSMB nor for travel expenses (CDC paid for all travel expenses related to serving on the DSMB). The DSMB has completed its work for the trial.

The following GDG members declared interests that were judged to be in conflict with some of the objectives of the meeting and were thus recused from some of the discussions: Lindsay MCKENNA declared non-commercial support to Treatment Action Group (TAG), her employer, from Stop TB Partnership; Bill & Melinda Gates Foundation; the US Department of Veteran Affairs (on behalf of CDC); Janssen Therapeutics for Hepatitis C and HIV projects and the Global Alliance for TB Drug Development (a public–private entity developing new drugs and regimens for TB treatment). She was thus recused from participating in the 9 November 2015 meeting session on Patients, Intervention, Comparator and Outcomes (PICO) question 1 on MDR-TB regimen composition for adults and children. José A CAMINERO stated in his biosketch that he is a staff consultant of the International Union Against Tuberculosis and Lung Disease (UNION), an agency directly involved in the implementation and evaluation of programmes using shorter MDR-TB regimens. He was therefore recused from the 10 November 2015 meeting session on PICO question 3 on shorter regimens for MDR-TB.

External Review GroupThe following ERG members declared no interest related to the objectives of this meeting: Chen-Yuan CHIANG, Celine GARFIN, Michael KIMERLING, Vaira LEIMANE, Gao MENGQIU, Norbert NDJEKA, Ejaz QADEER, Lee REICHMAN, Rohit SARIN and Irina VASILYEVA.

The following two ERG members declared interests which were judged not to be in conflict with the objectives of the guidelines. Guy MARKS declared research support from AERAS (US$ 450 000) related to the evaluation of latent TB infection and the rate of recurrence of TB after initial treatment in Viet Nam. He also declared being the Vice-President (and a board member) of the UNION and Editor-in-Chief of the International Journal of Tuberculosis and Lung Disease (for which he receives an honorarium). Dalene VON DELFT declared having received support from TAG, USAID, UNITAID, Janssen Pharmaceuticals, Critical Path to TB Drug Regimens (CPTR) and AERAS to cover travel costs and accommodation to give presentations/speeches on drug-resistant TB. She declared that in 2011 she received bedaquiline as part of her MDR-TB treatment through a compassionate use access programme.

Evidence ReviewersThe following reviewers declared interests that were judged not to be in conflict with the objectives of the meeting:

Gregory J FOX declared having received research and non-monetary support from the UNION (sponsored by Otsuka) valued at about US$ 5000 to attend the 2015 International UNION Conference and to receive the Young Innovator Award (he declares no work for Otsuka or any relationship of this award with any commercial or research activities with Otsuka).

Katherine FIELDING declared that her employer (LSHTM) was a recipient of an award from Médecins Sans Frontières (MSF) (£26 890) for the period February–December 2015 to provide statistical support for the TB-PRACTECAL study on which she is a co-investigator. The study is a Phase II–III randomized controlled trial (RCT) to evaluate the efficacy and safety of shorter MDR-TB regimens for adults.

Rebecca HARRIS declared she is consulting for a clinical research organization (Cromsource) working for Glaxo SmithKline (GSK) vaccines (~£90 000 in 2013); and on GSK vaccines not related to TB (~£10 000 since 2013) for Manpower Solutions.

David MOORE declared receiving research support from the Wellcome Trust Research Training Fellowship Programme to supervise a PhD student to study MDR-TB in Peru (£207 056 in 2014).


Anneke HESSELING declared that her employer (Stellenbosch University) is a recipient of an award from Otsuka Pharmaceutical (~US$ 70 000 to date) for her work on the Phase III delamanid clinical trials in children.

This information is included in the Declaration of interest section in the WHO treatment guidelines for drug-resistant tuberculosis, 2016 update, pages 2–5, available at: https://www.who.int/tb/areas-of-work/drug-resistant-tb/Annexes_8-10.pdf

A2.6 WHO guidelines for the programmatic management of drug-resistant tuberculosis, 2011 updateFunding for the meetings and reviews involved in the updating of the guidelines came entirely from the United States Agency for International Development (USAID). The experts on the Guideline Development Group (GDG) and the institutions where they work contributed time for the various discussions and other activities involved in the update process.

The Declaration of interest forms were completed by all non-WHO members of the GDG and the External Review Group, as well as the members of the academic centres who were involved in the reviews. Four members of the GDG declared interests that were judged to represent a potential conflict and were excused from the sessions of the meeting on 25–27 October 2010 during which recommendations relating to the drug regimens were discussed. Jaime BAYONA was a consultant for the development of clinical trial design for studies of an anti-tuberculosis drug manufactured by Otsuka Pharmaceutical Co. Ltd (OPC-67683). Charles L. DALEY was chairperson of drug-safety monitoring for two trials conducted by Otsuka Pharmaceutical Co. Ltd. Carole D. MITNICK served as a member of the Scientific Advisory Board of Otsuka Pharmaceutical Co. Ltd and had an advisory role on drug OPC-67683. Ma. Imelda QUELAPIO received support (monetary and non-monetary) for research from Otsuka Pharmaceutical Co. Ltd.

The following members of the academic centres, who performed the reviews of evidence from which the recommendations contained in these guidelines are derived, presented their findings at the meeting: Matthew ARENTZ, Melissa BAUER, Richard MENZIES, Carole D. MITNICK, Olivia OXLADE, Patricia PAVLINAC and Judd L. WALSON. They did not participate in the formulation of recommendations related to the respective reviews of evidence that they performed.

This information is included in the Funding and declarations of interest section in the Guidelines for the programmatic management of drug-resistant tuberculosis, 2011 update, page 2, available at: https://apps.who.int/iris/bitstream/handle/10665/44597/9789241501583_eng.pdf

https://www.who.int/tb/areas-of-work/drug-resistant-tb/Annexes_8-10.pdf



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(10.

3%)

97/5

99 (1

6.2%

)O

R 0.

6 (0

.4 to

0.

8)

6 fe

wer

pe

r 100

(fr

om

10 fe

wer

to

2 fe

wer

)b

VE

RY

LOW

CRIT

ICAL


Cert

aint

y as

sess

men

t№

of p

atie

nts

Effe

ct

Cert

aint

yIm

port

ance

№ o

f st

udie

sSt

udy

desi

gnRi

sk o

f bi

asIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

cons

ider

atio

ns

All-

oral

be

daqu

iline

-co

ntai

ning

sh

orte

r reg

imen

of

9–1

2 m

onth

s du

ratio

n

Shor

ter r

egim

en

reco

mm

ende

d by

WH

O

(with

inje

ctab

le)

Rela

tive

(95%

CI)

Abs

olut

e (9

5% C

I)

HIV

Neg

ativ

e: S

ucce

ss v

s. F

ailu

re/R

ecur

renc

e (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

195/

199

(98.

0%)

205/

228

(89.

9%)

OR

6.5

(1.4

to

29.5

)

7 m

ore

per 1

00

(from

2

mor

e to

12

mor

e)b

VE

RY

LOW

CRIT

ICAL

HIV

Neg

ativ

e: S

ucce

ss v

s. D

eath

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne19

5/23

4 (8

3.3%

)20

5/25

4 (8

0.7%

)O

R 1.

9 (1

.1 to

3.

5)

10 m

ore

per 1

00

(from

1

mor

e to

18

mor

e)b

VE

RY

LOW

CRIT

ICAL

HIV

Neg

ativ

e: S

ucce

ss v

s. F

ailu

re/R

ecur

renc

e/D

eath

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne19

5/23

8 (8

1.9%

)20

5/27

7 (7

4.0%

)O

R 2.

1 (1

.3 to

3.

6)

13 m

ore

per 1

00

(from

4

mor

e to

21

mor

e)b

VE

RY

LOW

CRIT

ICAL

HIV

Neg

ativ

e: S

ucce

ss v

s. A

ll O

ther

Out

com

es (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

195/

255

(76.

5%)

205/

327

(62.

7%)

OR

2.7

(1.7

to

4.3)

20 m

ore

per 1

00

(from

11

mor

e to

29

mor

e)b

VE

RY

LOW

CRIT

ICAL

HIV

Neg

ativ

e: L

ost v

s. A

ll O

ther

Out

com

es (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

18/2

55 (7

.1%

)61

/327

(18.

7%)

OR

0.3

(0.2

to

0.7)

10 fe

wer

pe

r 100

(fr

om

17 fe

wer

to

4 fe

wer

)b

VE

RY

LOW

CRIT

ICAL

AFB:

acid

-fas

t bac

illi; a

OR:

adj

uste

d od

ds ra

tio; A

RT: a

ntire

trovi

ral t

hera

py; C

I: co

nfid

ence

inte

rval

; HIV

: hum

an im

mun

odef

icien

cy v

irus;

MD

R/RR

-TB:

mul

tidru

g- o

r rifa

mpi

cin-r

esist

ant T

B; O

R: o

dds

ratio

; WH

O:

Wor

ld H

ealth

Org

aniz

atio

n.

Expl

anat

ions

a. F

or s

ome

patie

nts,

info

rmat

ion

was

miss

ing

on A

FB s

mea

r res

ult a

nd c

ultu

re re

sult

in th

e an

alys

is. P

atie

nts

with

unk

now

n ag

e, s

ex, o

r HIV

sta

tus

wer

e ex

clude

d fro

m a

ll an

alys

es.

b. O

utco

mes

and

cos

ts a

re s

imul

ated

usin

g a

mod

el th

at d

raw

s pa

ram

eter

est

imat

es fr

om m

ultip

le s

ourc

es, i

nclu

ding

the

aORs

for s

ucce

ss v

ersu

s de

ath/

failu

re d

escr

ibed

abo

ve.

c. T

he a

bsol

ute

effe

ct is

cal

cula

ted

afte

r mat

chin

g in

terv

entio

n an

d co

mpa

rato

r pop

ulat

ions

, and

per

form

ing

bino

mia

l reg

ress

ion

with

an

iden

tity

link.


Aut

hor(

s):

Rese

arch

Inst

itute

of t

he M

cGill

Univ

ersit

y H

ealth

Cen

tre

Que

stio

n:

Shou

ld a

n al

l-ora

l sho

rter

regi

men

of 9

–12

mon

ths’

dura

tion

inclu

ding

bed

aqui

line

vs lo

nger

regi

men

s with

out n

ew T

B dr

ugs

be u

sed

for

MD

R/RR

-TB

patie

nts

to s

afel

y im

prov

e ou

tcom

es?

Sett

ing:

In

tern

atio

nal

Dat

e:

April

202

0

Cert

aint

y as

sess

men

t№

of p

atie

nts

Effe

ct

Cert

aint

yIm

port

ance

№ o

f st

udie

sSt

udy

desi

gnRi

sk o

f bi

asIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

cons

ider

atio

ns

All-

oral

be

daqu

iline

-co

ntai

ning

sh

orte

r reg

imen

of

9–1

2 m

onth

s du

ratio

n

Long

er

regi

men

s w

ithou

t new

TB

drug

s

Rela

tive

(95%

CI)

Abs

olut

e (9

5% C

I)

Succ

ess

vs. F

ailu

re/R

ecur

renc

e (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

631/

653

(96.

6%)

679/

771

(88.

1%)

OR

3.7

(2.2

to

6.3)

8 m

ore

per 1

00

(from

5

mor

e to

11

mor

e)b,

c

VE

RY L

OW

CRIT

ICAL

Succ

ess

vs. D

eath

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne63

1/79

1 (7

9.8%

)67

9/10

44 (6

5.0%

)O

R 2.

3 (1

.8 to

3.

0)

15 m

ore

per 1

00

(from

10

mor

e to

19

mor

e)b,

c

VE

RY L

OW

CRIT

ICAL

Succ

ess

vs. F

ailu

re/R

ecur

renc

e/D

eath

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne63

1/81

3 (7

7.6%

)67

9/11

36 (5

9.8%

)O

R 2.

6 (2

.0 to

3.

3)

18 m

ore

per 1

00

(from

14

mor

e to

23

mor

e)b,

c

VE

RY L

OW

CRIT

ICAL

Succ

ess

vs. A

ll U

nfav

orab

le (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

631/

891

(70.

8%)

679/

1437

(47.

3%)

OR

2.8

(2.3

to

3.5)

23 m

ore

per 1

00

(from

18

mor

e to

27

mor

e)b,

c

VE

RY L

OW

CRIT

ICAL


Cert

aint

y as

sess

men

t№

of p

atie

nts

Effe

ct

Cert

aint

yIm

port

ance

№ o

f st

udie

sSt

udy

desi

gnRi

sk o

f bi

asIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

cons

ider

atio

ns

All-

oral

be

daqu

iline

-co

ntai

ning

sh

orte

r reg

imen

of

9–1

2 m

onth

s du

ratio

n

Long

er

regi

men

s w

ithou

t new

TB

drug

s

Rela

tive

(95%

CI)

Abs

olut

e (9

5% C

I)

Lost

vs.

All

Oth

er O

utco

mes

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne88

/891

(9.9

%)

368/

1437

(25.

6%)

OR

0.4

(0.3

to

0.5)

14 fe

wer

pe

r 100

(fr

om

17 fe

wer

to

10 fe

wer

)b,c

VE

RY L

OW

CRIT

ICAL

AFB

Sm

ear P

ositi

ve: S

ucce

ss v

s. F

ailu

re/R

ecur

renc

e (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

267/

274

(97.

4%)

248/

288

(86.

1%)

OR

8.9

(3.4

to

23.7

)

12 m

ore

per 1

00

(from

7

mor

e to

17

mor

e)b

VE

RY L

OW

CRIT

ICAL

AFB

Sm

ear P

ositi

ve: S

ucce

ss v

s. D

eath

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne26

7/34

1 (7

8.3%

)24

8/37

8 (6

5.6%

)O

R 2.

1 (1

.5 to

3.

1)

13 m

ore

per 1

00

(from

6

mor

e to

20

mor

e)b

VE

RY L

OW

CRIT

ICAL

AFB

Sm

ear P

ositi

ve: S

ucce

ss v

s. F

ailu

re/R

ecur

renc

e/D

eath

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne26

7/34

8 (7

6.7%

)24

8/41

8 (5

9.3%

)O

R 3.

0 (2

.1 to

4.

4)

19 m

ore

per 1

00

(from

12

mor

e to

26

mor

e)b

VE

RY L

OW

CRIT

ICAL

AFB

Sm

ear P

ositi

ve: S

ucce

ss v

s. A

ll U

nfav

orab

le (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

267/

378

(70.

6%)

248/

529

(46.

9%)

OR

2.9

(2.1

to

4.0)

24 m

ore

per 1

00

(from

17

mor

e to

31 m

ore)

b

VE

RY L

OW

CRIT

ICAL

AFB

Sm

ear P

ositi

ve: L

ost v

s. A

ll O

ther

Out

com

es (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

33/3

78 (8

.7%

)13

1/52

9 (2

4.8%

)O

R 0.

3 (0

.2 to

0.

6)

15 fe

wer

pe

r 100

(fr

om

20 fe

wer

to

9 fe

wer

)b

VE

RY L

OW

CRIT

ICAL


Cert

aint

y as

sess

men

t№

of p

atie

nts

Effe

ct

Cert

aint

yIm

port

ance

№ o

f st

udie

sSt

udy

desi

gnRi

sk o

f bi

asIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

cons

ider

atio

ns

All-

oral

be

daqu

iline

-co

ntai

ning

sh

orte

r reg

imen

of

9–1

2 m

onth

s du

ratio

n

Long

er

regi

men

s w

ithou

t new

TB

drug

s

Rela

tive

(95%

CI)

Abs

olut

e (9

5% C

I)

HIV

-Pos

itive

on

ART

: Suc

cess

vs.

Fai

lure

/Rec

urre

nce

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne42

9/44

6 (9

6.2%

)43

2/49

1 (8

8.0%

)O

R 4.

5 (2

.4 to

8.

4)

8 m

ore

per 1

00

(from

4

mor

e to

11

mor

e)b

VE

RY L

OW

CRIT

ICAL

HIV

-Pos

itive

on

ART

: Suc

cess

vs.

Dea

th (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

429/

541

(79.

3%)

432/

689

(62.

7%)

OR

2.7

(2.0

to

3.7)

18 m

ore

per 1

00

(from

12

mor

e to

23 m

ore)

b

VE

RY L

OW

CRIT

ICAL

HIV

-Pos

itive

on

ART

: Suc

cess

vs.

Fai

lure

/Rec

urre

nce/

Dea

th (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

429/

558

(76.

9%)

432/

748

(57.

8%)

OR

2.9

(2.2

to

3.9)

21 m

ore

per 1

00

(from

15

mor

e to

26 m

ore)

b

VE

RY L

OW

CRIT

ICAL

HIV

-Pos

itive

on

ART

: Suc

cess

vs.

All

Unf

avor

able

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne42

9/61

3 (7

0.0%

)43

2/91

9 (4

7.0%

)O

R 2.

7 (2

.1 to

3.

5)

23 m

ore

per 1

00

(from

17

mor

e to

28 m

ore)

b

VE

RY L

OW

CRIT

ICAL

HIV

-Pos

itive

on

ART

: Los

t vs.

All

Oth

er O

utco

mes

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne63

/613

(10.

3%)

214/

919

(23.

3%)

OR

0.4

(0.3

to

0.6)

11 fe

wer

pe

r 100

(fr

om

15 fe

wer

to

7 fe

wer

)b

VE

RY L

OW

CRIT

ICAL

HIV

Neg

ativ

e: S

ucce

ss v

s. F

ailu

re/R

ecur

renc

e (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

195/

199

(98.

0%)

227/

258

(88.

0%)

OR

6.7

(2.2

to

20.8

)

12 m

ore

per 1

00

(from

6

mor

e to

18

mor

e)b

VE

RY L

OW

CRIT

ICAL


Cert

aint

y as

sess

men

t№

of p

atie

nts

Effe

ct

Cert

aint

yIm

port

ance

№ o

f st

udie

sSt

udy

desi

gnRi

sk o

f bi

asIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

cons

ider

atio

ns

All-

oral

be

daqu

iline

-co

ntai

ning

sh

orte

r reg

imen

of

9–1

2 m

onth

s du

ratio

n

Long

er

regi

men

s w

ithou

t new

TB

drug

s

Rela

tive

(95%

CI)

Abs

olut

e (9

5% C

I)

HIV

Neg

ativ

e: S

ucce

ss v

s. D

eath

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne19

5/23

4 (8

3.3%

)22

7/30

2 (7

5.2%

)O

R 2.

1 (1

.2 to

3.

8)

13 m

ore

per 1

00

(from

5

mor

e to

21

mor

e)b

VE

RY L

OW

CRIT

ICAL

HIV

Neg

ativ

e: S

ucce

ss v

s. F

ailu

re/R

ecur

renc

e/D

eath

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne19

5/23

8 (8

1.9%

)22

7/33

3 (6

8.2%

)O

R 2.

5 (1

.6 to

3.

8)

17 m

ore

per 1

00

(from

9

mor

e to

26

mor

e)b

VE

RY L

OW

CRIT

ICAL

HIV

Neg

ativ

e: S

ucce

ss v

s. A

ll O

ther

Out

com

es (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

195/

255

(76.

5%)

227/

440

(51.

6%)

OR

3.5

(2.4

to

5.2)

28 m

ore

per 1

00

(from

20

mor

e to

37

mor

e)b

VE

RY L

OW

CRIT

ICAL

HIV

Neg

ativ

e: L

ost v

s. A

ll O

ther

Out

com

es (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

18/2

55 (7

.1%

)13

0/44

0 (2

9.5%

)O

R 0.

2 (0

.1 to

0.

4)

21 fe

wer

pe

r 100

(fr

om

28 fe

wer

to

14 fe

wer

)b

VE

RY L

OW

CRIT

ICAL

AFB:

acid

-fas

t bac

illi; a

OR:

adj

uste

d od

ds ra

tio; A

RT: a

ntire

trovi

ral t

hera

py; C

I: co

nfid

ence

inte

rval

; HIV

: hum

an im

mun

odef

icien

cy v

irus;

MD

R/RR

-TB:

mul

tidru

g- o

r rifa

mpi

cin-r

esist

ant T

B: O

R: o

dds

ratio

; WH

O:

Wor

ld H

ealth

Org

aniz

atio

n.

Expl

anat

ions

a. F

or s

ome

patie

nts,

info

rmat

ion

was

miss

ing

on A

FB s

mea

r res

ult a

nd c

ultu

re re

sult

in th

e an

alys

is. P

atie

nts

with

unk

now

n ag

e, s

ex, o

r HIV

sta

tus

wer

e ex

clude

d fro

m a

ll an

alys

es.

b. O

utco

mes

and

cos

ts a

re s

imul

ated

usin

g a

mod

el th

at d

raw

s pa

ram

eter

est

imat

es fr

om m

ultip

le s

ourc

es, i

nclu

ding

the

aORs

for s

ucce

ss v

ersu

s de

ath/

failu

re d

escr

ibed

abo

ve.

c. T

he a

bsol

ute

effe

ct is

cal

cula

ted

afte

r mat

chin

g in

terv

entio

n an

d co

mpa

rato

r pop

ulat

ions

, and

per

form

ing

bino

mia

l reg

ress

ion

with

an

iden

tity

link.


Aut

hor(

s):

Rese

arch

Inst

itute

of t

he M

cGill

Univ

ersit

y H

ealth

Cen

treQ

uest

ion:

Sh

ould

an

all-o

ral s

hort

er re

gim

en o

f 9–1

2 m

onth

s’ du

ratio

n in

cludi

ng b

edaq

uilin

e vs

long

er re

gim

ens c

onta

inin

g be

daqu

iline

be u

sed

in

MD

R/RR

-TB

patie

nts

to s

afel

y im

prov

e ou

tcom

es?

Sett

ing:

In

tern

atio

nal

Dat

e:

April

202

0

Cert

aint

y as

sess

men

t№

of p

atie

nts

Effe

ct

Cert

aint

yIm

port

ance

№ o

f st

udie

sSt

udy

desi

gnRi

sk o

f bi

asIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

cons

ider

atio

ns

All-

oral

be

daqu

iline

-co

ntai

ning

sh

orte

r reg

imen

of

9–1

2 m

onth

s du

ratio

n

Long

er

regi

men

s co

ntai

ning

be

daqu

iline

Rela

tive

(95%

CI)

Abs

olut

e (9

5% C

I)

Succ

ess

vs. F

ailu

re/R

ecur

renc

e (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

631/

653

(96.

6%)

268/

292

(91.

8%)

OR

3.9

(1.7

to

9.1)

5 m

ore

per 1

00

(from

1

mor

e to

9

mor

e)b,

c

VE

RY

LOW

CRIT

ICAL

Succ

ess

vs. D

eath

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne63

1/79

1 (7

9.8%

)26

8/33

8 (7

9.3%

)O

R 1.

0 (0

.6 to

1.

5)

4 fe

wer

pe

r 100

(fr

om

10 fe

wer

to

3 m

ore)

b,c

VE

RY

LOW

CRIT

ICAL

Succ

ess

vs. F

ailu

re/R

ecur

renc

e/D

eath

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne63

1/81

3 (7

7.6%

)26

8/36

2 (7

4.0%

) O

R 1.

4 (0

.9 to

2.

0)

2 m

ore

per 1

00

(from

4

few

er to

9

mor

e)b,

c

VE

RY

LOW

CRIT

ICAL

Succ

ess

vs. A

ll U

nfav

orab

le (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

631/

891

(70.

8%)

268/

440

(60.

9%)

OR

1.6

(1.2

to

2.2)

7 m

ore

per 1

00

(from

1

mor

e to

14

mor

e)b,

c

VE

RY

LOW

CRIT

ICAL


Cert

aint

y as

sess

men

t№

of p

atie

nts

Effe

ct

Cert

aint

yIm

port

ance

№ o

f st

udie

sSt

udy

desi

gnRi

sk o

f bi

asIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

cons

ider

atio

ns

All-

oral

be

daqu

iline

-co

ntai

ning

sh

orte

r reg

imen

of

9–1

2 m

onth

s du

ratio

n

Long

er

regi

men

s co

ntai

ning

be

daqu

iline

Rela

tive

(95%

CI)

Abs

olut

e (9

5% C

I)

Lost

vs.

All

Oth

er O

utco

mes

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne88

/891

(9.9

%)

88/4

40 (2

0.0%

) O

R 0.

5 (0

.4 to

0.

8)

8 fe

wer

pe

r 100

(fr

om

13 fe

wer

to

3 fe

wer

)b,c

VE

RY

LOW

CRIT

ICAL

AFB

Sm

ear P

ositi

ve: S

ucce

ss v

s. F

ailu

re/R

ecur

renc

e (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

267/

274

(97.

4%)

133/

148

(89.

9%)

OR

4.1

(1.4

to

12.2

)

6 m

ore

per 1

00

(from

1

few

er to

12

mor

e)b

VE

RY

LOW

CRIT

ICAL

AFB

Sm

ear P

ositi

ve: S

ucce

ss v

s. D

eath

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne26

7/34

1 (7

8.3%

)13

3/17

1 (7

7.8%

)O

R 0.

8 (0

.5 to

1.

4)

4 fe

wer

pe

r 100

(fr

om

13 fe

wer

to

5 m

ore)

b

VE

RY

LOW

CRIT

ICAL

AFB

Sm

ear P

ositi

ve: S

ucce

ss v

s. F

ailu

re/R

ecur

renc

e/D

eath

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne26

7/34

8 (7

6.7%

)13

3/18

6 (7

1.5%

)O

R 1.

5 (0

.9 to

2.

5)

4 m

ore

per 1

00

(from

5

few

er to

13

mor

e)b

VE

RY

LOW

CRIT

ICAL

AFB

Sm

ear P

ositi

ve: S

ucce

ss v

s. A

ll U

nfav

orab

le (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

267/

378

(70.

6%)

133/

223

(59.

6%)

OR

2.0

(1.3

to

3.1)

12 m

ore

per 1

00

(from

3

mor

e to

21

mor

e)b

VE

RY

LOW

CRIT

ICAL

AFB

Sm

ear P

ositi

ve: L

ost v

s. A

ll O

ther

Out

com

es (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

33/3

78 (8

.7%

)41

/223

(18.

4%)

OR

0.3

(0.2

to

0.6)

11 fe

wer

pe

r 100

(fr

om

17 fe

wer

to

5 fe

wer

)b

VE

RY

LOW

CRIT

ICAL


Cert

aint

y as

sess

men

t№

of p

atie

nts

Effe

ct

Cert

aint

yIm

port

ance

№ o

f st

udie

sSt

udy

desi

gnRi

sk o

f bi

asIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

cons

ider

atio

ns

All-

oral

be

daqu

iline

-co

ntai

ning

sh

orte

r reg

imen

of

9–1

2 m

onth

s du

ratio

n

Long

er

regi

men

s co

ntai

ning

be

daqu

iline

Rela

tive

(95%

CI)

Abs

olut

e (9

5% C

I)

HIV

-Pos

itive

on

ART

: Suc

cess

vs.

Fai

lure

/Rec

urre

nce

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne42

9/44

6 (9

6.2%

)19

1/20

5 (9

3.2%

)O

R 2.

8 (1

.0 to

8.

2)

4 m

ore

per 1

00

(from

0

few

er to

8

mor

e)b

VE

RY

LOW

CRIT

ICAL

HIV

-Pos

itive

on

ART

: Suc

cess

vs.

Dea

th (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

429/

541

(79.

3%)

191/

244

(78.

3%)

OR

1.0

(0.6

to

1.6)

1 fe

wer

pe

r 100

(fr

om

9 fe

wer

to

6 m

ore)

b

VE

RY

LOW

CRIT

ICAL

HIV

-Pos

itive

on

ART

: Suc

cess

vs.

Fai

lure

/Rec

urre

nce/

Dea

th (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

429/

558

(76.

9%)

191/

258

(74.

0%)

OR

1.2

(0.8

to

1.9)

1 m

ore

per 1

00

(from

6

few

er to

9

mor

e)b

VE

RY

LOW

CRIT

ICAL

HIV

-Pos

itive

on

ART

: Suc

cess

vs.

All

Unf

avor

able

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne42

9/61

3 (7

0.0%

)19

1/31

1 (6

1.4%

)O

R 2.

1 (1

.4 to

3.

1)

12 m

ore

per 1

00

(from

5

mor

e to

20

mor

e)b

VE

RY

LOW

CRIT

ICAL

HIV

-Pos

itive

on

ART

: Los

t vs.

All

Oth

er O

utco

mes

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne63

/613

(10.

3%)

62/3

11 (1

9.9%

)O

R 0.

3 (0

.2 to

0.

6)

12 fe

wer

pe

r 100

(fr

om

18 fe

wer

to

7 fe

wer

)b

VE

RY

LOW

CRIT

ICAL

HIV

Neg

ativ

e: S

ucce

ss v

s. F

ailu

re/R

ecur

renc

e (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

195/

199

(98.

0%)

73/8

2 (8

9.0%

)O

R 3.

5 (0

.8 to

15

.4)

8 m

ore

per 1

00

(from

1

few

er to

16

mor

e)b

VE

RY

LOW

CRIT

ICAL


Cert

aint

y as

sess

men

t№

of p

atie

nts

Effe

ct

Cert

aint

yIm

port

ance

№ o

f st

udie

sSt

udy

desi

gnRi

sk o

f bi

asIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

cons

ider

atio

ns

All-

oral

be

daqu

iline

-co

ntai

ning

sh

orte

r reg

imen

of

9–1

2 m

onth

s du

ratio

n

Long

er

regi

men

s co

ntai

ning

be

daqu

iline

Rela

tive

(95%

CI)

Abs

olut

e (9

5% C

I)

HIV

Neg

ativ

e: S

ucce

ss v

s. D

eath

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne19

5/23

4 (8

3.3%

)73

/87

(83.

9%)

OR

1.3

(0.5

to

3.3)

1 m

ore

per 1

00

(from

11

fewe

r to

13 m

ore)

b

VE

RY

LOW

CRIT

ICAL

HIV

Neg

ativ

e: S

ucce

ss v

s. F

ailu

re/R

ecur

renc

e/D

eath

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne19

5/23

8 (8

1.9%

)73

/96

(76.

0%)

OR

1.7

(0.8

to

3.7)

6 m

ore

per 1

00

(from

7

few

er to

18

mor

e)b

VE

RY

LOW

CRIT

ICAL

HIV

Neg

ativ

e: S

ucce

ss v

s. A

ll U

nfav

orab

le (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

195/

255

(76.

5%)

73/1

17 (6

2.4%

)O

R 1.

8 (0

.9 to

3.

4)

11 m

ore

per 1

00

(from

1

few

er to

24

mor

e)b

VE

RY

LOW

CRIT

ICAL

HIV

Neg

ativ

e: L

ost v

s. A

ll O

ther

Out

com

es (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

18/2

55 (7

.1%

)22

/117

(18.

8%)

OR

0.4

(0.2

to

0.9)

11 fe

wer

pe

r 100

(fr

om

20 fe

wer

to

2 fe

wer

)b

VE

RY

LOW

CRIT

ICAL

AFB:

acid

-fas

t bac

illi; a

OR:

adj

uste

d od

ds ra

tio; A

RT: a

ntire

trovi

ral t

hera

py; C

I: co

nfid

ence

inte

rval

; HIV

: hum

an im

mun

odef

icien

cy v

irus;

MD

R/RR

-TB:

mul

tidru

g- o

r rifa

mpi

cin-r

esist

ant T

B; O

R: o

dds

ratio

.

Expl

anat

ions

a. F

or s

ome

patie

nts,

info

rmat

ion

was

miss

ing

on A

FB s

mea

r res

ult a

nd c

ultu

re re

sult

in th

e an

alys

is. P

atie

nts

with

unk

now

n ag

e, s

ex, o

r HIV

sta

tus

wer

e ex

clude

d fro

m a

ll an

alys

es.

b. O

utco

mes

and

cos

ts a

re s

imul

ated

usin

g a

mod

el th

at d

raw

s pa

ram

eter

est

imat

es fr

om m

ultip

le s

ourc

es, i

nclu

ding

the

aORs

for s

ucce

ss v

ersu

s de

ath

or fa

ilure

des

crib

ed a

bove

.

c. T

he a

bsol

ute

effe

ct is

cal

cula

ted

afte

r mat

chin

g in

terv

entio

n an

d co

mpa

rato

r pop

ulat

ions

, and

per

form

ing

bino

mia

l reg

ress

ion

with

an

iden

tity

link.


Aut

hor(

s):

Rese

arch

Inst

itute

of t

he M

cGill

Univ

ersit

y H

ealth

Cen

tre

Que

stio

n:

Shou

ld a

n al

l-ora

l sho

rter

regi

men

of 9

–12

mon

ths d

urat

ion

inclu

ding

bed

aqui

line

vs lo

nger

regi

men

s con

tain

ing

beda

quilin

e an

d lin

ezol

id

be u

sed

in M

DR/

RR-T

B pa

tient

s to

saf

ely

impr

ove

outc

omes

?Se

ttin

g:

Inte

rnat

iona

lD

ate:

Ap

ril 2

020

Cert

aint

y as

sess

men

t№

of p

atie

nts

Effe

ct

Cert

aint

yIm

port

ance

№ o

f st

udie

sSt

udy

desi

gnRi

sk o

f bi

asIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

cons

ider

atio

ns

All-

oral

be

daqu

iline

-co

ntai

ning

sho

rter

re

gim

en o

f 9–1

2 m

onth

s du

ratio

n

Long

er

regi

men

s co

ntai

ning

be

daqu

iline

an

d lin

ezol

id

Rela

tive

(95%

CI)

Abs

olut

e (9

5% C

I)

Succ

ess

vs. F

ailu

re/R

ecur

renc

e (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

631/

653

(96.

6%)

103/

110

(93.

6%)

OR

1.8

(0.5

to

6.3)

3 m

ore

per 1

00

(from

3

few

er to

9

mor

e)b,

c

VE

RY

LOW

CRIT

ICAL

Succ

ess

vs. D

eath

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne63

1/79

1 (7

9.8%

)10

3/11

8 (8

7.3%

)O

R 1.

1 (0

.5 to

2.

6)

1 fe

wer

pe

r 100

(fr

om

10 fe

wer

to

8 m

ore)

b,c

VE

RY

LOW

CRIT

ICAL

Succ

ess

vs. F

ailu

re/R

ecur

renc

e/D

eath

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne63

1/81

3 (7

7.6%

)10

3/12

5 (8

2.4%

)O

R 0.

9 (0

.5 to

1.

8)

5 fe

wer

pe

r 100

(fr

om

15 fe

wer

to

5 m

ore)

b,c

VE

RY

LOW

CRIT

ICAL

Succ

ess

vs. A

ll U

nfav

orab

le (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

631/

891

(70.

8%)

103/

157

(65.

6%)

OR

2.1

(1.2

to

3.7)

13 m

ore

per 1

00

(from

3

mor

e to

23

mor

e)b,

c

VE

RY

LOW

CRIT

ICAL

Lost

vs.

All

Oth

er O

utco

mes

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne88

/891

(9.9

%)

36/1

57 (2

2.9%

)O

R 0.

4 (0

.1 to

0.

6)

15 fe

wer

pe

r 100

(fr

om

23 fe

wer

to

7 fe

wer

)b,c

VE

RY

LOW

CRIT

ICAL


Cert

aint

y as

sess

men

t№

of p

atie

nts

Effe

ct

Cert

aint

yIm

port

ance

№ o

f st

udie

sSt

udy

desi

gnRi

sk o

f bi

asIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

cons

ider

atio

ns

All-

oral

be

daqu

iline

-co

ntai

ning

sho

rter

re

gim

en o

f 9–1

2 m

onth

s du

ratio

n

Long

er

regi

men

s co

ntai

ning

be

daqu

iline

an

d lin

ezol

id

Rela

tive

(95%

CI)

Abs

olut

e (9

5% C

I)

HIV

-Pos

itive

on

ART

: Suc

cess

vs.

Fai

lure

/Rec

urre

nce

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne42

9/44

6 (9

6.2%

)80

/85

(94.

1%)

OR

2.6

(0.5

to

13.8

)

4 m

ore

per 1

00

(from

2

few

er to

10

mor

e)b

VE

RY

LOW

CRIT

ICAL

HIV

-Pos

itive

on

ART

: Suc

cess

vs.

Dea

th (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

429/

541

(79.

3%)

80/9

1 (8

7.9%

)O

R 0.

6 (0

.2 to

1.

4)

9 fe

wer

pe

r 100

(fr

om

20 fe

wer

to

2 m

ore)

b

VE

RY

LOW

CRIT

ICAL

HIV

-Pos

itive

on

ART

: Suc

cess

vs.

Fai

lure

/Rec

urre

nce/

Dea

th (f

ollo

w u

p: m

ean

18 m

onth

s)1

obse

rvat

iona

l st

udie

sse

rious

ano

t ser

ious

not s

erio

usno

t ser

ious

none

429/

558

(76.

9%)

80/9

6 (8

3.3%

)O

R 1.

0 (0

.4 to

2.

3)

3 fe

wer

pe

r 100

(fr

om

14 fe

wer

to

8 m

ore)

b

VE

RY

LOW

HIV

-Pos

itive

on

ART

: Suc

cess

vs.

All

Unf

avor

able

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usno

ne42

9/61

3 (7

0.0%

)80

/119

(67.

2%)

OR

1.8

(0.9

to

3.6)

11 m

ore

per 1

00

(from

0

few

er to

23

mor

e)b

VE

RY

LOW

CRIT

ICAL

HIV

-Pos

itive

on

ART

: Los

t vs.

All

Oth

er O

utco

mes

(fol

low

up:

mea

n 18

mon

ths)

1ob

serv

atio

nal

stud

ies

serio

usa

not s

erio

usno

t ser

ious

not s

erio

usst

rong

as

socia

tion

63/6

13 (1

0.3%

)26

/119

(21.

8%)

OR

0.3

(0.1

to

0.7)

15 fe

wer

pe

r 100

(fr

om

24 fe

wer

to

6 fe

wer

)b

VE

RY

LOW

CRIT

ICAL

aOR:

adj

uste

d od

ds ra

tio; A

RT: a

ntire

trovi

ral t

hera

py; C

I: co

nfid

ence

inte

rval

; HIV

: hum

an im

mun

odef

icien

cy v

irus;

MD

R/RR

-TB:

mul

tidru

g- o

r rifa

mpi

cin-r

esist

ant T

B; O

R: o

dds

ratio

.

Expl

anat

ions

a. F

or s

ome

patie

nts,

info

rmat

ion

was

miss

ing

on A

FB s

mea

r res

ult a

nd c

ultu

re re

sult

in th

e an

alys

is. P

atie

nts

with

unk

now

n ag

e, s

ex, o

r HIV

sta

tus

wer

e ex

clude

d fro

m a

ll an

alys

es.

b. O

utco

mes

and

cos

ts a

re s

imul

ated

usin

g a

mod

el th

at d

raw

s pa

ram

eter

est

imat

es fr

om m

ultip

le s

ourc

es, i

nclu

ding

the

aORs

for s

ucce

ss v

ersu

s de

ath

or fa

ilure

des

crib

ed a

bove

.

c. T

he a

bsol

ute

effe

ct is

cal

cula

ted

afte

r mat

chin

g in

terv

entio

n an

d co

mpa

rato

r pop

ulat

ions

, and

per

form

ing

bino

mia

l reg

ress

ion

with

an

iden

tity

link.


Aut

hor(

s):

TB A

llianc

e Q

uest

ion:

Sh

ould

trea

tmen

t reg

imen

last

ing

6–9

mon

ths c

ompo

sed

of b

edaq

uilin

e, p

reto

man

id a

nd lin

ezol

id v

s. lo

nger

regi

men

s con

tain

ing

beda

quilin

e an

d lin

ezol

id in

add

ition

to o

ther

ant

i-TB

drug

s be

used

for X

DR-

TB p

atie

nts o

r pat

ient

s who

are

trea

tmen

t int

oler

ant o

r with

non

-res

pons

ive

MD

R-TB

?Se

ttin

g:

Five

site

s in

Sou

th A

frica

Bi

blio

grap

hy:

Conr

adie

F, D

iaco

n AH

, Ngu

bane

N e

t al.

Trea

tmen

t of h

ighl

y dr

ug-r

esist

ant p

ulm

onar

y tu

berc

ulos

is, N

ew E

ngla

nd Jo

urna

l of M

edici

ne.

2020

; 382

(10)

: 893

–902

.

Cert

aint

y as

sess

men

t№

of p

atie

nts

Effe

ct

Cert

aint

yIm

port

ance

№ o

f st

udie

sSt

udy

desi

gnRi

sk o

f bi

asIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

cons

ider

atio

ns

trea

tmen

t re

gim

en la

stin

g 6–

9 m

onth

s co

mpo

sed

of

beda

quili

ne,

pret

oman

id a

nd

linez

olid

long

er re

gim

ens

cont

aini

ng

beda

quili

ne

and

linez

olid

in

add

ition

to

othe

r ant

i-TB

dr

ugs

Rela

tive

(95%

CI)

Abs

olut

e (9

5% C

I)

Succ

ess

vs. F

ailu

re/R

ecur

renc

e (f

ollo

w u

p: m

ean

24 m

onth

s)1a

obse

rvat

iona

l st

udie

s ve

ry

serio

usb

serio

usc

serio

usd

very

ser

ious

eno

ne

96/9

9 (9

7.0%

) 37

5/40

9 (9

1.7%

) O

R 3.

3 (0

.8 to

13

.7)

6 m

ore

per 1

00

(from

2

few

er to

14

mor

e)f,g

VE

RY

LOW

CRIT

ICAL

Succ

ess

vs. D

eath

(fol

low

up:

mea

n 24

mon

ths)

1aob

serv

atio

nal

stud

ies

very

se

rious

bse

rious

cse

rious

dve

ry s

erio

use

none

96

/103

(93.

2%)

375/

408

(91.

9%)

OR

1.0

(0.1

to

8.2)

1 m

ore

per 1

00

(from

7

few

er to

8

mor

e)f,g

VE

RY

LOW

CRIT

ICAL

Succ

ess

vs. F

ailu

re/R

ecur

renc

e/D

eath

(fol

low

up:

mea

n 24

mon

ths)

1aob

serv

atio

nal

stud

ies

very

se

rious

bse

rious

cse

rious

dve

ry s

erio

use

none

96

/106

(90.

6%)

375/

442

(84.

8%)

OR

1.8

(0.7

to

4.4)

6 m

ore

per 1

00

(from

4

few

er to

16

mor

e)f,g

VE

RY

LOW

CRIT

ICAL

Succ

ess

vs. A

ll U

nfav

orab

le (f

ollo

w u

p: m

ean

24 m

onth

s)1a

obse

rvat

iona

l st

udie

s ve

ry

serio

usb

serio

usc

serio

usd

very

ser

ious

eno

ne

96/1

08 (8

8.9%

) 37

5/45

6 (8

2.2%

) O

R 1.

2 (0

.5 to

3.

1)

2 m

ore

per 1

00

(from

7

few

er to

12

mor

e)f,g

VE

RY

LOW

CRIT

ICAL


Cert

aint

y as

sess

men

t№

of p

atie

nts

Effe

ct

Cert

aint

yIm

port

ance

№ o

f st

udie

sSt

udy

desi

gnRi

sk o

f bi

asIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

cons

ider

atio

ns

trea

tmen

t re

gim

en la

stin

g 6–

9 m

onth

s co

mpo

sed

of

beda

quili

ne,

pret

oman

id a

nd

linez

olid

long

er re

gim

ens

cont

aini

ng

beda

quili

ne

and

linez

olid

in

add

ition

to

othe

r ant

i-TB

dr

ugs

Rela

tive

(95%

CI)

Abs

olut

e (9

5% C

I)

Adv

erse

eve

nts

1 h

obse

rvat

iona

l st

udie

s ve

ry

serio

us i

not s

erio

us

serio

us

very

ser

ious

jno

ne

BPaL

reg

imen

: 1

(0.9

%)

patie

nt d

ied,

27

(25%

) pa

tient

s ex

perie

nced

ot

her

serio

us

adve

rse

even

ts

incl

udin

g ho

spita

lizat

ions

and

life

thr

eate

ning

eve

nts,

and

53 (

49%

) pa

tient

s ex

perie

nced

at l

east

one

Gra

de 3

–4 a

dver

se e

vent

s. D

rug

disc

ontin

uatio

n fo

r ad

vers

e ev

ents

: rel

ated

to a

ll th

ree

drug

s in

1 p

atie

nt, a

nd re

late

d to

line

zolid

(ini

tial d

ose

1200

m

g/da

y) d

iscon

tinue

d in

ano

ther

35

(32%

) pat

ient

s. O

nly

20

(18%

) pat

ient

s com

plet

ed a

full c

ours

e of

120

0 m

g/da

y. In

the

IPD

stud

ies (

90%

rece

ived

600

mg/

day

or le

ss),

the

pool

ed ra

te

of L

ZD p

erm

anen

t disc

ontin

uatio

n w

as 1

7.9%

, and

in th

e En

dTB

stud

y (a

ll pat

ient

s rec

eive

d 60

0mg/

day

or le

ss),

the

rate

of L

ZD

disc

ontin

uatio

n w

as 1

3.1%

. In

EndT

B: 9

per

sons

out

of 1

094

(0.8

%) d

ied

of a

pos

sibly/

prob

ably

drug

rela

ted

AE, i

nclu

ding

tw

o pe

rson

s with

sudd

en c

ardi

ac d

eath

and

QT

prol

onga

tion.

VE

RY

LOW

CRIT

ICAL

AE: a

dver

se e

vent

; BPa

L: b

edaq

uilin

e, p

reto

man

id a

nd li

nezo

lid; C

I: co

nfid

ence

inte

rval

; IPD

: ind

ivid

ual p

atie

nt d

ata;

LZD

: lin

ezol

id; M

DR/

RR-T

B: m

ultid

rug-

or r

ifam

picin

-res

istan

t TB;

OR:

odd

s ra

tio.

Expl

anat

ions

a. O

ne c

ohor

t stu

dy c

ompa

red

with

IPD

met

a-an

alys

is of

55

stud

ies.

b. T

his

was

a s

mal

l and

one

-arm

ed u

nblin

ded

coho

rt s

tudy

with

sub

stan

tial s

elec

tion

into

the

coh

ort;

follo

w-u

p da

ta t

o 24

mon

ths

wer

e no

t av

aila

ble

for

all p

atie

nts,

so e

nd-p

oint

s of

clin

ical f

ailu

re m

ay b

e un

dere

stim

ated

.

c. T

here

wer

e m

ajor

diff

eren

ces

betw

een

the

inte

rven

tion

and

com

para

tor g

roup

s (in

sel

ectio

n, c

hara

cter

istics

and

inte

nsity

of c

are)

, all

of w

hich

cou

ld h

ave

affe

cted

the

com

paris

on.

d. T

his

was

a s

mal

l, w

ell-r

esou

rced

, one

-arm

ed, u

nblin

ded

coho

rt s

tudy

that

was

com

pare

d w

ith c

ohor

ts a

nd ro

utin

ely

colle

cted

pro

gram

mat

ic da

ta in

the

IPD.

All

com

paris

ons

betw

een

the

inte

rven

tion

and

the

com

para

tor w

ere

indi

rect

.

e. T

his w

as a

smal

l stu

dy (1

08 p

atie

nts i

n to

tal in

mod

ified

inte

ntio

n-to

-tre

at a

nalys

is). I

t was

diff

icult

to p

erfo

rm a

dequ

ate

mat

chin

g in

the

anal

ysis,

so so

me

seco

ndar

y an

alys

es w

ere

even

mor

e lim

ited

by sm

all n

umbe

rs.

f. O

utco

mes

and

cos

ts w

ere

simul

ated

usin

g a

mod

el th

at d

raw

s pa

ram

eter

est

imat

es fr

om m

ultip

le s

ourc

es, i

nclu

ding

the

adju

sted

odd

s ra

tios

for s

ucce

ss v

ersu

s de

ath

or fa

ilure

des

crib

ed a

bove

.

g. T

he a

bsol

ute

effe

ct is

cal

cula

ted

afte

r mat

chin

g in

terv

entio

n an

d co

mpa

rato

r pop

ulat

ions

, and

per

form

ing

bino

mia

l reg

ress

ion

with

an

iden

tity

link.

h. O

ne c

ohor

t stu

dy (c

ompa

red

with

IPD

met

a-an

alys

is of

30

stud

ies

cont

aini

ng a

dver

se e

vent

info

rmat

ion

and

the

EndT

B ob

serv

atio

nal s

tudy

)

i. W

ithin

the

IPD,

adv

erse

eve

nt d

ata

are

only

con

siste

ntly

repo

rted

for i

ndiv

idua

ls w

ho p

erm

anen

tly s

topp

ed th

e dr

ug o

f int

eres

t; al

so, c

erta

in d

rugs

may

be

mor

e clo

sely

mon

itore

d fo

r tox

icitie

s (e

.g. b

edaq

uilin

e an

d lin

ezol

id).

j. Th

is w

as a

sm

all s

tudy

(109

pat

ient

s in

the

safe

ty a

naly

sis) c

ompa

red

with

30

diffe

rent

stu

dies

in th

e IP

D, w

hich

may

var

y in

the

inte

nsity

and

com

plet

enes

s of

adv

erse

eve

nt re

port

ing.


Aut

hor(

s):

Rese

arch

Inst

itute

of t

he M

cGill

Univ

ersit

y H

ealth

Cen

tre

Que

stio

n:

Shou

ld b

edaq

uilin

e fo

r mor

e th

an s

ix m

onth

s vs

. bed

aqui

line

for u

p to

six

mon

ths

be u

sed

in M

DR/

RR-T

B pa

tient

s as

par

t of t

he lo

nger

tre

atm

ent r

egim

ens?

Sett

ing:

In

tern

atio

nal

Bibl

iogr

aphy

: Un

publ

ished

dat

a fro

m th

e in

divi

dual

pat

ient

dat

aset

, 201

9 (h

eld

by M

cGill

Univ

ersit

y)

Cert

aint

y as

sess

men

t№

of p

atie

nts

Effe

ct

Cert

aint

yIm

port

ance

№ o

f st

udie

sSt

udy

desi

gnRi

sk o

f bi

asIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

cons

ider

atio

ns

beda

quili

ne fo

r m

ore

than

six

m

onth

s

beda

quili

ne

for u

p to

six

m

onth

s

Rela

tive

(95%

CI)

Abs

olut

e (9

5% C

I)

Succ

ess

vs. F

ailu

re (f

ollo

w u

p: m

ean

21 m

onth

s)1

obse

rvat

iona

l st

udie

s ve

ry

serio

usa

not s

erio

us

not s

erio

us

serio

usb

none

18

8/21

2 (8

8.7%

) 23

5/25

5 (9

2.2%

) O

R 1.

4 (0

.7 to

2.

7)

5 m

ore

per 1

00

(from

1

few

er to

11

mor

e)c,

d

VE

RY

LOW

CRIT

ICAL

Succ

ess

vs. D

eath

(fol

low

up:

mea

n 21

mon

ths)

1 ob

serv

atio

nal

stud

ies

very

se

rious

ano

t ser

ious

no

t ser

ious

se

rious

bno

ne

188/

200

(94.

0%)

235/

242

(97.

1%)

OR

0.8

(0.2

to

2.4)

4 fe

wer

pe

r 100

(fr

om

8 fe

wer

to

1 m

ore)

c,d

VE

RY

LOW

CRIT

ICAL

Succ

ess

vs. F

ailu

re/D

eath

(fol

low

up:

mea

n 21

mon

ths)

1 ob

serv

atio

nal

stud

ies

very

se

rious

ano

t ser

ious

no

t ser

ious

se

rious

bno

ne

188/

224

(83.

9%)

235/

262

(89.

7%)

OR

1.0

(0.5

to

1.7)

1 m

ore

per 1

00

(from

6

few

er to

7

mor

e)c,

d

VE

RY

LOW

CRIT

ICAL

Succ

ess

vs. A

ll U

nfav

orab

le (f

ollo

w u

p: m

ean

21 m

onth

s)1

obse

rvat

iona

l st

udie

s ve

ry

serio

usa

not s

erio

us

not s

erio

us

serio

usb

none

18

8/24

2 (7

7.7%

) 23

5/27

3 (8

6.1%

) O

R 0.

8 (0

.5 to

1.

2)

1 fe

wer

pe

r 100

(fr

om

8 fe

wer

to

6 m

ore)

c,d

VE

RY

LOW

CRIT

ICAL

CI: c

onfid

ence

inte

rval

; MD

R/RR

-TB:

mul

tidru

g- o

r rifa

mpi

cin-r

esist

ant t

uber

culo

sis; O

R: o

dds

ratio

.

Expl

anat

ions

a. D

ata

from

a si

ngle

coh

ort s

tudy

with

exc

elle

nt q

ualit

y of

info

rmat

ion,

but

reas

ons f

or b

edaq

uilin

e ex

tens

ion

varie

d by

pro

vider

and

site

, with

man

y de

cisio

ns in

divid

ualiz

ed. S

ome

sites

rare

ly ga

ve b

edaq

uilin

e fo

r mor

e th

an 6

mon

ths a

nd o

ther

s rar

ely

gave

bed

aqui

line

for l

ess t

han

or e

qual

to 6

mon

ths.

In m

ost s

ites,

how

ever

, dur

atio

n ap

pear

ed to

be

base

d at

leas

t par

tly o

n po

or re

spon

se to

ther

apy,

crea

ting

subs

tant

ial s

elec

tion

bias

.

b. S

tudy

invo

lved

rela

tivel

y sm

all n

umbe

rs w

ith b

edaq

uilin

e ex

tens

ion,

with

lim

ited

even

ts.

c. O

utco

mes

and

cos

ts a

re s

imul

ated

usin

g a

mod

el th

at d

raw

s pa

ram

eter

est

imat

es fr

om m

ultip

le s

ourc

es, i

nclu

ding

the

adju

sted

odd

s ra

tios

for s

ucce

ss v

ersu

s de

ath/

failu

re d

escr

ibed

abo

ve.

d. T

he a

bsol

ute

effe

ct is

cal

cula

ted

afte

r mat

chin

g in

terv

entio

n an

d co

mpa

rato

r pop

ulat

ions

, and

per

form

ing

bino

mia

l reg

ress

ion

with

an

iden

tity

link.


Aut

hor(

s):

Rese

arch

Inst

itute

of t

he M

cGill

Univ

ersit

y H

ealth

Cen

tre a

nd P

rofe

ssor

Kel

ly D

oole

y, Jo

hns

Hop

kins

Univ

ersit

yQ

uest

ion:

Sh

ould

con

curre

nt u

se o

f bed

aqui

line

and

dela

man

id v

s. no

con

curre

nt u

se o

f bed

aqui

line

and

dela

man

id b

e us

ed in

MD

R/RR

-TB

patie

nts

as p

art o

f the

long

er tr

eatm

ent r

egim

ens?

Sett

ing:

In

tern

atio

nal (

for t

he d

atas

et fr

om M

cGill

Univ

ersit

y) a

nd S

outh

Afri

ca a

nd P

eru

for t

he d

atas

et fr

om Jo

hns

Hop

kins

Univ

ersit

y Bi

blio

grap

hy:

Unpu

blish

ed d

ata

from

the

indi

vidua

l pat

ient

dat

aset

, 201

9 (h

eld

by M

cGill

Unive

rsity

) and

unp

ublis

hed

data

from

the

DEL

aman

Id B

Edaq

uilin

e fo

r Res

istAn

t Tub

Ercu

losis

(DEL

IBER

ATE)

tria

l, Jo

hns

Hop

kins

Univ

ersit

y

Cert

aint

y as

sess

men

t№

of p

atie

nts

Effe

ct

Cert

aint

yIm

port

ance

№ o

f st

udie

sSt

udy

desi

gnRi

sk o

f bi

asIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

cons

ider

atio

ns

conc

urre

nt u

se

of b

edaq

uilin

e an

d de

lam

anid

no c

oncu

rren

t us

e of

be

daqu

iline

and

de

lam

anid

Rela

tive

(95%

CI)

Abs

olut

e (9

5% C

I)

Succ

ess

vs. F

ailu

re (f

ollo

w u

p: m

ean

17.5

mon

ths)

4 ob

serv

atio

nal

stud

ies

very

se

rious

ase

rious

bno

t ser

ious

se

rious

cno

ne

52/5

8 (8

9.7%

) 28

5/30

6 (9

3.1%

) O

R 1.

6 (0

.5 to

5.

4)

6 m

ore

per 1

00

(from

6

few

er to

18

mor

e)d,

e

VE

RY

LOW

CRIT

ICAL

Succ

ess

vs. D

eath

(fol

low

up:

mea

n 17

.5 m

onth

s)4

obse

rvat

iona

l st

udie

s ve

ry

serio

usa

serio

usb

not s

erio

us

serio

usc

none

52

/69

(75.

4%)

285/

333

(85.

6%)

OR

0.8

(0.3

to

2.1)

1 fe

wer

pe

r 100

(fr

om

15 fe

wer

to

12 m

ore)

d,e

VE

RY

LOW

CRIT

ICAL

Succ

ess

vs. F

ailu

re/D

eath

(fol

low

up:

mea

n 17

.5 m

onth

s)4

obse

rvat

iona

l st

udie

s ve

ry

serio

usa

serio

usb

not s

erio

us

serio

usc

none

52

/75

(69.

3%)

285/

354

(80.

5%)

OR

1.2

(0.6

to

2.5)

5 m

ore

per 1

00

(from

10

few

er to

20

mor

e)d,

e

VE

RY

LOW

CRIT

ICAL

Succ

ess

vs. A

ll U

nfav

orab

le (f

ollo

w u

p: m

ean

17.5

mon

ths)

4 ob

serv

atio

nal

stud

ies

very

se

rious

ase

rious

bno

t ser

ious

se

rious

cno

ne

52/8

4 (6

1.9%

) 28

5/40

1 (7

1.1%

) O

R 0.

6 (0

.3 to

1.

1)

11 fe

wer

pe

r 100

(fr

om

25 fe

wer

to

2 m

ore)

d,e

VE

RY

LOW

CRIT

ICAL


Cert

aint

y as

sess

men

t№

of p

atie

nts

Effe

ct

Cert

aint

yIm

port

ance

№ o

f st

udie

sSt

udy

desi

gnRi

sk o

f bi

asIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

cons

ider

atio

ns

conc

urre

nt u

se

of b

edaq

uilin

e an

d de

lam

anid

no c

oncu

rren

t us

e of

be

daqu

iline

and

de

lam

anid

Rela

tive

(95%

CI)

Abs

olut

e (9

5% C

I)

Sudd

en c

ardi

ac d

eath

(fol

low

up:

mea

n 24

wee

ks; a

sses

sed

with

: QTc

F pr

olon

gatio

n m

easu

red

in m

illis

econ

ds c

hang

e fr

om b

asel

ine)

1 ra

ndom

ised

trial

s no

t se

rious

no

t ser

ious

se

rious

se

rious

fno

ne

The

prim

ary

aim

of t

he D

ELIB

ERAT

E tri

al w

as to

com

pare

the

mea

n ch

ange

from

bas

elin

e (a

vera

ged

over

wee

ks 8

–24)

in

QTc

F w

hen

beda

quilin

e an

d de

lam

anid

are

co-

adm

inist

ered

to

the

mea

n ch

ange

obs

erve

d w

hen

each

dru

g is

adm

inist

ered

al

one.

At w

eek

24, in

28

patie

nts w

ho re

ceive

d be

daqu

iline

as

part

of t

heir

MD

R -T

B tre

atm

ent r

egim

en th

e m

ean

incr

ease

in

QTc

F w

as 1

1.9

ms

(95%

CI 7

.4–1

6.4

ms)

. For

28

patie

nts

who

rece

ived

del

aman

id a

s pa

rt o

f the

ir M

DR-

TB tr

eatm

ent

regi

men

the

mea

n in

crea

se in

QTc

F w

as 8

.6 m

s (9

5% C

I 4.0

–13

.2 m

s). W

hen

28 p

atie

nts

rece

ived

con

curre

nt b

edaq

uilin

e an

d de

lam

anid

as

part

of t

heir

MD

R-TB

trea

tmen

t reg

imen

th

e m

ean

incr

ease

in Q

TcF

was

20.

7 m

s (95

% C

I 16.

1–25

.4 m

s).

The

addi

tive

effe

ct o

f add

ing

dela

man

id t

o a

regi

men

tha

t al

read

y co

ntai

ned

beda

quilin

e w

as d

eter

min

ed to

be

a m

ean

of 8

.8 m

s (9

5% C

I 2.3

–15.

3 m

s), w

here

as th

e ad

ditiv

e ef

fect

of

add

ing

beda

quilin

e to

a r

egim

en t

hat

alre

ady

cont

aine

d de

lam

anid

was

a m

ean

of 1

2.1

ms (

95%

CI 5

.6–1

8.6

ms).

The

re

wer

e no

Gra

de 3

or G

rade

4 Q

T ad

vers

e ev

ents

reco

rded

in

all t

hree

pat

ient

gro

ups,

inclu

ding

am

ong

thos

e w

ho re

ceive

d be

daqu

iline

and

dela

man

id c

oncu

rrent

ly.

LOW

CR

ITIC

AL

CI: c

onfid

ence

inte

rval

; MD

R-TB

: mul

tidru

g-re

sista

nt tu

berc

ulos

is; M

DR/

RR-T

B: m

ultid

rug-

or r

ifam

picin

-res

istan

t tub

ercu

losis

; OR:

odd

s ra

tio.

Expl

anat

ions

a.Fo

r th

e tw

o co

hort

stu

dies

with

the

inte

rven

tion,

the

smal

l num

ber

of p

atie

nts

repr

esen

ts le

ss th

an 3

% o

f all

patie

nts

in o

ne c

ohor

t stu

dy w

ith e

xcel

lent

qua

lity

of in

form

atio

n; h

ence

, the

re is

a p

ossib

ility

ofsu

bsta

ntia

l sel

ectio

n bi

as. T

he s

econ

d co

hort

also

had

sm

all n

umbe

rs, b

ut th

e pa

tient

s re

pres

ent a

lmos

t hal

f of a

ll co

hort

mem

bers

; hen

ce, t

here

is le

ss p

ossib

ility

of s

elec

tion

bias

.

b.Pa

tient

s fo

r the

inte

rven

tion

wer

e tre

ated

in tw

o ve

ry d

iffer

ent c

ohor

t stu

dies

, with

diff

eren

t cen

tres

or p

rovi

ders

and

pro

toco

ls. P

atie

nts

for t

he c

ompa

rato

r wer

e tre

ated

in fo

ur v

ery

diffe

rent

coh

ort s

tudi

es.

c.Th

ere

are

serio

us c

once

rns

abou

t thi

s st

udy,

give

n th

at s

mal

l num

bers

rece

ived

bed

aqui

line

and

dela

man

id c

onco

mita

ntly

(n=8

4).

d.O

utco

mes

and

cos

ts a

re s

imul

ated

usin

g a

mod

el th

at d

raw

s pa

ram

eter

est

imat

es fr

om m

ultip

le s

ourc

es, i

nclu

ding

the

adju

sted

odd

s ra

tios

for s

ucce

ss v

ersu

s de

ath/

failu

re d

escr

ibed

abo

ve.

e.Th

e ab

solu

te e

ffect

is c

alcu

late

d af

ter m

atch

ing

inte

rven

tion

and

com

para

tor p

opul

atio

ns, a

nd p

erfo

rmin

g bi

nom

ial r

egre

ssio

n w

ith a

n id

entit

y lin

k.

f. Im

prec

ision

is se

cond

ary

to th

e sm

all n

umbe

r of i

ndiv

idua

ls en

rolle

d. T

ypica

lly, f

or c

ontin

uous

out

com

es, a

sam

ple

size

of 4

00 m

akes

it p

ossib

le to

dra

w c

onclu

sions

with

con

fiden

ce, a

lthou

gh th

is is

a ge

nera

l rul

e.


A3.2 WHO treatment guidelines for isoniazid-resistant tuberculosis, 2018Refer to Annex 5: GRADE evidence summary tables in the WHO treatment guidelines for isoniazid-resistant tuberculosis (https://www.who.int/tb/publications/2018/WHO_treatment_guidelines_ isoniazid_resistant_TB_Online_GRADE_tables_Annexes.pdf, accessed 2 March 2019).

A3.3 WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2018 updateRefer to Annex 8: GRADE evidence summary tables in the WHO treatment guidelines for multidrug-and rifampicin-resistant tuberculosis, 2018 update (https://www.who.int/tb/areas-of-work/drug-resistant-tb/ Annexes_8–10.pdf, accessed 2 March 2019).

A3.4 Guidelines for the programmatic management of drug-resistant tuberculosis, 2011 updateRefer to Annex 2: GRADE glossary and summary of evidence tables (questions 6 and 7) in the Guidelines for the programmatic management of drug-resistant tuberculosis, 2011 update (https://apps.who.int/ iris/bitstream/handle/10665/70677/WHO_HTM_TB_2011.6b_eng.pdf, accessed 2 March 2019).

A3.5 WHO treatment guidelines for drug-resistant tuberculosis, 2016 updateRefer to Annex 4: GRADE tables (question 4) in the WHO treatment guidelines for drug-resistant tuberculosis, 2016 update (https://apps.who.int/iris/bitstream/handle/10665/250125/ 9789241549639-webannexes-eng.pdf, accessed 2 March 2019).

A3.6 Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 updateRefer to Annex 3: GRADE evidence profiles (questions 10 and 11) in the Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update (https://www.who.int/tb/publications/2017/ dstb_guidance_2017/en/, accessed 2 March 2019).



https://apps.who.int/iris/bitstream/handle/10665/250125/9789241549639-webannexes-eng.pdf?sequence=5&isAllowed=y



Anne

x 4:

GRA

DE

evid

ence

-to-

deci

sion

tabl

es

A4.

1 W

HO

trea

tmen

t gui

delin

es fo

r mul

tidru

g- o

r rifa

mpi

cin-

resi

stan

t tu

berc

ulos

is, 2

020

upda

teSh

ould

an

all-

oral

sho

rter

regi

men

of 9

–12

mon

ths’

dur

atio

n in

clud

ing

beda

quili

ne v

s a

shor

ter r

egim

en re

com

men

ded

by W

HO

(with

inje

ctab

le) b

e us

ed fo

r MD

R/RR

-TB

patie

nts

to s

afel

y im

prov

e ou

tcom

es?

POPU

LATI

ON

:M

DR-

/RR-

TB p

atie

nts

to s

afel

y im

prov

e ou

tcom

esIN

TERV

ENTI

ON

:Al

l-ora

l bed

aqui

line-

cont

aini

ng s

hort

er re

gim

en o

f 9–1

2 m

onth

s du

ratio

n (B

DQ

-LFX

/MFX

-ETO

-E-Z

-Hh -C

FZ)

COM

PARI

SON

:Sh

orte

r reg

imen

reco

mm

ende

d by

WH

O (w

ith a

n in

ject

able

age

nt)

MAI

N O

UTCO

MES

:Su

cces

s vs

. Fai

lure

/Rec

urre

nce;

Suc

cess

vs.

Dea

th; S

ucce

ss v

s. Fa

ilure

/Rec

urre

nce/

Dea

th; S

ucce

ss v

s. Al

l Unf

avou

rabl

e; L

ost v

s. Al

l Oth

er O

utco

mes

; AFB

Sm

ear

Posit

ive:

Suc

cess

vs.

Failu

re/R

ecur

renc

e; A

FB S

mea

r Pos

itive

: Suc

cess

vs.

Dea

th; A

FB S

mea

r Pos

itive

: Suc

cess

vs.

Failu

re/R

ecur

renc

e/D

eath

; AFB

Sm

ear P

ositi

ve:

Succ

ess

vs. A

ll Un

favo

urab

le; A

FB S

mea

r Pos

itive

: Los

t vs.

All O

ther

Out

com

es; H

IV-P

ositi

ve o

n AR

T: S

ucce

ss v

s. Fa

ilure

/Rec

urre

nce;

HIV

-Pos

itive

on

ART:

Suc

cess

vs

. Dea

th; H

IV-P

ositi

ve o

n AR

T: S

ucce

ss v

s. Fa

ilure

/Rec

urre

nce/

Dea

th; H

IV-P

ositi

ve o

n AR

T: S

ucce

ss v

s. Al

l Oth

er U

nfav

oura

ble;

HIV

-Pos

itive

on

ART:

Los

t vs.

All O

ther

Out

com

es; H

IV N

egat

ive:

Suc

cess

vs.

Failu

re/R

ecur

renc

e; H

IV N

egat

ive:

Suc

cess

vs.

Dea

th; H

IV N

egat

ive:

Suc

cess

vs.

Failu

re/R

ecur

renc

e/D

eath

; HIV

N

egat

ive:

Suc

cess

vs.

All O

ther

Out

com

es; H

IV N

egat

ive:

Los

t vs.

All O

ther

Out

com

es.

SETT

ING

:So

uth

Afric

a.

PERS

PECT

IVE:

Publ

ic he

alth

and

hea

lth s

yste

ms

pers

pect

ive

BACK

GRO

UND

:M

ultid

rug-

resis

tant

(MD

R-) a

nd ri

fam

picin

-res

istan

t tub

ercu

losis

(MD

R-/R

R-TB

) is

emer

ging

as

a m

ajor

pro

blem

due

to p

oor m

anag

emen

t of d

rug-

sens

itive

as

wel

l as

dru

g-re

sista

nt T

B. M

DR-

/RR-

TB is

trea

tabl

e, b

ut h

as re

quire

d th

e us

e of

long

er tr

eatm

ent r

egim

ens

whi

ch c

onta

in p

oten

tially

toxic

dru

gs. T

he in

tere

st in

redu

cing

the

dura

tion

of tr

eatm

ent f

or M

DR-

TB m

otiv

ated

a n

umbe

r of i

nitia

tives

in re

cent

yea

rs to

trea

t pat

ient

s w

ith s

hort

er re

gim

ens

unde

r pro

gram

mat

ic as

wel

l as

trial

co

nditi

ons.

In 2

016,

on

the

basis

of d

ata

from

obs

erva

tiona

l stu

dies

of t

he s

hort

er re

gim

ens

in d

iffer

ent A

sian

and

Afric

an c

ount

ries,

WH

O s

tart

ed to

reco

mm

end

a st

anda

rdiz

ed s

hort

er M

DR-

TB re

gim

en, c

onta

inin

g an

inje

ctab

le a

gent

, bas

ed o

n th

e on

es u

nder

stu

dy fo

r elig

ible

pat

ient

s. In

201

8, fu

rthe

r mod

ifica

tions

w

ere

mad

e to

the

earli

er re

com

men

ded

shor

ter r

egim

en, r

epla

cing

kana

myc

in b

y am

ikacin

(bas

ed o

n ev

iden

ce fr

om th

e co

mpa

rativ

e ef

fect

iven

ess

of th

ese

two

inje

ctab

le a

gent

s).

Evid

ence

of p

erm

anen

t effe

cts

attri

bute

d to

the

toxic

ity o

f inj

ecta

ble

agen

ts, h

ave

prom

pted

furt

her a

dvan

ces

in th

e de

velo

pmen

t of n

ew tr

eatm

ents

suc

h as

sh

orte

r inj

ecta

ble-

spar

ing

regi

men

s. In

par

ticul

ar, o

bser

vatio

nal d

ata

on a

n al

l-ora

l bed

aqui

line-

cont

aini

ng s

hort

er re

gim

en o

f 9–1

2 m

onth

s du

ratio

n be

cam

e av

aila

ble.

Thi

s is

of p

artic

ular

impo

rtan

ce g

iven

that

the

regi

men

may

offe

r pat

ient

s th

e lik

elih

ood

of b

ette

r tol

erat

ing

treat

men

t with

out s

igni

fican

t tox

icity.

CON

FLIC

T O

F IN

TERE

STS:

Albe

rto

Piub

ello

.


Ass

essm

ent

Prob

lem

Is th

e pr

oble

m a

prio

rity?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

No

○ P

roba

bly

no

○ P

roba

bly

yes

● Ye

s ○

Var

ies

○ D

on’t

know

Tube

rcul

osis

(TB)

rem

ains

a th

reat

to g

loba

l pub

lic h

ealth

and

is th

e to

pmos

t inf

ectio

us c

ause

of

dea

th in

the

wor

ld. I

n 20

18, a

n es

timat

ed 1

0 m

illion

peo

ple

deve

lope

d TB

and

1.4

milli

on

died

from

the

dise

ase.

Abo

ut 5

00 0

00 n

ew c

ases

of m

ultid

rug-

or r

ifam

picin

-res

istan

t TB

(MD

R/RR

-TB)

wer

e es

timat

ed to

em

erge

in 2

018.

Alth

ough

all

of th

ese

wou

ld h

ave

been

el

igib

le fo

r a s

econ

d-lin

e TB

trea

tmen

t reg

imen

, onl

y 15

6 07

1 en

rolm

ents

on

treat

men

t wer

e re

port

ed b

y co

untri

es in

201

8 –

abou

t 30%

of t

he e

stim

ated

cas

eloa

d. D

espi

te th

is, s

igni

fican

t im

prov

emen

ts in

the

avai

labi

lity

of e

nhan

ced

diag

nost

ics a

nd m

ore

effe

ctiv

e m

edici

nes

have

oc

curre

d in

rece

nt y

ears

and

hav

e le

d to

ear

lier d

etec

tion

and

high

er s

ucce

ss ra

tes

amon

g pa

tient

s w

ith M

DR/

RR-T

B in

a n

umbe

r of n

atio

nal p

rogr

amm

es. H

owev

er, t

hese

suc

cess

es h

ave

not b

een

repr

oduc

ed in

the

rest

of t

he w

orld

, and

the

over

all t

reat

men

t suc

cess

rate

wor

ldw

ide

reac

hed

only

56%

for p

atie

nts

with

MD

R/RR

-TB

who

sta

rted

on

treat

men

t in

2016

, and

onl

y 39

% fo

r pat

ient

s w

ith e

xten

sivel

y dr

ug-r

esist

ant T

B (X

DR-

TB).


Des

irab

le E

ffec

tsH

ow s

ubst

antia

l are

the

desi

rabl

e an

ticip

ated

eff

ects

?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Triv

ial

○ S

mal

l ○

Mod

erat

e ●

Larg

e ○

Var

ies

○ D

on’t

know

Out

com

esEf

fect

Rela

tive

Abs

olut

eSu

cces

s vs

. Fai

lure

/Rec

urre

nce

(follo

w u

p: m

ean

18 m

onth

s)O

R 2.

1 (1

.1 to

4.0

)3

mor

e pe

r 100

(1

mor

e to

6 m

ore)

Su

cces

s vs

. Dea

th (f

ollo

w u

p: m

ean

18 m

onth

s)O

R 1.

6 (1

.2 to

2.1

)8

mor

e pe

r 100

(3

mor

e to

13

mor

e)

Succ

ess

vs. F

ailu

re/R

ecur

renc

e/D

eath

(fol

low

up:

m

ean

18 m

onth

s)O

R 1.

7 (1

.3 to

2.2

)10

mor

e pe

r 100

(5

mor

e to

15

mor

e)

Succ

ess

vs. A

ll Un

favo

rabl

e (fo

llow

up:

mea

n 18

mon

ths)

OR

1.9

(1.6

to 2

.4)

14 m

ore

per 1

00

(9 m

ore

to 1

9 m

ore)

Lost

vs.

All O

ther

Out

com

es (f

ollo

w u

p: m

ean

18 m

onth

s)O

R 0.

5 (0

.4 to

0.7

)7

few

er p

er 1

00

(11

few

er to

4 fe

wer

)AF

B Sm

ear P

ositi

ve: S

ucce

ss v

s. Fa

ilure

/Rec

urre

nce

(follo

w u

p: m

ean

18 m

onth

s)O

R 4.

4 (1

.6 to

11.

9)8

mor

e pe

r 100

(3

mor

e to

13

mor

e)AF

B Sm

ear P

ositi

ve: S

ucce

ss v

s. D

eath

(fol

low

up:

m

ean

18 m

onth

s)O

R 1.

3 (0

.8 to

2.1

)5

mor

e pe

r 100

(3

few

er to

12

mor

e)AF

B Sm

ear P

ositi

ve: S

ucce

ss v

s. Fa

ilure

/Rec

urre

nce/

Dea

th (f

ollo

w u

p: m

ean

18 m

onth

s)O

R 1.

7 (1

.1 to

2.6

)10

mor

e pe

r 100

(2

mor

e to

17

mor

e)AF

B Sm

ear P

ositi

ve: S

ucce

ss v

s. Al

l Unf

avor

able

(fo

llow

up:

mea

n 18

mon

ths)

OR

2.3

(1.6

to 3

.3)

16 m

ore

per 1

00

(9 m

ore

to 2

4 m

ore)

AFB

Smea

r Pos

itive

: Los

t vs.

All O

ther

Out

com

es

(follo

w u

p: m

ean

18 m

onth

s)O

R 0.

4 (0

.2 to

0.6

)11

few

er p

er 1

00

(16

few

er to

5 fe

wer

)H

IV-P

ositi

ve o

n AR

T: S

ucce

ss v

s. Fa

ilure

/Rec

urre

nce

(follo

w u

p: m

ean

18 m

onth

s)O

R 1.

4 (0

.7 to

2.9

)2

mor

e pe

r 100

(2

few

er to

5 m

ore)

HIV

-Pos

itive

on

ART:

Suc

cess

vs.

Dea

th (f

ollo

w u

p:

mea

n 18

mon

ths)

OR

1.6

(1.2

to 2

.3)

8 m

ore

per 1

00

(3 m

ore

to 1

4 m

ore)

HIV

-Pos

itive

on

ART:

Suc

cess

vs.

Failu

re/R

ecur

renc

e/D

eath

(fol

low

up:

mea

n 18

mon

ths)

OR

1.6

(1.2

to 2

.2)

9 m

ore

per 1

00

(3 m

ore

to 1

5 m

ore)

HIV

-Pos

itive

on

ART:

Suc

cess

vs.

All O

ther

Un

favo

rabl

e (fo

llow

up:

mea

n 18

mon

ths)

OR

1.9

(1.4

to 2

.4)

14 m

ore

per 1

00

(8 m

ore

to 1

9 m

ore)

HIV

-Pos

itive

on

ART:

Los

t vs.

All O

ther

Out

com

es

(follo

w u

p: m

ean

18 m

onth

s)O

R 0.

6 (0

.4 to

0.8

)6

few

er p

er 1

00

(10

few

er to

2 fe

wer

)

Resu

lts fr

om th

e da

ta a

sses

smen

t com

miss

ione

d to

info

rm

thes

e re

com

men

datio

ns s

how

that

favo

urab

le o

utco

mes

w

ere

signi

fican

tly b

ette

r for

the

all-o

ral s

hort

er b

edaq

uilin

e-co

ntai

ning

sho

rter

regi

men

than

for a

sho

rter

regi

men

re

com

men

ded

by W

HO

(with

inje

ctab

le).


Und

esir

able

Eff

ects

How

sub

stan

tial a

re th

e un

desi

rabl

e an

ticip

ated

eff

ects

?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Lar

ge

○ M

oder

ate

○ S

mal

l ○

Triv

ial

○ V

arie

s ●

Don

’t kn

ow

The

Gui

delin

e D

evel

opm

ent G

roup

(GD

G) d

iscus

sed

earli

er re

sults

of t

he in

divi

dual

-pat

ient

da

ta (I

PD) m

eta-

anal

ysis

cond

ucte

d to

ass

ess

the

over

all b

alan

ce b

etw

een

bene

fits

and

harm

s of

indi

vidu

al a

gent

s. In

the

anal

ysis,

199

5 pa

tient

s re

ceiv

ed k

anam

ycin

and

268

(13.

4%)

expe

rienc

ed a

n ad

vers

e ev

ent c

ausin

g pe

rman

ent d

rug

disc

ontin

uatio

n; 4

106

patie

nts

rece

ived

am

ikacin

, of w

hom

235

(5.7

%) e

xper

ienc

ed a

n ad

vers

e ev

ent c

ausin

g pe

rman

ent

drug

disc

ontin

uatio

n; a

dditi

onal

ly, 1

932

rece

ived

cap

reom

ycin

and

161

(8.3

%) e

xper

ienc

ed

an a

dver

se e

vent

cau

sing

perm

anen

t dru

g di

scon

tinua

tion.

In c

ontra

st, 4

64 p

atie

nts

rece

ived

bed

aqui

line,

of w

hom

9 (1

.9%

) exp

erie

nced

an

adve

rse

even

t cau

sing

perm

anen

t dr

ug d

iscon

tinua

tion.

Thou

gh n

o m

ajor

sig

nals

of ri

sk w

ere

obse

rved

with

the

use

of th

e al

l-ora

l bed

aqui

line-

base

d sh

orte

r reg

imen

, the

GD

G

ackn

owle

dged

that

som

e un

cert

aint

ies

rem

aine

d gi

ven

the

lack

of s

yste

mat

ic co

llect

ion

of d

ata,

and

lack

of c

larit

y as

to

any

chan

ges

in th

e re

gim

en th

at c

ould

hav

e be

en in

form

ed

by th

e pr

esen

ce o

f adv

erse

eve

nts.

How

ever

, the

GD

G

reco

gniz

ed th

at th

e an

alys

is w

as n

ot c

ompl

etel

y ag

nost

ic ab

out s

afet

y, in

par

ticul

ar th

e ba

lanc

e be

twee

n de

sirab

le v

ersu

s un

desir

able

effe

cts,

and

the

grou

p w

as s

omew

hat r

eass

ured

th

at e

arlie

r sig

nals

attri

bute

d to

the

use

of b

edaq

uilin

e w

ere

not

obse

rved

, pre

sent

ing

no a

dditi

onal

saf

ety

conc

erns

. The

gro

up

re-e

mph

asiz

ed th

at a

lthou

gh 1

.9%

of p

atie

nts

usin

g be

daqu

iline

expe

rienc

e an

adv

erse

eve

nt th

at le

ads

to th

e di

scon

tinua

tion

of th

e dr

ug, t

his

cons

eque

nce

is no

t to

be c

onsid

ered

as“

trivi

al”,

and

that

for n

ow, s

afet

y da

ta a

re n

eede

d to

bet

ter u

nder

stan

d [s

afet

y] a

spec

ts o

f the

all-

oral

bed

aqui

line-

cont

aini

ng s

hort

er

regi

men

. saf

ety

data

are

nee

ded

to b

ette

r und

erst

and

[saf

ety]

as

pect

s of

the

all-o

ral b

edaq

uilin

e-co

ntai

ning

sho

rter

regi

men

.

Cert

aint

y of

evi

denc

eW

hat i

s th

e ov

eral

l cer

tain

ty o

f the

evi

denc

e of

eff

ects

?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S●

Very

low

○

Low

○

Mod

erat

e ○

Hig

h ○

No

inclu

ded

stud

ies

The

GD

G p

oint

ed o

ut th

at, o

n th

e ba

sis o

f the

evi

denc

e as

sess

ed –

nam

ely,

obse

rvat

iona

l dat

a an

d po

tent

ial r

esid

ual

conf

ound

ing

– th

e ov

eral

l cer

tain

ty re

gard

ing

the

estim

ates

of

effe

ct b

ased

was

judg

ed to

be

very

low,

with

the

effe

cts

for a

ll ou

tcom

es a

lso ra

ted

as “v

ery

low

”. Al

thou

gh d

oubl

e-ad

just

men

t in

prop

ensit

y sc

ore

mat

chin

g an

alys

es w

as c

arrie

d ou

t to

rem

ove

the

effe

cts

of c

onfo

undi

ng, m

embe

rs o

f the

GD

G

furt

her d

iscus

sed

that

alth

ough

thes

e ef

fort

s co

mpe

nsat

ed

for s

ome

pote

ntia

l con

foun

ders

, res

idua

l bia

s is

likel

y to

be

pres

ent.

The

grou

p ac

know

ledg

ed th

at a

lthou

gh th

e us

e of

pr

ogra

mm

atic

data

hol

ds g

reat

pro

mise

bec

ause

they

bet

ter

refle

ct re

al p

ract

ice, s

ome

cons

ider

atio

ns in

term

s of

the

exte

nt

to w

hich

thes

e fin

ding

s co

uld

be a

pplie

d to

oth

er s

ettin

gs a

re

to b

e co

ntem

plat

ed. F

or in

stan

ce, s

pecif

ic cli

nica

l cha

ract

erist

ics

of th

e po

pula

tion

(e.g

. HIV

pre

vale

nce

and

drug

-res

istan

ce

patte

rns)

as

wel

l as

qual

ity o

f hea

lth c

are

serv

ices,

mod

els

of

care

, and

trea

tmen

t adh

eren

ce s

trate

gies

.


Valu

esIs

ther

e im

port

ant u

ncer

tain

ty a

bout

or v

aria

bilit

y in

how

muc

h pe

ople

val

ue th

e m

ain

outc

omes

?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Impo

rtan

t un

cert

aint

y or

va

riabi

lity

○ P

ossib

ly im

port

ant

unce

rtai

nty

or

varia

bilit

y ○

Pro

babl

y no

im

port

ant u

ncer

tain

ty

or v

aria

bilit

y ●

No

impo

rtan

t un

cert

aint

y or

va

riabi

lity

A qu

alita

tive

stud

y un

dert

aken

to h

ighl

ight

the

pers

pect

ives

of k

ey s

take

hold

ers,

mai

nly,

patie

nt

and

civil

socie

ty re

pres

enta

tives

(n =

16)

look

ed a

t gen

eral

pre

fere

nces

and

val

ues

rega

rdin

g di

ffere

nt a

spec

ts o

f tre

atm

ent r

egim

ens

for d

rug-

resis

tant

TB,

suc

h as

dur

atio

n, p

ill bu

rden

, use

of

inje

ctab

le a

gent

s an

d po

tent

ial f

or e

xper

ienc

ing

adve

rse

even

ts.

Part

icipa

nts

had

the

oppo

rtun

ity to

disc

uss

impo

rtan

t adv

erse

effe

cts,

inclu

ding

per

man

ent

sens

orin

eura

l hea

ring

loss

, nep

hrot

oxici

ty, e

lect

roly

te a

bnor

mal

ities

, inj

ectio

n pa

in a

nd lo

cal

inje

ctio

n-sit

e co

mpl

icatio

ns. F

rom

a p

atie

nt p

ersp

ectiv

e, a

dver

se e

vent

s su

ch a

s op

tic n

eurit

is,

hear

ing

impa

irmen

t, m

enta

l sta

tus

chan

ges

due

to u

rem

ia, a

nd e

lect

roly

te a

bnor

mal

ities

are

la

te e

ffect

s am

ong

othe

rs a

ssoc

iate

d w

ith th

e us

e of

spe

cific

seco

nd-li

ne a

gent

s, in

cludi

ng

inje

ctab

le a

gent

s, an

d w

ere

deem

ed u

nacc

epta

ble.

.

Pref

eren

ces

abou

t tre

atm

ent a

ppea

red

to b

e ro

oted

in c

ore

valu

es, i

nclu

ding

min

imal

disr

uptio

n to

nor

mal

life

. Rel

ativ

ely

few

pat

ient

s se

emed

to p

refe

r a s

hort

regi

men

that

was

tied

to

mor

e se

rious

sid

e-ef

fect

s, bu

t onl

y if

the

side-

effe

cts

wer

e ra

re

or re

vers

ible

. In

addi

tion,

in te

rms

of th

e du

ratio

n of

trea

tmen

t, pr

efer

ence

s se

emed

to b

e gu

ided

firs

t by

side-

effe

cts

and

seco

nd b

y ef

ficac

y of

trea

tmen

t reg

imen

s.

Bala

nce

of e

ffec

tsD

oes

the

bala

nce

betw

een

desi

rabl

e an

d un

desi

rabl

e ef

fect

s fa

vor t

he in

terv

entio

n or

the

com

paris

on?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Fav

ors

the

com

paris

on

○ P

roba

bly

favo

rs th

e co

mpa

rison

○

Doe

s no

t fav

or

eith

er th

e in

terv

entio

n or

the

com

paris

on

○ P

roba

bly

favo

rs th

e in

terv

entio

n ●

Favo

rs th

e in

terv

entio

n ○

Var

ies

○ D

on’t

know

The

GD

G c

onsid

ered

whe

ther

the

bala

nce

betw

een

desir

able

an

d un

desir

able

effe

cts

favo

ured

the

inte

rven

tion.

Dat

a as

sess

men

t sho

wed

that

the

over

all r

ate

of a

dver

se e

vent

s at

tribu

ted

to b

edaq

uilin

e as

com

pare

d w

ith in

ject

able

age

nts

was

two

times

less

. At t

he s

ame

time,

the

GD

G n

oted

a 5

0%

redu

ctio

n in

dea

th, a

ttrib

utin

g th

is ef

fect

to th

e ad

ditio

n of

be

daqu

iline.

How

ever

, the

gro

up e

mph

asiz

ed th

e po

tent

ial

harm

s if

this

beda

quilin

e-co

ntai

ning

regi

men

wer

e to

be

impl

emen

ted

with

out e

nsur

ing

prop

er d

rug-

susc

eptib

ility

test

ing

(DST

), an

d th

e po

tent

ial f

or a

mpl

ifica

tion

of re

sista

nce

patte

rns.

Whe

n de

cidin

g on

whe

ther

or n

ot th

e ba

lanc

e of

ef

fect

s fa

vour

ed th

e in

terv

entio

n or

the

com

para

tor,

the

grou

p pr

ocee

ded

to v

ote.

Tota

l vot

ing

mem

bers

pre

sent

: 29

expe

rts

(plu

s 1

conf

lict o

f int

eres

t). V

otin

g pr

ocee

ded

as fo

llow

s: Pr

obab

ly, 1

3; fa

vour

s th

e in

terv

entio

n, 1

4; v

arie

s, 1;

abs

tent

ion,

1;

plu

s on

e vo

ting

mem

ber w

ho a

bsta

ined

due

to c

onfli

ct

of in

tere

st.


Reso

urce

s re

quir

edH

ow la

rge

are

the

reso

urce

requ

irem

ents

(cos

ts)?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Lar

ge c

osts

○

Mod

erat

e co

sts

○ N

eglig

ible

cos

ts

and

savi

ngs

● M

oder

ate

savi

ngs

○ L

arge

sav

ings

○

Var

ies

○ D

on’t

know

Com

pare

d w

ith th

e in

ject

able

-con

tain

ing

shor

ter r

egim

en, t

he 9

–12-

mon

th a

ll-or

al re

gim

en is

pr

ojec

ted

to b

e bo

th c

ost-

savi

ng a

nd m

ore

effe

ctiv

e th

an th

e in

ject

able

-con

tain

ing

shor

ter

regi

men

und

er n

early

all

mod

elle

d co

nditi

ons.

The

proj

ecte

d co

st s

avin

gs a

vera

ge U

S$ 1

000

(201

9) in

Sou

th A

frica

and

dep

end

prim

arily

on

the

exte

nt to

whi

ch h

ighe

r dru

g co

sts

are

outw

eigh

ed b

y th

e re

duce

d co

sts

of d

eliv

erin

g in

ject

able

age

nts,

and

treat

ing

recu

rrent

and

se

cond

ary

case

s (a

bout

US$

200

0 pe

r pat

ient

is s

aved

in s

ettin

gs w

ith tw

o-tim

es-h

ighe

r hea

lth

care

cos

ts, v

ersu

s <U

S$ 1

00 s

aved

in s

ettin

gs w

ith h

igh

drug

cos

ts b

ut lo

w h

ealth

car

e co

sts)

.

An im

port

ant i

ssue

ack

now

ledg

ed b

y th

e G

DG

was

that

al

thou

gh th

e al

l-ora

l bed

aqui

line-

cont

aini

ng re

gim

en s

eem

ed

to b

e bo

th c

ost-s

avin

g an

d m

ore

effe

ctiv

e as

com

pare

d w

ith th

e sh

orte

r reg

imen

reco

mm

ende

d by

WH

O (w

ith a

n in

ject

able

), co

sts

are

not e

xpec

ted

to a

utom

atica

lly e

limin

ated

or

decr

ease

d. S

ever

al o

ther

key

fact

ors

mus

t also

be

cons

ider

ed,

inclu

ding

the

exist

ing

stoc

k of

sec

ond-

line

med

icatio

ns w

hile

tra

nsiti

onin

g fro

m a

n in

ject

able

-bas

ed re

gim

en to

an

all-o

ral

one,

dia

gnos

tic c

apac

ity to

iden

tify

elig

ible

indi

vidu

als

into

cu

rrent

ly re

com

men

ded

regi

men

s (b

ased

on

drug

-sus

cept

ibilit

y pa

ttern

s, et

c.),

and

capa

city

to c

ondu

ct re

gula

r act

ive

TB d

rug

safe

ty m

onito

ring

and

man

agem

ent.

How

ever

, the

re w

ere

no d

ata

for d

eter

min

ing

the

exac

t res

ourc

es th

at w

ould

be

cons

umed

with

the

impl

emen

tatio

n of

this

all-o

ral b

edaq

uilin

e-co

ntai

ning

regi

men

.Th

e G

DG

did

agr

ee th

at, o

vera

ll, sa

ving

s ca

n be

con

sider

ed

in te

rms

of fu

ture

retre

atm

ents

pre

vent

ed, a

s w

ell a

s re

duce

d ho

spita

lizat

ion

rate

s re

sulti

ng fr

om le

ss a

dver

se re

actio

ns.

Cert

aint

y of

evi

denc

e of

req

uire

d re

sour

ces

Wha

t is

the

cert

aint

y of

the

evid

ence

of r

esou

rce

requ

irem

ents

(cos

ts)?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Ver

y lo

w

○ L

ow

● M

oder

ate

○ H

igh

○ N

o in

clude

d st

udie

s

The

cost

sav

ings

rela

tive

to a

sho

rt in

ject

able

-con

tain

ing

regi

men

are

also

robu

st, e

xcep

t at

ext

rem

es w

ith d

rug

cost

s, he

alth

car

e co

sts

or th

e co

st o

f bed

aqui

line

and

othe

r co

mpa

nion

dru

gs.

Thou

gh th

e un

cert

aint

y ar

ound

the

estim

ates

of e

ffect

was

ac

know

ledg

ed, t

he G

DG

agr

eed

that

ther

e se

emed

to b

e m

oder

ate

cost

sav

ings

, bec

ause

of r

educ

ed h

ospi

taliz

atio

n ra

tes

resu

lting

from

few

er a

dver

se re

actio

ns, l

ess

mon

itorin

g/vi

sits

(for

inje

ctab

le u

se),

and

few

er tr

eatm

ent i

nter

rupt

ions

bec

ause

of

bette

r adh

eren

ce.


Cost

eff

ecti

vene

ssD

oes

the

cost

-eff

ectiv

enes

s of

the

inte

rven

tion

favo

r the

inte

rven

tion

or th

e co

mpa

rison

?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Fav

ors

the

com

paris

on

○ P

roba

bly

favo

rs th

e co

mpa

rison

○

Doe

s no

t fav

or

eith

er th

e in

terv

entio

n or

the

com

paris

on

● Pr

obab

ly fa

vors

the

inte

rven

tion

○ F

avor

s th

e in

terv

entio

n ○

Var

ies

○ N

o in

clude

d st

udie

s

A co

st–e

ffect

iven

ess

mod

el w

as d

evel

oped

, inc

orpo

ratin

g es

timat

ed h

ealth

sys

tem

cos

ts w

ith

drug

pro

cure

men

t, he

alth

car

e de

liver

y, ad

vers

e ev

ents

, ret

reat

men

ts, s

econ

dary

cas

es, a

nd

mor

bidi

ty a

nd m

orta

lity

asso

ciate

d w

ith T

B m

orta

lity

and

recu

rrenc

e, tr

eatm

ent d

urat

ion,

dru

g to

xicity

and

TB

trans

miss

ion.

Cos

ts a

nd c

ost–

effe

ctiv

enes

s w

ere

eval

uate

d in

Sou

th A

frica

, w

ith s

ensit

ivity

ana

lyse

s re

pres

entin

g a

rang

e of

dru

g an

d he

alth

car

e co

sts,

high

and

low

H

IV c

o-pr

eval

ence

, 95%

CIs

for e

stim

ates

of r

elat

ive

effic

acy

deriv

ed fr

om s

tatis

tical

ana

lysis

of

pat

ient

coh

ort d

ata,

and

unc

erta

inty

in th

e va

lues

of p

aram

eter

s re

pres

entin

g th

e na

tura

l hi

stor

y of

TB.

Com

pare

d w

ith th

e in

ject

able

-con

tain

ing

shor

ter r

egim

en, t

he 9

–12-

mon

th a

ll-or

al re

gim

en

is pr

ojec

ted

to b

e bo

th c

ost s

avin

g an

d m

ore

effe

ctiv

e th

an th

e in

ject

able

-con

tain

ing

shor

ter r

egim

en u

nder

nea

rly a

ll m

odel

led

cond

ition

s. Th

e pr

ojec

ted

cost

sav

ings

ave

rage

US

$ 10

00 (2

019)

in S

outh

Afri

ca a

nd d

epen

d pr

imar

ily o

n th

e ex

tent

to w

hich

hig

her d

rug

cost

s ar

e ou

twei

ghed

by

redu

ced

cost

s of

del

iver

ing

inje

ctab

le a

gent

s, an

d tre

atin

g re

curre

nt a

nd

seco

ndar

y ca

ses

(abo

ut U

S$ 2

000

save

d pe

r pat

ient

is s

aved

in s

ettin

gs w

ith tw

o-tim

es-h

ighe

r he

alth

car

e co

sts,

vers

us <

US$

100

save

d in

set

tings

with

hig

h dr

ug c

osts

but

low

hea

lth c

are

cost

s). I

n a

scen

ario

whe

re th

e al

l-ora

l reg

imen

was

no

long

er c

ost-s

avin

g be

caus

e be

daqu

iline

price

s w

ere

four

fold

hig

her t

han

curre

nt p

ricin

g in

Sou

th A

frica

or v

ia th

e G

DF,

the

incr

emen

tal

cost

–effe

ctiv

enes

s ra

tio o

f the

all-

oral

regi

men

was

US$

400

per

disa

bilit

y ad

just

ed li

fe-y

ear

aver

ted

(rang

e: U

S$ 1

00–U

S$ 9

00 a

cros

s 95

% C

I for

rela

tive

regi

men

effi

cacy

).

Equi

tyW

hat w

ould

be

the

impa

ct o

n he

alth

equ

ity?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Red

uced

○

Pro

babl

y re

duce

d ○

Pro

babl

y no

impa

ct

○ P

roba

bly

incr

ease

d ●

Incr

ease

d ○

Var

ies

○ D

on’t

know

A qu

alita

tive

stud

y un

dert

aken

to h

ighl

ight

the

pers

pect

ives

of k

ey s

take

hold

ers,

mai

nly,

patie

nt

and

civil

socie

ty re

pres

enta

tives

(n=1

6) lo

oked

at g

ener

al p

refe

renc

es a

nd v

alue

s re

gard

ing

diffe

rent

asp

ects

of t

reat

men

t reg

imen

s fo

r dru

g-re

sista

nt T

B tre

atm

ent,

such

as

dura

tion,

pill

burd

en, u

se o

f inj

ecta

ble

agen

ts a

nd p

oten

tial f

or e

xper

ienc

ing

adve

rse

even

ts.

Part

icipa

nts

cons

ider

ed a

nyth

ing

less

than

uni

vers

al a

nd im

med

iate

acc

ess

to n

ew tr

eatm

ents

to

be u

neth

ical,

but w

hen

prom

pted

to c

onsid

er th

is pr

efer

ence

aga

inst

a li

mite

d su

pply

of d

rugs

, a

few

wou

ld p

riorit

ize

the

youn

gest

and

sick

est,

as w

ell a

s th

ose

who

are

adh

eren

t and

cou

ld

be m

onito

red

for a

dver

se e

vent

s. Pa

tient

s w

ho fa

ce s

ocio

econ

omic

chal

leng

es to

adh

eren

ce,

or w

ho li

ve in

rem

ote,

rura

l or p

oore

r com

mun

ities

that

lack

tech

nica

l skil

l or e

quip

men

t for

tre

atm

ent m

onito

ring,

cou

ld th

en b

e di

spro

port

iona

tely

and

unj

ustly

pla

ced

at a

disa

dvan

tage

The

GD

G a

gree

d th

at in

ject

able

-spa

ring

regi

men

s w

ould

be

eas

ier t

o de

cent

raliz

e an

d, th

eref

ore,

in re

mot

e an

d un

ders

ervi

ced

setti

ngs

and

disa

dvan

tage

d po

pula

tions

, w

ould

hel

p to

alle

viat

e he

alth

ineq

uitie

s, w

ithou

t ant

icipa

ting

diffe

renc

es in

out

com

es in

spe

cific

popu

latio

ns. F

urth

er, t

he

grou

p al

so n

oted

that

bec

ause

aud

iom

etry

wou

ld n

ot b

e re

quire

d, it

mig

ht b

e ea

sier t

o m

onito

r ind

ivid

uals

in s

pite

of

incr

ease

d re

quire

men

ts fo

r ele

ctro

card

iogr

aphy

, whi

ch is

a

prer

equi

site

for t

he u

se o

f bed

aqui

line-

cont

aini

ng re

gim

ens.

How

ever

, the

gro

up s

tress

ed th

at th

e us

e of

ele

ctro

card

iogr

aphy

sh

ould

not

be

a di

ffere

ntia

ting

elem

ent b

etw

een

thes

e tw

o re

gim

ens,

beca

use

patie

nts

rece

ivin

g in

ject

able

age

nts

such

as

am

ikacin

sho

uld

also

hav

e re

gula

r car

diac

mon

itorin

g. T

he

grou

p ac

know

ledg

ed th

at it

is p

ossib

le th

at, i

n so

me

setti

ngsk

no

t all

patie

nts

will

be a

ble

to u

nder

go e

lect

roca

rdio

grap

hic

mon

itorin

g; h

owev

er, i

t was

also

not

ed th

at th

e in

crea

sing

acce

ss to

ele

ctro

card

iogr

aphy

at p

erip

hery

leve

ls m

ight

im

prov

e eq

uity.


Cost

eff

ecti

vene

ssD

oes

the

cost

-eff

ectiv

enes

s of

the

inte

rven

tion

favo

r the

inte

rven

tion

or th

e co

mpa

rison

?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Fav

ors

the

com

paris

on

○ P

roba

bly

favo

rs th

e co

mpa

rison

○

Doe

s no

t fav

or

eith

er th

e in

terv

entio

n or

the

com

paris

on

● Pr

obab

ly fa

vors

the

inte

rven

tion

○ F

avor

s th

e in

terv

entio

n ○

Var

ies

○ N

o in

clude

d st

udie

s

A co

st–e

ffect

iven

ess

mod

el w

as d

evel

oped

, inc

orpo

ratin

g es

timat

ed h

ealth

sys

tem

cos

ts w

ith

drug

pro

cure

men

t, he

alth

car

e de

liver

y, ad

vers

e ev

ents

, ret

reat

men

ts, s

econ

dary

cas

es, a

nd

mor

bidi

ty a

nd m

orta

lity

asso

ciate

d w

ith T

B m

orta

lity

and

recu

rrenc

e, tr

eatm

ent d

urat

ion,

dru

g to

xicity

and

TB

trans

miss

ion.

Cos

ts a

nd c

ost–

effe

ctiv

enes

s w

ere

eval

uate

d in

Sou

th A

frica

, w

ith s

ensit

ivity

ana

lyse

s re

pres

entin

g a

rang

e of

dru

g an

d he

alth

car

e co

sts,

high

and

low

H

IV c

o-pr

eval

ence

, 95%

CIs

for e

stim

ates

of r

elat

ive

effic

acy

deriv

ed fr

om s

tatis

tical

ana

lysis

of

pat

ient

coh

ort d

ata,

and

unc

erta

inty

in th

e va

lues

of p

aram

eter

s re

pres

entin

g th

e na

tura

l hi

stor

y of

TB.

Com

pare

d w

ith th

e in

ject

able

-con

tain

ing

shor

ter r

egim

en, t

he 9

–12-

mon

th a

ll-or

al re

gim

en

is pr

ojec

ted

to b

e bo

th c

ost s

avin

g an

d m

ore

effe

ctiv

e th

an th

e in

ject

able

-con

tain

ing

shor

ter r

egim

en u

nder

nea

rly a

ll m

odel

led

cond

ition

s. Th

e pr

ojec

ted

cost

sav

ings

ave

rage

US

$ 10

00 (2

019)

in S

outh

Afri

ca a

nd d

epen

d pr

imar

ily o

n th

e ex

tent

to w

hich

hig

her d

rug

cost

s ar

e ou

twei

ghed

by

redu

ced

cost

s of

del

iver

ing

inje

ctab

le a

gent

s, an

d tre

atin

g re

curre

nt a

nd

seco

ndar

y ca

ses

(abo

ut U

S$ 2

000

save

d pe

r pat

ient

is s

aved

in s

ettin

gs w

ith tw

o-tim

es-h

ighe

r he

alth

car

e co

sts,

vers

us <

US$

100

save

d in

set

tings

with

hig

h dr

ug c

osts

but

low

hea

lth c

are

cost

s). I

n a

scen

ario

whe

re th

e al

l-ora

l reg

imen

was

no

long

er c

ost-s

avin

g be

caus

e be

daqu

iline

price

s w

ere

four

fold

hig

her t

han

curre

nt p

ricin

g in

Sou

th A

frica

or v

ia th

e G

DF,

the

incr

emen

tal

cost

–effe

ctiv

enes

s ra

tio o

f the

all-

oral

regi

men

was

US$

400

per

disa

bilit

y ad

just

ed li

fe-y

ear

aver

ted

(rang

e: U

S$ 1

00–U

S$ 9

00 a

cros

s 95

% C

I for

rela

tive

regi

men

effi

cacy

).

Equi

tyW

hat w

ould

be

the

impa

ct o

n he

alth

equ

ity?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Red

uced

○

Pro

babl

y re

duce

d ○

Pro

babl

y no

impa

ct

○ P

roba

bly

incr

ease

d ●

Incr

ease

d ○

Var

ies

○ D

on’t

know

A qu

alita

tive

stud

y un

dert

aken

to h

ighl

ight

the

pers

pect

ives

of k

ey s

take

hold

ers,

mai

nly,

patie

nt

and

civil

socie

ty re

pres

enta

tives

(n=1

6) lo

oked

at g

ener

al p

refe

renc

es a

nd v

alue

s re

gard

ing

diffe

rent

asp

ects

of t

reat

men

t reg

imen

s fo

r dru

g-re

sista

nt T

B tre

atm

ent,

such

as

dura

tion,

pill

burd

en, u

se o

f inj

ecta

ble

agen

ts a

nd p

oten

tial f

or e

xper

ienc

ing

adve

rse

even

ts.

Part

icipa

nts

cons

ider

ed a

nyth

ing

less

than

uni

vers

al a

nd im

med

iate

acc

ess

to n

ew tr

eatm

ents

to

be u

neth

ical,

but w

hen

prom

pted

to c

onsid

er th

is pr

efer

ence

aga

inst

a li

mite

d su

pply

of d

rugs

, a

few

wou

ld p

riorit

ize

the

youn

gest

and

sick

est,

as w

ell a

s th

ose

who

are

adh

eren

t and

cou

ld

be m

onito

red

for a

dver

se e

vent

s. Pa

tient

s w

ho fa

ce s

ocio

econ

omic

chal

leng

es to

adh

eren

ce,

or w

ho li

ve in

rem

ote,

rura

l or p

oore

r com

mun

ities

that

lack

tech

nica

l skil

l or e

quip

men

t for

tre

atm

ent m

onito

ring,

cou

ld th

en b

e di

spro

port

iona

tely

and

unj

ustly

pla

ced

at a

disa

dvan

tage

The

GD

G a

gree

d th

at in

ject

able

-spa

ring

regi

men

s w

ould

be

eas

ier t

o de

cent

raliz

e an

d, th

eref

ore,

in re

mot

e an

d un

ders

ervi

ced

setti

ngs

and

disa

dvan

tage

d po

pula

tions

, w

ould

hel

p to

alle

viat

e he

alth

ineq

uitie

s, w

ithou

t ant

icipa

ting

diffe

renc

es in

out

com

es in

spe

cific

popu

latio

ns. F

urth

er, t

he

grou

p al

so n

oted

that

bec

ause

aud

iom

etry

wou

ld n

ot b

e re

quire

d, it

mig

ht b

e ea

sier t

o m

onito

r ind

ivid

uals

in s

pite

of

incr

ease

d re

quire

men

ts fo

r ele

ctro

card

iogr

aphy

, whi

ch is

a

prer

equi

site

for t

he u

se o

f bed

aqui

line-

cont

aini

ng re

gim

ens.

How

ever

, the

gro

up s

tress

ed th

at th

e us

e of

ele

ctro

card

iogr

aphy

sh

ould

not

be

a di

ffere

ntia

ting

elem

ent b

etw

een

thes

e tw

o re

gim

ens,

beca

use

patie

nts

rece

ivin

g in

ject

able

age

nts

such

as

am

ikacin

sho

uld

also

hav

e re

gula

r car

diac

mon

itorin

g. T

he

grou

p ac

know

ledg

ed th

at it

is p

ossib

le th

at, i

n so

me

setti

ngsk

no

t all

patie

nts

will

be a

ble

to u

nder

go e

lect

roca

rdio

grap

hic

mon

itorin

g; h

owev

er, i

t was

also

not

ed th

at th

e in

crea

sing

acce

ss to

ele

ctro

card

iogr

aphy

at p

erip

hery

leve

ls m

ight

im

prov

e eq

uity.

Acc

epta

bilit

yIs

the

inte

rven

tion

acce

ptab

le to

key

sta

keho

lder

s?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

No

○ P

roba

bly

no

○ P

roba

bly

yes

● Ye

s ○

Var

ies

○ D

on’t

know

A qu

alita

tive

stud

y un

dert

aken

to h

ighl

ight

the

pers

pect

ives

of k

ey s

take

hold

ers,

mai

nly

patie

nt a

nd c

ivil

socie

ty re

pres

enta

tives

(n =

16)

, loo

ked

at g

ener

al p

refe

renc

es a

nd v

alue

s re

gard

ing

diffe

rent

asp

ects

of t

reat

men

t reg

imen

s fo

r dru

g-re

sista

nt T

B, s

uch

as d

urat

ion,

pill

burd

en, u

se o

f inj

ecta

ble

agen

ts a

nd p

oten

tial f

or e

xper

ienc

ing

adve

rse

even

ts. T

he re

sults

of

this

qual

itativ

e an

alys

is su

gges

ted

that

mos

t pat

ient

s w

ould

prio

ritiz

e a

regi

men

with

few

er

and

less

-sev

ere

side-

effe

cts

abov

e al

l else

, bec

ause

it w

ould

allo

w th

em to

con

tinue

rout

ine

activ

ities

. Of n

ote,

sur

vivo

rs o

f dru

g-re

sista

nt T

B re

mar

ked

that

they

wou

ld a

ccep

t a lo

nger

tre

atm

ent t

hat p

rom

ised

few

er s

ever

e ad

vers

e ef

fect

s ov

er a

sho

rter

regi

men

tied

to m

ore

seve

re s

ide-

effe

cts,

even

if tr

eatm

ent w

as e

xper

imen

tal o

r effi

cacy

was

unc

lear

. Thi

s co

ntra

sted

w

ith c

ompa

rativ

ely

few

par

ticip

ants

who

prio

ritiz

ed ra

pid

retu

rn to

nor

mal

life

and

wou

ld ra

ther

as

sum

e th

e ris

k of

mor

e se

rious

sid

e-ef

fect

s w

ithin

a s

hort

er re

gim

en, e

ven

if tre

atm

ent w

as

expe

rimen

tal a

nd e

ffica

cy u

ncle

ar.

The

GD

G n

oted

that

pat

ient

s re

cogn

ize

that

thei

r exp

erie

nces

an

d pe

rcep

tions

are

hig

hly

pers

on-

and

cont

ext-d

epen

dent

, th

ough

pre

fere

nce

for t

his

[sho

rter

] reg

imen

see

med

to b

e co

nditi

onal

upo

n ad

vers

e ev

ents

bei

ng ra

re o

r rev

ersib

le.

Nev

erth

eles

s, ov

eral

l, a

shor

t, in

ject

ion-

free

regi

men

with

few

to

no p

hysic

al a

nd m

enta

l hea

lth s

ide-

effe

cts

and

a lo

w p

ill bu

rden

ap

pear

ed to

be

the

mos

t acc

epta

ble.


Feas

ibili

tyIs

the

inte

rven

tion

feas

ible

to im

plem

ent?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

No

○ P

roba

bly

no

○ P

roba

bly

yes

○ Y

es

● Va

ries

○ D

on’t

know

A qu

alita

tive

stud

y un

dert

aken

to h

ighl

ight

the

pers

pect

ives

of k

ey s

take

hold

ers,

mai

nly

patie

nts

and

civil

socie

ty re

pres

enta

tives

(n =

16)

look

ed a

t gen

eral

pre

fere

nces

and

val

ues

rega

rdin

g di

ffere

nt a

spec

ts o

f tre

atm

ent r

egim

ens

for d

rug-

resis

tant

TB,

suc

h as

dur

atio

n, p

ill bu

rden

, use

of

inje

ctab

le a

gent

s an

d po

tent

ial f

or e

xper

ienc

ing

adve

rse

even

ts.

This

stud

y re

veal

ed th

at a

s th

e re

gim

en, i

n pa

rticu

lar t

he e

xpan

sion

of b

edaq

uilin

e ac

cess

to

all p

atie

nts,

is he

ld b

ack

in s

ome

setti

ngs

as a

resu

lt of

rest

rictiv

e el

igib

ility

(i.e.

prio

ritiz

atio

n of

spe

cific

grou

ps) c

riter

ia, l

ack

of fu

ndin

g, o

r lac

k of

ade

quat

e in

frast

ruct

ure

in p

lace

(e.g

. di

agno

stics

), th

e op

erat

iona

lizat

ion

and

imm

edia

te ro

llout

of t

he a

ll-or

al b

edaq

uilin

e-co

ntai

ning

re

gim

en m

ay b

e ha

mpe

red.

One

impo

rtan

t req

uire

men

t hig

hlig

hted

by

the

GD

G w

as th

at

of e

nsur

ing

the

care

ful s

elec

tion

of p

atie

nts

who

are

to b

enef

it fro

m th

is re

gim

en, c

ondu

ctin

g ra

pid

and

accu

rate

DST

, and

the

mon

itorin

g of

bed

aqui

line

resis

tanc

e. T

he im

plem

enta

tion

of th

e re

gim

en m

ay b

e lim

ited

by th

e ne

ed fo

r im

prov

ed la

bora

tory

in

frast

ruct

ure.

Alth

ough

cou

ntrie

s ar

e im

plem

entin

g ra

pid

mol

ecul

ar te

sts

to id

entif

y rif

ampi

cin re

sista

nce,

labo

rato

ry

capa

city

need

s to

be

effe

ctiv

ely

esta

blish

ed to

con

duct

ge

noty

pic

and

phen

otyp

ic te

stin

g fo

r oth

er im

port

ant a

gent

s in

the

regi

men

. Also

, alth

ough

the

prev

alen

ce o

f ide

ntifi

ed

mut

atio

ns c

onfe

rrin

g lo

w-le

vel d

rug

resis

tanc

e is

very

low,

co

untri

es a

re to

stre

ngth

en la

bora

tory

cap

acity

and

to m

onito

r th

e ac

quisi

tion

of re

sista

nce

to b

edaq

uilin

e th

ough

thei

r nat

iona

l re

fere

nce

labo

rato

ries

or T

B su

pran

atio

nal r

efer

ence

site

s. Th

is is

espe

cially

impo

rtan

t giv

en th

e pi

pelin

e of

new

ant

i-TB

regi

men

s th

at a

re re

lyin

g on

bed

aqui

line

as a

bac

kbon

e.Th

e re

mov

al o

f inj

ecta

ble

agen

ts, a

s di

scus

sed

by th

e G

DG

, al

so p

oint

ed to

war

ds th

e co

nven

ienc

e (fo

r hea

lth c

are

wor

kers

) of

not

hav

ing

to d

eliv

er d

aily

inje

ctio

ns, a

nd m

ore

so, f

or

patie

nts

not h

avin

g to

end

ure

the

pain

and

oth

er s

igni

fican

t ad

vers

e ev

ents

.Th

e im

plem

enta

tion

of th

e re

gim

en is

per

ceiv

ed to

go

beyo

nd

secu

ring

of fu

ndin

g, b

ut it

furt

her r

equi

res

mak

ing

long

-te

rm, s

usta

inab

le s

yste

ms

chan

ge to

ens

ure

rapi

d tra

nsiti

on,

cons

ider

ing

the

regi

stra

tion

of b

edaq

uilin

e an

d ot

her n

ew

agen

ts, u

nint

erru

pted

sup

ply

of q

ualit

y-as

sure

d dr

ugs

and

activ

e TB

dru

g sa

fety

mon

itorin

g an

d m

anag

emen

t sys

tem

in

coor

dina

tion

with

exis

ting

phar

mac

ovig

ilanc

e st

ruct

ures

at t

he

coun

try

leve

l.Al

so, t

he im

plem

enta

tion

of th

is re

gim

en (a

nd a

ny o

ther

nov

el

regi

men

) will

requ

ire d

ecisi

on-m

akin

g to

war

ds m

ultis

ecto

ral

polic

ies,

tailo

ring

patie

nt c

entre

d pr

ogra

mm

es w

hich

also

co

nsid

er a

spec

ts s

uch

as m

enta

l hea

lth a

nd m

anag

emen

t of

othe

r com

orbi

ditie

s, fa

cilita

ting

coun

sellin

g an

d su

ppor

t dur

ing

treat

men

t, an

d af

ter c

ompl

etio

n, fa

cilita

ting

full

reco

very

.


Sum

mar

y of

judg

emen

ts

JUD

GEM

ENT

PRO

BLEM

Ye

sVa

ries

Don

’t kn

owD

ESIR

ABLE

EFF

ECTS

Triv

ial

Smal

lM

oder

ate

Larg

eVa

ries

Don

’t kn

owUN

DES

IRAB

LE E

FFEC

TSLa

rge

Mod

erat

eSm

all

Triv

ial

Varie

sD

on’t

know

CERT

AIN

TY O

F EV

IDEN

CEVe

ry lo

wLo

wM

oder

ate

Hig

hN

o in

clude

d st

udie

sVA

LUES

Impo

rtan

t un

cert

aint

y or

va

riabi

lity

Poss

ibly

impo

rtan

t un

cert

aint

y or

va

riabi

lity

Prob

ably

no

impo

rtan

t un

cert

aint

y or

va

riabi

lity

No

impo

rtan

t un

cert

aint

y or

va

riabi

lity

BALA

NCE

OF

EFFE

CTS

Favo

rs th

e co

mpa

rison

Prob

ably

favo

rs th

e co

mpa

rison

Doe

s no

t fav

or

eith

er th

e in

terv

entio

n or

the

com

paris

on

Prob

ably

favo

rs th

e in

terv

entio

nFa

vors

the

inte

rven

tion

Varie

sD

on’t

know

RESO

URCE

S RE

QUI

RED

Larg

e co

sts

Mod

erat

e co

sts

Neg

ligib

le c

osts

and

sa

ving

sM

oder

ate

savi

ngs

Larg

e sa

ving

sVa

ries

Don

’t kn

ow

CERT

AIN

TY O

F EV

IDEN

CE

OF

REQ

UIRE

D R

ESO

URCE

SVe

ry lo

wLo

wM

oder

ate

Hig

hN

o in

clude

d st

udie

s

COST

EFF

ECTI

VEN

ESS

Favo

rs th

e co

mpa

rison

Prob

ably

favo

rs th

e co

mpa

rison

Doe

s no

t fav

or

eith

er th

e in

terv

entio

n or

the

com

paris

on

Prob

ably

favo

rs

the

inte

rven

tion

Favo

rs th

e in

terv

entio

nVa

ries

No

inclu

ded

stud

ies

EQUI

TYRe

duce

dPr

obab

ly re

duce

dPr

obab

ly n

o im

pact

Prob

ably

incr

ease

dIn

crea

sed

Varie

sD

on’t

know

ACCE

PTAB

ILIT

YN

oPr

obab

ly n

oPr

obab

ly y

esYe

sVa

ries

Don

’t kn

owFE

ASIB

ILIT

YN

oPr

obab

ly n

oPr

obab

ly y

esYe

sVa

ries

Don

’t kn

ow

Type

of r

ecom

men

datio

nSt

rong

reco

mm

enda

tion

agai

nst

the

inte

rven

tion

○

Cond

ition

al re

com

men

datio

n ag

ains

t the

inte

rven

tion

○

Cond

ition

al re

com

men

datio

n fo

r eith

er th

e in

terv

entio

n or

the

com

paris

on○

Cond

ition

al re

com

men

datio

n fo

r the

inte

rven

tion

●

Stro

ng re

com

men

datio

n fo

r the

in

terv

entio

n○


Conc

lusi

ons

Reco

mm

enda

tion

A sh

orte

r, al

l-ora

l, be

daqu

iline-

cont

aini

ng re

gim

en o

f 9–1

2 m

onth

s’ du

ratio

n is

reco

mm

ende

d in

elig

ible

pat

ient

s w

ith c

onfir

med

MD

R/RR

-TB

who

hav

e no

t bee

n ex

pose

d to

trea

tmen

t w

ith s

econ

d-lin

e TB

med

icine

s us

ed in

this

regi

men

for m

ore

than

1 m

onth

and

in w

hom

resis

tanc

e to

fluo

roqu

inol

ones

has

bee

n ex

clude

d.

(Con

ditio

nal r

ecom

men

datio

n, v

ery

low

cer

tain

ty in

the

evid

ence

)

Just

ifica

tion

Ove

rall,

the

GD

G n

oted

that

the

cert

aint

y of

the

evid

ence

on

the

effic

acy

of th

e al

l-ora

l sho

rter

regi

men

was

ver

y lo

w, a

ttrib

utab

le n

amel

y to

con

cern

s of

ser

ious

risk

of b

ias,

desp

ite

effo

rts

to b

alan

ce b

asel

ine

cova

riate

s. H

owev

er, t

he g

roup

reco

gniz

ed th

at th

e cu

rrent

evi

denc

e as

sess

men

t of t

he a

ll-or

al, b

edaq

uilin

e-co

ntai

ning

sho

rter

regi

men

sho

wed

a b

ette

r ra

tio o

f suc

cess

ver

sus

unfa

vour

able

out

com

es a

nd a

sig

nific

ant r

educ

tion

in lo

ss to

follo

w-u

p. W

hen

decid

ing

on th

e st

reng

th o

f the

reco

mm

enda

tion,

the

GD

G re

ache

d a

unan

imou

s de

cisio

n on

the

cond

ition

ality

of t

he re

com

men

datio

n, m

ainl

y at

tribu

ted

to th

e ve

ry lo

w c

erta

inty

in th

e ev

iden

ce a

nd re

quire

men

ts to

bui

ld la

bora

tory

cap

acity

and

ens

ure

DST

.O

ther

gro

unds

for t

he s

treng

th a

nd d

irect

ion

of th

is re

com

men

datio

n ar

e as

follo

ws:

• Th

e an

alys

is co

nduc

ted

to in

form

the

deve

lopm

ent o

f thi

s re

com

men

datio

n w

as b

ased

on

obse

rvat

iona

l pro

gram

mat

ic da

ta fr

om S

outh

Afri

ca w

here

the

stan

dard

ized

sho

rter

, all-

oral

, be

daqu

iline-

cont

aini

ng re

gim

en (B

DQ

-LFX

/MFX

-ETO

-E-Z

-Hh -C

FZ) w

as u

sed

for p

atie

nts

with

MD

R/RR

-TB.

• Th

ough

no

maj

or s

igna

ls of

risk

wer

e ob

serv

ed w

ith th

e us

e of

the

all-o

ral b

edaq

uilin

e-ba

sed

shor

ter r

egim

en, t

here

also

rem

aine

d so

me

unce

rtai

ntie

s, gi

ven

the

lack

of s

yste

mat

ic co

llect

ion

of d

ata,

and

giv

en th

e la

ck o

f cla

rity

as to

any

cha

nges

in th

e re

gim

en th

at c

ould

hav

e be

en in

form

ed b

y th

e pr

esen

ce o

f adv

erse

eve

nts.

• Co

st–e

ffect

iven

ess

mod

ellin

g of

the

all-o

ral,

shor

ter,

beda

quilin

e-co

ntai

ning

regi

men

sho

wed

robu

st c

ost s

avin

gs re

lativ

e to

eith

er a

long

er o

ral r

egim

en o

r a s

hort

inje

ctab

le-

cont

aini

ng re

gim

en.

–Th

e G

DG

judg

ed th

at m

any

elig

ible

pat

ient

s w

ould

pre

fer t

he a

ll-or

al, b

edaq

uilin

e-co

ntai

ning

regi

men

of 9

–12

mon

ths’

dura

tion.

Thi

s is

supp

orte

d by

lim

ited

obse

rvat

ions

invo

lvin

g 16

sur

vivo

rs o

f dru

g-re

sista

nt T

B. In

add

ition

, thi

s re

gim

en m

ay h

elp

prom

ote

heal

th e

quity

or m

itiga

te th

e w

orse

ning

of h

ealth

ineq

uitie

s. Al

thou

gh th

e pa

nel r

ecog

nize

d th

at

impl

emen

tatio

n an

d sc

ale-

up o

f thi

s re

gim

en m

ay b

e slo

w d

ue p

rere

quisi

tes

on la

bora

tory

cap

acity

and

mon

itorin

g.Su

bgro

up c

onsi

dera

tions

The

anal

ysis

atte

mpt

ed to

des

crib

e th

e ba

lanc

e of

effe

cts

and

cons

ider

atio

ns fo

r var

ious

sub

grou

ps o

r spe

cial p

opul

atio

ns. H

owev

er, t

he e

vide

nce

revi

ewed

sup

port

ed th

e us

e of

this

on

the

follo

win

g, w

ith s

pecif

ic ca

veat

s:•

Peop

le li

ving

with

HIV

infe

ctio

n: T

he d

ata

eval

uate

d co

rresp

onde

d to

a s

ettin

g w

ith a

hig

h pr

eval

ence

of H

IV, a

nd o

f par

ticul

ar s

igni

fican

ce, m

ost P

LHIV

(>95

%) w

ho s

tart

ed th

e al

l-or

al b

edaq

uilin

e-co

ntai

ning

regi

men

wer

e re

ceiv

ing

antir

etro

vira

l the

rapy

(ART

). In

vie

w o

f the

trea

tmen

t out

com

es d

escr

ibed

in th

e an

alys

is, th

ere

wer

e no

gro

unds

to b

elie

ve th

at th

e re

gim

en w

ould

per

form

any

diff

eren

tly in

PLH

IV. I

t is

nece

ssar

y to

con

sider

sig

nific

ant c

linica

l int

erac

tions

that

may

incr

ease

bed

aqui

line

expo

sure

or t

hat o

f oth

er a

gent

s w

ith p

oten

tial

for c

ardi

otox

icity

whe

n th

ese

are

co-a

dmin

ister

ed w

ith a

ntire

trovi

rals.

• Ch

ildre

n: A

lthou

gh n

o di

rect

out

com

e es

timat

ions

cou

ld b

e dr

awn

for t

his

popu

latio

n, e

xtra

pola

tion

was

dee

med

reas

onab

le. H

owev

er, b

ecau

se b

edaq

uilin

e is

curre

ntly

reco

mm

ende

d fo

r chi

ldre

n an

d ad

oles

cent

s ag

ed 6

–17

year

s, th

e G

DG

con

clude

d th

at th

e al

l-ora

l bed

aqui

line-

cont

aini

ng re

gim

en m

ay b

e us

ed in

elig

ible

chi

ldre

n w

ithin

this

age

grou

p, ta

king

into

ac

coun

t spe

cifica

tions

for r

egim

en c

ompa

nion

dru

gs –

in p

artic

ular

, bed

aqui

line.

• Pr

egna

nt a

nd la

ctat

ing

wom

en: M

ore

evid

ence

is n

eede

d to

bet

ter i

nfor

m th

e us

e of

the

all-o

ral,

beda

quilin

e-co

ntai

ning

sho

rter

regi

men

(BD

Q-L

FX/M

FX-E

TO-E

-Z-H

h -CFZ

). O

ne

of th

e ag

ents

in th

is al

l-ora

l sho

rter

regi

men

, eth

iona

mid

e, is

usu

ally

con

train

dica

ted

in p

regn

ancy

, and

with

hold

ing

this

agen

t or r

epla

cing

it w

ith a

noth

er o

ne c

ould

ser

ious

ly

com

prom

ise th

e ef

fect

iven

ess

of th

e re

gim

en. I

n th

e ca

se o

f pre

gnan

t and

lact

atin

g w

omen

, it i

s th

eref

ore

reco

mm

ende

d th

at a

n in

divi

dual

ized

, all-

oral

long

er re

gim

en (w

ith in

clusio

n of

bed

aqui

line)

is u

sed

in th

is po

pula

tion

(see

Rec

omm

enda

tions

on

the

use

of lo

nger

regi

men

s fo

r MD

R/RR

-TB)

. –Ex

trapu

lmon

ary

dise

ase:

In v

iew

of t

he u

nava

ilabi

lity

of e

vide

nce

on s

urro

gate

s fo

r sev

erity

or e

xten

t of d

iseas

e, c

linica

l jud

gem

ent i

s ad

vise

d to

dec

ide

on th

e us

e of

this

regi

men

in

patie

nts

with

ext

ensiv

e TB

dise

ase

or s

ever

e fo

rms

of e

xtra

pulm

onar

y TB

.


Impl

emen

tatio

n co

nsid

erat

ions

The

inte

rest

in re

ducin

g th

e du

ratio

n of

trea

tmen

t for

MD

R/RR

-TB

has

mot

ivat

ed a

num

ber o

f stu

dies

in re

cent

yea

rs to

trea

t pat

ient

s w

ith s

hort

er re

gim

ens

unde

r pro

gram

mat

ic as

wel

l as

tria

l con

ditio

ns. F

ollo

win

g ex

perie

nces

in v

ario

us s

ettin

gs, [

elig

ible

] pat

ient

s no

w h

ave

an o

ptio

n to

be

treat

ed w

ith a

sho

rter

, inj

ecta

ble-

spar

ing

regi

men

of 9

–12

mon

ths’

dura

tion.

To

ensu

re th

at th

e re

gim

en a

chie

ves

its d

esira

ble

effe

cts,

prev

ent t

he a

cqui

sitio

n (o

r am

plifi

catio

n) o

f add

ition

al d

rug

resis

tanc

e, w

hile

regi

men

com

pone

nts

are

prot

ecte

d, c

ount

ries

are

to

cons

ider

the

follo

win

g:•

Patie

nt s

elec

tion

and

decis

ions

to s

tart

the

all-o

ral s

hort

er re

gim

en: P

atie

nts

with

con

firm

ed M

DR/

RR-T

B an

d w

ith re

sista

nce

to fl

uoro

quin

olon

es ru

led

out a

re e

xpec

ted

to b

enef

it th

e m

ost f

rom

this

regi

men

. Pro

per p

atie

nt s

elec

tion

wou

ld n

ot o

nly

lead

to im

prov

ed tr

eatm

ent o

utco

mes

but

will

also

con

tribu

te to

pro

tect

ing

agai

nst t

he d

evel

opm

ent o

f bed

aqui

line

resis

tanc

e. In

this

resp

ect,

the

regi

men

is to

onl

y be

impl

emen

ted

in s

ettin

gs w

here

rout

ine

DST

for r

ifam

picin

and

fluo

roqu

inol

ones

can

be

guar

ante

ed.

It is

very

impo

rtan

t tha

t the

impl

emen

tatio

n of

thes

e re

com

men

datio

ns is

acc

ompa

nied

by

cont

inue

d ef

fort

s to

incr

ease

acc

ess

to D

ST fo

r all

med

icine

s fo

r whi

ch re

liabl

e m

etho

ds

exist

, as

wel

l as

for t

he d

evel

opm

ent a

nd ro

llout

of D

ST m

etho

ds fo

r new

er m

edici

nes.

In th

e ab

senc

e of

a d

rug-

susc

eptib

ility

test

, ass

ays

spec

ific

for b

edaq

uilin

e re

sista

nce

shou

ld b

e m

onito

red

thro

ugh

asse

ssm

ent o

f MIC

s of

bed

aqui

line.

• Re

sista

nce

to o

ther

ant

i-TB

drug

s sh

ould

be

mon

itore

d in

acc

orda

nce

to W

HO

reco

mm

enda

tions

.•

Use

of li

nezo

lid: T

he e

vide

nce

mad

e av

aila

ble

to in

form

this

reco

mm

enda

tion

focu

sed

on th

e as

sess

men

t of a

regi

men

com

pose

d of

bed

aqui

line,

levo

floxa

cin/m

oxifl

oxac

in,

ethi

onam

ide,

eth

ambu

tol,

pyra

zina

mid

e, h

igh-

dose

ison

iazi

d, c

lofa

zim

ine

and

pyra

zina

mid

e. H

owev

er, s

econ

dary

ana

lyse

s (o

nly

in lo

nger

regi

men

s co

ntai

ning

bed

aqui

line

and

beda

quilin

e pl

us li

nezo

lid) s

how

ed fa

vour

able

out

com

es w

hen

treat

men

t reg

imen

s in

clude

d bo

th li

nezo

lid a

nd b

edaq

uilin

e. T

he b

asis

for t

he a

dditi

on o

f lin

ezol

id w

as to

pro

tect

the

regi

men

– in

par

ticul

ar, b

edaq

uilin

e –

whi

le a

wai

ting

susc

eptib

ility

resu

lts o

n ad

ditio

nal r

esist

ance

to fl

uoro

quin

olon

es a

nd o

ther

dru

gs. T

he G

DG

dec

ided

that

, unt

il ne

w e

vide

nce

is av

aila

ble

on s

hort

er re

gim

ens

that

inclu

de b

oth

of th

ese

agen

ts, t

he a

ll-or

al b

edaq

uilin

e-co

ntai

ning

sho

rter

regi

men

adv

ised

here

in s

houl

d no

t inc

lude

line

zolid

. How

ever

, the

gro

up

enco

urag

ed c

ount

ries

to c

onsid

er th

e us

e of

a m

odifie

d al

l-ora

l bed

aqui

line-

and

linez

olid

-con

tain

ing

regi

men

onl

y un

der o

pera

tiona

l res

earc

h un

til n

ew e

viden

ce b

ecom

es a

vaila

ble.

• Pa

tient

-cen

tred

appr

oach

: Effo

rts

are

requ

ired

to p

rovi

de p

atie

nt s

uppo

rt to

ena

ble

full

adhe

renc

e to

trea

tmen

t.M

onito

ring

and

eval

uatio

n•

The

impl

emen

tatio

n of

this

regi

men

requ

ires

the

use

of ro

utin

e D

ST n

ot o

nly

for p

atie

nt s

elec

tion

but a

lso to

mon

itor t

he a

cqui

sitio

n of

resis

tanc

e.•

Alth

ough

the

data

ass

esse

d di

d no

t une

arth

any

maj

or s

igna

ls of

risk

, act

ive

TB d

rug

safe

ty m

onito

ring

and

man

agem

ent s

yste

ms

mus

t be

func

tiona

l in

orde

r to

cond

uct r

igor

ous

activ

e m

onito

ring

of a

dver

se e

vent

s an

d to

det

ect,

man

age,

and

repo

rt s

uspe

cted

or c

onfir

med

dru

g to

xiciti

es in

a ti

mel

y m

anne

r.

Rese

arch

prio

ritie

sM

embe

rs o

f the

GD

G d

iscus

sed

the

rese

arch

gap

s to

info

rm th

e de

velo

pmen

t of p

ublic

hea

lth re

com

men

datio

ns fo

r the

man

agem

ent a

nd c

are

of o

f pat

ient

s w

ith M

DR/

RR-T

B, a

nd

high

light

ed th

e fo

llow

ing

prio

ritie

s:•

stud

ies

asse

ssin

g co

mpa

rison

s of

all-

oral

sho

rter

regi

men

s w

hich

inclu

de b

oth

beda

quilin

e an

d lin

ezol

id, i

n ad

ditio

n to

oth

er c

ompa

nion

dru

gs;

• st

udie

s as

sess

ing

com

paris

ons

of a

ll-or

al s

hort

er re

gim

ens

amon

g di

ffere

nt s

ubgr

oups

and

spe

cial p

opul

atio

ns, i

nclu

ding

pre

gnan

t and

lact

atin

g w

omen

;•

rand

omiz

ed, c

ontro

lled

trial

s or

ope

ratio

nal r

esea

rch

of th

e ef

fect

iven

ess

and

safe

ty o

f all-

oral

sho

rter

regi

men

s, in

crea

sing

the

cert

aint

y in

the

evid

ence

;•

stud

ies

expl

orin

g m

echa

nism

s of

acq

uisit

ion

of re

sista

nce

to b

edaq

uilin

e an

d ge

netic

mar

kers

to id

entif

y re

sista

nce;

and

• ef

fort

s to

det

erm

ine

best

way

s to

sta

ndar

dize

dat

a co

llect

ion

so th

at c

ount

ries

can

cont

ribut

e to

dev

elop

men

t of g

loba

l rec

omm

enda

tions

.

ART:

ant

iretro

vira

l the

rapy

; DST

: dru

g-su

scep

tibilit

y te

stin

g; G

DF:

Glo

bal D

rug

Facil

ity; G

DG

: Gui

delin

e D

evel

opm

ent

Gro

up; M

DR/

RR-T

B: m

ultid

rug-

resis

tant

or

rifam

picin

-res

istan

t tu

berc

ulos

is; M

IC: m

inim

um

inhi

bito

ry c

once

ntra

tion;

WH

O: W

orld

Hea

lth O

rgan

izat

ion.


Shou

ld a

n al

l-or

al s

hort

er re

gim

en o

f 9–1

2 m

onth

s’ d

urat

ion

incl

udin

g be

daqu

iline

vs

long

er re

gim

ens

cont

aini

ng b

edaq

uilin

e be

use

d fo

r MD

R/RR

-TB

patie

nts

to s

afel

y im

prov

e ou

tcom

es?

POPU

LATI

ON

:M

DR-

/RR-

TB p

atie

nts

to s

afel

y im

prov

e ou

tcom

esIN

TERV

ENTI

ON

:Al

l-ora

l bed

aqui

line-

cont

aini

ng s

hort

er re

gim

en o

f 9–1

2 m

onth

s du

ratio

n (B

DQ

-LFX

/MFX

-ETO

-E-Z

-Hh -C

FZ)

COM

PARI

SON

:Lo

nger

bed

aqui

line-

cont

aini

ng re

gim

en

MAI

N O

UTCO

MES

:Su

cces

s vs

. Fai

lure

/Rec

urre

nce;

Suc

cess

vs.

Dea

th; S

ucce

ss v

s. Fa

ilure

/Rec

urre

nce/

Dea

th; S

ucce

ss v

s. Al

l Unf

avou

rabl

e; L

ost v

s. Al

l Oth

er O

utco

mes

; AF

B Sm

ear P

ositi

ve: S

ucce

ss v

s. Fa

ilure

/Rec

urre

nce;

AFB

Sm

ear P

ositi

ve: S

ucce

ss v

s. D

eath

; AFB

Sm

ear P

ositi

ve: S

ucce

ss v

s. Fa

ilure

/Rec

urre

nce/

Dea

th; A

FB S

mea

r Pos

itive

: Suc

cess

vs.

All U

nfav

oura

ble;

AFB

Sm

ear P

ositi

ve: L

ost v

s. Al

l Oth

er O

utco

mes

; HIV

-Pos

itive

on

ART:

Suc

cess

vs.

Failu

re/R

ecur

renc

e; H

IV-P

ositi

ve o

n AR

T: S

ucce

ss v

s. D

eath

; HIV

-Pos

itive

on

ART:

Suc

cess

vs.

Failu

re/R

ecur

renc

e/D

eath

; HIV

-Pos

itive

on

ART:

Su

cces

s vs

. All

Oth

er U

nfav

oura

ble;

HIV

-Pos

itive

on

ART:

Los

t vs.

All O

ther

Out

com

es; H

IV N

egat

ive:

Suc

cess

vs.

Failu

re/R

ecur

renc

e; H

IV N

egat

ive:

Su

cces

s vs

. Dea

th; H

IV N

egat

ive:

Suc

cess

vs.

Failu

re/R

ecur

renc

e/D

eath

; HIV

Neg

ativ

e: S

ucce

ss v

s. Al

l Oth

er O

utco

mes

; HIV

Neg

ativ

e: L

ost v

s. Al

l O

ther

Out

com

es.

SETT

ING

:So

uth

Afric

a.

PERS

PECT

IVE:

Publ

ic he

alth

and

hea

lth s

yste

ms

pers

pect

ive

BACK

GRO

UND

:M

ultid

rug-

resis

tant

(MD

R-) a

nd ri

fam

picin

-res

istan

t tub

ercu

losis

(MD

R-/R

R-TB

) is

emer

ging

as

a m

ajor

pro

blem

due

to p

oor m

anag

emen

t of d

rug-

sens

itive

as

wel

l as

drug

-res

istan

ce T

B. M

DR-

/RR-

TB is

trea

tabl

e, b

ut h

as re

quire

d th

e us

e of

long

er tr

eatm

ent r

egim

ens

whi

ch c

onta

in p

oten

tially

to

xic d

rugs

. The

inte

rest

in re

ducin

g th

e du

ratio

n of

trea

tmen

t for

MD

R-TB

mot

ivat

ed a

num

ber o

f ini

tiativ

es in

rece

nt y

ears

to tr

eat p

atie

nts

with

sh

orte

r reg

imen

s un

der p

rogr

amm

atic

as w

ell a

s tri

al c

ondi

tions

. In

2016

, on

the

basis

of d

ata

from

obs

erva

tiona

l stu

dies

of t

he s

hort

er re

gim

ens

in

diffe

rent

Asia

n an

d Af

rican

cou

ntrie

s, W

HO

sta

rted

to re

com

men

d a

stan

dard

ised

shor

ter M

DR-

TB re

gim

en, c

onta

inin

g an

inje

ctab

le a

gent

, bas

ed

on th

e on

es u

nder

stu

dy fo

r elig

ible

pat

ient

s. In

201

8, fu

rthe

r mod

ifica

tions

wer

e m

ade

to th

e ea

rlier

reco

mm

ende

d sh

orte

r reg

imen

, rep

lacin

g ka

nam

ycin

by

amika

cin (b

ased

on

evid

ence

from

the

com

para

tive

effe

ctiv

enes

s of

thes

e tw

o in

ject

able

age

nts)

. Ev

iden

ce o

f per

man

ent e

ffect

s at

tribu

ted

to th

e to

xicity

of i

njec

tabl

e ag

ents

, hav

e pr

ompt

ed fu

rthe

r adv

ance

s in

the

deve

lopm

ent o

f new

trea

tmen

ts

such

as

shor

ter i

njec

tabl

e-sp

arin

g re

gim

ens.

In p

artic

ular

, obs

erva

tiona

l dat

a on

an

all-o

ral b

edaq

uilin

e-co

ntai

ning

sho

rter

regi

men

of 9

–12

mon

ths

dura

tion

beca

me

avai

labl

e. T

his

is of

par

ticul

ar im

port

ance

giv

en th

at th

e re

gim

en m

ay o

ffer p

atie

nts

the

likel

ihoo

d of

bet

ter t

oler

atin

g tre

atm

ent

with

out s

igni

fican

t tox

icity.

CON

FLIC

T O

F IN

TERE

STS:

Albe

rto

Piub

ello

.


Ass

essm

ent

Prob

lem

Is th

e pr

oble

m a

prio

rity?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

No

○ P

roba

bly

no

○ P

roba

bly

yes

● Ye

s ○

Var

ies

○ D

on’t

know

TB re

mai

ns a

thre

at to

glo

bal p

ublic

hea

lth a

nd is

the

top

infe

ctio

us c

ause

of d

eath

in th

e w

orld

. In

201

8, a

n es

timat

ed 1

0 m

illion

peo

ple

deve

lope

d TB

and

1.4

milli

on d

ied

from

the

dise

ase.

Ab

out 5

00 0

00 n

ew c

ases

of m

ultid

rug-

or r

ifam

picin

-res

istan

t TB

(MD

R/RR

-TB)

wer

e es

timat

ed

to e

mer

ge in

201

8. A

lthou

gh a

ll of

thes

e w

ould

hav

e be

en e

ligib

le fo

r a s

econ

d-lin

e TB

trea

tmen

t re

gim

en, o

nly

156

071

enro

lmen

ts in

trea

tmen

t wer

e re

port

ed b

y co

untri

es in

201

8 –

abou

t 30%

of

the

estim

ated

cas

eloa

d. D

espi

te th

is, s

igni

fican

t im

prov

emen

ts in

the

avai

labi

lity

of e

nhan

ced

diag

nost

ics a

nd m

ore

effe

ctiv

e m

edici

nes

have

occ

urre

d in

rece

nt y

ears

, and

hav

e le

d to

ear

lier

dete

ctio

n an

d hi

gher

suc

cess

rate

s am

ong

patie

nts

with

MD

R/RR

-TB

in a

num

ber o

f nat

iona

l pr

ogra

mm

es. H

owev

er, t

hese

suc

cess

es h

ave

not b

een

repr

oduc

ed in

the

rest

of t

he w

orld

, and

th

e ov

eral

l tre

atm

ent s

ucce

ss ra

te w

orld

wid

e re

ache

d on

ly 5

6% fo

r pat

ient

s w

ith M

DR/

RR-T

B w

ho

star

ted

treat

men

t in

2016

, and

onl

y 39

% fo

r pat

ient

s w

ith e

xten

sivel

y dr

ug-r

esist

ant T

B (X

DR-

TB).


Des

irab

le E

ffec

tsH

ow s

ubst

antia

l are

the

desi

rabl

e an

ticip

ated

eff

ects

?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Triv

ial

● Sm

all

○ M

oder

ate

○ L

arge

○

Var

ies

○ D

on’t

know

The

anal

ysis

also

sug

gest

ed th

at w

hen

the

all-o

ral s

hort

er re

gim

en w

as c

ompa

red

with

an

inje

ctab

le-f

ree

long

er4 re

gim

en c

onta

inin

g be

daqu

iline,

ther

e se

emed

to b

e no

mar

ked

diffe

renc

es

in th

e ou

tcom

es o

bser

ved

earli

er; h

owev

er, r

elat

ivel

y m

odes

t ben

efici

al e

ffect

s w

ere

note

d in

the

dire

ctio

n of

the

inte

rven

tion;

in p

artic

ular

, suc

cess

vs

failu

re/r

ecur

renc

e (a

OR

3.9,

95%

CI 1

.7–9

.1),

succ

ess

vs a

ll un

favo

urab

le o

utco

mes

(aO

R 1.

6, 9

5% C

I 1.2

–2.2

) and

loss

to fo

llow

up

(aO

R 0.

5,

95%

CI 0

.4–0

.8),

all f

avou

ring

the

use

of th

e al

l-ora

l sho

rter

regi

men

.

Out

com

en/

N(B

dq s

hort

)

n/N

(Lon

g,

new

dru

gs)

Num

ber

of Pairs

aOR

(95%

CI)

aRD

(9

5% C

I)

Succ

ess

vs.

Failu

re/R

ecur

renc

e63

1/65

326

8/29

228

53.

9 (1

.7, 9

.1)

5 (1

, 9)

Succ

ess

vs. D

eath

631/

791

268/

338

328

1.0

(0.6

, 1.5

)-4

(-10

, 3)

Succ

ess

vs. F

ailu

re/

Recu

rrenc

e/ D

eath

*63

1/81

326

8/36

235

21.

4 (0

.9, 2

.0)

2 (-

4, 9

)Su

cces

s vs

. All

Unfa

vora

ble

631/

891

268/

440

427

1.6

(1.2

, 2.2

)7

(1, 1

4)

Lost

vs.

All O

ther

O

utco

mes

88/8

9188

/440

427

0.5

(0.4

, 0.8

)-8

(-13

, -3)

The

GD

G ju

dged

the

desir

able

ant

icipa

ted

effe

cts

to

be s

mal

l. Th

e gr

oup

argu

ed th

at w

hen

a dr

ug s

uch

as

beda

quilin

e is

inclu

ded

in a

regi

men

– a

s se

en in

the

anal

ysis

– th

e ou

tcom

es in

the

inte

rven

tion

and

com

paris

on

grou

ps a

re n

ot to

o di

stan

t. In

act

ualit

y, th

e da

ta e

valu

ated

se

emed

to in

dica

te th

at th

e al

l-ora

l bed

aqui

line-

cont

aini

ng

shor

ter r

egim

en o

f 9–1

2 m

onth

s’ du

ratio

n w

as ju

st a

s go

od a

s al

l-ora

l lon

ger r

egim

ens

cont

aini

ng b

edaq

uilin

e.

The

mai

n ad

vant

ages

of t

he a

ll-or

al s

hort

er re

gim

en a

s ob

serv

ed in

the

anal

ysis

was

mos

tly in

term

s of

dec

reas

ed

rate

s of

loss

to fo

llow

-up.

Und

esir

able

Eff

ects

How

sub

stan

tial a

re th

e un

desi

rabl

e an

ticip

ated

eff

ects

?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Lar

ge

○ M

oder

ate

○ S

mal

l ○

Triv

ial

● Va

ries

○ D

on’t

know

In

pas

t yea

rs, t

he in

crea

sed

use

of b

edaq

uilin

e ha

s re

assu

red

the

TB c

omm

unity

of t

he p

oten

tial f

or a

dver

se

even

ts a

ssoc

iate

d w

ith th

is ag

ent.

The

GD

G a

ntici

pate

d th

at th

e un

desir

able

ant

icipa

ted

effe

cts

on th

e us

e of

regi

men

s m

ay n

ot b

e so

diff

eren

t be

twee

n an

all-

oral

sho

rter

and

an

all-o

ral l

onge

r reg

imen

w

hen

both

con

tain

bed

aqui

line.

How

ever

, the

se e

ffect

s m

ay v

ary,

depe

ndin

g on

, for

exa

mpl

e, th

e se

lect

ion

or

allo

catio

n of

pat

ient

s in

to re

gim

ens

cont

aini

ng b

edaq

uilin

e,

seve

rity

of d

iseas

e, d

rug-

resis

tanc

e pa

ttern

s, qu

ality

of c

are

and

mon

itorin

g.

4 Re

com

men

datio

ns re

leas

ed b

y W

HO

in D

ecem

ber 2

018

emph

asiz

ed th

at fu

lly o

ral [

long

er] r

egim

ens

shou

ld b

e pr

iorit

ized

and

bec

ome

the

pref

erre

d op

tion

for m

ost p

atie

nts,

and

that

inje

ctab

le a

gent

s w

ere

no lo

nger

am

ong

the

prio

rity

med

icine

s to

con

sider

whe

n de

signi

ng lo

nger

MD

R-TB

regi

men

s.


Cert

aint

y of

evi

denc

eW

hat i

s th

e ov

eral

l cer

tain

ty o

f the

evi

denc

e of

eff

ects

?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S●

Very

low

○

Low

○

Mod

erat

e ○

Hig

h ○

No

inclu

ded

stud

ies

Th

e G

DG

poi

nted

out

that

on

the

basis

of t

he e

vide

nce

asse

ssed

– n

amel

y, ob

serv

atio

nal d

ata

and

pote

ntia

l re

sidua

l con

foun

ding

–th

e ov

eral

l cer

tain

ty in

the

estim

ates

of

effe

ct w

as ju

dged

to b

e ve

ry lo

w, w

ith th

e ef

fect

s fo

r al

l out

com

es a

lso ra

ted

as “v

ery

low

”. Al

thou

gh d

oubl

e ad

just

men

t in

prop

ensit

y sc

ore

mat

chin

g an

alys

es w

as

carr

ied

out t

o re

mov

e th

e ef

fect

s of

con

foun

ding

, mem

bers

of

the

GD

G fu

rthe

r not

ed th

at a

lthou

gh th

ese

effo

rts

com

pens

ated

for s

ome

pote

ntia

l con

foun

ders

, res

idua

l bi

as is

like

ly to

be

pres

ent.

The

grou

p ac

know

ledg

ed

that

alth

ough

the

use

of p

rogr

amm

atic

data

hol

ds g

reat

pr

omise

bec

ause

they

bet

ter r

efle

ct re

al p

ract

ice, s

ome

cons

ider

atio

ns in

term

s of

the

exte

nt to

whi

ch th

ese

findi

ngs

coul

d be

app

lied

to o

ther

set

tings

are

to b

e co

ntem

plat

ed. F

or in

stan

ce, s

pecif

ic cli

nica

l cha

ract

erist

ics

of th

e po

pula

tion

(e.g

. HIV

pre

vale

nce

and

drug

-re

sista

nce

patte

rns)

may

hav

e an

effe

ct, a

s m

ay q

ualit

y of

hea

lth c

are

serv

ices,

mod

els

of c

are,

and

trea

tmen

t ad

here

nce

stra

tegi

es.

Valu

esIs

ther

e im

port

ant u

ncer

tain

ty a

bout

or v

aria

bilit

y in

how

muc

h pe

ople

val

ue th

e m

ain

outc

omes

?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Impo

rtan

t un

cert

aint

y or

va

riabi

lity

○ P

ossib

ly im

port

ant

unce

rtai

nty

or

varia

bilit

y ○

Pro

babl

y no

im

port

ant u

ncer

tain

ty

or v

aria

bilit

y ●

No

impo

rtan

t un

cert

aint

y or

va

riabi

lity

A qu

alita

tive

stud

y un

dert

aken

to h

ighl

ight

the

pers

pect

ives

of k

ey s

take

hold

ers,

mai

nly

patie

nt a

nd

civil

socie

ty re

pres

enta

tives

(n=1

6) lo

oked

at g

ener

al p

refe

renc

es a

nd v

alue

s re

gard

ing

diffe

rent

as

pect

s of

dru

g-re

sista

nt T

B tre

atm

ent r

egim

ens,

such

as

dura

tion,

pill

burd

en, u

se o

f inj

ecta

ble

agen

ts a

nd p

oten

tial f

or e

xper

ienc

ing

adve

rse

even

ts.

Part

icipa

nts

had

the

oppo

rtun

ity to

disc

uss

impo

rtan

t adv

erse

effe

cts

inclu

ding

per

man

ent

sens

orin

eura

l hea

ring

loss

, nep

hrot

oxici

ty, e

lect

roly

te a

bnor

mal

ities

, inj

ectio

n pa

in a

nd lo

cal

inje

ctio

n-sit

e co

mpl

icatio

ns. F

rom

a p

atie

nt p

ersp

ectiv

e, a

dver

se e

vent

s (e

.g. o

ptic

neur

itis,

hear

ing

impa

irmen

t and

men

tal s

tatu

s ch

ange

s du

e to

ure

mia

or e

lect

roly

te a

bnor

mal

ities

) ass

ocia

ted

with

th

e us

e of

spe

cific

seco

nd-li

ne a

gent

s, in

cludi

ng in

ject

able

age

nts,

wer

e de

emed

una

ccep

tabl

e.

Pref

eren

ces

rega

rdin

g tre

atm

ent a

ppea

red

to b

e ro

oted

in

cor

e va

lues

, inc

ludi

ng m

inim

al d

isrup

tion

to n

orm

al li

fe.

Rela

tivel

y fe

w p

atie

nts

seem

ed to

pre

fer a

sho

rt re

gim

en

that

is ti

ed to

mor

e se

rious

sid

e-ef

fect

s, an

d th

en o

nly

if th

e sid

e-ef

fect

s w

ere

rare

or r

ever

sible

. In

addi

tion,

in

term

s of

trea

tmen

t dur

atio

n, p

refe

renc

es s

eem

ed to

be

guid

ed fi

rst b

y sid

e-ef

fect

s an

d se

cond

by

effic

acy

of

treat

men

t reg

imen

s.


Bala

nce

of e

ffec

tsD

oes

the

bala

nce

betw

een

desi

rabl

e an

d un

desi

rabl

e ef

fect

s fa

vor t

he in

terv

entio

n or

the

com

paris

on?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Fav

ors

the

com

paris

on

○ P

roba

bly

favo

rs th

e co

mpa

rison

○

Doe

s no

t fav

or

eith

er th

e in

terv

entio

n or

the

com

paris

on

● Pr

obab

ly fa

vors

the

inte

rven

tion

○ F

avor

s th

e in

terv

entio

n ○

Var

ies

○ D

on’t

know

Reso

urce

s re

quir

edH

ow la

rge

are

the

reso

urce

requ

irem

ents

(cos

ts)?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Lar

ge c

osts

○

Mod

erat

e co

sts

○ N

eglig

ible

cos

ts

and

savi

ngs

● M

oder

ate

savi

ngs

○ L

arge

sav

ings

○

Var

ies

○ D

on’t

know

The

proj

ecte

d co

st s

avin

g is

near

ly U

S$ 3

000

(201

9 US

$) in

Sou

th A

frica

, and

var

ies

acro

ss s

ettin

gs,

larg

ely

in p

ropo

rtio

n to

hea

lth c

are

and

drug

cos

ts (w

ith s

avin

gs o

f >US

$ 20

00 e

ven

in a

low

-in

com

e se

tting

and

afte

r red

uctio

n in

dru

g co

sts

to h

alf o

f cur

rent

Glo

bal D

rug

Facil

ity [G

DF]

pric

es).

Smal

ler i

f lin

ezol

id is

not

inclu

ded.

Cert

aint

y of

evi

denc

e of

req

uire

d re

sour

ces

Wha

t is

the

cert

aint

y of

the

evid

ence

of r

esou

rce

requ

irem

ents

(cos

ts)?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Ver

y lo

w

○ L

ow

○ M

oder

ate

○ H

igh

● N

o in

clude

d st

udie

s


Cost

eff

ecti

vene

ssD

oes

the

cost

-eff

ectiv

enes

s of

the

inte

rven

tion

favo

r the

inte

rven

tion

or th

e co

mpa

rison

?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Fav

ors

the

com

paris

on

○ P

roba

bly

favo

rs th

e co

mpa

rison

○

Doe

s no

t fav

or

eith

er th

e in

terv

entio

n or

the

com

paris

on

● Pr

obab

ly fa

vors

the

inte

rven

tion

○ F

avor

s th

e in

terv

entio

n ○

Var

ies

○ N

o in

clude

d st

udie

s

A co

st–e

ffect

iven

ess

mod

el w

as d

evel

oped

, inc

orpo

ratin

g es

timat

ed h

ealth

sys

tem

cos

ts w

ith d

rug

proc

urem

ent,

heal

th c

are

deliv

ery,

adve

rse

even

ts, r

etre

atm

ents

, sec

onda

ry c

ases

, and

mor

bidi

ty

and

mor

talit

y as

socia

ted

with

TB

mor

talit

y an

d re

curre

nce,

trea

tmen

t dur

atio

n, d

rug

toxic

ity, a

nd

TB tr

ansm

issio

n. C

osts

and

cos

t–ef

fect

iven

ess

wer

e ev

alua

ted

in S

outh

Afri

ca, w

ith s

ensit

ivity

an

alys

es re

pres

entin

g a

rang

e of

dru

g an

d he

alth

car

e co

sts,

high

and

low

HIV

co-

prev

alen

ce,

95%

con

fiden

ce in

terv

als

(Cis)

for e

stim

ates

of r

elat

ive

effic

acy

deriv

ed fr

om s

tatis

tical

ana

lysis

of

patie

nt c

ohor

t dat

a, a

nd u

ncer

tain

ty in

the

valu

es o

f par

amet

ers

repr

esen

ting

TB n

atur

al h

istor

y. Co

mpa

red

an 1

8–20

-mon

th a

ll-or

al re

gim

en (m

odel

led

as c

onta

inin

g W

HO

gro

up A

dru

gs

inclu

ding

bed

aqui

line

and

linez

olid

), a

9–12

-mon

th a

ll-or

al, b

edaq

uilin

e-co

ntai

ning

regi

men

is

proj

ecte

d to

be

both

cos

t sav

ing

and

effe

ctiv

e un

der a

ll m

odel

led

scen

ario

s. Be

caus

e th

e sh

orte

r or

al re

gim

en d

omin

ated

ove

r the

long

er re

gim

en in

all

scen

ario

s m

odel

led,

cos

t–ef

fect

iven

ess

was

no

t cal

cula

ted.

Equi

tyW

hat w

ould

be

the

impa

ct o

n he

alth

equ

ity?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Red

uced

○

Pro

babl

y re

duce

d ○

Pro

babl

y no

impa

ct

○ P

roba

bly

incr

ease

d ●

Incr

ease

d ○

Var

ies

○ D

on’t

know

A qu

alita

tive

stud

y un

dert

aken

to h

ighl

ight

the

pers

pect

ives

of k

ey s

take

hold

ers,

mai

nly

patie

nts

and

civil

socie

ty re

pres

enta

tives

(n =

16)

, loo

ked

at g

ener

al p

refe

renc

es a

nd v

alue

s re

gard

ing

diffe

rent

asp

ects

of t

reat

men

t reg

imen

s fo

r dru

g-re

sista

nt T

B, s

uch

as d

urat

ion,

pill

burd

en, u

se o

f in

ject

able

age

nts,

and

pote

ntia

l for

exp

erie

ncin

g ad

vers

e ev

ents

.Pa

rtici

pant

s co

nsid

ered

any

thin

g le

ss th

an u

nive

rsal

and

imm

edia

te a

cces

s to

new

trea

tmen

ts to

be

une

thica

l, bu

t whe

n pr

ompt

ed to

con

sider

this

pref

eren

ce a

gain

st a

lim

ited

supp

ly o

f dru

gs, a

fe

w w

ould

prio

ritiz

e th

e yo

unge

st a

nd s

ickes

t, as

wel

l as

thos

e w

ho w

ere

adhe

rent

and

cou

ld b

e m

onito

red

for a

dver

se e

vent

s. Pa

tient

s w

ho fa

ce s

ocio

econ

omic

chal

leng

es to

adh

eren

ce o

r who

liv

e in

rem

ote,

rura

l or p

oore

r com

mun

ities

that

lack

tech

nica

l skil

l or e

quip

men

t for

trea

tmen

t m

onito

ring,

cou

ld th

en b

e di

spro

port

iona

tely

and

unj

ustly

pla

ced

at a

disa

dvan

tage

.

The

GD

G a

gree

d th

at in

ject

able

-spa

ring

regi

men

s w

ould

be

eas

ier t

o de

cent

raliz

e an

d th

eref

ore

to u

se in

rem

ote

and

unde

rser

vice

d se

tting

s an

d di

sadv

anta

ged

popu

latio

ns,

help

ing

to a

llevi

ate

heal

th in

equi

ties,

with

out a

ntici

patin

g di

ffere

nces

in o

utco

mes

in s

pecif

ic po

pula

tions

. The

gr

oup

also

not

ed th

at b

ecau

se a

udio

met

ry w

ould

not

be

requ

ired,

it m

ight

be

easie

r to

mon

itor i

ndiv

idua

ls, in

spi

te

of in

crea

sed

requ

irem

ents

for e

lect

roca

rdio

grap

hy, w

hich

is

a pr

ereq

uisit

e fo

r the

use

of b

edaq

uilin

e-co

ntai

ning

re

gim

ens.

How

ever

, the

gro

up s

tress

ed th

at th

e us

e of

el

ectro

card

iogr

aphy

sho

uld

not b

e a

diffe

rent

iatin

g el

emen

t be

twee

n th

ese

two

regi

men

s, be

caus

e pa

tient

s re

ceiv

ing

inje

ctab

le a

gent

s su

ch a

s am

ikacin

sho

uld

also

hav

e re

gula

r car

diac

mon

itorin

g. T

he g

roup

ack

now

ledg

ed th

at

it is

poss

ible

that

in s

ome

setti

ngs

not a

ll pa

tient

s w

ould

be

abl

e to

und

ergo

ele

ctro

card

iogr

aphi

c m

onito

ring;

ho

wev

er, t

he g

roup

also

not

ed th

at th

e in

crea

sing

acce

ss to

ele

ctro

card

iogr

aphy

at p

erip

hera

l lev

els

mig

ht

impr

ove

equi

ty.


Acc

epta

bilit

yIs

the

inte

rven

tion

acce

ptab

le to

key

sta

keho

lder

s?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

No

○ P

roba

bly

no

○ P

roba

bly

yes

● Ye

s ○

Var

ies

○ D

on’t

know

A qu

alita

tive

stud

y un

dert

aken

to h

ighl

ight

the

pers

pect

ives

of k

ey s

take

hold

ers,

mai

nly

patie

nts

and

civil

socie

ty re

pres

enta

tives

(n =

16)

, loo

ked

at g

ener

al p

refe

renc

es a

nd v

alue

s re

gard

ing

diffe

rent

asp

ects

of t

reat

men

t reg

imen

s fo

r dru

g-re

sista

nt T

B, s

uch

as d

urat

ion,

pill

burd

en, u

se

of in

ject

able

age

nts,

and

pote

ntia

l for

exp

erie

ncin

g ad

vers

e ev

ents

. The

resu

lts o

f thi

s qu

alita

tive

anal

ysis

sugg

este

d th

at m

ost p

atie

nts

wou

ld p

riorit

ize

a re

gim

en w

ith fe

wer

and

less

sev

ere

side-

effe

cts

abov

e al

l else

, bec

ause

it w

ould

allo

w th

em to

con

tinue

rout

ine

activ

ities

. Of n

ote,

sur

vivo

rs

of d

rug-

resis

tant

TB

rem

arke

d th

at th

ey w

ould

acc

ept a

long

er tr

eatm

ent t

hat p

rom

ised

less

se

vere

adv

erse

eff

ects

ove

r a s

hort

er re

gim

en ti

ed to

mor

e se

vere

sid

e-ef

fect

s, ev

en if

trea

tmen

t w

as e

xper

imen

tal o

r effi

cacy

unc

lear

. Thi

s co

ntra

sted

with

the

com

para

tivel

y fe

w p

artic

ipan

ts w

ho

prio

ritiz

ed ra

pid

retu

rn to

nor

mal

life

and

wou

ld ra

ther

ass

ume

the

risk

of m

ore

serio

us s

ide-

effe

cts

with

in a

sho

rter

regi

men

, eve

n if

treat

men

t was

exp

erim

enta

l and

effi

cacy

unc

lear

.

The

GD

G n

oted

that

pat

ient

s re

cogn

ize

that

thei

r ex

perie

nces

and

per

cept

ions

are

hig

hly

pers

on-

and

cont

ext-d

epen

dent

, tho

ugh

pref

eren

ce fo

r thi

s [s

hort

er]

regi

men

see

med

to b

e co

nditi

onal

upo

n ad

vers

e ev

ents

be

ing

rare

or r

ever

sible

. N

ever

thel

ess,

over

all,

a sh

ort,

inje

ctio

n-fre

e re

gim

en w

ith

few

to n

o ph

ysica

l and

men

tal h

ealth

sid

e-ef

fect

s an

d a

low

pi

ll bu

rden

app

eare

d to

be

the

mos

t acc

epta

ble.


Feas

ibili

tyIs

the

inte

rven

tion

feas

ible

to im

plem

ent?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

No

○ P

roba

bly

no

○ P

roba

bly

yes

● Ye

s ○

Var

ies

○ D

on’t

know

A qu

alita

tive

stud

y un

dert

aken

to h

ighl

ight

the

pers

pect

ives

of k

ey s

take

hold

ers,

mai

nly

patie

nts

and

civil

socie

ty re

pres

enta

tives

(n=1

6) lo

oked

at g

ener

al p

refe

renc

es a

nd v

alue

s re

gard

ing

diffe

rent

as

pect

s of

dru

g-re

sista

nt T

B tre

atm

ent r

egim

ens,

such

as

dura

tion,

pill

burd

en, u

se o

f inj

ecta

ble

agen

ts a

nd p

oten

tial f

or e

xper

ienc

ing

adve

rse

even

ts.

This

stud

y re

veal

ed th

at a

s th

e re

gim

en, i

n pa

rticu

lar t

he e

xpan

sion

of b

edaq

uilin

e ac

cess

to a

ll pa

tient

s is

held

bac

k is

som

e se

tting

s as

a re

sult

of re

stric

tive

elig

ibilit

y (i.

e. p

riorit

izat

ion

of s

pecif

ic gr

oups

) crit

eria

, lac

k of

fund

ing

or la

ck o

f ade

quat

e in

frast

ruct

ure

in p

lace

(e.g

. dia

gnos

tics)

; th

eref

ore,

the

oper

atio

naliz

atio

n an

d im

med

iate

roll-

out o

f the

all-

oral

bed

aqui

line-

cont

aini

ng

regi

men

may

be

ham

pere

d.

One

impo

rtan

t req

uire

men

t hig

hlig

hted

by

the

GD

G w

as

that

of e

nsur

ing

the

care

ful s

elec

tion

of p

atie

nts

who

ar

e to

ben

efit

from

this

regi

men

, con

duct

ing

rapi

d an

d ac

cura

te D

ST, a

nd m

onito

ring

beda

quilin

e re

sista

nce.

The

im

plem

enta

tion

of th

e re

gim

en m

ay b

e lim

ited

by th

e ne

ed fo

r im

prov

ed la

bora

tory

infra

stru

ctur

e. A

lthou

gh

coun

tries

are

impl

emen

ting

rapi

d m

olec

ular

test

s to

id

entif

y rif

ampi

cin re

sista

nce,

labo

rato

ry c

apac

ity n

eeds

to

be

effe

ctiv

ely

esta

blish

ed to

con

duct

gen

otyp

ic an

d ph

enot

ypic

test

ing

for o

ther

impo

rtan

t age

nts

in th

e re

gim

en. A

lso, a

lthou

gh th

e pr

eval

ence

of i

dent

ified

m

utat

ions

con

ferr

ing

low

-leve

l dru

g re

sista

nce

is ve

ry lo

w,

coun

tries

are

to s

treng

then

labo

rato

ry c

apac

ity a

nd to

m

onito

r the

acq

uisit

ion

of re

sista

nce

to b

edaq

uilin

e th

ough

th

eir n

atio

nal r

efer

ence

labo

rato

ries

or T

B su

pran

atio

nal

refe

renc

e ne

twor

k sit

es. T

his

is es

pecia

lly im

port

ant g

iven

th

e pi

pelin

e of

new

ant

i-TB

regi

men

s th

at a

re re

lyin

g on

be

daqu

iline

as a

bac

kbon

e.Th

e re

mov

al o

f inj

ecta

ble

agen

ts, a

s di

scus

sed

by th

e G

DG

, also

poi

nted

tow

ards

the

conv

enie

nce

(for h

ealth

ca

re w

orke

rs) o

f not

hav

ing

to d

eliv

er d

aily

inje

ctio

ns, a

nd

mor

e so

, for

pat

ient

s no

t hav

ing

to e

ndur

e pa

in a

nd o

ther

sig

nific

ant a

dver

se e

vent

s.Th

e im

plem

enta

tion

of th

e re

gim

en is

per

ceiv

ed to

go

beyo

nd s

ecur

ing

of fu

ndin

g, b

ut it

furt

her r

equi

res

mak

ing

long

-ter

m, s

usta

inab

le s

yste

ms

chan

ges

to e

nsur

e ra

pid

trans

ition

, con

sider

ing

the

regi

stra

tion

of b

edaq

uilin

e an

d ot

her n

ew a

gent

s, un

inte

rrup

ted

supp

ly o

f qua

lity-

assu

red

drug

s, an

d ac

tive

TB d

rug

safe

ty m

onito

ring

and

man

agem

ent s

yste

m in

coo

rdin

atio

n w

ith e

xistin

g ph

arm

acov

igila

nce

stru

ctur

es a

t the

cou

ntry

leve

l.Al

so, t

he im

plem

enta

tion

of th

is re

gim

en (a

nd a

ny o

ther

no

vel r

egim

en) w

ill re

quire

dec

ision

-mak

ing

tow

ards

m

ultis

ecto

ral p

olici

es, t

ailo

ring

patie

nt-c

entre

d pr

ogra

mm

es

that

also

con

sider

asp

ects

suc

h as

men

tal h

ealth

and

m

anag

emen

t of o

ther

com

orbi

ditie

s, fa

cilita

ting

coun

sellin

g an

d su

ppor

t dur

ing

treat

men

t, an

d af

ter c

ompl

etio

n,

facil

itatin

g fu

ll re

cove

ry.


Sum

mar

y of

judg

emen

ts

JUD

GEM

ENT

PRO

BLEM

No

Prob

ably

no

Prob

ably

yes

Yes

Varie

sD

on’t

know

DES

IRAB

LE E

FFEC

TSTr

ivia

lSm

all

Mod

erat

eLa

rge

Varie

sD

on’t

know

UND

ESIR

ABLE

EFF

ECTS

Larg

eM

oder

ate

Smal

lTr

ivia

lVa

ries

Don

’t kn

owCE

RTAI

NTY

OF

EVID

ENCE

Very

low

Low

Mod

erat

eH

igh

No

inclu

ded

stud

ies

VALU

ESIm

port

ant

unce

rtai

nty

or

varia

bilit

y

Poss

ibly

impo

rtan

t un

cert

aint

y or

va

riabi

lity

Prob

ably

no

impo

rtan

t un

cert

aint

y or

va

riabi

lity

No

impo

rtan

t un

cert

aint

y or

va

riabi

lity

BALA

NCE

OF

EFFE

CTS

Favo

rs th

e co

mpa

rison

Prob

ably

favo

rs th

e co

mpa

rison

Doe

s not

favo

r eith

er

the

inte

rven

tion

or

the

com

paris

on

Prob

ably

favo

rs

the

inte

rven

tion

Favo

rs th

e in

terv

entio

nVa

ries

Don

’t kn

ow

RESO

URCE

S RE

QUI

RED

Larg

e co

sts

Mod

erat

e co

sts

Neg

ligib

le c

osts

and

sa

ving

sM

oder

ate

savi

ngs

Larg

e sa

ving

sVa

ries

Don

’t kn

ow

CERT

AIN

TY O

F EV

IDEN

CE

OF

REQ

UIRE

D R

ESO

URCE

SVe

ry lo

wLo

wM

oder

ate

Hig

hN

o in

clude

d st

udie

s

COST

EFF

ECTI

VEN

ESS

Favo

rs th

e co

mpa

rison

Prob

ably

favo

rs th

e co

mpa

rison

Doe

s not

favo

r eith

er

the

inte

rven

tion

or

the

com

paris

on

Prob

ably

favo

rs

the

inte

rven

tion

Favo

rs th

e in

terv

entio

nVa

ries

No

inclu

ded

stud

ies

EQUI

TYRe

duce

dPr

obab

ly re

duce

dPr

obab

ly n

o im

pact

Prob

ably

incr

ease

dIn

crea

sed

Varie

sD

on’t

know

ACCE

PTAB

ILIT

YN

oPr

obab

ly n

oPr

obab

ly y

esYe

sVa

ries

Don

’t kn

owFE

ASIB

ILIT

YN

oPr

obab

ly n

oPr

obab

ly y

esYe

sVa

ries

Don

’t kn

ow

Type

of r

ecom

men

datio

nSt

rong

reco

mm

enda

tion

agai

nst

the

inte

rven

tion

○

Cond

ition

al re

com

men

datio

n ag

ains

t the

inte

rven

tion

○

Cond

ition

al re

com

men

datio

n fo

r eith

er th

e in

terv

entio

n or

the

com

paris

on○

Cond

ition

al re

com

men

datio

n fo

r the

inte

rven

tion

●

Stro

ng re

com

men

datio

n fo

r the

in

terv

entio

n○


Conc

lusi

ons

Reco

mm

enda

tion

A sh

orte

r, al

l-ora

l, be

daqu

iline-

cont

aini

ng re

gim

en o

f 9–1

2 m

onth

s du

ratio

n is

reco

mm

ende

d in

elig

ible

pat

ient

s w

ith c

onfir

med

MD

R/RR

-TB

who

hav

e no

t bee

n ex

pose

d to

trea

tmen

t w

ith s

econ

d-lin

e TB

med

icine

s us

ed in

this

regi

men

for m

ore

than

one

mon

th a

nd in

who

m re

sista

nce

to fl

uoro

quin

olon

es h

as b

een

exclu

ded.

(Con

ditio

nal r

ecom

men

datio

n, v

ery

low

cer

tain

ty in

the

evid

ence

)Ju

stifi

catio

nO

vera

ll, th

e G

DG

not

ed th

at th

e ce

rtai

nty

of th

e ev

iden

ce re

gard

ing

the

effic

acy

of th

e al

l-ora

l sho

rter

regi

men

was

“ver

y lo

w”,

attri

buta

ble

to c

once

rns

of s

erio

us ri

sk o

f bia

s, de

spite

ef

fort

s to

bal

ance

bas

elin

e co

varia

tes.

How

ever

, the

gro

up re

cogn

ized

that

the

curre

nt e

vide

nce

asse

ssm

ent o

f the

all-

oral

, bed

aqui

line-

cont

aini

ng s

hort

er re

gim

en h

as s

ome

addi

tiona

l ad

vant

ages

as

com

pare

d w

ith a

ll-or

al lo

nger

regi

men

s, na

mel

y in

term

s of

low

er lo

ss to

follo

w-u

p (d

esira

ble

effe

ct) a

nd o

bvio

us s

hort

er d

urat

ion

(acc

epta

bilit

y).

Whe

n de

cidin

g on

the

stre

ngth

of t

he re

com

men

datio

n, th

e G

DG

reac

hed

a un

anim

ous

decis

ion

on th

e co

nditi

onal

ity o

f the

reco

mm

enda

tion,

mai

nly

attri

bute

d to

the

very

low

cer

tain

ty

in th

e ev

iden

ce a

nd re

quire

men

ts to

bui

ld la

bora

tory

cap

acity

and

ens

ure

DST

.O

ther

gro

unds

for t

he s

treng

th a

nd d

irect

ion

of th

is re

com

men

datio

n ar

e as

follo

ws:

• Th

e an

alys

is co

nduc

ted

to in

form

the

deve

lopm

ent o

f thi

s re

com

men

datio

n w

as b

ased

on

obse

rvat

iona

l pro

gram

mat

ic da

ta fr

om S

outh

Afri

ca w

here

the

stan

dard

ized

sho

rter

, all-

oral

, be

daqu

iline-

cont

aini

ng re

gim

en (B

DQ

-LFX

/MFX

-ETO

-E-Z

-Hh -C

FZ) w

as u

sed

for p

atie

nts

with

MD

R/RR

-TB.

• Th

ough

no

maj

or s

igna

ls of

risk

wer

e ob

serv

ed w

ith th

e us

e of

the

all-o

ral b

edaq

uilin

e-ba

sed

shor

ter r

egim

en, t

here

also

rem

aine

d so

me

unce

rtai

ntie

s gi

ven

the

lack

of s

yste

mat

ic co

llect

ion

of d

ata,

and

the

lack

of c

larit

y as

to a

ny c

hang

es in

the

regi

men

that

cou

ld h

ave

been

info

rmed

by

the

pres

ence

of a

dver

se e

vent

s.•

Cost

–effe

ctiv

enes

s m

odel

ling

of th

e al

l-ora

l, sh

orte

r, be

daqu

iline-

cont

aini

ng re

gim

en s

how

ed ro

bust

cos

t sav

ings

rela

tive

to e

ither

a lo

nger

ora

l reg

imen

or a

sho

rt in

ject

able

-co

ntai

ning

regi

men

.•

The

GD

G ju

dged

that

man

y el

igib

le p

atie

nts

wou

ld p

refe

r the

all-

oral

, bed

aqui

line-

cont

aini

ng re

gim

en o

f 9–1

2 m

onth

s’ du

ratio

n. T

his

is su

ppor

ted

by li

mite

d ob

serv

atio

ns in

volv

ing

16 s

urvi

vors

of d

rug-

resis

tant

TB.

In a

dditi

on, t

his

regi

men

may

hel

p pr

omot

e he

alth

equ

ity o

r miti

gate

the

wor

seni

ng o

f hea

lth in

equi

ties.

How

ever

, the

pan

el re

cogn

ized

that

im

plem

enta

tion

and

scal

e-up

of t

his

regi

men

mig

ht b

e slo

w b

ecau

se o

f pre

requ

isite

s re

gard

ing

labo

rato

ry c

apac

ity a

nd m

onito

ring.

Subg

roup

con

side

ratio

nsTh

e at

tem

pted

to d

escr

ibe

the

bala

nce

of e

ffect

s an

d co

nsid

erat

ions

for v

ario

us s

ubgr

oups

or s

pecia

l pop

ulat

ions

. How

ever

, the

evi

denc

e re

view

ed s

uppo

rted

the

use

of th

is in

the

follo

win

g se

tting

s, w

ith s

pecif

ic ca

veat

s:•

Peop

le li

ving

with

HIV

infe

ctio

n (P

LHIV

): Th

e da

ta e

valu

ated

cor

resp

onde

d to

a s

ettin

g w

ith a

hig

h pr

eval

ence

of H

IV, a

nd o

f par

ticul

ar s

igni

fican

ce, m

ost P

LHIV

(>95

%) w

ho s

tart

ed

the

all-o

ral b

edaq

uilin

e-co

ntai

ning

regi

men

wer

e re

ceiv

ing

antir

etro

vira

l the

rapy

(ART

). In

vie

w o

f the

trea

tmen

t out

com

es d

escr

ibed

in th

e an

alys

is, th

ere

wer

e no

gro

unds

to b

elie

ve

that

the

regi

men

wou

ld p

erfo

rm a

ny d

iffer

ently

in P

LHIV

. It i

s ne

cess

ary

to c

onsid

er s

igni

fican

t clin

ical i

nter

actio

ns th

at m

ay in

crea

se b

edaq

uilin

e ex

posu

re o

r tha

t of o

ther

age

nts

with

po

tent

ial f

or c

ardi

otox

icity

whe

n th

ese

are

co-a

dmin

ister

ed w

ith a

ntire

trovi

rals.

• Ch

ildre

n: A

lthou

gh n

o di

rect

out

com

e es

timat

ions

cou

ld b

e dr

awn

for t

his

popu

latio

n, e

xtra

pola

tion

was

dee

med

reas

onab

le. H

owev

er, b

ecau

se b

edaq

uilin

e is

curre

ntly

reco

mm

ende

d fo

r chi

ldre

n an

d ad

oles

cent

s ag

ed 6

–17

year

s, th

e G

DG

con

clude

d th

at th

e al

l-ora

l bed

aqui

line-

cont

aini

ng re

gim

en m

ay b

e us

ed in

elig

ible

chi

ldre

n w

ithin

this

age

grou

p, ta

king

into

ac

coun

t spe

cifica

tions

for r

egim

en c

ompa

nion

dru

gs, i

n pa

rticu

lar,

beda

quilin

e.•

Preg

nant

and

lact

atin

g w

omen

: Mor

e ev

iden

ce is

nee

ded

to b

ette

r inf

orm

the

use

of th

e al

l-ora

l, be

daqu

iline-

cont

aini

ng s

hort

er re

gim

en (B

DQ

-LFX

/MFX

-ETO

-E-Z

-Hh -C

FZ).

One

of

the

agen

ts in

this

all-o

ral s

hort

er re

gim

en, e

thio

nam

ide,

is u

sual

ly c

ontra

indi

cate

d in

pre

gnan

cy, a

nd w

ithho

ldin

g th

is ag

ent o

r rep

lacin

g it

with

ano

ther

one

cou

ld s

erio

usly

co

mpr

omise

the

effe

ctiv

enes

s of

the

regi

men

. For

pre

gnan

t and

lact

atin

g w

omen

, it i

s th

eref

ore

reco

mm

ende

d th

at a

n in

divi

dual

ized

, all-

oral

long

er re

gim

en (i

nclu

ding

bed

aqui

line)

be

use

d (s

ee R

ecom

men

datio

ns o

n th

e us

e of

long

er re

gim

ens

for M

DR/

RR-T

B).

• Ex

trapu

lmon

ary

dise

ase:

In v

iew

of t

he u

nava

ilabi

lity

of e

vide

nce

rega

rdin

g su

rroga

tes

for s

ever

ity o

r ext

ent o

f dise

ase,

it is

adv

isabl

e to

use

clin

ical j

udge

men

t to

decid

e on

the

use

of

this

regi

men

in p

atie

nts

with

ext

ensiv

e TB

dise

ase

or s

ever

e fo

rms

of e

xtra

pulm

onar

y TB

.


Impl

emen

tatio

n co

nsid

erat

ions

The

inte

rest

in re

ducin

g th

e du

ratio

n of

trea

tmen

t for

MD

R/RR

-TB

has

mot

ivat

ed a

num

ber o

f stu

dies

in re

cent

yea

rs o

f tre

atin

g pa

tient

s w

ith s

hort

er re

gim

ens

unde

r pro

gram

mat

ic as

wel

l as

trial

con

ditio

ns. B

ecau

se o

f exp

erie

nces

in v

ario

us s

ettin

gs, [

elig

ible

] pat

ient

s no

w h

ave

an o

ptio

n to

be

treat

ed w

ith a

sho

rter

, inj

ecta

ble-

spar

ing

regi

men

of 9

–12

mon

ths’

dura

tion.

To e

nsur

e th

at th

e re

gim

en a

chie

ves

its d

esira

ble

effe

cts

and

to p

reve

nt th

e ac

quisi

tion

(or a

mpl

ifica

tion)

of a

dditi

onal

dru

g re

sista

nce

(whi

le p

rote

ctin

g re

gim

en c

ompo

nent

s),

coun

tries

are

to c

onsid

er th

e fo

llow

ing:

• Pa

tient

sel

ectio

n an

d de

cisio

ns to

sta

rt th

e al

l-ora

l sho

rter

regi

men

: Pat

ient

s w

ith c

onfir

med

MD

R/RR

-TB

and

with

resis

tanc

e to

fluo

roqu

inol

ones

rule

d ou

t are

exp

ecte

d to

ben

efit

the

mos

t fro

m th

is re

gim

en. P

rope

r pat

ient

sel

ectio

n w

ill no

t onl

y le

ad to

impr

oved

trea

tmen

t out

com

es, b

ut w

ill al

so c

ontri

bute

to a

void

ing

the

deve

lopm

ent o

f res

istan

ce to

bed

aqui

line.

In

this

resp

ect,

the

regi

men

is to

onl

y be

impl

emen

ted

in s

ettin

gs w

here

rout

ine

DST

for r

ifam

picin

and

fluo

roqu

inol

ones

can

be

guar

ante

ed.

–It

is ve

ry im

port

ant t

hat t

he im

plem

enta

tion

of th

ese

reco

mm

enda

tions

is a

ccom

pani

ed b

y co

ntin

ued

effo

rts

to in

crea

se a

cces

s to

DST

for a

ll m

edici

nes

for w

hich

relia

ble

met

hods

ex

ist, a

s w

ell a

s fo

r the

dev

elop

men

t and

rollo

ut o

f DST

met

hods

for n

ewer

med

icine

s. In

the

abse

nce

of a

dru

g-su

scep

tibilit

y te

st, a

ssay

s sp

ecifi

c fo

r bed

aqui

line

resis

tanc

e sh

ould

be

mon

itore

d th

roug

h as

sess

men

t of m

inim

um in

hibi

tory

con

cent

ratio

ns (M

ICs)

of b

edaq

uilin

e. –Re

sista

nce

to o

ther

ant

i-TB

drug

s sh

ould

be

mon

itore

d in

acc

orda

nce

with

WH

O re

com

men

datio

ns.

• Us

e of

line

zolid

: The

evi

denc

e m

ade

avai

labl

e to

info

rm th

is re

com

men

datio

n fo

cuse

d on

the

asse

ssm

ent o

f a re

gim

en c

ompo

sed

of b

edaq

uilin

e, le

voflo

xacin

/mox

iflox

acin

, et

hion

amid

e, e

tham

buto

l, py

razi

nam

ide,

hig

h-do

se is

onia

zid,

clo

fazi

min

e, a

nd p

yraz

inam

ide.

How

ever

, sec

onda

ry a

naly

ses

(onl

y in

long

er re

gim

ens

cont

aini

ng b

edaq

uilin

e an

d be

daqu

iline

plus

line

zolid

) sho

wed

favo

urab

le o

utco

mes

whe

n tre

atm

ent r

egim

ens

inclu

ded

both

line

zolid

and

bed

aqui

line.

The

bas

is fo

r the

add

ition

of l

inez

olid

was

to p

rote

ct

the

regi

men

, in

part

icula

r, be

daqu

iline,

whi

le a

wai

ting

susc

eptib

ility

resu

lts o

n ad

ditio

nal r

esist

ance

to fl

uoro

quin

olon

es a

nd o

ther

dru

gs. T

he G

DG

dec

ided

that

unt

il ne

w e

vide

nce

is av

aila

ble

on s

hort

er re

gim

ens

that

inclu

de b

oth

of th

ese

agen

ts, t

he a

ll-or

al b

edaq

uilin

e-co

ntai

ning

sho

rter

regi

men

adv

ised

here

in s

houl

d no

t inc

lude

line

zolid

. How

ever

, the

gro

up

enco

urag

ed c

ount

ries

to c

onsid

er th

e us

e of

a m

odifie

d al

l-ora

l bed

aqui

line-

and

linez

olid

-con

tain

ing

only

unde

r ope

ratio

nal r

esea

rch

until

new

evid

ence

bec

omes

ava

ilabl

e.•

Patie

nt-c

entre

d ap

proa

ch: E

ffort

s ar

e re

quire

d to

pro

vide

pat

ient

sup

port

to e

nabl

e fu

ll ad

here

nce

to tr

eatm

ent.

Mon

itorin

g an

d ev

alua

tion

• Th

e im

plem

enta

tion

of th

is re

gim

en re

quire

s th

e us

e of

rout

ine

DST

not

onl

y fo

r pat

ient

sel

ectio

n, b

ut a

lso fo

r mon

itorin

g of

the

acqu

isitio

n of

resis

tanc

e.•

Alth

ough

the

data

ass

esse

d di

d no

t une

arth

any

maj

or s

igna

ls of

risk

, act

ive

TB d

rug

safe

ty m

onito

ring

and

man

agem

ent s

yste

ms

mus

t be

func

tiona

l in

orde

r to

cond

uct r

igor

ous

activ

e m

onito

ring

of a

dver

se e

vent

s an

d to

det

ect,

man

age

and

repo

rt s

uspe

cted

or c

onfir

med

dru

g to

xiciti

es in

a ti

mel

y m

anne

r.

Rese

arch

prio

ritie

sM

embe

rs o

f the

GD

G d

iscus

sed

the

rese

arch

gap

s to

info

rm th

e de

velo

pmen

t of p

ublic

hea

lth re

com

men

datio

ns fo

r the

man

agem

ent o

f MD

R/RR

-TB,

and

hig

hlig

hted

the

follo

win

g pr

iorit

ies:

• st

udie

s as

sess

ing

com

paris

ons

of a

ll-or

al s

hort

er re

gim

ens

whi

ch in

clude

bed

aqui

line

and

linez

olid

, in

addi

tion

to o

ther

com

pani

on d

rugs

;•

stud

ies

asse

ssin

g co

mpa

rison

s of

all-

oral

sho

rter

regi

men

s am

ong

diffe

rent

sub

grou

ps a

nd s

pecia

l pop

ulat

ions

, inc

ludi

ng p

regn

ant a

nd la

ctat

ing

wom

en;

• ra

ndom

ized

-con

trolle

d tri

als

or o

pera

tiona

l res

earc

h of

the

effe

ctiv

enes

s an

d sa

fety

of a

ll-or

al s

hort

er re

gim

ens,

incr

easin

g th

e ce

rtai

nty

of th

e ev

iden

ce;

• st

udie

s ex

plor

ing

mec

hani

sms

of a

cqui

sitio

n of

resis

tanc

e to

bed

aqui

line

and

gene

tic m

arke

rs to

iden

tify

resis

tanc

e; a

nd•

effo

rts

to d

eter

min

e be

st w

ays

to s

tand

ardi

ze th

e co

llect

ion

of d

ata

so th

at c

ount

ries

can

cont

ribut

e to

the

deve

lopm

ent o

f glo

bal r

ecom

men

datio

ns.

aOR:

adj

uste

d od

ds ra

tio; A

RT: a

ntire

trovi

ral t

hera

py; d

rug-

susc

eptib

ility

test

ing;

GD

F: G

loba

l Dru

g Fa

cility

; GD

G: G

uide

line

Dev

elop

men

t Gro

up; M

DR/

RR-T

B: m

ultid

rug-

or r

ifam

picin

-res

istan

t TB;

MIC

: min

imum

in

hibi

tory

con

cent

ratio

n; P

LHIV

: peo

ple

livin

g w

ith h

uman

imm

unod

efici

ency

viru

s; TB

: tub

ercu

losis

; WH

O: W

orld

Hea

lth O

rgan

izat

ion.


Shou

ld a

n al

l-or

al s

hort

er re

gim

en o

f 9–1

2 m

onth

s’ d

urat

ion

incl

udin

g be

daqu

iline

vs

long

er re

gim

ens

with

out n

ew T

B dr

ugs

be u

sed

for M

DR-

/RR-

TB p

atie

nts

to s

afel

y im

prov

e ou

tcom

es?

POPU

LATI

ON

:M

DR-

/RR-

TB p

atie

nts

to s

afel

y im

prov

e ou

tcom

esIN

TERV

ENTI

ON

:Al

l-ora

l bed

aqui

line-

cont

aini

ng s

hort

er re

gim

en o

f 9–1

2 m

onth

s du

ratio

n (B

DQ

-LFX

/MFX

-ETO

-E-Z

-Hh -C

FZ)

COM

PARI

SON

:Lo

nger

regi

men

s w

ithou

t new

TB

drug

sM

AIN

OUT

COM

ES:

Succ

ess

vs. F

ailu

re/R

ecur

renc

e; S

ucce

ss v

s. D

eath

; Suc

cess

vs.

Failu

re/R

ecur

renc

e/D

eath

; Suc

cess

vs.

All U

nfav

oura

ble;

Los

t vs.

All O

ther

Out

com

es; A

FB

Smea

r Pos

itive

: Suc

cess

vs.

Failu

re/R

ecur

renc

e; A

FB S

mea

r Pos

itive

: Suc

cess

vs.

Dea

th; A

FB S

mea

r Pos

itive

: Suc

cess

vs.

Failu

re/R

ecur

renc

e/D

eath

; AFB

Sm

ear

Posit

ive:

Suc

cess

vs.

All U

nfav

oura

ble;

AFB

Sm

ear P

ositi

ve: L

ost v

s. Al

l Oth

er O

utco

mes

; HIV

-Pos

itive

on

ART:

Suc

cess

vs.

Failu

re/R

ecur

renc

e; H

IV-P

ositi

ve o

n AR

T: S

ucce

ss v

s. D

eath

; HIV

-Pos

itive

on

ART:

Suc

cess

vs.

Failu

re/R

ecur

renc

e/D

eath

; HIV

-Pos

itive

on

ART:

Suc

cess

vs.

All O

ther

Unf

avou

rabl

e; H

IV-P

ositi

ve

on A

RT: L

ost v

s. Al

l Oth

er O

utco

mes

; HIV

Neg

ativ

e: S

ucce

ss v

s. Fa

ilure

/Rec

urre

nce;

HIV

Neg

ativ

e: S

ucce

ss v

s. D

eath

; HIV

Neg

ativ

e: S

ucce

ss v

s. Fa

ilure

/Re

curre

nce/

Dea

th; H

IV N

egat

ive:

Suc

cess

vs.

All O

ther

Out

com

es; H

IV N

egat

ive:

Los

t vs.

All O

ther

Out

com

es.

SETT

ING

:So

uth

Afric

a.

PERS

PECT

IVE:

Publ

ic he

alth

and

hea

lth s

yste

ms

pers

pect

ive

BACK

GRO

UND

:M

ultid

rug-

resis

tant

(MD

R-) a

nd ri

fam

picin

-res

istan

t tub

ercu

losis

(MD

R-/R

R-TB

) is

emer

ging

as

a m

ajor

pro

blem

due

to p

oor m

anag

emen

t of d

rug-

sens

itive

as

wel

l as

drug

-res

istan

t TB.

MD

R-/R

R-TB

is tr

eata

ble,

but

has

requ

ired

the

use

of lo

nger

trea

tmen

t reg

imen

s w

hich

con

tain

pot

entia

lly to

xic d

rugs

. The

in

tere

st in

redu

cing

the

dura

tion

of tr

eatm

ent f

or M

DR-

TB m

otiv

ated

a n

umbe

r of i

nitia

tives

in re

cent

yea

rs to

trea

t pat

ient

s w

ith s

hort

er re

gim

ens

unde

r pr

ogra

mm

atic

as w

ell a

s tri

al c

ondi

tions

. In

2016

, on

the

basis

of d

ata

from

obs

erva

tiona

l stu

dies

of t

he s

hort

er re

gim

ens

in d

iffer

ent A

sian

and

Afric

an

coun

tries

, WH

O s

tart

ed to

reco

mm

end

a st

anda

rdiz

ed s

hort

er M

DR-

TB re

gim

en, c

onta

inin

g an

inje

ctab

le a

gent

, bas

ed o

n th

e on

es u

nder

stu

dy fo

r elig

ible

pa

tient

s. In

201

8, fu

rthe

r mod

ifica

tions

wer

e m

ade

to th

e ea

rlier

reco

mm

ende

d sh

orte

r reg

imen

, rep

lacin

g ka

nam

ycin

by

amika

cin (b

ased

on

evid

ence

from

th

e co

mpa

rativ

e ef

fect

iven

ess

of th

ese

two

inje

ctab

le a

gent

s).

Evid

ence

of p

erm

anen

t effe

cts

attri

bute

d to

the

toxic

ity o

f inj

ecta

ble

agen

ts, h

ave

prom

pted

furt

her a

dvan

ces

in th

e de

velo

pmen

t of n

ew tr

eatm

ents

su

ch a

s sh

orte

r inj

ecta

ble-

spar

ing

regi

men

s. In

par

ticul

ar, o

bser

vatio

nal d

ata

on a

n al

l-ora

l bed

aqui

line-

cont

aini

ng s

hort

er re

gim

en o

f 9–1

2 m

onth

s du

ratio

n be

cam

e av

aila

ble.

Thi

s is

of p

artic

ular

impo

rtan

ce g

iven

that

the

regi

men

may

offe

r pat

ient

s th

e lik

elih

ood

of b

ette

r tol

erat

ing

treat

men

t with

out

signi

fican

t tox

icity.

CON

FLIC

T O

F IN

TERE

STS:

Albe

rto

Piub

ello

.

Ass

essm

ent

Prob

lem

Is th

e pr

oble

m a

prio

rity?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

No

○ P

roba

bly

no

○ P

roba

bly

yes

● Ye

s ○

Var

ies

○ D

on’t

know

Tube

rcul

osis

(TB)

rem

ains

a th

reat

to g

loba

l pub

lic h

ealth

and

is th

e to

pmos

t inf

ectio

us c

ause

of

deat

h in

the

wor

ld. I

n 20

18, a

n es

timat

ed 1

0 m

illion

peo

ple

deve

lope

d TB

and

1.4

milli

on d

ied

from

the

dise

ase.

Abo

ut 5

00 0

00 n

ew c

ases

of m

ultid

rug-

or r

ifam

picin

-res

istan

t TB

(MD

R/RR

-TB)

w

ere

estim

ated

to e

mer

ge in

201

8. A

lthou

gh a

ll of

thes

e w

ould

hav

e be

en e

ligib

le fo

r a s

econ

d-lin

e TB

trea

tmen

t reg

imen

, onl

y 15

6 07

1 en

rolm

ents

in tr

eatm

ent w

ere

repo

rted

by

coun

tries

in

201

8 –

abou

t 30%

of t

he e

stim

ated

cas

eloa

d. D

espi

te th

is, s

igni

fican

t im

prov

emen

ts in

the

avai

labi

lity

of e

nhan

ced

diag

nost

ics a

nd m

ore

effe

ctiv

e m

edici

nes

has

occu

rred

in re

cent

yea

rs

and

has

led

to e

arlie

r det

ectio

n an

d hi

gher

suc

cess

rate

s am

ong

patie

nts

with

MD

R/RR

-TB

in a

nu

mbe

r of n

atio

nal p

rogr

amm

es. H

owev

er, t

hese

suc

cess

es h

ave

not b

een

repr

oduc

ed in

the

rest

of t

he w

orld

, and

the

over

all t

reat

men

t suc

cess

rate

wor

ldw

ide

reac

hed

only

56%

for p

atie

nts

with

MD

R/RR

-TB

who

sta

rted

trea

tmen

t in

2016

, and

onl

y 39

% fo

r pat

ient

s w

ith e

xtre

mel

y dr

ug-

resis

tant

TB

(XD

R-TB

).


Des

irab

le E

ffec

tsH

ow s

ubst

antia

l are

the

desi

rabl

e an

ticip

ated

eff

ects

?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Triv

ial

○ S

mal

l ○

Mod

erat

e ●

Larg

e ○

Var

ies

○ D

on’t

know

The

prim

ary

anal

ysis

also

illu

stra

ted

the

effe

ct o

f an

all-o

ral s

hort

er b

edaq

uilin

e-ba

sed

regi

men

as

com

pare

d w

ith lo

ng re

gim

ens

that

did

not

con

tain

any

new

dru

gs. T

he s

hort

er re

gim

en

perfo

rmed

sig

nific

antly

bet

ter a

cros

s al

l out

com

es a

nd a

ll su

bgro

ups

as c

ompa

red

with

trea

tmen

t ou

tcom

es w

hen

long

er re

gim

es w

ithou

t new

dru

gs w

ere

impl

emen

ted.

Out

com

en/

N

(Bdq

sho

rt)

n/N

(L

ong,

no

new

dru

gs)

Num

ber

of Pairs

aOR

(95%

CI

)aR

D (9

5%

CI)

Succ

ess

vs. F

ailu

re/

Recu

rrenc

e63

1/65

367

9/77

158

03.

7 (2

.2, 6

.3)

8

(5, 1

1)Su

cces

s vs

. Dea

th63

1/79

167

9/10

4474

72.

3 (1

.8, 3

.0)

15

(10,

19)

Succ

ess

vs. F

ailu

re/R

ec./

Dea

th63

1/81

367

9/11

3677

12.

6 (2

.0, 3

.3)

18

(14,

23)

Succ

ess

vs. A

ll Un

favo

rabl

e63

1/89

167

9/14

3785

92.

8 (2

.3, 3

.5)

23

(18,

27)

Lost

vs.

All O

ther

O

utco

mes

88/8

9136

8/14

3785

90.

4 (0

.3, 0

.5)

-14

(-17

, -10

)

Und

esir

able

Eff

ects

How

sub

stan

tial a

re th

e un

desi

rabl

e an

ticip

ated

eff

ects

?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Lar

ge

○ M

oder

ate

○ S

mal

l ●

Triv

ial

○ V

arie

s ○

Don

’t kn

ow

The

GD

G d

iscus

sed

earli

er re

sults

of t

he in

divi

dual

-pat

ient

dat

a (IP

D) m

eta-

anal

ysis

cond

ucte

d to

as

sess

the

over

all b

alan

ce b

etw

een

bene

fits

and

harm

s of

indi

vidu

al a

gent

s. In

the

anal

ysis,

199

5 pa

tient

s re

ceiv

ed k

anam

ycin

and

268

(13.

4%) e

xper

ienc

ed a

n ad

vers

e ev

ent c

ausin

g pe

rman

ent

drug

disc

ontin

uatio

n; 4

106

patie

nts

rece

ived

am

ikacin

, of w

hom

235

(5.7

%) e

xper

ienc

ed a

n ad

vers

e ev

ent c

ausin

g pe

rman

ent d

rug

disc

ontin

uatio

n; a

dditi

onal

ly, 1

932

rece

ived

cap

reom

ycin

an

d 16

1 (8

.3%

) exp

erie

nced

an

adve

rse

even

t cau

sing

perm

anen

t dru

g di

scon

tinua

tion.

In

cont

rast

, 464

pat

ient

s re

ceiv

ed b

edaq

uilin

e, o

f who

m n

ine

(1.9

%),

nine

(1.9

%) e

xper

ienc

ed a

n ad

vers

e ev

ent c

ausin

g pe

rman

ent d

rug

disc

ontin

uatio

n.

The

GD

G a

gree

d th

at th

ere

is ev

iden

ce o

f pat

ient

s ex

perie

ncin

g ad

vers

e ev

ents

afte

r the

use

of b

edaq

uilin

e. H

owev

er, i

t was

em

phas

ized

that

com

pare

d w

ith th

e al

tern

ativ

e, a

nd o

n th

e ba

sis o

f the

IPD

met

a-an

alys

is, th

ese

even

ts s

eem

to b

e sig

nific

antly

few

er.

Som

e m

embe

rs o

f the

GD

G d

id e

mph

asiz

e th

at a

lthou

gh

the

unde

sirab

le e

ffect

s of

the

all-o

ral b

edaq

uilin

e-co

ntai

ning

sh

orte

r reg

imen

see

med

to b

e tri

vial

com

pare

d w

ith th

ose

of

long

er re

gim

ens

with

out n

ew T

B dr

ugs,

ther

e w

ere

still

adve

rse

even

ts a

ssoc

iate

d w

ith th

e dr

ugs

used

in th

e al

l-ora

l reg

imen

.


Cert

aint

y of

evi

denc

eW

hat i

s th

e ov

eral

l cer

tain

ty o

f the

evi

denc

e of

eff

ects

?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S●

Very

low

○

Low

○

Mod

erat

e ○

Hig

h ○

No

inclu

ded

stud

ies

Th

e G

DG

poi

nted

out

that

on

the

basis

of t

he e

vide

nce

asse

ssed

– n

amel

y ob

serv

atio

nal d

ata

and

pote

ntia

l res

idua

l co

nfou

ndin

g –

the

over

all c

erta

inty

of t

he e

stim

ates

of e

ffect

w

as ju

dged

to b

e “v

ery

low

”, w

ith th

e ef

fect

s fo

r all

outc

omes

al

so ra

ted

as “v

ery

low

”.Al

thou

gh d

oubl

e ad

just

men

t in

prop

ensit

y sc

ore

mat

chin

g an

alys

es w

as c

arrie

d ou

t to

rem

ove

the

effe

cts

of c

onfo

undi

ng,

mem

bers

of t

he G

DG

furt

her n

oted

that

alth

ough

thes

e ef

fort

s co

mpe

nsat

ed fo

r som

e po

tent

ial c

onfo

unde

rs, r

esid

ual b

ias

was

lik

ely

to b

e pr

esen

t. Th

e gr

oup

ackn

owle

dged

that

alth

ough

th

e us

e of

pro

gram

mat

ic da

ta h

olds

gre

at p

rom

ise b

ecau

se

they

bet

ter r

efle

ct re

al p

ract

ice, s

ome

cons

ider

atio

ns in

term

s of

the

exte

nt to

whi

ch th

ese

findi

ngs

coul

d be

app

lied

to

othe

r set

tings

are

to b

e co

ntem

plat

ed, s

uch

as s

pecif

ic cli

nica

l ch

arac

teris

tics

of th

e po

pula

tion

(e.g

. HIV

pre

vale

nce;

dru

g-re

sista

nce

patte

rns)

, as

wel

l as

qual

ity o

f hea

lth c

are

serv

ices,

mod

els

of c

are,

and

trea

tmen

t adh

eren

ce s

trate

gies

.

Valu

esIs

ther

e im

port

ant u

ncer

tain

ty a

bout

or v

aria

bilit

y in

how

muc

h pe

ople

val

ue th

e m

ain

outc

omes

?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Impo

rtan

t un

cert

aint

y or

va

riabi

lity

○ P

ossib

ly

impo

rtan

t un

cert

aint

y or

va

riabi

lity

○ P

roba

bly

no im

port

ant

unce

rtai

nty

or

varia

bilit

y ●

No

impo

rtan

t un

cert

aint

y or

va

riabi

lity

A qu

alita

tive

stud

y un

dert

aken

to h

ighl

ight

the

pers

pect

ives

of k

ey s

take

hold

ers,

mai

nly

patie

nts

and

civil

socie

ty re

pres

enta

tives

(n =

16)

, loo

ked

at g

ener

al p

refe

renc

es a

nd v

alue

s re

gard

ing

diffe

rent

asp

ects

of t

reat

men

t reg

imen

s fo

r dru

g-re

sista

nt T

B, s

uch

as d

urat

ion,

pill

burd

en, u

se o

f in

ject

able

age

nts,

and

pote

ntia

l for

exp

erie

ncin

g ad

vers

e ev

ents

.Pr

efer

ence

s fo

r tre

atm

ent d

urat

ion

seem

ed to

be

guid

ed fi

rst b

y sid

e-ef

fect

s an

d se

cond

by

effic

acy.

The

qual

itativ

e st

udy,

thou

gh s

mal

l, hi

ghlig

hted

how

mos

t pat

ient

s w

ould

pre

fer a

long

er

regi

men

with

less

sev

ere

side-

effe

cts

over

a s

hort

er re

gim

en w

ith m

ore

seve

re s

ide-

effe

cts..

Pref

eren

ces

rega

rdin

g tre

atm

ent a

ppea

red

to b

e ro

oted

in c

ore

valu

es, i

nclu

ding

min

imal

disr

uptio

n to

nor

mal

life

. Rel

ativ

ely

few

pat

ient

s se

emed

to p

refe

r a s

hort

regi

men

that

was

tied

to

mor

e se

rious

sid

e-ef

fect

s, an

d th

en o

nly

if th

e sid

e-ef

fect

s w

ere

rare

or r

ever

sible

. In

addi

tion,

in te

rms

of th

e du

ratio

n of

trea

tmen

t, pr

efer

ence

s se

emed

to b

e gu

ided

firs

t by

side-

effe

cts

and

seco

nd b

y ef

ficac

y of

trea

tmen

t reg

imen

s.


Bala

nce

of e

ffec

tsD

oes

the

bala

nce

betw

een

desi

rabl

e an

d un

desi

rabl

e ef

fect

s fa

vor t

he in

terv

entio

n or

the

com

paris

on?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Fav

ors

the

com

paris

on

○ P

roba

bly

favo

rs

the

com

paris

on

○ D

oes

not

favo

r eith

er th

e in

terv

entio

n or

the

com

paris

on

○ P

roba

bly

favo

rs

the

inte

rven

tion

● Fa

vors

the

inte

rven

tion

○ V

arie

s ○

Don

’t kn

ow

Th

e di

scus

sed

whe

ther

the

bala

nce

betw

een

desir

able

and

un

desir

able

effe

cts

favo

ured

the

inte

rven

tion.

Dat

a as

sess

ed

show

ed th

at th

e ov

eral

l rat

e of

adv

erse

eve

nts

attri

bute

d to

be

daqu

iline

as c

ompa

red

with

inje

ctab

le a

gent

s w

as tw

o tim

e le

ss. A

t the

sam

e tim

e, th

e G

DG

not

ed a

50%

redu

ctio

n in

de

aths

, attr

ibut

ing

this

effe

ct to

the

addi

tion

of b

edaq

uilin

e.

How

ever

, the

gro

up e

mph

asiz

ed th

e po

tent

ial h

arm

s if

this

beda

quilin

e-co

ntai

ning

regi

men

wer

e to

be

impl

emen

ted

with

out e

nsur

ing

prop

er D

ST, a

nd th

e po

tent

ial f

or a

mpl

ifica

tion

of re

sista

nce

patte

rns.

Reso

urce

s re

quir

edH

ow la

rge

are

the

reso

urce

requ

irem

ents

(cos

ts)?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Lar

ge c

osts

○

Mod

erat

e co

sts

○ N

eglig

ible

cos

ts

and

savi

ngs

● M

oder

ate

savi

ngs

○ L

arge

sav

ings

○

Var

ies

○ D

on’t

know

Th

e G

DG

did

agr

ee th

at, o

vera

ll, sa

ving

s ca

n be

con

sider

ed

in te

rms

of fu

ture

retre

atm

ents

pre

vent

ed, a

s w

ell a

s re

duce

d ho

spita

lizat

ion

rate

s re

sulti

ng fr

om fe

wer

adv

erse

reac

tions

.

Cert

aint

y of

evi

denc

e of

req

uire

d re

sour

ces

Wha

t is

the

cert

aint

y of

the

evid

ence

of r

esou

rce

requ

irem

ents

(cos

ts)?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Ver

y lo

w

○ L

ow

● M

oder

ate

○ H

igh

○ N

o in

clude

d st

udie

s

The

GD

G a

ntici

pate

d th

e co

st s

avin

gs to

be

robu

st, w

ith s

avin

gs

on d

rugs

, hea

lth c

are

deliv

ery,

few

er a

dver

se e

vent

s an

d lo

wer

re

treat

men

t and

loss

-to-

follo

w-u

p ra

tes.


Cost

eff

ecti

vene

ssD

oes

the

cost

-eff

ectiv

enes

s of

the

inte

rven

tion

favo

r the

inte

rven

tion

or th

e co

mpa

rison

?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Fav

ors

the

com

paris

on

○ P

roba

bly

favo

rs

the

com

paris

on

○ D

oes

not

favo

r eith

er th

e in

terv

entio

n or

the

com

paris

on

○ P

roba

bly

favo

rs

the

inte

rven

tion

● Fa

vors

the

inte

rven

tion

○ V

arie

s ○

No

inclu

ded

stud

ies

No

cost

–effe

ctiv

enes

s an

alys

is w

as p

erfo

rmed

onl

y fo

r cur

rent

ly re

com

men

ded

com

para

tor

regi

men

s. A

long

er re

gim

en c

onta

inin

g no

new

TB

drug

s w

as n

ot s

epar

atel

y m

odel

led.

Al

thou

gh th

e an

alyt

ic-de

cisio

n m

odel

did

not

focu

s on

co

mpa

ring

cost

sav

ings

and

cos

t–ef

fect

iven

ess

rela

tive

to

long

er re

gim

ens

with

out t

he u

se o

f any

new

dru

gs, t

he G

DG

di

d ac

know

ledg

e th

at th

e sh

orte

ning

of t

he re

gim

en a

nd

the

switc

h fro

m in

ject

able

s to

ora

l dru

gs a

re e

stim

ated

to b

e re

sour

ce s

avin

g as

a re

sult

of s

avin

gs o

n dr

ugs,

heal

th c

are

deliv

ery,

and

redu

ced

rate

s of

adv

erse

eve

nts.

Equi

tyW

hat w

ould

be

the

impa

ct o

n he

alth

equ

ity?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Red

uced

○

Pro

babl

y re

duce

d ○

Pro

babl

y no

im

pact

○

Pro

babl

y in

crea

sed

● In

crea

sed

○ V

arie

s ○

Don

’t kn

ow

A qu

alita

tive

stud

y un

dert

aken

to h

ighl

ight

the

pers

pect

ives

of k

ey s

take

hold

ers,

mai

nly

patie

nts

and

civil

socie

ty re

pres

enta

tives

(n =

16)

, loo

ked

at g

ener

al p

refe

renc

es a

nd v

alue

s re

gard

ing

diffe

rent

asp

ects

of t

reat

men

t reg

imen

s fo

r dru

g-re

sista

nt T

B, s

uch

as d

urat

ion,

pill

burd

en, u

se o

f in

ject

able

age

nts,

and

pote

ntia

l for

exp

erie

ncin

g ad

vers

e ev

ents

.Pa

rtici

pant

s co

nsid

ered

any

thin

g le

ss th

an u

nive

rsal

and

imm

edia

te a

cces

s to

new

trea

tmen

ts to

be

une

thica

l, bu

t whe

n pr

ompt

ed to

con

sider

this

pref

eren

ce a

gain

st a

lim

ited

supp

ly o

f dru

gs, a

fe

w w

ould

prio

ritiz

e th

e yo

unge

st a

nd s

ickes

t, as

wel

l as

thos

e w

ho w

ere

adhe

rent

and

cou

ld b

e m

onito

red

for a

dver

se e

vent

s. Pa

tient

s w

ho fa

ce s

ocio

econ

omic

chal

leng

es to

adh

eren

ce o

r who

liv

e in

rem

ote,

rura

l, or

poo

rer c

omm

uniti

es th

at la

ck te

chni

cal s

kill o

r equ

ipm

ent f

or tr

eatm

ent

mon

itorin

g co

uld

then

be

disp

ropo

rtio

nate

ly a

nd u

njus

tly p

lace

d at

a d

isadv

anta

ge.

The

GD

G a

gree

d th

at th

e al

l-ora

l sho

rter

regi

men

wou

ld b

e ea

sier t

o de

cent

raliz

e an

d th

eref

ore

mak

e av

aila

ble

to re

mot

e an

d un

ders

ervi

ced

setti

ngs

and

disa

dvan

tage

d po

pula

tions

, he

lpin

g to

alle

viat

e he

alth

ineq

uitie

s, w

ithou

t ant

icipa

ting

diffe

renc

es in

out

com

es in

spe

cific

popu

latio

ns. F

urth

er, t

he

grou

p no

ted

that

bec

ause

aud

iom

etry

wou

ld n

ot b

e re

quire

d,

it m

ight

be

easie

r to

mon

itor i

ndiv

idua

ls, in

spi

te o

f inc

reas

ed

requ

irem

ents

for e

lect

roca

rdio

grap

hy, w

hich

is a

pre

requ

isite

fo

r the

use

of b

edaq

uilin

e-co

ntai

ning

regi

men

s. H

owev

er,

the

grou

p st

ress

ed th

at th

e us

e of

ele

ctro

card

iogr

aphy

sh

ould

not

be

a di

ffere

ntia

ting

elem

ent b

etw

een

thes

e tw

o re

gim

ens,

beca

use

patie

nts

rece

ivin

g in

ject

able

age

nts

such

as

am

ikacin

sho

uld

also

hav

e re

gula

r car

diac

mon

itorin

g. T

he

grou

p ac

know

ledg

ed th

at it

is p

ossib

le th

at, i

n so

me

setti

ngs,

not a

ll pa

tient

s w

ill be

abl

e to

und

ergo

ele

ctro

card

iogr

aphi

c m

onito

ring;

how

ever

, mem

bers

also

not

ed th

at th

e in

crea

sing

acce

ss to

ele

ctro

card

iogr

aphy

at p

erip

hera

l lev

els

mig

ht

impr

ove

equi

ty.


Acc

epta

bilit

yIs

the

inte

rven

tion

acce

ptab

le to

key

sta

keho

lder

s?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

No

○ P

roba

bly

no

○ P

roba

bly

yes

● Ye

s ○

Var

ies

○ D

on’t

know

A qu

alita

tive

stud

y un

dert

aken

to h

ighl

ight

the

pers

pect

ives

of k

ey s

take

hold

ers,

mai

nly

patie

nts

and

civil

socie

ty re

pres

enta

tives

(n =

16)

, loo

ked

at g

ener

al p

refe

renc

es a

nd v

alue

s re

gard

ing

diffe

rent

asp

ects

of t

reat

men

t reg

imen

s fo

r dru

g-re

sista

nt T

B, s

uch

as d

urat

ion,

pill

burd

en,

use

of in

ject

able

age

nts,

and

pote

ntia

l for

exp

erie

ncin

g ad

vers

e ev

ents

. The

resu

lts o

f thi

s qu

alita

tive

anal

ysis

sugg

este

d th

at m

ost p

atie

nts

wou

ld p

riorit

ize

a re

gim

en w

ith fe

wer

and

less

se

vere

sid

e-ef

fect

s ab

ove

all e

lse, b

ecau

se it

wou

ld a

llow

them

to c

ontin

ue ro

utin

e ac

tiviti

es. O

f no

te, s

urvi

vors

of d

rug-

resis

tant

TB

rem

arke

d th

at th

ey w

ould

acc

ept a

long

er tr

eatm

ent t

hat

prom

ised

less

sev

ere

adve

rse

effe

cts

over

a s

hort

er re

gim

en ti

ed to

mor

e se

vere

sid

e-ef

fect

s, ev

en if

trea

tmen

t was

exp

erim

enta

l or e

ffica

cy w

as u

ncle

ar. T

his

cont

rast

ed w

ith c

ompa

rativ

ely

few

par

ticip

ants

who

prio

ritiz

ed a

rapi

d re

turn

to n

orm

al li

fe a

nd w

ould

rath

er a

ssum

e th

e ris

k of

mor

e se

rious

sid

e-ef

fect

s w

ithin

a s

hort

er re

gim

en, e

ven

if tre

atm

ent w

as e

xper

imen

tal a

nd

effic

acy

was

unc

lear

.

The

GD

G n

oted

that

pat

ient

s re

cogn

ize

that

thei

r exp

erie

nces

an

d pe

rcep

tions

are

hig

hly

pers

on-

and

cont

ext-d

epen

dent

, th

ough

pre

fere

nce

over

this

[sho

rter

] reg

imen

see

med

to b

e co

nditi

onal

upo

n ad

vers

e ev

ents

bei

ng ra

re o

r rev

ersib

le.

Nev

erth

eles

s, ov

eral

l, a

shor

t, in

ject

ion-

free

regi

men

with

few

to

no p

hysic

al a

nd m

enta

l hea

lth s

ide-

effe

cts

and

a lo

w p

ill bu

rden

ap

pear

ed to

be

the

mos

t acc

epta

ble.


Feas

ibili

tyIs

the

inte

rven

tion

feas

ible

to im

plem

ent?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

No

○ P

roba

bly

no

○ P

roba

bly

yes

○ Y

es

● Va

ries

○ D

on’t

know

A qu

alita

tive

stud

y un

dert

aken

to h

ighl

ight

the

pers

pect

ives

of k

ey s

take

hold

ers,

mai

nly

patie

nts

and

civil

socie

ty re

pres

enta

tives

(n =

16)

, loo

ked

at g

ener

al p

refe

renc

es a

nd v

alue

s re

gard

ing

diffe

rent

asp

ects

of t

reat

men

t reg

imen

s fo

r dru

g-re

sista

nt T

B, s

uch

as d

urat

ion,

pill

burd

en, u

se o

f in

ject

able

age

nts,

and

pote

ntia

l for

exp

erie

ncin

g ad

vers

e ev

ents

.Th

is st

udy

reve

aled

that

bec

ause

the

regi

men

– in

par

ticul

ar th

e ex

pans

ion

of b

edaq

uilin

e ac

cess

to

all

patie

nts

– is

held

bac

k in

som

e se

tting

s as

a re

sult

of re

stric

tive

elig

ibilit

y (i.

e. p

riorit

izat

ion

of s

pecif

ic gr

oups

) crit

eria

, lac

k of

fund

ing,

or l

ack

of a

dequ

ate

infra

stru

ctur

e in

pla

ce (e

.g.

diag

nost

ics),

the

oper

atio

naliz

atio

n an

d im

med

iate

rollo

ut o

f the

all-

oral

bed

aqui

line-

cont

aini

ng

regi

men

mig

ht b

e ha

mpe

red.

One

impo

rtan

t req

uire

men

t hig

hlig

hted

by

the

GD

G w

as th

at

of e

nsur

ing

the

care

ful s

elec

tion

of p

atie

nts

who

are

to b

enef

it fro

m th

is re

gim

en, c

ondu

ctin

g ra

pid

and

accu

rate

DST

, and

m

onito

ring

beda

quilin

e re

sista

nce.

The

impl

emen

tatio

n of

the

regi

men

may

be

limite

d by

the

need

for i

mpr

oved

labo

rato

ry

infra

stru

ctur

e. A

lthou

gh c

ount

ries

are

impl

emen

ting

rapi

d m

olec

ular

test

s to

iden

tify

rifam

picin

resis

tanc

e, la

bora

tory

ca

pacit

y ne

eds

to b

e ef

fect

ivel

y es

tabl

ished

to c

ondu

ct

geno

typi

c an

d ph

enot

ypic

test

ing

for o

ther

impo

rtan

t age

nts

in th

e re

gim

en. A

lso, a

lthou

gh th

e pr

eval

ence

of i

dent

ified

m

utat

ions

con

ferr

ing

low

-leve

l dru

g re

sista

nce

is ve

ry lo

w,

coun

tries

are

to s

treng

then

labo

rato

ry c

apac

ity a

nd to

mon

itor

the

acqu

isitio

n of

resis

tanc

e to

bed

aqui

line

thou

gh th

eir

natio

nal r

efer

ence

labo

rato

ries

or T

B su

pran

atio

nal r

efer

ence

ne

twor

k sit

es. T

his

is es

pecia

lly im

port

ant g

iven

the

pipe

line

of n

ew a

nti-T

B re

gim

ens

that

are

rely

ing

on b

edaq

uilin

e as

a

back

bone

.Th

e re

mov

al o

f inj

ecta

ble

agen

ts, a

s di

scus

sed

by th

e G

DG

, also

po

inte

d to

war

ds th

e co

nven

ienc

e (fo

r hea

lth c

are

wor

kers

) of

not h

avin

g to

del

iver

dai

ly in

ject

ions

, and

mor

e so

, for

pat

ient

s no

t hav

ing

to e

ndur

e pa

in a

nd o

ther

sig

nific

ant a

dver

se e

vent

s.Th

e im

plem

enta

tion

of th

e re

gim

en is

per

ceiv

ed to

go

beyo

nd

secu

ring

of fu

ndin

g, b

ut it

furt

her r

equi

res

mak

ing

long

-te

rm, s

usta

inab

le s

yste

ms

chan

ges

to e

nsur

e ra

pid

trans

ition

, co

nsid

erin

g th

e re

gist

ratio

n of

bed

aqui

line

and

othe

r new

ag

ents

, uni

nter

rupt

ed s

uppl

y of

qua

lity-

assu

red

drug

s, an

d ac

tive

TB d

rug

safe

ty m

onito

ring

and

man

agem

ent s

yste

m in

co

ordi

natio

n w

ith e

xistin

g ph

arm

acov

igila

nce

stru

ctur

es a

t the

co

untr

y le

vel.

Also

, the

impl

emen

tatio

n of

this

regi

men

(and

any

oth

er n

ovel

re

gim

en) w

ill re

quire

dec

ision

-mak

ing

tow

ards

mul

tisec

tora

l po

licie

s, ta

ilorin

g pa

tient

-cen

tred

prog

ram

mes

that

also

co

nsid

er a

spec

ts s

uch

as m

enta

l hea

lth a

nd m

anag

emen

t of

othe

r com

orbi

ditie

s, fa

cilita

ting

coun

sellin

g an

d su

ppor

t dur

ing

treat

men

t, an

d af

ter c

ompl

etio

n, fa

cilita

ting

full

reco

very

.


Sum

mar

y of

judg

emen

ts

JUD

GEM

ENTS

PRO

BLEM

No

Prob

ably

no

Prob

ably

yes

Yes

Varie

sD

on’t

know

DES

IRAB

LE E

FFEC

TSTr

ivia

lSm

all

Mod

erat

eLa

rge

Varie

sD

on’t

know

UND

ESIR

ABLE

EFF

ECTS

Larg

eM

oder

ate

Smal

lTr

ivia

lVa

ries

Don

’t kn

owCE

RTAI

NTY

OF

EVID

ENCE

Very

low

Low

Mod

erat

eH

igh

No

inclu

ded

stud

ies

VALU

ESIm

port

ant

unce

rtai

nty

or

varia

bilit

y

Poss

ibly

impo

rtan

t un

cert

aint

y or

va

riabi

lity

Prob

ably

no

impo

rtan

t un

cert

aint

y or

va

riabi

lity

No

impo

rtan

t un

cert

aint

y or

va

riabi

lity

BALA

NCE

OF

EFFE

CTS

Favo

rs th

e co

mpa

rison

Prob

ably

favo

rs th

e co

mpa

rison

Doe

s no

t fav

or

eith

er th

e in

terv

entio

n or

the

com

paris

on

Prob

ably

favo

rs th

e in

terv

entio

nFa

vors

the

inte

rven

tion

Varie

sD

on’t

know

RESO

URCE

S RE

QUI

RED

Larg

e co

sts

Mod

erat

e co

sts

Neg

ligib

le c

osts

and

sa

ving

sM

oder

ate

savi

ngs

Larg

e sa

ving

sVa

ries

Don

’t kn

ow

CERT

AIN

TY O

F EV

IDEN

CE

OF

REQ

UIRE

D R

ESO

URCE

SVe

ry lo

wLo

wM

oder

ate

Hig

hN

o in

clude

d st

udie

s

COST

EFF

ECTI

VEN

ESS

Favo

rs th

e co

mpa

rison

Prob

ably

favo

rs th

e co

mpa

rison

Doe

s no

t fav

or

eith

er th

e in

terv

entio

n or

the

com

paris

on

Prob

ably

favo

rs th

e in

terv

entio

nFa

vors

the

inte

rven

tion

Varie

sN

o in

clude

d st

udie

s

EQUI

TYRe

duce

dPr

obab

ly re

duce

dPr

obab

ly n

o im

pact

Prob

ably

incr

ease

dIn

crea

sed

Varie

sD

on’t

know

ACCE

PTAB

ILIT

YN

oPr

obab

ly n

oPr

obab

ly y

esYe

sVa

ries

Don

’t kn

owFE

ASIB

ILIT

YN

oPr

obab

ly n

oPr

obab

ly y

esYe

sVa

ries

Don

’t kn

ow

Type

of r

ecom

men

datio

nSt

rong

reco

mm

enda

tion

agai

nst

the

inte

rven

tion

○

Cond

ition

al re

com

men

datio

n ag

ains

t the

inte

rven

tion

○

Cond

ition

al re

com

men

datio

n fo

r eith

er th

e in

terv

entio

n or

the

com

paris

on○

Cond

ition

al re

com

men

datio

n fo

r th

e in

terv

entio

n●

Stro

ng re

com

men

datio

n fo

r the

in

terv

entio

n○


Conc

lusi

ons

Reco

mm

enda

tion

A sh

orte

r, al

l-ora

l, be

daqu

iline-

cont

aini

ng re

gim

en o

f 9–1

2 m

onth

s’ du

ratio

n is

reco

mm

ende

d in

elig

ible

pat

ient

s w

ith c

onfir

med

MD

R/RR

-TB

who

hav

e no

t bee

n ex

pose

d to

trea

tmen

t w

ith s

econ

d-lin

e TB

med

icine

s us

ed in

this

regi

men

for m

ore

than

one

mon

th a

nd in

who

m re

sista

nce

to fl

uoro

quin

olon

es h

as b

een

exclu

ded.

(Con

ditio

nal r

ecom

men

datio

n, v

ery

low

cer

tain

ty in

the

evid

ence

)Ju

stifi

catio

nO

vera

ll, th

e G

DG

not

ed th

at th

e ce

rtai

nty

of th

e ev

iden

ce re

gard

ing

the

effic

acy

of th

e al

l-ora

l sho

rter

regi

men

was

“ver

y lo

w”,

attri

buta

ble

nam

ely

to c

once

rns

of s

erio

us ri

sk o

f bia

s, de

spite

effo

rts

to b

alan

ce b

asel

ine

cova

riate

s. H

owev

er, t

he g

roup

reco

gniz

ed th

at th

e cu

rrent

evi

denc

e as

sess

men

t of t

he a

ll-or

al, b

edaq

uilin

e-co

ntai

ning

sho

rter

regi

men

has

som

e ad

ditio

nal a

dvan

tage

s as

com

pare

d w

ith a

ll-or

al lo

nger

regi

men

s, na

mel

y in

term

s of

low

er lo

ss to

follo

w-u

p (d

esira

ble

effe

ct) a

nd o

bvio

us s

hort

er d

urat

ion

(acc

epta

bilit

y).

Whe

n de

cidin

g on

the

stre

ngth

of t

he re

com

men

datio

n, th

e G

DG

reac

hed

a un

anim

ous

decis

ion

on th

e co

nditi

onal

ity o

f the

reco

mm

enda

tion,

mai

nly

attri

bute

d to

the

very

low

cer

tain

ty

in th

e ev

iden

ce a

nd re

quire

men

ts to

bui

ld la

bora

tory

cap

acity

and

ens

ure

DST

.O

ther

gro

unds

for t

he s

treng

th a

nd d

irect

ion

of th

is re

com

men

datio

n ar

e as

follo

ws:

• Th

e an

alys

is co

nduc

ted

to in

form

the

deve

lopm

ent o

f thi

s re

com

men

datio

n w

as b

ased

on

obse

rvat

iona

l pro

gram

mat

ic da

ta fr

om S

outh

Afri

ca w

here

the

stan

dard

ized

sho

rter

, all-

oral

, be

daqu

iline-

cont

aini

ng re

gim

en (B

DQ

-LFX

/MFX

-ETO

-E-Z

-Hh -C

FZ) w

as u

sed

for p

atie

nts

with

MD

R/RR

-TB.

• Th

ough

no

maj

or s

igna

ls of

risk

wer

e ob

serv

ed w

ith th

e us

e of

the

all-o

ral b

edaq

uilin

e-ba

sed

shor

ter r

egim

en, t

here

also

rem

aine

d so

me

unce

rtai

ntie

s gi

ven

the

lack

of s

yste

mat

ic co

llect

ion

of d

ata,

and

the

lack

of c

larit

y as

to a

ny c

hang

es in

the

regi

men

that

cou

ld h

ave

been

info

rmed

by

the

pres

ence

of a

dver

se e

vent

s.•

Cost

–effe

ctiv

enes

s m

odel

ling

of th

e al

l-ora

l, sh

orte

r, be

daqu

iline-

cont

aini

ng re

gim

en s

how

ed ro

bust

cos

t sav

ings

rela

tive

to e

ither

a lo

nger

ora

l reg

imen

or a

sho

rt in

ject

able

-co

ntai

ning

regi

men

.•

The

GD

G ju

dged

that

man

y el

igib

le p

atie

nts

wou

ld p

refe

r the

all-

oral

, bed

aqui

line-

cont

aini

ng re

gim

en o

f 9–1

2 m

onth

s’ du

ratio

n. T

his

is su

ppor

ted

by li

mite

d ob

serv

atio

ns in

volv

ing

16 s

urvi

vors

of d

rug-

resis

tant

TB.

In a

dditi

on, t

his

regi

men

may

hel

p pr

omot

e he

alth

equ

ity o

r miti

gate

the

wor

seni

ng o

f hea

lth in

equi

ties.

How

ever

, the

pan

el re

cogn

ized

that

im

plem

enta

tion

and

scal

e-up

of t

his

regi

men

mig

ht b

e slo

w b

ecau

se o

f pre

requ

isite

s re

gard

ing

labo

rato

ry c

apac

ity a

nd m

onito

ring.

Subg

roup

con

side

ratio

nsTh

e an

alys

is at

tem

pted

to d

escr

ibe

the

bala

nce

of e

ffect

s an

d co

nsid

erat

ions

for v

ario

us s

ubgr

oups

or s

pecia

l pop

ulat

ions

. How

ever

, the

evi

denc

e re

view

ed s

uppo

rted

the

use

of th

is in

th

e fo

llow

ing

setti

ngs,

with

spe

cific

cave

ats:

• Pe

ople

livi

ng w

ith H

IV in

fect

ion

(PLH

IV):

The

data

eva

luat

ed c

orre

spon

ded

to a

set

ting

with

a h

igh

prev

alen

ce o

f HIV

, and

of p

artic

ular

sig

nific

ance

, mos

t PLH

IV (>

95%

) who

sta

rted

th

e al

l-ora

l bed

aqui

line-

cont

aini

ng re

gim

en w

ere

rece

ivin

g an

tiret

rovi

ral t

hera

py (A

RT)..

In v

iew

of t

he tr

eatm

ent o

utco

mes

des

crib

ed in

the

anal

ysis,

ther

e w

ere

no g

roun

ds to

bel

ieve

th

at th

e re

gim

en w

ould

per

form

any

diff

eren

tly in

PLH

IV. I

t is

nece

ssar

y to

con

sider

sig

nific

ant c

linica

l int

erac

tions

that

may

incr

ease

bed

aqui

line

expo

sure

or t

hat o

f oth

er a

gent

s w

ith

pote

ntia

l for

car

diot

oxici

ty w

hen

thes

e ar

e co

-adm

inist

ered

with

ant

iretro

vira

ls.•

Child

ren:

Alth

ough

no

dire

ct o

utco

me

estim

atio

ns c

ould

be

draw

n fo

r thi

s po

pula

tion,

ext

rapo

latio

n w

as d

eem

ed re

ason

able

. How

ever

, bec

ause

bed

aqui

line

is cu

rrent

ly re

com

men

ded

for c

hild

ren

and

adol

esce

nts

aged

6–1

7 ye

ars,

the

GD

G c

onclu

ded

that

the

all-o

ral b

edaq

uilin

e-co

ntai

ning

regi

men

may

be

used

in e

ligib

le c

hild

ren

with

in th

is ag

e gr

oup,

takin

g in

to

acco

unt s

pecif

icatio

ns fo

r reg

imen

com

pani

on d

rugs

, in

part

icula

r, be

daqu

iline.

• Pr

egna

nt a

nd la

ctat

ing

wom

en: M

ore

evid

ence

is n

eede

d to

bet

ter i

nfor

m th

e us

e of

the

all-o

ral,

beda

quilin

e-co

ntai

ning

sho

rter

regi

men

(BD

Q-L

FX/M

FX-E

TO-E

-Z-H

h -CFZ

). O

ne

of th

e ag

ents

in th

is al

l-ora

l sho

rter

regi

men

, eth

iona

mid

e, is

usu

ally

con

train

dica

ted

in p

regn

ancy

, and

with

hold

ing

this

agen

t or r

epla

cing

it w

ith a

noth

er o

ne c

ould

ser

ious

ly

com

prom

ise th

e ef

fect

iven

ess

of th

e re

gim

en. F

or p

regn

ant a

nd la

ctat

ing

wom

en, i

t is

ther

efor

e re

com

men

ded

that

an

indi

vidu

aliz

ed, a

ll-or

al lo

nger

regi

men

(with

inclu

sion

of

beda

quilin

e) b

e us

ed (s

ee R

ecom

men

datio

ns o

n th

e us

e of

long

er re

gim

ens

for M

DR/

RR-T

B).

–Ex

trapu

lmon

ary

dise

ase:

In v

iew

of t

he u

nava

ilabi

lity

of e

vide

nce

rega

rdin

g su

rroga

tes

for s

ever

ity o

r ext

ent o

f dise

ase,

it is

adv

isabl

e to

use

clin

ical j

udge

men

t to

decid

e on

the

use

of th

is re

gim

en in

pat

ient

s w

ith e

xten

sive

TB d

iseas

e or

sev

ere

form

s of

ext

rapu

lmon

ary

TB.


Impl

emen

tatio

n co

nsid

erat

ions

The

inte

rest

in re

ducin

g th

e du

ratio

n of

trea

tmen

t for

MD

R/RR

-TB

has

mot

ivat

ed a

num

ber o

f stu

dies

in re

cent

yea

rs to

trea

t pat

ient

s w

ith s

hort

er re

gim

ens

unde

r pro

gram

mat

ic as

wel

l as

tria

l con

ditio

ns. B

ecau

se o

f exp

erie

nces

in v

ario

us s

ettin

gs, [

elig

ible

] pat

ient

s no

w h

ave

an o

ptio

n to

be

treat

ed w

ith a

sho

rter

, inj

ecta

ble-

spar

ing

regi

men

of 9

–12

mon

ths’

dura

tion.

To

ensu

re th

at th

e re

gim

en a

chie

ves

its d

esira

ble

effe

cts

and

prev

ent t

he a

cqui

sitio

n (o

r am

plifi

catio

n) o

f add

ition

al d

rug

resis

tanc

e (w

hile

pro

tect

ing

regi

men

com

pone

nts)

, cou

ntrie

s ar

e to

co

nsid

er th

e fo

llow

ing:

• Pa

tient

sel

ectio

n an

d de

cisio

ns to

sta

rt th

e al

l-ora

l sho

rter

regi

men

: Pat

ient

s w

ith c

onfir

med

MD

R/RR

-TB

and

with

resis

tanc

e to

fluo

roqu

inol

ones

rule

d ou

t are

exp

ecte

d to

ben

efit

the

mos

t fro

m th

is re

gim

en. P

rope

r pat

ient

sel

ectio

n w

ill no

t onl

y le

ad to

impr

oved

trea

tmen

t out

com

es, b

ut w

ill al

so c

ontri

bute

to a

void

ing

the

deve

lopm

ent o

f res

istan

ce to

bed

aqui

line.

In

this

resp

ect,

the

regi

men

is to

onl

y be

impl

emen

ted

in s

ettin

gs w

here

rout

ine

DST

for r

ifam

picin

and

fluo

roqu

inol

ones

can

be

guar

ante

ed.

It is

very

impo

rtan

t tha

t the

impl

emen

tatio

n of

thes

e re

com

men

datio

ns is

acc

ompa

nied

by

cont

inue

d ef

fort

s to

incr

ease

acc

ess

to D

ST fo

r all

med

icine

s fo

r whi

ch re

liabl

e m

etho

ds

exist

, as

wel

l as

for t

he d

evel

opm

ent a

nd ro

llout

of D

ST m

etho

ds fo

r new

er m

edici

nes.

In th

e ab

senc

e of

a d

rug-

susc

eptib

ility

test

, ass

ays

spec

ific

for b

edaq

uilin

e re

sista

nce

shou

ld b

e m

onito

red

thro

ugh

asse

ssm

ent o

f min

imum

inhi

bito

ry c

once

ntra

tions

(MIC

s) o

f bed

aqui

line.

Resis

tanc

e to

oth

er a

nti-T

B dr

ugs

shou

ld b

e m

onito

red

in a

ccor

danc

e w

ith W

HO

reco

mm

enda

tions

.•

Use

of li

nezo

lid: T

he e

vide

nce

mad

e av

aila

ble

to in

form

this

reco

mm

enda

tion

focu

sed

on th

e as

sess

men

t of a

regi

men

com

pose

d of

bed

aqui

line,

levo

floxa

cin/m

oxifl

oxac

in,

ethi

onam

ide,

eth

ambu

tol,

pyra

zina

mid

e, h

igh-

dose

ison

iazi

d, c

lofa

zim

ine,

and

pyr

azin

amid

e. H

owev

er, s

econ

dary

ana

lyse

s (o

nly

in lo

nger

regi

men

s co

ntai

ning

bed

aqui

line

and

beda

quilin

e pl

us li

nezo

lid) s

how

ed fa

vour

able

out

com

es w

hen

treat

men

t reg

imen

s in

clude

d bo

th li

nezo

lid a

nd b

edaq

uilin

e. T

he b

asis

for t

he a

dditi

on o

f lin

ezol

id w

as to

pro

tect

the

regi

men

– in

par

ticul

ar, b

edaq

uilin

e –

whi

le a

wai

ting

susc

eptib

ility

resu

lts o

n ad

ditio

nal r

esist

ance

to fl

uoro

quin

olon

es a

nd o

ther

dru

gs. T

he G

DG

dec

ided

that

unt

il ne

w e

vide

nce

is av

aila

ble

on s

hort

er re

gim

ens

that

inclu

de b

oth

of th

ese

agen

ts, t

he a

ll-or

al b

edaq

uilin

e-co

ntai

ning

sho

rter

regi

men

adv

ised

here

in s

houl

d no

t inc

lude

line

zolid

. How

ever

, the

gro

up

enco

urag

ed c

ount

ries

to c

onsid

er th

e us

e of

a m

odifie

d al

l-ora

l bed

aqui

line-

and

linez

olid

-con

tain

ing

only

unde

r ope

ratio

nal r

esea

rch

until

new

evid

ence

bec

omes

ava

ilabl

e.•

Patie

nt-c

entre

d ap

proa

ch: E

ffort

s ar

e re

quire

d to

pro

vide

pat

ient

sup

port

to e

nabl

e fu

ll ad

here

nce

to tr

eatm

ent.

Mon

itorin

g an

d ev

alua

tion

• Th

e im

plem

enta

tion

of th

is re

gim

en re

quire

s th

e us

e of

rout

ine

DST

not

onl

y fo

r pat

ient

sel

ectio

n, b

ut a

lso fo

r mon

itorin

g of

the

acqu

isitio

n of

resis

tanc

e.•

Alth

ough

the

data

ass

esse

d di

d no

t une

arth

any

maj

or s

igna

ls of

risk

, act

ive

TB d

rug

safe

ty m

onito

ring

and

man

agem

ent s

yste

ms

mus

t be

func

tiona

l in

orde

r to

cond

uct r

igor

ous

activ

e m

onito

ring

of a

dver

se e

vent

s an

d to

det

ect,

man

age

and

repo

rt s

uspe

cted

or c

onfir

med

dru

g to

xiciti

es in

a ti

mel

y m

anne

r.

Rese

arch

prio

ritie

sM

embe

rs o

f the

GD

G d

iscus

sed

the

rese

arch

gap

s to

info

rm th

e de

velo

pmen

t of p

ublic

hea

lth re

com

men

datio

ns fo

r the

man

agem

ent a

nd c

are

of p

atie

nts

with

MD

R/RR

-TB,

and

hi

ghlig

hted

the

follo

win

g pr

iorit

ies:

• st

udie

s as

sess

ing

com

paris

ons

of a

ll-or

al s

hort

er re

gim

ens

whi

ch in

clude

bed

aqui

line

and

linez

olid

, in

addi

tion

to o

ther

com

pani

on d

rugs

;•

stud

ies

asse

ssin

g co

mpa

rison

s of

all-

oral

sho

rter

regi

men

s am

ong

diffe

rent

sub

grou

ps a

nd s

pecia

l pop

ulat

ions

, inc

ludi

ng p

regn

ant a

nd la

ctat

ing

wom

en;

• ra

ndom

ized

-con

trolle

d tri

als

or o

pera

tiona

l res

earc

h of

the

effe

ctiv

enes

s an

d sa

fety

of a

ll-or

al s

hort

er re

gim

ens,

incr

easin

g th

e ce

rtai

nty

of th

e ev

iden

ce;

• st

udie

s ex

plor

ing

mec

hani

sms

of a

cqui

sitio

n of

resis

tanc

e to

bed

aqui

line

and

gene

tic m

arke

rs to

iden

tify

resis

tanc

e; a

nd•

effo

rts

to d

eter

min

e be

st w

ays

to s

tand

ardi

ze th

e co

llect

ion

of d

ata

so th

at c

ount

ries

can

cont

ribut

e to

the

deve

lopm

ent o

f glo

bal r

ecom

men

datio

ns.

aOR:

adj

uste

d od

ds ra

tio; A

RT: a

ntire

trovi

ral t

hera

py; d

rug-

susc

eptib

ility

test

ing;

GD

F: G

loba

l Dru

g Fa

cility

; GD

G: G

uide

line

Dev

elop

men

t Gro

up; M

DR/

RR-T

B: m

ultid

rug-

or r

ifam

picin

-res

istan

t TB;

MIC

: min

imum

in

hibi

tory

con

cent

ratio

n; P

LHIV

: peo

ple

livin

g w

ith h

uman

imm

unod

efici

ency

viru

s; TB

: tub

ercu

losis

; WH

O: W

orld

Hea

lth O

rgan

izat

ion.


Shou

ld a

trea

tmen

t reg

imen

last

ing

6–9

mon

ths

com

pose

d of

bed

aqui

line,

pre

tom

anid

and

line

zolid

vs

long

er re

gim

ens

cont

aini

ng b

edaq

uilin

e an

d lin

ezol

id in

add

ition

to

oth

er a

nti-

TB d

rugs

be

used

for X

DR-

TB p

atie

nts

or p

atie

nts

who

are

trea

tmen

t int

oler

ant o

r with

non

-res

pons

ive

MD

R-TB

?PO

PULA

TIO

N:

XDR-

TB p

atie

nts

or p

atie

nts

who

are

trea

tmen

t int

oler

ant o

r with

non

-res

pons

ive

MD

R-TB

INTE

RVEN

TIO

N:

Trea

tmen

t reg

imen

last

ing

6–9

mon

ths

com

pose

d of

bed

aqui

line,

pre

tom

anid

and

line

zolid

CO

MPA

RISO

N:

Long

er re

gim

ens

cont

aini

ng b

edaq

uilin

e an

d lin

ezol

id in

add

ition

to o

ther

ant

i-TB

drug

s M

AIN

OUT

COM

ES:

Succ

ess

vs. F

ailu

re/R

ecur

renc

e; S

ucce

ss v

s. D

eath

; Suc

cess

vs.

Failu

re/R

ecur

renc

e/D

eath

; Suc

cess

vs.

All U

nfav

orab

le; A

dver

se e

vent

s;SE

TTIN

G:

Trea

tmen

t of M

DR-

TB p

atie

nts

with

add

ition

al fl

uoro

quin

olon

e re

sista

nce

and

/ or M

DR-

TB p

atie

nts

who

are

trea

tmen

t int

oler

ant o

r who

had

not

resp

onde

d to

pre

viou

s M

DR-

TB tr

eatm

ent,

usin

g a

shor

ter r

egim

en c

ompo

sed

of b

edaq

uilin

e, p

reto

man

id a

nd li

nezo

lid (B

PaL)

of 6

–9 m

onth

s du

ratio

n in

a c

ombi

natio

n of

hos

pita

l and

am

bula

tory

car

e se

tting

s in

Sou

th A

frica

. The

dat

a w

ere

deriv

ed fr

om th

e N

ix-TB

stu

dy, w

ith 1

08 p

atie

nts

inclu

ded

for a

naly

sis (t

he w

hole

stu

dy

popu

latio

n w

as 1

09 p

atie

nts,

how

ever

one

pat

ient

with

drew

con

sent

and

this

pers

on w

as n

ot in

clude

d in

the

effic

acy

anal

yses

)PE

RSPE

CTIV

E:Pu

blic

heal

th a

nd h

ealth

sys

tem

sBA

CKG

ROUN

D:

Trea

tmen

t of e

xten

sivel

y dr

ug-r

esist

ant f

orm

s of

TB

pres

ents

mul

tiple

cha

lleng

es to

clin

ician

s an

d na

tiona

l TB

prog

ram

mes

bot

h du

e to

the

limite

d ra

nge

of

med

icine

s av

aila

ble

and

the

life-

thre

aten

ing

natu

re o

f the

dise

ase.

Pat

ient

s w

ith M

DR/

RR-T

B an

d ad

ditio

nal f

luor

oqui

nolo

ne re

sista

nce

have

typi

cally

exp

erie

nced

po

or tr

eatm

ent o

utco

mes

sin

ce th

e de

scrip

tion

of X

DR-

TB w

as fi

rst u

sed

in 2

006.

5 Bas

ed o

n da

ta re

port

ed b

y M

embe

r Sta

tes

to W

HO

, for

the

coho

rt o

f XD

R-TB

pa

tient

s w

ho s

tart

ed tr

eatm

ent i

n 20

16 (a

nd fo

r who

m tr

eatm

ent o

utco

mes

wer

e av

aila

ble

in 2

018)

, onl

y 39

% c

ompl

eted

trea

tmen

t suc

cess

fully

, whi

le 2

6% d

ied,

tre

atm

ent f

aile

d fo

r 18%

and

an

addi

tiona

l 18%

wer

e lo

st to

follo

w u

p or

wer

e no

t eva

luat

ed.6 T

he p

ress

ing

need

for m

ore

effe

ctiv

e tre

atm

ent r

egim

ens

for p

atie

nts

with

ext

ensiv

e dr

ug re

sista

nce,

inclu

ding

fluo

roqu

inol

one

resis

tanc

e an

d m

ore

exte

nsiv

e dr

ug re

sista

nce

prof

iles,

has

mot

ivat

ed a

num

ber o

f stu

dies

and

initi

ativ

es

to te

st m

ore

effe

ctiv

e an

d no

vel t

reat

men

t reg

imen

s, in

clusiv

e of

new

er a

nd re

purp

osed

med

icine

s. O

ne su

ch st

udy

is th

e N

ix-TB

stud

y,7 con

duct

ed b

y TB

Allia

nce.

The

Nix-

TB st

udy

was

a o

ne a

rm, p

hase

thre

e, o

pen

labe

l pro

spec

tive

coho

rt st

udy

that

ass

esse

d th

e sa

fety

, effi

cacy

, tol

erab

ility

and

phar

mac

okin

etic

prop

ertie

s of a

6 m

onth

trea

tmen

t reg

imen

com

pose

d of

bed

aqui

line,

pre

tom

anid

8 an

d lin

ezol

id (B

PaL)

, ext

enda

ble

to 9

mon

ths f

or th

ose

who

miss

ed d

oses

or f

or p

atie

nts w

ho re

mai

ned

cultu

re p

ositi

ve o

r rev

erte

d fro

m c

ultu

re n

egat

ive to

pos

itive

bet

wee

n m

onth

s 4 to

6 o

f tre

atm

ent.

The

stud

y w

as c

ondu

cted

bet

wee

n 20

14 a

nd 2

019

at th

ree

stud

y sit

es, a

ll in

Sou

th A

frica

, with

the

first

pat

ient

enr

olle

d in

Apr

il 20

15. E

ligib

le p

atie

nts w

ere

aged

14

year

s and

abo

ve, w

eigh

ed ≥

35kg

, had

a d

ocum

ente

d H

IV re

sult

and

had

bact

erio

logi

cally

con

firm

ed sp

utum

cul

ture

pos

itive

XD

R-TB

or b

acte

riolo

gica

lly

conf

irmed

MD

R/RR

-TB

but w

ho w

ere

treat

men

t int

oler

ant o

r non

-res

pons

ive to

pre

vious

MD

R/RR

-TB

treat

men

t. A

num

ber o

f oth

er in

clusio

n cr

iteria

wer

e ap

plie

d.Pa

tient

s w

ere

follo

wed

up

for a

per

iod

of u

p to

24

mon

ths

post

trea

tmen

t com

plet

ion.

The

prim

ary

outc

ome

mea

sure

was

the

incid

ence

of b

acte

riolo

gic

failu

re o

r re

laps

e or

clin

ical f

ailu

re th

roug

h fo

llow

up

until

6 m

onth

s af

ter t

he e

nd o

f tre

atm

ent (

TB A

llianc

e, N

ix-TB

stu

dy p

roto

col,

avai

labl

e at

: http

s://c

linica

ltria

ls.go

v/ct

2/sh

ow/N

CT02

3337

99).

Seco

ndar

y ou

tcom

e m

easu

res

com

prise

d:

1. In

ciden

ce o

f bac

terio

logi

c fa

ilure

or r

elap

se o

r clin

ical f

ailu

re th

roug

h fo

llow

up

until

24

mon

ths

afte

r the

end

of t

reat

men

t (as

a c

onfir

mat

ory

anal

ysis)

. 2.

Tim

e to

spu

tum

cul

ture

con

vers

ion

to n

egat

ive

stat

us th

roug

h th

e tre

atm

ent p

erio

d.

3. T

he p

ropo

rtio

n of

sub

ject

s w

ith s

putu

m c

ultu

re c

onve

rsio

n to

neg

ativ

e st

atus

at 4

, 6, 8

, 12,

16

and

26 o

r 39

wee

ks.

4. L

inez

olid

dos

ing

(act

ual)

and

effic

acy.

5. C

hang

e fro

m b

asel

ine

in T

B sy

mpt

oms.

6. C

hang

e fro

m b

asel

ine

in P

atie

nt R

epor

ted

Hea

lth S

tatu

s. 7.

Cha

nge

from

bas

elin

e in

wei

ght (

TB A

llianc

e, N

ix-TB

stu

dy p

roto

col,

avai

labl

e at

: http

s://c

linica

ltria

ls.go

v/ct

2/sh

ow/N

CT02

3337

99).

The

Nix-

TB s

tudy

regi

men

com

prise

d pr

etom

anid

adm

inist

ered

at 2

00m

g on

ce d

aily,

bed

aqui

line

adm

inist

ered

at 4

00m

g on

ce d

aily

for t

he fi

rst t

wo

wee

ks o

f tre

atm

ent (

days

1 to

14)

and

then

200

mg

thre

e tim

es a

wee

k th

erea

fter,

and

linez

olid

com

men

ced

at 1

200m

g pe

r day

(add

ition

al in

form

atio

n on

line

zolid

dos

ing

is in

clude

d un

der I

mpl

emen

tatio

n co

nsid

erat

ions

, bel

ow).

Clos

e m

icrob

iolo

gic,

clin

ical a

nd a

dver

se e

vent

mon

itorin

g w

ere

feat

ures

of t

he N

ix-TB

stu

dy.

5 Em

erge

nce

of X

DR-

TB [w

ebsit

e]. G

enev

a, S

witz

erla

nd W

orld

Hea

lth O

rgan

izat

ion

2006

(http

s://w

ww.

who

.int/

med

iace

ntre

/new

s/no

tes/

2006

/np2

3/en

, acc

esse

d 28

Feb

ruar

y 20

20).

6 W

HO

con

solid

ated

gui

delin

es o

n dr

ug re

sista

nt tu

berc

ulos

is tre

atm

ent.

Gen

eva,

Sw

itzer

land

: Wor

ld H

ealth

Org

aniz

atio

n; 2

019

(http

s://a

pps.w

ho.in

t/iri

s/bi

tstre

am/h

andl

e/10

665/

3113

89/9

7892

4155

0529

-eng

.pd

f?ua

=1, a

cces

sed

20 M

arch

202

0).

7 Th

e N

ix-TB

stu

dy p

roto

col i

s av

aila

ble

at: h

ttps:/

/clin

icaltr

ials.

gov/

ct2/

show

/NCT

0233

3799

. A p

ublic

atio

n on

the

resu

lts o

f the

stu

dy is

ava

ilabl

e at

: http

s://w

ww.

nejm

.org

/doi

/full/

10.1

056/

NEJ

Moa

1901

814.

8 Pr

etom

anid

is a

new

che

mica

l ent

ity a

nd a

mem

ber o

f a c

lass

of c

ompo

unds

kno

wn

as n

itroi

mid

azo-

oxaz

ines

, whi

ch p

osse

ss s

igni

fican

t ant

i-TB

activ

ity a

nd a

uni

que

mec

hani

sm o

f act

ion.

https://clinicaltrials.gov/ct2/show/NCT02333799

https://clinicaltrials.gov/ct2/show/NCT02333799

https://www.who.int/mediacentre/news/notes/2006/np23/en


The

evid

ence

to in

form

this

PICO

que

stio

n w

as d

eriv

ed fr

om th

e N

ix-TB

stu

dy a

nd in

clude

d in

form

atio

n on

108

pat

ient

s. Th

e to

tal s

tudy

pop

ulat

ion

was

109

pa

tient

s; ho

wev

er, o

ne p

atie

nt w

ithdr

ew in

form

ed c

onse

nt to

par

ticip

ate

in th

e st

udy

and

this

pers

on w

as in

clude

d in

saf

ety

anal

yses

but

not

in th

e an

alys

es fo

r ef

fect

iven

ess.

Thes

e da

ta w

ere

com

pare

d to

a s

ubse

t of d

ata

from

the

indi

vidu

al p

atie

nt d

atas

et (I

PD) w

hich

ove

rall

inclu

des

13 2

73 in

divi

dual

pat

ient

reco

rds

from

55

diff

eren

t stu

dies

/cen

tres

in 3

8 co

untri

es. F

or th

e pr

imar

y an

alys

es, t

he c

ompa

rato

r gro

up in

clude

d pa

tient

s fro

m th

e IP

D o

n lo

nger

trea

tmen

t reg

imen

s (w

ith

a m

ean

dura

tion

of tr

eatm

ent o

f 21.

0–25

.5 m

onth

s), w

ho re

ceiv

ed b

oth

beda

quilin

e an

d lin

ezol

id a

s pa

rt o

f the

regi

men

(no

patie

nts

rece

ived

pre

tom

anid

in th

e IP

D).

This

com

paris

on g

roup

inclu

ded

456

patie

nts

who

wer

e tre

ated

in B

elar

us, I

ndia

, Fra

nce,

Rus

sia a

nd in

cou

ntrie

s in

Asia

. The

inte

rven

tion

and

com

paris

on

grou

ps w

ere

mat

ched

exa

ctly

for X

DR,

MD

R an

d flu

oroq

uino

lone

resis

tanc

e an

d H

IV s

tatu

s, w

ith p

rope

nsity

sco

re m

atch

ing

for t

he v

aria

bles

of a

ge, s

ex, b

asel

ine

cultu

re re

sult,

ext

ent o

f dise

ase

(det

erm

ined

by

base

line

AFB

smea

r or c

hest

x-r

ay fi

ndin

gs o

f cav

itatio

n or

bila

tera

l dise

ase

if AF

B sm

ear r

esul

t was

miss

ing)

and

co

untr

y in

com

e le

vel (

Wor

ld B

ank

Atla

s m

etho

d). T

reat

men

t out

com

es u

sed

in th

ese

anal

yses

com

prise

d th

e in

vest

igat

or d

efin

ed o

utco

mes

for t

he in

terv

entio

n gr

oup

(for t

he N

ix-TB

stu

dy) a

nd tr

eatm

ent o

utco

mes

larg

ely

defin

ed a

ccor

ding

to W

HO

def

initi

ons

(Las

erso

n KF

et a

l., 20

05; W

orld

Hea

lth O

rgan

izat

ion,

201

3:

http

s://w

ww.

who

.int/

tb/p

ublic

atio

ns/d

efin

ition

s/en

/) fo

r the

com

para

tor g

roup

(for

the

patie

nts

inclu

ded

in th

e IP

D).

In o

rder

to a

llow

an

equa

l opp

ortu

nity

for

treat

men

t out

com

es to

occ

ur fr

om th

e st

art o

f tre

atm

ent w

hen

com

parin

g th

e tw

o gr

oups

, all

outc

omes

wer

e in

clude

d fro

m th

e st

art o

f tre

atm

ent t

o 24

mon

ths

post

trea

tmen

t sta

rt. T

his

mea

nt th

at in

the

inte

rven

tion

grou

p th

ese

outc

omes

occ

urre

d po

st tr

eatm

ent c

ompl

etio

n an

d fo

r the

com

para

tor g

roup

the

outc

omes

w

ere

end

of tr

eatm

ent o

utco

mes

(as

patie

nts

in th

e IP

D re

ceiv

ed a

long

er re

gim

en a

nd w

ere

not f

ollo

wed

up

post

trea

tmen

t com

plet

ion)

. Thr

ee o

ther

com

para

tor

grou

ps fr

om th

e IP

D in

clude

d pa

tient

s on

long

er tr

eatm

ent r

egim

ens

who

rece

ived

a re

gim

en w

hich

inclu

ded

beda

quilin

e, o

r a re

gim

en w

hich

inclu

ded

linez

olid

, or

a re

gim

en w

ith n

eith

er b

edaq

uilin

e or

line

zolid

inclu

ded.

The

initi

al in

tent

ion

of th

e G

DG

was

to a

sses

s th

e in

terv

entio

n re

gim

en a

gain

st a

ll th

ree

com

paris

on

grou

ps h

owev

er, d

urin

g th

eir d

elib

erat

ions

the

pane

l agr

eed

that

the

judg

emen

ts s

houl

d be

bas

ed o

n th

e co

mpa

rison

gro

up w

ho re

ceiv

ed b

edaq

uilin

e an

d lin

ezol

id a

s pa

rt o

f the

ir re

gim

en, a

s th

ese

patie

nts

mos

t clo

sely

rese

mbl

e pa

tient

s w

ho w

ould

rece

ive

curre

ntly

reco

mm

ende

d lo

nger

regi

men

s co

mpo

sed

with

med

icine

s fro

m G

roup

s A

, B a

nd C

. How

ever

, a d

irect

com

paris

on o

f BPa

L w

ith a

ll-or

al lo

nger

regi

men

s co

nstru

cted

acc

ordi

ng to

the

mos

t rec

ent W

HO

re

com

men

datio

ns is

sued

in M

ay 2

019

was

not

pos

sible

as

thes

e re

gim

ens

may

hav

e on

ly b

een

in u

se s

ince

mid

-201

9, a

nd tr

eatm

ent o

utco

mes

for t

hese

pat

ient

s ar

e no

t yet

ava

ilabl

e. A

dditi

onal

dat

a re

view

ed b

y th

e G

uide

line

Dev

elop

men

t Gro

up re

leva

nt to

this

PICO

que

stio

n w

ere

a co

st e

ffect

iven

ess

anal

ysis,

a s

tudy

on

the

acce

ptab

ility

and

likel

ihoo

d of

impl

emen

tatio

n of

the

BPaL

regi

men

, mod

elle

d ph

arm

aco-

kinet

ic da

ta b

ased

on

the

deve

lopm

ent o

f a p

harm

aco-

kinet

ic to

xicod

ynam

ic m

odel

and

a s

umm

ary

revi

ew o

f pre

clini

cal a

nd e

arly

clin

ical d

ata

on p

reto

man

id. T

he c

ost e

ffect

iven

ess

anal

ysis,

acc

epta

bilit

y st

udy

and

mod

elle

d ph

arm

acok

inet

ic st

udie

s w

ere

cond

ucte

d as

par

t of t

he N

ix-TB

stu

dy a

nd w

ere

spon

sore

d by

TB

Allia

nce.

CON

FLIC

T O

F IN

TERE

STS:

Susa

n AB

DEL

-RAH

MAN

, Dan

iela

CIR

ILLO

, Agn

es G

EBH

ARD,

Ale

na S

KRAH

INA

, And

rew

VER

NO

N


Ass

essm

ent

Prob

lem

Is th

e pr

oble

m a

prio

rity?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

No

○ P

roba

bly

no

○ P

roba

bly

yes

● Ye

s ○

Var

ies

○ D

on’t

know

Tube

rcul

osis

(TB)

rem

ains

a th

reat

to g

loba

l pub

lic h

ealth

and

is th

e to

p in

fect

ious

cau

se o

f dea

th in

the

wor

ld. I

n 20

18, a

n es

timat

ed 1

0 m

illion

peo

ple

deve

lope

d TB

and

1.4

milli

on d

ied

from

the

dise

ase.

Abo

ut 5

00 0

00 n

ew c

ases

of

mul

tidru

g- o

r rifa

mpi

cin-r

esist

ant T

B (M

DR/

RR-T

B) w

ere

estim

ated

to e

mer

ge in

20

18. W

hile

all

of th

ese

wou

ld h

ave

been

elig

ible

for a

sec

ond-

line

TB tr

eatm

ent

regi

men

, onl

y 15

6 07

1 en

rolm

ents

on

treat

men

t wer

e re

port

ed b

y co

untri

es

in 2

018

– ab

out 3

0% o

f the

est

imat

ed c

asel

oad.

In a

dditi

on, t

he a

vera

ge

prop

ortio

n of

MD

R-TB

cas

es w

ith e

xten

sivel

y dr

ug-r

esist

ant T

B (X

DR-

TB) i

s ap

prox

imat

ely

6.2%

(95%

con

fiden

ce in

terv

al [C

I]: 4

.4–8

.2%

). D

espi

te th

is,

signi

fican

t im

prov

emen

ts in

the

avai

labi

lity

of e

nhan

ced

diag

nost

ics a

nd m

ore

effe

ctiv

e m

edici

nes

has

occu

rred

in re

cent

yea

rs, a

nd h

as le

d to

ear

lier d

etec

tion

and

high

er s

ucce

ss ra

tes

amon

g pa

tient

s w

ith M

DR/

RR-T

B in

a n

umbe

r of

natio

nal p

rogr

amm

es. H

owev

er, t

hese

suc

cess

es h

ave

not b

een

repr

oduc

ed in

th

e re

st o

f the

wor

ld, a

nd th

e ov

eral

l tre

atm

ent s

ucce

ss ra

te w

orld

wid

e re

ache

d on

ly 5

6% fo

r MD

R/RR

-TB

patie

nts

who

sta

rted

on

treat

men

t in

2016

, and

onl

y 39

% fo

r pat

ient

s w

ith X

DR-

TB.


Des

irab

le E

ffec

tsH

ow s

ubst

antia

l are

the

desi

rabl

e an

ticip

ated

eff

ects

?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Triv

ial

○ S

mal

l ●

Mod

erat

e ○

Lar

ge

○ V

arie

s ○

Don

’t kn

ow

Out

com

es

With

long

er

regi

men

s co

ntai

ning

be

daqu

iline

an

d lin

ezol

id

in a

dditi

on to

ot

her a

nti-

TB

drug

s

With

trea

tmen

t re

gim

en la

stin

g 6–

9 m

onth

s co

mpo

sed

of

beda

quili

ne,

pret

oman

id

and

linez

olid

Diff

eren

ce

Rela

tive

effe

ct

(95%

CI

)

Succ

ess

vs. F

ailu

re/

Recu

rrenc

e fo

llow

up:

mea

n 24

mon

ths

92 p

er 1

0097

per

100

(9

0 to

99)

6 m

ore

per

100

(2 fe

wer

to

8 m

ore)

OR

3.3

(0.8

to

13.7

)

Succ

ess

vs.

Dea

th

follo

w u

p: m

ean

24 m

onth

s

92 p

er 1

0092

per

100

(5

3 to

99)

0 fe

wer

pe

r 10

0 (3

9 fe

wer

to

7 m

ore)

OR

1.0

(0.1

to

8.2)

Succ

ess

vs. F

ailu

re/

Recu

rrenc

e/D

eath

fo

llow

up:

mea

n 24

mon

ths

85 p

er 1

0091

per

100

(8

0 to

96)

6 m

ore

per

100

(5 fe

wer

to

11 m

ore)

OR

1.8

(0.7

to

4.4)

Succ

ess

vs. A

ll Un

favo

rabl

e fo

llow

up:

mea

n 24

mon

ths

82 p

er 1

0085

per

100

(7

0 to

93)

3 m

ore

per

100

(12

few

er to

11

mor

e)

OR

1.2

(0.5

to

3.1)

Adve

rse

even

tsBP

aL re

gim

en: 1

(0.9

%) p

atie

nt d

ied,

27

(25%

) pat

ient

s ex

perie

nced

oth

er s

erio

us a

dver

se e

vent

s in

cludi

ng

hosp

italiz

atio

ns a

nd li

fe-t

hrea

teni

ng e

vent

s, an

d 53

(49%

) pa

tient

s ex

perie

nced

at l

east

one

Gra

de 3

–4 a

dver

se e

vent

s. D

rug

disc

ontin

uatio

n fo

r adv

erse

eve

nts:

rela

ted

to a

ll th

ree

drug

s in

1 p

atie

nt, a

nd re

late

d to

line

zolid

(ini

tial d

ose

1200

m

g/da

y) d

iscon

tinue

d in

ano

ther

35

(32%

) pat

ient

s. O

nly

20

(18%

) pat

ient

s co

mpl

eted

a fu

ll co

urse

of 1

200

mg/

day.

In th

e IP

D s

tudi

es (9

0% re

ceiv

ed ≤

600m

g/da

y), t

he p

oole

d ra

te o

f lin

ezol

id p

erm

anen

t disc

ontin

uatio

n w

as 1

7.9%

, and

in th

e En

dTB

stud

y (a

ll pa

tient

s re

ceiv

ed 6

00 m

g/da

y or

less

), th

e ra

te o

f lin

ezol

id d

iscon

tinua

tion

was

13.

1%. I

n En

dTB:

9 o

ut

of 1

094

part

icipa

nts

(0.8

%) d

ied

of a

pos

sibly

or p

roba

bly

drug

rela

ted

adve

rse

even

t, in

cludi

ng tw

o pa

rtici

pant

s w

ith

sudd

en c

ardi

ac d

eath

and

QT

prol

onga

tion.

The

GD

G p

anel

not

ed th

at th

e ev

iden

ce w

as u

ncer

tain

, ref

lect

ed in

the

cert

aint

y ra

ting

of “v

ery

low

”. Th

ey a

lso a

ckno

wle

dged

the

over

all h

igh

succ

ess

rate

s in

th

e N

ix-TB

stu

dy.

The

pane

l vot

ed o

n th

e m

agni

tude

of t

he d

esira

ble

effe

cts,

with

17

votin

g “s

mal

l” an

d 7

votin

g “tr

ivia

l”. O

ne a

bsta

ined

, and

5 re

port

ed c

onfli

cts

of in

tere

st.

The

pane

l the

n re

-eva

luat

ed th

e di

ffere

ntia

l des

irabl

e ef

fect

s of

the

shor

ter

regi

men

with

rega

rd to

bur

den

(whi

ch is

a d

esira

ble

effe

ct if

is re

duce

d by

th

e in

terv

entio

n). T

his

re-e

valu

atio

n w

as b

roug

ht u

p w

hen

the

bala

nce

of th

e ef

fect

s w

as fo

und

to b

e in

cons

isten

t with

the

crite

ria n

oted

und

er d

esira

ble

and

unde

sirab

le e

ffect

s.Pa

tient

repr

esen

tativ

es ra

ised

the

issue

s of

oth

er c

onse

quen

ces

of a

long

er

dura

tion

of tr

eatm

ent;

thes

e in

clude

a la

rger

pill

burd

en a

nd m

ay in

clude

de

pres

sion

and

othe

r und

esira

ble

effe

cts.

The

pane

l not

ed th

at lo

ss to

follo

w-u

p do

es n

ot c

aptu

re a

ll of

the

burd

en o

f diff

erin

g M

DR/

RR-T

B re

gim

ens

on p

atie

nts.

Afte

r the

se a

dditi

onal

disc

ussio

ns, t

he G

DG

cam

e to

con

sens

us (t

hrou

gh v

otin

g)

that

the

diffe

renc

e in

the

desir

able

effe

cts

wer

e m

oder

ate.

The

vot

es w

ere

tallie

d as

5 fo

r “sm

all”

and

18 fo

r “m

oder

ate”

. One

mem

ber a

bsta

ined

and

5 m

embe

rs

repo

rted

con

flict

s of

inte

rest

; ano

ther

GD

G m

embe

r was

not

pre

sent

at t

he

mee

ting

by th

is po

int.

Addi

tiona

l evi

denc

e pr

esen

ted

inclu

ded

mod

elle

d ph

arm

acok

inet

ic da

ta b

ased

on

the

deve

lopm

ent o

f a p

harm

acok

inet

ic–to

xicod

ynam

ic m

odel

des

igne

d to

qua

ntify

the

rela

tions

hip

betw

een

phar

mac

okin

etic

and

toxic

qua

litie

s of

lin

ezol

id a

s pa

rt o

f a 6

-mon

th B

PaL

regi

men

. The

se a

naly

ses

wer

e sp

onso

red

by th

e TB

Allia

nce

and

wer

e ba

sed

on d

ata

from

the

Nix-

TB s

tudy

. Inf

orm

atio

n on

mod

elle

d da

ta fr

om 8

8 pa

tient

s w

ho re

ceiv

ed li

nezo

lid in

the

Nix-

TB s

tudy

w

as p

rese

nted

. Thi

s pa

tient

pop

ulat

ion

inclu

ded

info

rmat

ion

on 7

pat

ient

s w

ho h

ad d

ied;

21

indi

vidu

als

from

the

Nix-

TB s

tudy

wer

e ex

clude

d fro

m th

ese

anal

yses

bec

ause

16

had

inco

mpl

ete

dosin

g hi

stor

ies

(i.e.

they

wer

e re

ceiv

ing

ongo

ing

treat

men

t at t

he ti

me

of a

naly

sis) a

nd 5

had

unv

erifi

able

dos

ing

hist

orie

s. Am

ong

the

109

patie

nts

in th

e N

ix-TB

stu

dy, a

naem

ia w

as re

port

ed

in 3

7% a

nd p

erip

hera

l sen

sory

neu

ropa

thy

was

repo

rted

in 6

9%. O

n th

e ba

sis

of th

e m

odel

led

data

, it w

as c

onclu

ded

that

the

phar

mac

okin

etics

rela

ted

to

linez

olid

are

non

linea

r in

patie

nts

with

XD

R-TB

and

that

indi

vidu

al li

nezo

lid

conc

entra

tion

times

are

the

best

pre

dict

or o

f tox

icity.

Hig

her t

oxici

ty ra

tes

wer

e ob

serv

ed a

t hig

her t

otal

dai

ly d

oses

, with

com

para

ble

toxic

ity ra

tes

for B

ID a

nd

QD

dos

ing

sche

dule

s. An

aem

ia c

an b

e m

anag

ed b

y clo

sely

mon

itorin

g ch

ange

s in

hae

mog

lobi

n ov

er th

e fir

st 4

wee

ks o

f tre

atm

ent (

in p

artic

ular

, cha

nges

in

haem

oglo

bin

that

repr

esen

t a >

10%

incr

ease

from

bas

elin

e sh

ould

trig

ger a

re

duct

ion

in th

e do

se o

f lin

ezol

id –

hae

mog

lobi

n le

vels

reco

ver w

ell a

fter d

ose

redu

ctio

ns).

Perip

hera

l neu

ropa

thy

shou

ld b

e clo

sely

mon

itore

d; w

hen

it do

es

occu

r, it

is re

vers

ible

for m

ost p

atie

nts

with

in 3

mon

ths.

Thro

mbo

cyto

peni

a is

pote

ntia

lly n

ot a

maj

or c

once

rn w

ith h

igh-

dose

line

zolid

for p

atie

nts

with

XD

R-TB

.


Des

irab

le E

ffec

tsH

ow s

ubst

antia

l are

the

desi

rabl

e an

ticip

ated

eff

ects

?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Triv

ial

○ S

mal

l ●

Mod

erat

e ○

Lar

ge

○ V

arie

s ○

Don

’t kn

ow

Out

com

es

With

long

er

regi

men

s co

ntai

ning

be

daqu

iline

an

d lin

ezol

id

in a

dditi

on to

ot

her a

nti-

TB

drug

s

With

trea

tmen

t re

gim

en la

stin

g 6–

9 m

onth

s co

mpo

sed

of

beda

quili

ne,

pret

oman

id

and

linez

olid

Diff

eren

ce

Rela

tive

effe

ct

(95%

CI

)

Succ

ess

vs. F

ailu

re/

Recu

rrenc

e fo

llow

up:

mea

n 24

mon

ths

92 p

er 1

0097

per

100

(9

0 to

99)

6 m

ore

per

100

(2 fe

wer

to

8 m

ore)

OR

3.3

(0.8

to

13.7

)

Succ

ess

vs.

Dea

th

follo

w u

p: m

ean

24 m

onth

s

92 p

er 1

0092

per

100

(5

3 to

99)

0 fe

wer

pe

r 10

0 (3

9 fe

wer

to

7 m

ore)

OR

1.0

(0.1

to

8.2)

Succ

ess

vs. F

ailu

re/

Recu

rrenc

e/D

eath

fo

llow

up:

mea

n 24

mon

ths

85 p

er 1

0091

per

100

(8

0 to

96)

6 m

ore

per

100

(5 fe

wer

to

11 m

ore)

OR

1.8

(0.7

to

4.4)

Succ

ess

vs. A

ll Un

favo

rabl

e fo

llow

up:

mea

n 24

mon

ths

82 p

er 1

0085

per

100

(7

0 to

93)

3 m

ore

per

100

(12

few

er to

11

mor

e)

OR

1.2

(0.5

to

3.1)

Adve

rse

even

tsBP

aL re

gim

en: 1

(0.9

%) p

atie

nt d

ied,

27

(25%

) pat

ient

s ex

perie

nced

oth

er s

erio

us a

dver

se e

vent

s in

cludi

ng

hosp

italiz

atio

ns a

nd li

fe-t

hrea

teni

ng e

vent

s, an

d 53

(49%

) pa

tient

s ex

perie

nced

at l

east

one

Gra

de 3

–4 a

dver

se e

vent

s. D

rug

disc

ontin

uatio

n fo

r adv

erse

eve

nts:

rela

ted

to a

ll th

ree

drug

s in

1 p

atie

nt, a

nd re

late

d to

line

zolid

(ini

tial d

ose

1200

m

g/da

y) d

iscon

tinue

d in

ano

ther

35

(32%

) pat

ient

s. O

nly

20

(18%

) pat

ient

s co

mpl

eted

a fu

ll co

urse

of 1

200

mg/

day.

In th

e IP

D s

tudi

es (9

0% re

ceiv

ed ≤

600m

g/da

y), t

he p

oole

d ra

te o

f lin

ezol

id p

erm

anen

t disc

ontin

uatio

n w

as 1

7.9%

, and

in th

e En

dTB

stud

y (a

ll pa

tient

s re

ceiv

ed 6

00 m

g/da

y or

less

), th

e ra

te o

f lin

ezol

id d

iscon

tinua

tion

was

13.

1%. I

n En

dTB:

9 o

ut

of 1

094

part

icipa

nts

(0.8

%) d

ied

of a

pos

sibly

or p

roba

bly

drug

rela

ted

adve

rse

even

t, in

cludi

ng tw

o pa

rtici

pant

s w

ith

sudd

en c

ardi

ac d

eath

and

QT

prol

onga

tion.

The

GD

G p

anel

not

ed th

at th

e ev

iden

ce w

as u

ncer

tain

, ref

lect

ed in

the

cert

aint

y ra

ting

of “v

ery

low

”. Th

ey a

lso a

ckno

wle

dged

the

over

all h

igh

succ

ess

rate

s in

th

e N

ix-TB

stu

dy.

The

pane

l vot

ed o

n th

e m

agni

tude

of t

he d

esira

ble

effe

cts,

with

17

votin

g “s

mal

l” an

d 7

votin

g “tr

ivia

l”. O

ne a

bsta

ined

, and

5 re

port

ed c

onfli

cts

of in

tere

st.

The

pane

l the

n re

-eva

luat

ed th

e di

ffere

ntia

l des

irabl

e ef

fect

s of

the

shor

ter

regi

men

with

rega

rd to

bur

den

(whi

ch is

a d

esira

ble

effe

ct if

is re

duce

d by

th

e in

terv

entio

n). T

his

re-e

valu

atio

n w

as b

roug

ht u

p w

hen

the

bala

nce

of th

e ef

fect

s w

as fo

und

to b

e in

cons

isten

t with

the

crite

ria n

oted

und

er d

esira

ble

and

unde

sirab

le e

ffect

s.Pa

tient

repr

esen

tativ

es ra

ised

the

issue

s of

oth

er c

onse

quen

ces

of a

long

er

dura

tion

of tr

eatm

ent;

thes

e in

clude

a la

rger

pill

burd

en a

nd m

ay in

clude

de

pres

sion

and

othe

r und

esira

ble

effe

cts.

The

pane

l not

ed th

at lo

ss to

follo

w-u

p do

es n

ot c

aptu

re a

ll of

the

burd

en o

f diff

erin

g M

DR/

RR-T

B re

gim

ens

on p

atie

nts.

Afte

r the

se a

dditi

onal

disc

ussio

ns, t

he G

DG

cam

e to

con

sens

us (t

hrou

gh v

otin

g)

that

the

diffe

renc

e in

the

desir

able

effe

cts

wer

e m

oder

ate.

The

vot

es w

ere

tallie

d as

5 fo

r “sm

all”

and

18 fo

r “m

oder

ate”

. One

mem

ber a

bsta

ined

and

5 m

embe

rs

repo

rted

con

flict

s of

inte

rest

; ano

ther

GD

G m

embe

r was

not

pre

sent

at t

he

mee

ting

by th

is po

int.

Addi

tiona

l evi

denc

e pr

esen

ted

inclu

ded

mod

elle

d ph

arm

acok

inet

ic da

ta b

ased

on

the

deve

lopm

ent o

f a p

harm

acok

inet

ic–to

xicod

ynam

ic m

odel

des

igne

d to

qua

ntify

the

rela

tions

hip

betw

een

phar

mac

okin

etic

and

toxic

qua

litie

s of

lin

ezol

id a

s pa

rt o

f a 6

-mon

th B

PaL

regi

men

. The

se a

naly

ses

wer

e sp

onso

red

by th

e TB

Allia

nce

and

wer

e ba

sed

on d

ata

from

the

Nix-

TB s

tudy

. Inf

orm

atio

n on

mod

elle

d da

ta fr

om 8

8 pa

tient

s w

ho re

ceiv

ed li

nezo

lid in

the

Nix-

TB s

tudy

w

as p

rese

nted

. Thi

s pa

tient

pop

ulat

ion

inclu

ded

info

rmat

ion

on 7

pat

ient

s w

ho h

ad d

ied;

21

indi

vidu

als

from

the

Nix-

TB s

tudy

wer

e ex

clude

d fro

m th

ese

anal

yses

bec

ause

16

had

inco

mpl

ete

dosin

g hi

stor

ies

(i.e.

they

wer

e re

ceiv

ing

ongo

ing

treat

men

t at t

he ti

me

of a

naly

sis) a

nd 5

had

unv

erifi

able

dos

ing

hist

orie

s. Am

ong

the

109

patie

nts

in th

e N

ix-TB

stu

dy, a

naem

ia w

as re

port

ed

in 3

7% a

nd p

erip

hera

l sen

sory

neu

ropa

thy

was

repo

rted

in 6

9%. O

n th

e ba

sis

of th

e m

odel

led

data

, it w

as c

onclu

ded

that

the

phar

mac

okin

etics

rela

ted

to

linez

olid

are

non

linea

r in

patie

nts

with

XD

R-TB

and

that

indi

vidu

al li

nezo

lid

conc

entra

tion

times

are

the

best

pre

dict

or o

f tox

icity.

Hig

her t

oxici

ty ra

tes

wer

e ob

serv

ed a

t hig

her t

otal

dai

ly d

oses

, with

com

para

ble

toxic

ity ra

tes

for B

ID a

nd

QD

dos

ing

sche

dule

s. An

aem

ia c

an b

e m

anag

ed b

y clo

sely

mon

itorin

g ch

ange

s in

hae

mog

lobi

n ov

er th

e fir

st 4

wee

ks o

f tre

atm

ent (

in p

artic

ular

, cha

nges

in

haem

oglo

bin

that

repr

esen

t a >

10%

incr

ease

from

bas

elin

e sh

ould

trig

ger a

re

duct

ion

in th

e do

se o

f lin

ezol

id –

hae

mog

lobi

n le

vels

reco

ver w

ell a

fter d

ose

redu

ctio

ns).

Perip

hera

l neu

ropa

thy

shou

ld b

e clo

sely

mon

itore

d; w

hen

it do

es

occu

r, it

is re

vers

ible

for m

ost p

atie

nts

with

in 3

mon

ths.

Thro

mbo

cyto

peni

a is

pote

ntia

lly n

ot a

maj

or c

once

rn w

ith h

igh-

dose

line

zolid

for p

atie

nts

with

XD

R-TB

.

The

GD

G c

onsid

ered

the

desir

able

effe

ct o

f tre

atm

ent s

ucce

ss, w

hich

was

hig

her

in th

e in

terv

entio

n gr

oups

than

in th

e co

mpa

rato

r gro

ups,

for a

ll fo

ur tr

eatm

ent

outc

omes

that

wer

e as

sess

ed. O

vera

ll, w

hen

com

parin

g tre

atm

ent s

ucce

ss w

ith

failu

re/r

ecur

renc

e, th

e tre

atm

ent s

ucce

ss ra

te in

the

Nix-

TB s

tudy

was

97.

0%,

com

pare

d w

ith 9

1.7%

in th

e co

mpa

rato

r gro

up (r

esul

ting

in 6

mor

e tre

atm

ent

succ

esse

s pe

r 100

pat

ient

s). F

or tr

eatm

ent s

ucce

ss v

ersu

s de

ath,

trea

tmen

t su

cces

s w

as 9

3.2%

in th

e N

ix-TB

stu

dy c

ompa

red

with

91.

9% in

the

com

para

tor

grou

p (re

sulti

ng in

1 m

ore

treat

men

t suc

cess

per

100

pat

ient

s). T

he G

DG

co

nsid

ered

rate

s of

loss

to fo

llow

-up

to b

e a

desir

able

effe

ct; t

he p

ropo

rtio

n of

pa

tient

s w

ho w

ere

lost

to fo

llow

-up

was

low

er in

the

inte

rven

tion

grou

p (1

.8%

) co

mpa

red

with

the

com

paris

on g

roup

(3.1

%).

The

unce

rtai

nty

in th

e ev

iden

ce

was

ack

now

ledg

ed b

y th

e pa

nel w

hen

mak

ing

thei

r jud

gem

ent o

n th

e de

sirab

le

(and

und

esira

ble)

effe

cts.

The

BPaL

regi

men

was

ass

ocia

ted

with

a h

igh

rate

of a

dver

se e

vent

s, co

nsid

ered

to

be

rela

ted

to th

e st

udy

drug

s. Th

is in

clude

d th

e de

ath

of 1

(0.9

%) p

artic

ipan

t; ot

her s

erio

us a

dver

se e

vent

s (in

cludi

ng h

ospi

taliz

atio

ns a

nd li

fe-t

hrea

teni

ng

even

ts) i

n 27

(25%

) par

ticip

ants

and

at l

east

one

Gra

de 3

–4 a

dver

se e

vent

in 5

3 (4

9%) p

artic

ipan

ts. T

his

led

to d

iscon

tinua

tion

of a

ll th

ree

drug

s fo

r 1 p

atie

nt,

and

disc

ontin

uatio

n of

line

zolid

(ini

tial d

ose

1200

mg/

day)

for a

noth

er 3

5 (3

2%) p

atie

nts.

Onl

y 18

(17%

) pat

ient

s co

mpl

eted

a fu

ll co

urse

of l

inez

olid

at

1200

mg/

day.

The

GD

G n

oted

that

it is

diff

icult

to c

ompa

re th

ese

adve

rse

even

t rat

es w

ith

othe

r stu

dies

bec

ause

of m

ajor

and

impo

rtan

t diff

eren

ces

in a

dver

se e

vent

as

cert

ainm

ent,

asse

ssm

ent,

and

repo

rtin

g. H

owev

er, i

n th

e IP

D s

tudi

es (w

here

90

% o

f pat

ient

s re

ceiv

ed a

line

zolid

dos

e of

≤60

0 m

g/da

y), t

he p

oole

d ra

te

of p

erm

anen

t disc

ontin

uatio

n of

line

zolid

was

17.

9%, a

nd in

the

EndT

B tri

al

(whe

re a

ll pa

tient

s re

ceiv

ed ≤

600

mg/

day

of li

nezo

lid),

the

rate

of l

inez

olid

di

scon

tinua

tion

was

13.

1%. I

n bo

th o

f the

se s

tudi

es, >

80%

of p

atie

nts

rece

ived

a

star

ting

dose

of l

inez

olid

of 6

00 m

g/da

y. In

the

EndT

B st

udy,

prel

imin

ary

anal

yses

su

gges

ted

that

9 o

f 109

4 pa

rtici

pant

s (0

.8%

) die

d of

a p

ossib

ly o

r pro

babl

y dr

ug-r

elat

ed a

dver

se e

vent

, inc

ludi

ng 2

par

ticip

ants

with

sud

den

card

iac

deat

h


Und

esir

able

Eff

ects

How

sub

stan

tial a

re th

e un

desi

rabl

e an

ticip

ated

eff

ects

?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Lar

ge

● M

oder

ate

○ S

mal

l ○

Triv

ial

○ V

arie

s ○

Don

’t kn

ow

Out

com

es

With

long

er

regi

men

s co

ntai

ning

be

daqu

iline

an

d lin

ezol

id

in a

dditi

on to

ot

her a

nti-

TB

drug

s

With

tr

eatm

ent

regi

men

la

stin

g 6–

9 m

onth

s co

mpo

sed

of

beda

quili

ne,

pret

oman

id

and

linez

olid

Diff

eren

ce

Rela

tive

effe

ct

(95%

CI

)

Succ

ess

vs. F

ailu

re/

Recu

rrenc

e fo

llow

up:

m

ean

24

mon

ths

92 p

er 1

0097

per

100

(9

0 to

99)

6 m

ore

per

100

(2 fe

wer

to

8 m

ore)

OR

3.3

(0.8

to

13.7

)

Succ

ess

vs.

Dea

th

follo

w u

p:

mea

n 24

m

onth

s

92 p

er 1

0092

per

100

(5

3 to

99)

0 fe

wer

pe

r 10

0 (3

9 fe

wer

to

7 m

ore)

OR

1.0

(0.1

to

8.2)

Succ

ess

vs. F

ailu

re/

Recu

rrenc

e/D

eath

fo

llow

up:

m

ean

24

mon

ths

85 p

er 1

0091

per

100

(8

0 to

96)

6 m

ore

per

100

(5 fe

wer

to

11 m

ore)

OR

1.8

(0.7

to

4.4)

Succ

ess

vs. A

ll Un

favo

rabl

e fo

llow

up:

m

ean

24

mon

ths

82 p

er 1

0085

per

100

(7

0 to

93)

3 m

ore

per

100

(12

few

er to

11

mor

e)

OR

1.2

(0.5

to

3.1)

The

issue

of s

erio

us a

dver

se e

vent

s, pa

rticu

larly

thos

e re

late

d to

line

zolid

, and

po

tent

ial s

afet

y sig

nals

rela

ted

to m

ale

infe

rtilit

y ob

serv

ed in

ani

mal

(mur

ine)

m

odel

s, w

ere

of c

once

rn to

the

pane

l. Th

e G

DG

hig

hlig

hted

the

pote

ntia

l di

fficu

lties

in m

onito

ring

of in

fert

ility

in a

pro

gram

mat

ic se

tting

. Add

ition

al

hum

an s

perm

stu

dies

reco

mm

ende

d by

the

US F

ood

and

Dru

g Ad

min

istra

tion

will

be c

arrie

d ou

t by

the

TB A

llianc

e; h

owev

er, t

hese

dat

a w

ere

not a

vaila

ble

for

the

GD

G to

con

sider

at t

he ti

me

of th

e m

eetin

g (a

nd th

ey w

ill no

t be

avai

labl

e fo

r a fe

w y

ears

). Th

e G

DG

det

erm

ined

that

infe

rtilit

y is

a se

rious

issu

e be

caus

e it

affe

cts

not o

nly

patie

nts

but a

lso th

eir f

amilie

s. Th

e G

DG

also

ack

now

ledg

ed

that

, at t

he ti

me

the

Nix-

TB s

tudy

sta

rted

, the

re w

ere

few

trea

tmen

t opt

ions

for

patie

nts

and

ther

e w

as a

hig

h ca

se fa

talit

y ra

te, w

hich

mea

ns th

at p

atie

nts

mig

ht

have

pla

ced

a di

ffere

nt v

alue

on

pote

ntia

l mal

e in

fert

ility

than

they

mig

ht n

ow.

Addi

tiona

l evi

denc

e pr

esen

ted

inclu

ded

mod

elle

d ph

arm

acok

inet

ic da

ta b

ased

on

the

deve

lopm

ent o

f a p

harm

acok

inet

ic–to

xicod

ynam

ic m

odel

des

igne

d to

qua

ntify

the

betw

een

phar

mac

okin

etics

and

toxic

ity o

f lin

ezol

id a

s pa

rt o

f a

6-m

onth

BPa

L re

gim

en. T

hese

ana

lyse

s w

ere

spon

sore

d by

the

TB A

llianc

e an

d w

ere

base

d on

dat

a fro

m th

e N

ix-TB

stu

dy. I

nfor

mat

ion

on m

odel

led

data

fro

m 8

8 pa

rtici

pant

s w

ho re

ceiv

ed li

nezo

lid in

the

Nix-

TB s

tudy

was

pre

sent

ed.

The

info

rmat

ion

on th

is po

pula

tion

inclu

ded

data

on

7 pa

tient

s w

ho h

ad d

ied.

Tw

enty

-one

indi

vidu

als

from

the

Nix-

TB s

tudy

wer

e ex

clude

d fro

m th

ese

anal

yses

be

caus

e 16

had

inco

mpl

ete

dosin

g hi

stor

ies

(i.e.

they

wer

e re

ceiv

ing

ongo

ing

treat

men

t at t

he ti

me

of a

naly

sis) a

nd 5

had

unv

erifi

able

dos

ing

hist

orie

s. Am

ong

the

109

patie

nts

in th

e N

ix-TB

stu

dy, a

naem

ia w

as re

port

ed in

37%

of

pat

ient

s an

d pe

riphe

ral s

enso

ry n

euro

path

y w

as re

port

ed in

69%

. On

the

basis

of t

he m

odel

led

data

, it w

as c

onclu

ded

that

the

phar

mac

okin

etics

rela

ted

to li

nezo

lid a

re n

onlin

ear i

n pa

tient

s w

ith X

DR-

TB a

nd th

at in

divi

dual

line

zolid

co

ncen

tratio

n tim

es a

re th

e be

st p

redi

ctor

of t

oxici

ty. H

ighe

r tox

icity

rate

s w

ere

obse

rved

at h

ighe

r tot

al d

aily

dos

es, w

ith c

ompa

rabl

e to

xicity

rate

s fo

r BID

and

Q

D d

osin

g sc

hedu

les.

Anae

mia

can

be

man

aged

by

close

ly m

onito

ring

chan

ges

in h

aem

oglo

bin

over

the

first

4 w

eeks

of t

reat

men

t (in

par

ticul

ar, i

ncre

ases

in

haem

oglo

bin

of >

10%

ove

r bas

elin

e sh

ould

trig

ger a

redu

ctio

n in

the

dose

of

linez

olid

; hae

mog

lobi

n le

vels

reco

ver w

ell a

fter d

ose

redu

ctio

ns).

Perip

hera

l ne

urop

athy

sho

uld

be c

lose

ly m

onito

red;

whe

n it

does

occ

ur, i

t is

reve

rsib

le fo

r m

ost p

atie

nts

with

in 3

mon

ths.

Thro

mbo

cyto

peni

a is

pote

ntia

lly n

ot a

maj

or

conc

ern

with

hig

h-do

se li

nezo

lid fo

r pat

ient

s w

ith X

DR-

TB.


Und

esir

able

Eff

ects

How

sub

stan

tial a

re th

e un

desi

rabl

e an

ticip

ated

eff

ects

?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Lar

ge

● M

oder

ate

○ S

mal

l ○

Triv

ial

○ V

arie

s ○

Don

’t kn

ow

Out

com

es

With

long

er

regi

men

s co

ntai

ning

be

daqu

iline

an

d lin

ezol

id

in a

dditi

on to

ot

her a

nti-

TB

drug

s

With

tr

eatm

ent

regi

men

la

stin

g 6–

9 m

onth

s co

mpo

sed

of

beda

quili

ne,

pret

oman

id

and

linez

olid

Diff

eren

ce

Rela

tive

effe

ct

(95%

CI

)

Succ

ess

vs. F

ailu

re/

Recu

rrenc

e fo

llow

up:

m

ean

24

mon

ths

92 p

er 1

0097

per

100

(9

0 to

99)

6 m

ore

per

100

(2 fe

wer

to

8 m

ore)

OR

3.3

(0.8

to

13.7

)

Succ

ess

vs.

Dea

th

follo

w u

p:

mea

n 24

m

onth

s

92 p

er 1

0092

per

100

(5

3 to

99)

0 fe

wer

pe

r 10

0 (3

9 fe

wer

to

7 m

ore)

OR

1.0

(0.1

to

8.2)

Succ

ess

vs. F

ailu

re/

Recu

rrenc

e/D

eath

fo

llow

up:

m

ean

24

mon

ths

85 p

er 1

0091

per

100

(8

0 to

96)

6 m

ore

per

100

(5 fe

wer

to

11 m

ore)

OR

1.8

(0.7

to

4.4)

Succ

ess

vs. A

ll Un

favo

rabl

e fo

llow

up:

m

ean

24

mon

ths

82 p

er 1

0085

per

100

(7

0 to

93)

3 m

ore

per

100

(12

few

er to

11

mor

e)

OR

1.2

(0.5

to

3.1)

The

issue

of s

erio

us a

dver

se e

vent

s, pa

rticu

larly

thos

e re

late

d to

line

zolid

, and

po

tent

ial s

afet

y sig

nals

rela

ted

to m

ale

infe

rtilit

y ob

serv

ed in

ani

mal

(mur

ine)

m

odel

s, w

ere

of c

once

rn to

the

pane

l. Th

e G

DG

hig

hlig

hted

the

pote

ntia

l di

fficu

lties

in m

onito

ring

of in

fert

ility

in a

pro

gram

mat

ic se

tting

. Add

ition

al

hum

an s

perm

stu

dies

reco

mm

ende

d by

the

US F

ood

and

Dru

g Ad

min

istra

tion

will

be c

arrie

d ou

t by

the

TB A

llianc

e; h

owev

er, t

hese

dat

a w

ere

not a

vaila

ble

for

the

GD

G to

con

sider

at t

he ti

me

of th

e m

eetin

g (a

nd th

ey w

ill no

t be

avai

labl

e fo

r a fe

w y

ears

). Th

e G

DG

det

erm

ined

that

infe

rtilit

y is

a se

rious

issu

e be

caus

e it

affe

cts

not o

nly

patie

nts

but a

lso th

eir f

amilie

s. Th

e G

DG

also

ack

now

ledg

ed

that

, at t

he ti

me

the

Nix-

TB s

tudy

sta

rted

, the

re w

ere

few

trea

tmen

t opt

ions

for

patie

nts

and

ther

e w

as a

hig

h ca

se fa

talit

y ra

te, w

hich

mea

ns th

at p

atie

nts

mig

ht

have

pla

ced

a di

ffere

nt v

alue

on

pote

ntia

l mal

e in

fert

ility

than

they

mig

ht n

ow.

Addi

tiona

l evi

denc

e pr

esen

ted

inclu

ded

mod

elle

d ph

arm

acok

inet

ic da

ta b

ased

on

the

deve

lopm

ent o

f a p

harm

acok

inet

ic–to

xicod

ynam

ic m

odel

des

igne

d to

qua

ntify

the

betw

een

phar

mac

okin

etics

and

toxic

ity o

f lin

ezol

id a

s pa

rt o

f a

6-m

onth

BPa

L re

gim

en. T

hese

ana

lyse

s w

ere

spon

sore

d by

the

TB A

llianc

e an

d w

ere

base

d on

dat

a fro

m th

e N

ix-TB

stu

dy. I

nfor

mat

ion

on m

odel

led

data

fro

m 8

8 pa

rtici

pant

s w

ho re

ceiv

ed li

nezo

lid in

the

Nix-

TB s

tudy

was

pre

sent

ed.

The

info

rmat

ion

on th

is po

pula

tion

inclu

ded

data

on

7 pa

tient

s w

ho h

ad d

ied.

Tw

enty

-one

indi

vidu

als

from

the

Nix-

TB s

tudy

wer

e ex

clude

d fro

m th

ese

anal

yses

be

caus

e 16

had

inco

mpl

ete

dosin

g hi

stor

ies

(i.e.

they

wer

e re

ceiv

ing

ongo

ing

treat

men

t at t

he ti

me

of a

naly

sis) a

nd 5

had

unv

erifi

able

dos

ing

hist

orie

s. Am

ong

the

109

patie

nts

in th

e N

ix-TB

stu

dy, a

naem

ia w

as re

port

ed in

37%

of

pat

ient

s an

d pe

riphe

ral s

enso

ry n

euro

path

y w

as re

port

ed in

69%

. On

the

basis

of t

he m

odel

led

data

, it w

as c

onclu

ded

that

the

phar

mac

okin

etics

rela

ted

to li

nezo

lid a

re n

onlin

ear i

n pa

tient

s w

ith X

DR-

TB a

nd th

at in

divi

dual

line

zolid

co

ncen

tratio

n tim

es a

re th

e be

st p

redi

ctor

of t

oxici

ty. H

ighe

r tox

icity

rate

s w

ere

obse

rved

at h

ighe

r tot

al d

aily

dos

es, w

ith c

ompa

rabl

e to

xicity

rate

s fo

r BID

and

Q

D d

osin

g sc

hedu

les.

Anae

mia

can

be

man

aged

by

close

ly m

onito

ring

chan

ges

in h

aem

oglo

bin

over

the

first

4 w

eeks

of t

reat

men

t (in

par

ticul

ar, i

ncre

ases

in

haem

oglo

bin

of >

10%

ove

r bas

elin

e sh

ould

trig

ger a

redu

ctio

n in

the

dose

of

linez

olid

; hae

mog

lobi

n le

vels

reco

ver w

ell a

fter d

ose

redu

ctio

ns).

Perip

hera

l ne

urop

athy

sho

uld

be c

lose

ly m

onito

red;

whe

n it

does

occ

ur, i

t is

reve

rsib

le fo

r m

ost p

atie

nts

with

in 3

mon

ths.

Thro

mbo

cyto

peni

a is

pote

ntia

lly n

ot a

maj

or

conc

ern

with

hig

h-do

se li

nezo

lid fo

r pat

ient

s w

ith X

DR-

TB.

Adve

rse

even

tsBP

aL re

gim

en: 1

(0.9

%) p

atie

nt d

ied,

27

(25%

) pat

ient

s ex

perie

nced

oth

er s

erio

us a

dver

se e

vent

s in

cludi

ng

hosp

italiz

atio

ns a

nd li

fe-t

hrea

teni

ng e

vent

s, an

d 53

(49%

) pa

tient

s ex

perie

nced

at l

east

one

Gra

de 3

–4 a

dver

se e

vent

s. D

rug

disc

ontin

uatio

n fo

r adv

erse

eve

nts:

rela

ted

to a

ll th

ree

drug

s in

1 p

atie

nt, a

nd re

late

d to

line

zolid

(ini

tial d

ose

1200

m

g/da

y) d

iscon

tinue

d in

ano

ther

35

(32%

) pat

ient

s. O

nly

20

(18%

) pat

ient

s co

mpl

eted

a fu

ll co

urse

of 1

200

mg/

day.

In

the

IPD

stu

dies

(90%

rece

ived

600

mg/

day

or le

ss),

the

pool

ed

rate

of L

ZD p

erm

anen

t disc

ontin

uatio

n w

as 1

7.9%

, and

in th

e En

dTB

stud

y (a

ll pa

tient

s re

ceiv

ed 6

00m

g/da

y or

less

), th

e ra

te o

f LZD

disc

ontin

uatio

n w

as 1

3.1%

. In

EndT

B: 9

per

sons

ou

t of 1

094

(0.8

%) d

ied

of a

pos

sibly

/pro

babl

y dr

ug re

late

d AE

, inc

ludi

ng tw

o pe

rson

s w

ith s

udde

n ca

rdia

c de

ath

and

QT

prol

onga

tion.

Anot

her u

ndes

irabl

e ef

fect

that

the

GD

G c

onsid

ered

was

the

inco

nsist

ency

of

evid

ence

on

the

reve

rsib

ility

of p

erip

hera

l neu

ropa

thy;

the

evid

ence

sug

gest

ed

eith

er c

ompl

ete

or in

com

plet

e re

vers

ibilit

y of

per

iphe

ral n

euro

path

y. Bo

th

patie

nts

and

clini

cians

who

wer

e pa

nel m

embe

rs d

escr

ibed

the

pote

ntia

lly

debi

litat

ing

effe

cts

of ir

reve

rsib

le p

erip

hera

l neu

ropa

thy,

whi

ch w

ere

of c

once

rn.

GD

G m

embe

rs a

lso c

onsid

ered

the

fact

that

long

er re

gim

ens

for M

DR/

RR-T

B ca

rry

a su

bsta

ntia

lly h

ighe

r pill

burd

en, w

hich

may

be

view

ed a

s un

desir

able

for

man

y pa

tient

s.Ri

sk o

f bia

s w

ith re

gard

to th

e co

mpa

rison

was

men

tione

d by

pan

el m

embe

rs

(mon

itorin

g of

adv

erse

effe

cts

was

mor

e fre

quen

t in

the

Nix-

TB s

tudy

than

in th

e co

mpa

rison

gro

up, w

hich

inclu

des

prog

ram

mat

ic da

ta).

This

was

not

nec

essa

rily

a pr

oble

m w

ith th

e IP

D c

ohor

ts, b

ut p

osed

a p

robl

em w

ith th

e la

ck o

f a c

ontro

l gr

oup

in th

e st

udy

that

test

ed th

e in

terv

entio

n.

The

GD

G c

onsid

ered

the

desir

able

effe

ct o

f tre

atm

ent s

ucce

ss, w

hich

was

hig

her

in th

e in

terv

entio

n gr

oups

than

in th

e co

mpa

rato

r gro

ups,

for a

ll fo

ur tr

eatm

ent

outc

omes

that

wer

e as

sess

ed. O

vera

ll, w

hen

com

parin

g tre

atm

ent s

ucce

ss w

ith

failu

re/r

ecur

renc

e, th

e tre

atm

ent s

ucce

ss ra

te in

the

Nix-

TB s

tudy

was

97.

0%,

com

pare

d w

ith 9

1.7%

in th

e co

mpa

rato

r gro

up (r

esul

ting

in 6

mor

e tre

atm

ent

succ

esse

s pe

r 100

pat

ient

s). F

or tr

eatm

ent s

ucce

ss v

ersu

s de

ath,

trea

tmen

t su

cces

s w

as 9

3.2%

in th

e N

ix-TB

stu

dy c

ompa

red

with

91.

9% in

the

com

para

tor

grou

p (re

sulti

ng in

1 m

ore

treat

men

t suc

cess

per

100

pat

ient

s). T

he G

DG

co

nsid

ered

rate

s of

loss

to fo

llow

-up

to b

e a

desir

able

effe

ct; t

he p

ropo

rtio

n of

pa

tient

s w

ho w

ere

lost

to fo

llow

-up

was

low

er in

the

inte

rven

tion

grou

p (1

.8%

) co

mpa

red

with

the

com

paris

on g

roup

(3.1

%).

The

unce

rtai

nty

in th

e ev

iden

ce

was

ack

now

ledg

ed b

y th

e pa

nel w

hen

mak

ing

thei

r jud

gem

ent o

n th

e de

sirab

le

(and

und

esira

ble)

effe

cts.

The

BPaL

regi

men

was

ass

ocia

ted

with

a h

igh

rate

of a

dver

se e

vent

s, co

nsid

ered

to

be

rela

ted

to th

e st

udy

drug

s. Th

is in

clude

d th

e de

ath

of 1

(0.9

%) p

artic

ipan

t; ot

her s

erio

us a

dver

se e

vent

s (in

cludi

ng h

ospi

taliz

atio

ns a

nd li

fe-t

hrea

teni

ng

even

ts) i

n 27

(25%

) par

ticip

ants

and

at l

east

one

Gra

de 3

–4 a

dver

se e

vent

in 5

3 (4

9%) p

artic

ipan

ts. T

his

led

to d

iscon

tinua

tion

of a

ll th

ree

drug

s fo

r 1 p

atie

nt,

and

disc

ontin

uatio

n of

line

zolid

(ini

tial d

ose

1200

mg/

day)

for a

noth

er 3

5 (3

2%) p

atie

nts.

Onl

y 18

(17%

) pat

ient

s co

mpl

eted

a fu

ll co

urse

of l

inez

olid

at

1200

mg/

day.

The

GD

G n

oted

that

it is

diff

icult

to c

ompa

re th

ese

adve

rse

even

t rat

es w

ith

othe

r stu

dies

bec

ause

of m

ajor

and

impo

rtan

t diff

eren

ces

in a

dver

se e

vent

as

cert

ainm

ent,

asse

ssm

ent,

and

repo

rtin

g. H

owev

er, i

n th

e IP

D s

tudi

es (w

here

90

% o

f pat

ient

s re

ceiv

ed a

line

zolid

dos

e of

≤60

0 m

g/da

y), t

he p

oole

d ra

te

of p

erm

anen

t disc

ontin

uatio

n of

line

zolid

was

17.

9%, a

nd in

the

EndT

B tri

al

(whe

re a

ll pa

tient

s re

ceiv

ed ≤

600

mg/

day

of li

nezo

lid),

the

rate

of l

inez

olid

di

scon

tinua

tion

was

13.

1%. I

n bo

th o

f the

se s

tudi

es, >

80%

of p

atie

nts

rece

ived

a

star

ting

dose

of l

inez

olid

of 6

00 m

g/da

y. In

the

EndT

B st

udy,

prel

imin

ary

anal

yses

su

gges

ted

that

9 o

f 109

4 pa

rtici

pant

s (0

.8%

) die

d of

a p

ossib

ly o

r pro

babl

y dr

ug-r

elat

ed a

dver

se e

vent

, inc

ludi

ng 2

par

ticip

ants

with

sud

den

card

iac

deat

h


Cert

aint

y of

evi

denc

eW

hat i

s th

e ov

eral

l cer

tain

ty o

f the

evi

denc

e of

eff

ects

?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S●

Very

low

○

Low

○

Mod

erat

e ○

Hig

h ○

No

inclu

ded

stud

ies

The

prim

ary

sour

ce o

f evi

denc

e fo

r thi

s PI

CO q

uest

ion

is th

e N

ix-TB

stu

dy,

whi

ch w

as c

ompo

sed

of 1

09 p

atie

nts

recr

uite

d in

a o

ne-a

rm, p

hase

III,

open

-la

bel s

tudy

that

ass

esse

d th

e sa

fety

, effi

cacy

, tol

erab

ility,

and

phar

mac

okin

etic

prop

ertie

s of

a 6

-mon

th tr

eatm

ent r

egim

en c

ompo

sed

of b

edaq

uilin

e,

pret

oman

id a

nd li

nezo

lid (B

PaL)

in S

outh

Afri

ca. T

he e

vide

nce

was

gen

erat

ed,

in th

e co

ntex

t of t

horo

ugh

mon

itorin

g an

d fo

llow

-up,

at b

asel

ine,

thro

ugho

ut

treat

men

t, an

d fo

r 24

mon

ths

afte

r tre

atm

ent c

ompl

etio

n. T

here

wer

e 10

9 pa

tient

s in

the

inte

ntio

n-to

-tre

at p

opul

atio

n an

d 10

8 in

the

mod

ified

inte

ntio

n-to

-tre

at p

opul

atio

n. T

hese

dat

a w

ere

com

pare

d w

ith th

e da

ta fr

om th

e IP

D

beca

use

the

stud

y w

as n

ot a

rand

omiz

ed, c

ontro

lled

trial

. Ove

rall,

the

cert

aint

y of

the

evid

ence

was

cla

ssifi

ed a

s “v

ery

low

”. Th

e ch

air o

f the

GD

G p

anel

not

ed

that

con

fiden

ce in

terv

als

(CIs)

aro

und

the

estim

ates

of e

ffect

hav

e lim

ited

appl

icatio

n in

the

cont

ext o

f ver

y lo

w e

vide

nce.

Valu

esIs

ther

e im

port

ant u

ncer

tain

ty a

bout

or v

aria

bilit

y in

how

muc

h pe

ople

val

ue th

e m

ain

outc

omes

?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Impo

rtan

t un

cert

aint

y or

va

riabi

lity

● Po

ssib

ly

impo

rtan

t un

cert

aint

y or

va

riabi

lity

○ P

roba

bly

no im

port

ant

unce

rtai

nty

or

varia

bilit

y ○

No

impo

rtan

t un

cert

aint

y or

va

riabi

lity

No

rese

arch

evi

denc

e w

as id

entif

ied.

Al

thou

gh n

o re

sear

ch e

vide

nce

was

iden

tifie

d, th

e pa

nel f

elt t

hat t

here

was

po

ssib

ly im

port

ant u

ncer

tain

ty o

r var

iabi

lity

in h

ow m

uch

peop

le w

ould

val

ue

the

mai

n ou

tcom

es. F

ertil

ity w

as ra

ised

as a

n ou

tcom

e fo

r whi

ch th

ere

is le

ss

info

rmat

ion.

The

pan

el th

ough

t tha

t thi

s w

ould

incr

ease

the

com

plex

ity o

f the

ju

dgem

ent a

bout

how

muc

h pe

ople

wou

ld v

alue

the

outc

omes

. The

GD

G

dete

rmin

ed th

at in

fert

ility

is a

serio

us is

sue

beca

use

it af

fect

s no

t onl

y pa

tient

s bu

t also

thei

r fam

ilies.

The

pane

l not

ed th

at th

ere

are

othe

r saf

ety

outc

omes

(e.g

. ot

her a

dver

se e

vent

s, in

cludi

ng p

erip

hera

l neu

ropa

thy)

that

may

var

y an

d th

at

peop

le m

ay v

alue

diff

eren

tly.

Indi

rect

evi

denc

e w

as c

onsid

ered

by

the

pane

l in

the

form

of a

sep

arat

e qu

alita

tive

stud

y co

nduc

ted

amon

g 16

pat

ient

s w

ith d

rug-

resis

tant

TB

who

wer

e fro

m h

igh

TB b

urde

n co

untri

es (w

hich

info

rmed

the

judg

emen

ts o

n PI

CO 1

). Th

e ai

m o

f the

stu

dy w

as to

det

erm

ine

the

mos

t acc

epta

ble

treat

men

t reg

imen

for

drug

-res

istan

t TB.

On

the

basis

of t

he re

sults

of t

his

stud

y, th

e pr

efer

red

regi

men

w

as s

hort

and

inje

ctio

n-fre

e w

ith fe

w to

no

phys

ical o

r men

tal h

ealth

sid

e-ef

fect

s an

d w

ith a

low

pill

burd

en. R

anke

d pr

efer

ence

s fo

r tre

atm

ent o

f dru

g-re

sista

nt T

B in

clude

d (1

) adv

erse

eve

nts,

(2) d

urat

ion,

(3) i

njec

tion

(free

) and

(4) p

ill bu

rden

.


Bala

nce

of e

ffec

tsD

oes

the

bala

nce

betw

een

desi

rabl

e an

d un

desi

rabl

e ef

fect

s fa

vor t

he in

terv

entio

n or

the

com

paris

on?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Fav

ors

the

com

paris

on

○ P

roba

bly

favo

rs

the

com

paris

on

● D

oes

not

favo

r eith

er th

e in

terv

entio

n or

the

com

paris

on

○ P

roba

bly

favo

rs

the

inte

rven

tion

○ F

avor

s th

e in

terv

entio

n ○

Var

ies

○ D

on’t

know

The

pane

l not

ed th

e m

oder

ate

desir

able

effe

cts

and

the

mod

erat

e un

desir

able

ef

fect

s (a

nd th

e lo

w c

erta

inty

of t

he e

vide

nce

over

all).

and

took

this

into

acc

ount

w

hen

mak

ing

thei

r jud

gem

ent a

bout

the

bala

nce

of e

ffect

s, w

hich

wer

e fe

lt to

no

t fav

our e

ither

the

inte

rven

tion

or th

e co

mpa

rison

.

The

pane

l con

sider

ed a

t len

gth

the

desir

able

and

und

esira

ble

effe

cts

and

the

bala

nce

of th

ese

effe

cts,

notin

g th

e ve

ry lo

w c

erta

inty

of t

he e

vide

nce

and

ackn

owle

dgin

g th

e ef

fort

s to

mat

ch p

atie

nts

in th

e in

terv

entio

n an

d co

mpa

rato

r gr

oups

(thr

ough

exa

ct a

nd p

rope

nsity

sco

re-b

ased

mat

chin

g). T

he G

DG

not

ed

that

rand

omiz

ed, c

ontro

lled

trial

s ar

e ne

eded

in th

e fu

ture

, whi

ch m

ay a

llow

fo

r a m

ore

close

ly a

ligne

d co

mpa

rison

gro

up w

ith le

ss p

oten

tial f

or re

sidua

l co

nfou

ndin

g. T

hrou

gh a

vot

ing

proc

ess,

the

pane

l con

clude

d th

at th

e ba

lanc

e of

effe

cts

does

not

favo

ur e

ither

the

inte

rven

tion

or th

e co

mpa

rison

. Fift

een

pane

l mem

bers

vot

ed th

at th

e ba

lanc

e of

effe

cts

does

not

favo

ur e

ither

the

inte

rven

tion

or th

e co

mpa

rison

, 5 v

oted

that

the

bala

nce

of e

ffect

s pr

obab

ly

does

favo

ur th

e co

mpa

rison

and

4 v

oted

that

they

did

not

kno

w. O

ne m

embe

r ab

stai

ned,

and

5 re

port

ed c

onfli

cts

of in

tere

st.


Reso

urce

s re

quir

edH

ow la

rge

are

the

reso

urce

requ

irem

ents

(cos

ts)?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Lar

ge c

osts

○

Mod

erat

e co

sts

○ N

eglig

ible

cos

ts

and

savi

ngs

○ M

oder

ate

savi

ngs

● La

rge

savi

ngs

○ V

arie

s ○

Don

’t kn

ow

No

rese

arch

evi

denc

e w

as id

entif

ied.

Th

e G

DG

con

sider

ed e

vide

nce

from

a c

ost–

effe

ctiv

enes

s an

alys

is st

udy

whi

ch

was

con

duct

ed b

y st

aff f

rom

the

Lond

on S

choo

l of H

ygie

ne &

Trop

ical M

edici

ne

on b

ehal

f of t

he T

B Al

lianc

e. T

he G

DG

not

ed th

at th

e an

alys

is w

as n

ot d

one

for t

his

–evi

denc

e to

dec

ision

fram

ewor

k –

that

is, u

ndes

irabl

e ef

fect

s w

ere

not

cons

ider

ed a

ccor

ding

to th

e G

DG

’s ju

dgem

ents

. Thi

s m

ade

the

cost

–effe

ctiv

enes

s an

alys

es in

form

ativ

e bu

t not

dire

ctly

bas

ed o

n th

e ev

iden

ce th

at th

e G

DG

w

as a

sses

sing.

The

anal

yses

wer

e ba

sed

on G

eorg

ia, t

he P

hilip

pine

s, an

d So

uth

Afric

a. T

he

aim

s of

the

rese

arch

wer

e to

est

imat

e th

e co

st–e

ffect

iven

ess

of a

new

regi

men

co

ntai

ning

bed

aqui

line,

pre

tom

anid

, and

line

zolid

(BPa

L) c

ompa

red

with

the

stan

dard

of c

are

at a

giv

en p

rice,

and

to e

stim

ate

the

max

imum

dru

g pr

ice a

t w

hich

the

BPaL

regi

men

cou

ld b

e co

nsid

ered

cos

t-effe

ctiv

e or

cos

t-neu

tral i

n ea

ch s

ettin

g. T

he p

ersp

ectiv

e ta

ken

was

a h

ealth

ser

vice

one

, and

the

stud

y as

sum

ed B

PaL

to b

e ef

fect

ive.

Whe

n as

sess

ing

the

pote

ntia

l cos

t–ef

fect

iven

ess

of B

PaL

for t

he tr

eatm

ent o

f XD

R-TB

, the

GD

G o

bser

ved

that

in a

ll th

ree

setti

ngs

this

regi

men

has

the

pote

ntia

l to

be c

ost-s

avin

g at

a g

iven

dru

g pr

ice o

f US$

364

pe

r tre

atm

ent c

ours

e fo

r pre

tom

anid

. The

stu

dy fo

und

that

cos

t-sav

ings

are

a

func

tion

of th

e co

st o

f car

e an

d th

e m

agni

tude

of X

DR-

TB b

urde

n, a

nd a

re

abou

t US$

449

0 –

not i

nclu

ding

ant

iretro

vira

l the

rapy

(ART

) cos

ts –

in S

outh

Af

rica;

US$

406

0 in

Geo

rgia

and

US$

386

0 in

the

Philip

pine

s. In

hig

h H

IV-T

B pr

eval

ence

set

tings

suc

h as

Sou

th A

frica

, rel

ated

futu

re c

osts

suc

h as

thos

e fro

m

the

HIV

pro

gram

me

(ART

cos

ts) r

educ

e th

e m

agni

tude

of e

xpec

ted

cost

sav

ings

to

US$

140

0 pe

r pat

ient

. Ove

rall,

whe

n BP

aL is

intro

duce

d to

a la

rger

pop

ulat

ion

(inclu

ding

thos

e w

ith M

DR-

TB tr

eatm

ent f

ailu

re a

nd th

ose

with

trea

tmen

t in

tole

ranc

e), t

he G

DG

obs

erve

d an

incr

ease

in th

e in

crem

enta

l ben

efits

, bot

h in

te

rms

of d

eath

s an

d di

sabi

lity

adju

sted

life

-yea

rs a

vert

ed a

nd in

crem

enta

l cos

ts.

Food

cos

ts w

ere

not i

nclu

ded

in th

e co

st–e

ffect

iven

ess

anal

ysis

and

wou

ld n

eed

to b

e co

nsid

ered

whe

n BP

aL is

impl

emen

ted.

Dur

ing

the

Nix-

TB s

tudy

, all

stud

y m

edica

tions

wer

e ad

min

ister

ed w

ith fo

od (b

ecau

se o

f the

adm

inist

ratio

n of

be

daqu

iline,

whi

ch w

ill al

so n

ow fe

atur

e as

a c

ore

med

icine

in lo

nger

trea

tmen

t re

gim

ens

for M

DR/

RR-T

B). T

he c

ost o

f the

BPa

L re

gim

en is

US$

104

0 ac

cord

ing

to th

e G

loba

l Dru

g Fa

cility

(GFD

), ba

sed

on G

DF-

wei

ghte

d av

erag

e ta

blet

pric

e.

Cert

aint

y of

evi

denc

e of

req

uire

d re

sour

ces

Wha

t is

the

cert

aint

y of

the

evid

ence

of r

esou

rce

requ

irem

ents

(cos

ts)?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Ver

y lo

w

○ L

ow

○ M

oder

ate

○ H

igh

● N

o in

clude

d st

udie

s

No

rese

arch

evi

denc

e w

as id

entif

ied.


Cost

eff

ecti

vene

ssD

oes

the

cost

-eff

ectiv

enes

s of

the

inte

rven

tion

favo

r the

inte

rven

tion

or th

e co

mpa

rison

?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Fav

ors

the

com

paris

on

○ P

roba

bly

favo

rs

the

com

paris

on

○ D

oes

not

favo

r eith

er th

e in

terv

entio

n or

the

com

paris

on

○ P

roba

bly

favo

rs

the

inte

rven

tion

○ F

avor

s th

e in

terv

entio

n ○

Var

ies

● N

o in

clude

d st

udie

s

No

rese

arch

evi

denc

e w

as id

entif

ied.

Th

e G

DG

con

sider

ed e

vide

nce

from

a c

ost–

effe

ctiv

enes

s an

alys

is st

udy

that

was

co

nduc

ted

by s

taff

from

the

Lond

on S

choo

l of H

ygie

ne &

Trop

ical M

edici

ne o

n be

half

of th

e TB

Allia

nce.

The

GD

G n

oted

that

the

cost

–effe

ctiv

enes

s an

alys

is w

as

not d

one

for t

his

evid

ence

to d

ecisi

on fr

amew

ork

– th

at is

, und

esira

ble

effe

cts

wer

e no

t con

sider

ed a

ccor

ding

to th

e G

DG

’s ju

dgem

ents

. Thi

s m

ade

the

cost

–ef

fect

iven

ess

anal

yses

info

rmat

ive

but n

ot d

irect

ly b

ased

on

the

evid

ence

that

the

GD

G w

as a

sses

sing.

The

anal

yses

wer

e ba

sed

on G

eorg

ia, t

he P

hilip

pine

s, an

d So

uth

Afric

a. T

he

aim

s of

the

rese

arch

wer

e to

est

imat

e th

e co

st–e

ffect

iven

ess

of a

new

regi

men

co

ntai

ning

bed

aqui

line,

pre

tom

anid

and

line

zolid

(BPa

L) c

ompa

red

with

the

stan

dard

of c

are

at a

giv

en p

rice,

and

to e

stim

ate

the

max

imum

dru

g pr

ice a

t w

hich

the

BPaL

regi

men

cou

ld b

e co

nsid

ered

cos

t-effe

ctiv

e or

cos

t-neu

tral i

n ea

ch s

ettin

g. T

he p

ersp

ectiv

e ta

ken

was

a h

ealth

ser

vice

one

, and

the

stud

y as

sum

ed B

PaL

to b

e ef

fect

ive.

Whe

n as

sess

ing

the

pote

ntia

l cos

t–ef

fect

iven

ess

of B

PaL

for t

he tr

eatm

ent o

f XD

R-TB

, the

GD

G o

bser

ved

that

in a

ll th

ree

setti

ngs,

this

regi

men

has

the

pote

ntia

l to

be c

ost s

avin

g at

a g

iven

dru

g pr

ice o

f US$

364

pe

r tre

atm

ent c

ours

e fo

r pre

tom

anid

. The

stu

dy fo

und

that

cos

t sav

ings

are

a

func

tion

of th

e co

st o

f car

e an

d th

e m

agni

tude

of X

DR-

TB b

urde

n, a

nd a

re

abou

t US$

449

0 –

not i

nclu

ding

ant

iretro

vira

l the

rapy

(ART

) cos

ts –

in S

outh

Af

rica;

US$

406

0 in

Geo

rgia

and

US$

386

0 in

the

Philip

pine

s.. In

hig

h H

IV-T

B pr

eval

ence

set

tings

, suc

h as

Sou

th A

frica

, rel

ated

futu

re c

osts

suc

h as

thos

e fro

m th

e H

IV p

rogr

amm

e (A

RT c

osts

) red

uce

the

mag

nitu

de o

f exp

ecte

d co

st

savi

ngs

to U

S$ 1

400

per p

atie

nt. O

vera

ll, w

hen

BPaL

is in

trodu

ced

to a

larg

er

popu

latio

n (in

cludi

ng p

atie

nts

with

failu

re o

f MD

R-TB

trea

tmen

t and

thos

e w

ho

cann

ot to

lera

te tr

eatm

ent),

the

GD

G o

bser

ved

an in

crea

se in

the

incr

emen

tal

bene

fits,

both

in te

rms

of d

eath

s an

d di

sabi

lity

adju

sted

life

yea

rs a

vert

ed a

nd

incr

emen

tal c

osts

.Fo

od c

osts

wer

e no

t inc

lude

d in

the

cost

–effe

ctiv

enes

s an

alys

is an

d w

ould

nee

d to

be

cons

ider

ed w

hen

BPaL

is im

plem

ente

d. D

urin

g th

e N

ix-TB

stu

dy, a

ll st

udy

med

icatio

ns w

ere

adm

inist

ered

with

food

(bec

ause

of t

he a

dmin

istra

tion

of

beda

quilin

e, w

hich

will

also

now

feat

ure

as a

cor

e m

edici

ne in

long

er tr

eatm

ent

regi

men

s fo

r MD

R/RR

-TB)

.


Equi

tyW

hat w

ould

be

the

impa

ct o

n he

alth

equ

ity?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

Red

uced

○

Pro

babl

y re

duce

d ○

Pro

babl

y no

im

pact

●

Prob

ably

in

crea

sed

○ In

crea

sed

○ V

arie

s ○

Don

’t kn

ow

No

rese

arch

evi

denc

e w

as id

entif

ied.

Alth

ough

no

rese

arch

evi

denc

e w

as id

entif

ied,

the

GD

G p

anel

felt

that

the

impa

ct o

n he

alth

equ

ity w

ould

be

a pr

obab

le in

crea

se, g

iven

the

optio

n of

a

shor

ter r

egim

en th

at c

ould

be

avai

labl

e gl

obal

ly (i

.e. a

vaila

ble

to a

ll pa

tient

s).

The

GD

F ha

s id

entif

ied

a pr

ice fo

r pre

tom

anid

and

sta

ted

that

it w

ill m

ake

the

BPaL

regi

men

ava

ilabl

e to

nat

iona

l TB

prog

ram

mes

, dep

ende

nt u

pon

the

reco

mm

enda

tion

from

the

pane

l. Th

e G

DF

repr

esen

tativ

e no

ted

that

two

bottl

es o

f bed

aqui

line

will

need

to b

e or

dere

d fo

r any

one

who

is re

ceiv

ing

the

BPaL

regi

men

. Chi

ldre

n an

d pr

egna

nt w

omen

wer

e in

elig

ible

for i

nclu

sion

in

the

Nix-

TB s

tudy

and

ther

efor

e w

ill no

t be

an e

ligib

le p

opul

atio

n fo

r BPa

L if

it is

reco

mm

ende

d, w

hich

may

be

an e

quity

issu

e.


Acc

epta

bilit

yIs

the

inte

rven

tion

acce

ptab

le to

key

sta

keho

lder

s?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

No

○ P

roba

bly

no

● Pr

obab

ly y

es

○ Y

es

○ V

arie

s ○

Don

’t kn

ow

The

GD

G p

anel

thou

ght t

hat t

he ju

dgem

ent w

as p

roba

bly

yes b

ecau

se th

e co

ncer

ns re

gard

ing

repr

oduc

tive

toxic

ities

wer

e no

t disc

usse

d as

par

t of t

he

acce

ptab

ility

stud

y co

nduc

ted

by K

NCV

(bec

ause

this

was

not

kno

wn

to th

e st

udy

inve

stig

ator

s at

the

time)

and

the

com

para

tor u

sed

in th

is st

udy

was

not

th

e sa

me

as th

at fo

r the

evi

denc

e th

at w

as a

sses

sed.

The

GD

G c

onsid

ered

evi

denc

e fro

m a

n ac

cept

abilit

y an

d fe

asib

ility

stud

y co

nduc

ted

by K

NCV

on

beha

lf of

the

TB A

llianc

e. T

he o

bjec

tives

of t

he s

tudy

w

ere

to a

sses

s th

e ac

cept

abilit

y an

d lik

elih

ood

of im

plem

enta

tion

of th

e BP

aL

regi

men

as

antic

ipat

ed b

y ke

y st

akeh

olde

rs a

nd b

ased

on

a nu

mbe

r of c

riter

ia

(inclu

ding

the

perc

eive

d be

nefit

s an

d ch

alle

nges

of i

mpl

emen

tatio

n of

BPa

L an

d lo

nger

indi

vidu

aliz

ed tr

eatm

ent r

egim

ens,

and

othe

r pra

ctica

l req

uire

men

ts o

f im

plem

enta

tion)

. The

stu

dy w

as a

mixe

d-m

etho

ds, m

ultic

ount

ry, c

ross

-sec

tiona

l in

vest

igat

ion

cond

ucte

d in

–20

18–2

019

amon

g st

akeh

olde

rs in

Indo

nesia

, Ky

rgys

tan

and

Nig

eria

. Vie

ws

wer

e of

fere

d by

a to

tal o

f 188

par

ticip

ants

, in

cludi

ng c

areg

iver

s, pr

ogra

mm

atic

stak

ehol

ders

(inc

ludi

ng n

atio

nal a

nd

inte

rnat

iona

l pro

gram

mat

ic st

akeh

olde

rs a

nd p

atie

nt-a

dvoc

acy

grou

ps) a

nd

publ

ic an

d pr

ivat

e la

bora

tory

sta

keho

lder

s. O

n th

e ba

sis o

f sev

en a

sses

smen

t ca

tego

ries

(rang

ing

from

pat

ient

frie

ndlin

ess

to tr

eatm

ent s

afet

y m

onito

ring)

, th

e ac

cept

abilit

y of

BPa

L w

hen

com

pare

d w

ith a

long

er tr

eatm

ent r

egim

en fo

r M

DR-

TB w

as h

ighe

r for

eve

ry c

ateg

ory.

Acce

ptab

ility

was

hig

her f

or B

PaL

than

fo

r the

long

er M

DR-

TB re

gim

ens

in s

ix of

the

seve

n ca

tego

ries

asse

ssed

, with

the

exce

ptio

n of

trea

tmen

t saf

ety

mon

itorin

g, w

here

the

diffe

renc

e w

as n

eglig

ible

. Th

e m

ain

driv

ers

of a

ccep

tabi

lity

of B

PaL

wer

e th

e sh

orte

r dur

atio

n, a

bsen

ce o

f in

ject

able

s, lo

wer

pill

burd

en, a

ntici

pate

d pa

tient

pre

fere

nces

and

low

er fi

nanc

ial

burd

en fo

r pat

ient

s, an

ticip

ated

hig

her t

reat

men

t suc

cess

, low

er c

osts

for t

he

heal

th s

yste

m, m

inim

al a

dditi

onal

requ

irem

ents

for d

iagn

ostic

pro

cess

es, a

nd

a lo

wer

ant

icipa

ted

per-p

atie

nt b

urde

n to

the

TB la

bora

tory

for b

acte

riolo

gica

l tre

atm

ent m

onito

ring.

Indi

rect

evi

denc

e w

as c

onsid

ered

by

the

pane

l in

the

form

of

a s

epar

ate

qual

itativ

e st

udy

cond

ucte

d am

ong

16 p

atie

nts

with

dru

g-re

sista

nt

TB w

ho w

ere

from

hig

h bu

rden

cou

ntrie

s (w

hich

info

rmed

the

judg

emen

ts o

n PI

CO 1

). Th

e ai

m o

f the

stu

dy w

as to

det

erm

ine

the

mos

t acc

epta

ble

treat

men

t re

gim

en fo

r dru

g-re

sista

nt T

B. O

n th

e ba

sis o

f the

resu

lts o

f thi

s st

udy,

the

pref

erre

d re

gim

en w

as s

hort

and

inje

ctio

n-fre

e w

ith fe

w to

no

phys

ical o

r men

tal

heal

th s

ide-

effe

cts

and

a lo

w p

ill bu

rden

. Ran

ked

pref

eren

ces

for d

rug

resis

tant

TB

trea

tmen

t wer

e as

follo

ws:

(1) a

dver

se e

vent

s, (2

) dur

atio

n, (3

) inj

ectio

n (fr

ee)

and

(4) p

ill bu

rden

.


Feas

ibili

tyIs

the

inte

rven

tion

feas

ible

to im

plem

ent?

JUD

GEM

ENT

RESE

ARC

H E

VID

ENCE

AD

DIT

ION

AL

CON

SID

ERAT

ION

S○

No

○ P

roba

bly

no

● Pr

obab

ly y

es

○ Y

es

○ V

arie

s ○

Don

’t kn

ow

The

GD

G c

onsid

ered

evi

denc

e fro

m a

n ac

cept

abilit

y an

d fe

asib

ility

stud

y co

nduc

ted

by K

NCV

on

beha

lf of

the

TB A

llianc

e. T

he o

bjec

tives

of t

he s

tudy

w

ere

to a

sses

s th

e ac

cept

abilit

y an

d lik

elih

ood

of im

plem

enta

tion

of th

e BP

aL

regi

men

as

antic

ipat

ed b

y ke

y st

akeh

olde

rs a

nd o

n th

e ba

sis o

f a n

umbe

r of

crite

ria, i

nclu

ding

the

perc

eive

d be

nefit

s an

d ch

alle

nges

of i

mpl

emen

tatio

n of

BPa

L an

d lo

nger

indi

vidu

aliz

ed tr

eatm

ent r

egim

ens,

and

othe

r pra

ctica

l re

quire

men

ts o

f im

plem

enta

tion.

The

stu

dy w

as a

mixe

d-m

etho

ds, m

ultic

ount

ry,

cros

s-se

ctio

nal i

nves

tigat

ion

cond

ucte

d in

201

8–20

19 a

mon

g st

akeh

olde

rs

in In

done

sia, K

yrgy

zsta

n an

d N

iger

ia. A

tota

l of 1

88 p

artic

ipan

ts o

ffere

d th

eir

view

s, in

cludi

ng c

areg

iver

s, pr

ogra

mm

atic

stak

ehol

ders

(inc

ludi

ng n

atio

nal a

nd

inte

rnat

iona

l pro

gram

mat

ic st

akeh

olde

rs a

nd p

atie

nt-a

dvoc

acy

grou

ps),

and

publ

ic an

d pr

ivat

e la

bora

tory

sta

keho

lder

s. O

n th

e ba

sis o

f sev

en a

sses

smen

t ca

tego

ries (

rang

ing

from

frie

ndlin

ess f

or p

atie

nts t

o tre

atm

ent s

afet

y m

onito

ring)

, th

e ac

cept

abilit

y of

BPa

L w

hen

com

pare

d w

ith a

long

er tr

eatm

ent r

egim

en fo

r M

DR-

TB w

as h

ighe

r for

eve

ry c

ateg

ory.

Acce

ptab

ility

was

hig

her f

or B

PaL

than

fo

r the

long

er M

DR-

TB re

gim

ens

in s

ix of

the

seve

n ca

tego

ries

asse

ssed

, with

the

exce

ptio

n of

trea

tmen

t saf

ety

mon

itorin

g, w

here

the

diffe

renc

e w

as n

eglig

ible

. In

line

with

the

over

all h

igh

acce

ptab

ility

of th

e BP

aL re

gim

en, t

he o

vera

ll lik

elin

ess

of im

plem

entin

g th

e BP

aL re

gim

en a

s a

stan

dard

of c

are

for t

he tr

eatm

ent o

f pa

tient

s w

ith X

DR-

TB a

nd M

DR-

TB tr

eatm

ent f

ailu

re/in

tole

ranc

e sc

ored

at 8

8;

only

1%

of t

he 1

66 p

artic

ipan

ts s

core

d th

at im

plem

enta

tion

as “u

nlike

ly,” a

nd

11%

had

a n

eutra

l opi

nion

. The

like

lines

s of

impl

emen

tatio

n w

as s

imila

r (84

%) t

o th

at fo

r the

BPa

L re

gim

en a

s a

stan

dard

of c

are

for p

atie

nts

with

MD

R-TB

with

flu

oroq

uino

lone

resis

tanc

e, re

gard

less

of a

dditi

onal

resis

tanc

e to

sec

ond-

line

inje

ctab

les.

This

indi

cate

d th

at th

e re

gim

en m

ay b

e fe

asib

le to

impl

emen

t fro

m

the

pers

pect

ive

of th

ose

inte

rvie

wed

.


Sum

mar

y of

judg

emen

ts

JUD

GEM

ENT

PRO

BLEM

No

Prob

ably

no

Prob

ably

yes

Yes

Varie

sD

on’t

know

DES

IRAB

LE E

FFEC

TSTr

ivia

lSm

all

Mod

erat

eLa

rge

Varie

sD

on’t

know

UND

ESIR

ABLE

EFF

ECTS

Larg

eM

oder

ate

Smal

lTr

ivia

lVa

ries

Don

’t kn

owCE

RTAI

NTY

OF

EVID

ENCE

Very

low

Low

Mod

erat

eH

igh

No

inclu

ded

stud

ies

VALU

ESIm

port

ant

unce

rtai

nty

or

varia

bilit

y

Poss

ibly

impo

rtan

t un

cert

aint

y or

va

riabi

lity

Prob

ably

no

impo

rtan

t un

cert

aint

y or

va

riabi

lity

No

impo

rtan

t un

cert

aint

y or

va

riabi

lity

BALA

NCE

OF

EFFE

CTS

Favo

rs th

e co

mpa

rison

Prob

ably

favo

rs th

e co

mpa

rison

Doe

s no

t fav

or

eith

er th

e in

terv

entio

n or

the

com

paris

on

Prob

ably

favo

rs th

e in

terv

entio

nFa

vors

the

inte

rven

tion

Varie

sD

on’t

know

RESO

URCE

S RE

QUI

RED

Larg

e co

sts

Mod

erat

e co

sts

Neg

ligib

le c

osts

and

sa

ving

sM

oder

ate

savi

ngs

Larg

e sa

ving

sVa

ries

Don

’t kn

ow

CERT

AIN

TY O

F EV

IDEN

CE

OF

REQ

UIRE

D R

ESO

URCE

SVe

ry lo

wLo

wM

oder

ate

Hig

hN

o in

clude

d st

udie

s

COST

EFF

ECTI

VEN

ESS

Favo

rs th

e co

mpa

rison

Prob

ably

favo

rs th

e co

mpa

rison

Doe

s no

t fav

or e

ither

th

e in

terv

entio

n or

th

e co

mpa

rison

Prob

ably

favo

rs th

e in

terv

entio

nFa

vors

the

inte

rven

tion

Varie

sN

o in

clud

ed

stud

ies

EQUI

TYRe

duce

dPr

obab

ly re

duce

dPr

obab

ly n

o im

pact

Prob

ably

incr

ease

dIn

crea

sed

Varie

sD

on’t

know

ACCE

PTAB

ILIT

YN

oPr

obab

ly n

oPr

obab

ly y

esYe

sVa

ries

Don

’t kn

owFE

ASIB

ILIT

YN

oPr

obab

ly n

oPr

obab

ly y

esYe

sVa

ries

Don

’t kn

ow

Type

of r

ecom

men

datio

nSt

rong

reco

mm

enda

tion

agai

nst

the

inte

rven

tion

○

Cond

ition

al re

com

men

datio

n ag

ains

t the

inte

rven

tion

○

Cond

ition

al re

com

men

datio

n fo

r eith

er th

e in

terv

entio

n or

the

com

paris

on●

Cond

ition

al re

com

men

datio

n fo

r th

e in

terv

entio

n○

Stro

ng re

com

men

datio

n fo

r the

in

terv

entio

n○


Conc

lusi

ons

Reco

mm

enda

tion

A tre

atm

ent r

egim

en la

stin

g 6–

9 m

onth

s co

mpo

sed

of b

edaq

uilin

e, p

reto

man

id a

nd li

nezo

lid (B

PaL)

may

be

used

und

er o

pera

tiona

l res

earc

h co

nditi

ons

in M

DR-

TB p

atie

nts

with

TB

that

is re

sista

nt to

fluo

roqu

inol

ones

who

hav

e ha

d no

pre

viou

s ex

posu

re to

bed

aqui

line

and

linez

olid

for m

ore

than

two

wee

ks (c

ondi

tiona

l rec

omm

enda

tion,

ver

y lo

w c

erta

inty

in th

e es

timat

es o

f effe

ct).

Just

ifica

tion

Trea

tmen

t of p

atie

nts

with

form

s of

ext

ensiv

ely

drug

-res

istan

t TB

(XD

R-TB

) pre

sent

s m

ultip

le c

halle

nges

to c

linici

ans

and

natio

nal T

B pr

ogra

mm

es, b

oth

beca

use

of th

e lim

ited

rang

e of

med

icine

s av

aila

ble

and

the

life-

thre

aten

ing

natu

re o

f the

dise

ase.

Pat

ient

s w

ith M

DR/

RR-T

B an

d ad

ditio

nal f

luor

oqui

nolo

ne re

sista

nce

have

typi

cally

exp

erie

nced

poo

r tre

atm

ent

outc

omes

sin

ce th

e de

scrip

tion

of X

DR-

TB w

as fi

rst u

sed

in 2

006.

9 The

dat

a re

port

ed b

y m

embe

r sta

tes

to W

HO

, for

the

coho

rt o

f pat

ient

s w

ith X

DR-

TB w

ho s

tart

ed tr

eatm

ent i

n 20

16 (a

nd fo

r who

m tr

eatm

ent o

utco

mes

wer

e av

aila

ble

in 2

018)

sho

w th

at o

nly

39%

com

plet

ed tr

eatm

ent s

ucce

ssfu

lly, w

here

as 2

6% d

ied,

18%

exp

erie

nced

trea

tmen

t fai

lure

, and

an

add

ition

al 1

8% w

ere

lost

to fo

llow

-up

or w

ere

not e

valu

ated

.10 T

he p

ress

ing

need

for m

ore

effe

ctiv

e tre

atm

ent r

egim

ens

for p

atie

nts

with

ext

ensiv

e dr

ug re

sista

nce,

inclu

ding

flu

oroq

uino

lone

resis

tanc

e an

d m

ore

exte

nsiv

e dr

ug re

sista

nce

prof

iles,

has

mot

ivat

ed a

num

ber o

f stu

dies

and

initi

ativ

es to

test

mor

e ef

fect

ive

and

nove

l tre

atm

ent r

egim

ens,

inclu

ding

ne

wer

and

repu

rpos

ed m

edici

nes.

One

suc

h st

udy

is th

e N

ix-TB

stu

dy, c

ondu

cted

by

the

TB A

llianc

e. T

he N

ix-TB

stu

dy w

as a

one

-arm

, pha

se II

I, op

en-la

bel p

rosp

ectiv

e co

hort

stu

dy th

at a

sses

sed

the

safe

ty, e

ffica

cy,

tole

rabi

lity,

and

phar

mac

okin

etic

prop

ertie

s of

a 6

-mon

th tr

eatm

ent r

egim

en c

ompo

sed

of b

edaq

uilin

e, p

reto

man

id a

nd li

nezo

lid (B

PaL)

, ext

enda

ble

to 9

mon

ths

for t

hose

who

miss

ed

dose

s or

for p

atie

nts

who

rem

aine

d cu

lture

pos

itive

or r

ever

ted

from

cul

ture

neg

ativ

e to

cul

ture

pos

itive

bet

wee

n m

onth

s 4

and

6 of

trea

tmen

t. Th

e st

udy

was

con

duct

ed b

etw

een

2014

an

d 20

19 a

t thr

ee s

tudy

site

s, al

l in

Sout

h Af

rica,

with

the

first

pat

ient

enr

olle

d in

Apr

il 20

15. E

ligib

le p

atie

nts

wer

e ag

ed 1

4 ye

ars

or o

lder

, wei

ghed

≥35

kg,

had

a d

ocum

ente

d H

IV re

sult,

an

d ha

d ba

cter

iolo

gica

lly c

onfir

med

spu

tum

cul

ture

pos

itive

XD

R-TB

or b

acte

riolo

gica

lly c

onfir

med

MD

R/RR

-TB

but c

ould

not

tole

rate

trea

tmen

t or h

ad d

iseas

e th

at d

id n

ot re

spon

d to

pr

evio

us M

DR/

RR-T

B tre

atm

ent.

A nu

mbe

r of o

ther

inclu

sion

crite

ria w

ere

appl

ied.

Patie

nts

wer

e fo

llow

ed u

p fo

r a p

erio

d of

up

to 2

4 m

onth

s af

ter c

ompl

etio

n of

trea

tmen

t. Th

e pr

imar

y ou

tcom

e m

easu

re w

as th

e in

ciden

ce o

f bac

terio

logi

cal f

ailu

re o

r rel

apse

or c

linica

l fa

ilure

thro

ugh

follo

w-u

p un

til 6

mon

ths

afte

r the

end

of t

reat

men

t.11 S

econ

dary

out

com

e m

easu

res

wer

e as

follo

ws:

1. In

ciden

ce o

f bac

terio

logi

cal f

ailu

re o

r rel

apse

or c

linica

l fai

lure

thro

ugh

follo

w u

p un

til 2

4 m

onth

s af

ter t

he e

nd o

f tre

atm

ent (

as a

con

firm

ator

y an

alys

is).

2. T

ime

to s

putu

m c

ultu

re c

onve

rsio

n to

neg

ativ

e st

atus

thro

ugh

the

treat

men

t per

iod.

3. P

ropo

rtio

n of

sub

ject

s w

ith s

putu

m c

ultu

re c

onve

rsio

n to

neg

ativ

e st

atus

at 4

, 6, 8

, 12,

16

and

26 o

r 39

wee

ks.

4. L

inez

olid

dos

ing

(act

ual)

and

effic

acy.

5. C

hang

e fro

m b

asel

ine

in T

B sy

mpt

oms.

6. C

hang

e fro

m b

asel

ine

in p

atie

nt re

port

ed h

ealth

sta

tus.

7. C

hang

e fro

m b

asel

ine

in w

eigh

t (TB

Allia

nce,

Nix-

TB s

tudy

pro

toco

l, av

aila

ble

at: h

ttps:/

/clin

icaltr

ials.

gov/

ct2/

show

/NCT

0233

3799

).Th

e N

ix-TB

stu

dy re

gim

en c

ompr

ised

pret

oman

id a

dmin

ister

ed a

t 200

mg/

day,

beda

quilin

e ad

min

ister

ed a

t 400

mg/

day

for t

he fi

rst 2

wee

ks o

f tre

atm

ent (

days

1–1

4) a

nd 2

00 m

g th

ree

times

a w

eek

ther

eafte

r, an

d lin

ezol

id c

omm

encin

g at

120

0 m

g/da

y (a

dditi

onal

info

rmat

ion

on li

nezo

lid d

osin

g is

inclu

ded

unde

r “Im

plem

enta

tion

cons

ider

atio

ns”).

Clo

se m

icrob

iolo

gic,

cli

nica

l and

adv

erse

eve

nt m

onito

ring

wer

e fe

atur

es o

f the

Nix-

TB s

tudy

.

9 Em

erge

nce

of X

DR-

TB. G

enev

a, S

witz

erla

nd W

orld

Hea

lth O

rgan

izat

ion

2006

(http

s://w

ww.

who

.int/

med

iace

ntre

/new

s/no

tes/

2006

/np2

3/en

, acc

esse

d 28

Feb

ruar

y 20

20).

10

Glo

bal t

uber

culo

sis re

port

201

9 (W

HO

/CD

S/TB

/201

9.15

). G

enev

a, S

witz

erla

nd W

orld

Hea

lth O

rgan

izat

ion;

201

9 (h

ttps:/

/ww

w.w

ho.in

t/tb

/pub

licat

ions

/glo

bal_r

epor

t/en

/, ac

cess

ed 2

9 M

ay 2

020)

.11

Sa

fety

and

effi

cacy

of v

ario

us d

oses

and

trea

tmen

t dur

atio

ns o

f lin

ezol

id p

lus b

edaq

uilin

e an

d pr

etom

anid

in p

artic

ipan

ts w

ith p

ulm

onar

y TB

, XD

R-TB

, Pre

- XD

R-TB

or n

on-r

espo

nsiv

e/In

tole

rant

MD

R-TB

(ZeN

iX)

[web

site]

. Mar

ylan

d, U

nite

d St

ates

of A

mer

ica U

.S. N

atio

nal L

ibra

ry o

f Med

icine

; 201

7 (h

ttps:/

/clin

icaltr

ials.

gov/

ct2/

show

/NCT

0308

6486

, acc

esse

d 20

Mar

ch 2

020)

.


The

evid

ence

to in

form

this

PICO

que

stio

n w

as d

erive

d fro

m th

e N

ix-TB

stud

y an

d in

clude

d in

form

atio

n on

108

pat

ient

s. Th

e to

tal s

tudy

pop

ulat

ion

was

109

pat

ient

s; ho

wev

er, 1

pat

ient

w

ithdr

ew in

form

ed c

onse

nt to

par

ticip

ate

in th

e st

udy

and

was

inclu

ded

in sa

fety

ana

lyses

but

not

in a

nalys

es fo

r effe

ctive

ness

. The

se d

ata

wer

e co

mpa

red

with

a su

bset

of d

ata

from

the

IPD,

whi

ch o

vera

ll in

clude

s 13

273

indi

vidua

l pat

ient

reco

rds f

rom

55

diffe

rent

stud

ies o

r cen

tres i

n 38

cou

ntrie

s. Fo

r the

prim

ary

anal

yses

, the

com

para

tor g

roup

inclu

ded

patie

nts f

rom

the

IPD

rece

iving

long

er tr

eatm

ent r

egim

ens (

with

a m

ean

dura

tion

of tr

eatm

ent r

angi

ng b

etw

een

21.0

–25.

5 m

onth

s), w

ho re

ceive

d bo

th b

edaq

uilin

e an

d lin

ezol

id a

s par

t of t

he re

gim

en (n

o pa

tient

s rec

eive

d pr

etom

anid

in th

e IP

D).

This

com

paris

on g

roup

inclu

ded

456

patie

nts w

ho w

ere

treat

ed in

Bel

arus

(Rep

ublic

of),

Fra

nce,

Indi

a, a

nd R

ussia

, and

in c

ount

ries i

n As

ia. T

he

inte

rven

tion

and

com

paris

on g

roup

s wer

e m

atch

ed e

xact

ly fo

r XD

R-TB

stat

us, M

DR-

TB st

atus

, flu

oroq

uino

lone

resis

tanc

e, a

nd H

IV st

atus

, with

pro

pens

ity sc

ore

mat

chin

g fo

r the

var

iabl

es

of a

ge, s

ex, b

asel

ine

cultu

re re

sult,

ext

ent o

f dise

ase

(det

erm

ined

by

base

line

AFB

smea

r or c

hest

X-r

ay fi

ndin

gs o

f cav

itatio

n or

by

bila

tera

l dise

ase

if AF

B sm

ear r

esul

t was

miss

ing)

and

co

untr

y in

com

e le

vel (

Wor

ld B

ank

Atla

s met

hod)

. Tre

atm

ent o

utco

mes

use

d in

thes

e an

alys

es c

ompr

ised

the

inve

stig

ator

-def

ined

out

com

es fo

r the

inte

rven

tion

grou

p (fo

r the

Nix-

TB

stud

y) a

nd tr

eatm

ent o

utco

mes

larg

ely

defin

ed a

ccor

ding

to W

HO

def

initi

ons12

for t

he c

ompa

rato

r gro

up (f

or th

e pa

tient

s inc

lude

d in

the

IPD

). To

allo

w a

n eq

ual o

ppor

tuni

ty fo

r tre

atm

ent

outc

omes

to o

ccur

from

the

star

t of t

reat

men

t whe

n co

mpa

ring

the

two

grou

ps, a

ll ou

tcom

es w

ere

inclu

ded

from

the

star

t of t

reat

men

t to

24 m

onth

s afte

r the

star

t of t

reat

men

t. Th

is m

eant

that

, in

the

inte

rven

tion

grou

p, th

ese

outc

omes

occ

urre

d af

ter c

ompl

etio

n of

trea

tmen

t, an

d fo

r the

com

para

tor g

roup

, the

out

com

es w

ere

end-

of-t

reat

men

t out

com

es (b

ecau

se

patie

nts i

n th

e IP

D re

ceive

d a

long

er re

gim

en a

nd w

ere

not m

onito

red

afte

r tre

atm

ent c

ompl

etio

n). T

hree

oth

er c

ompa

rato

r gro

ups f

rom

the

IPD

inclu

ded

patie

nts r

ecei

ving

long

er

treat

men

t reg

imen

s whi

ch in

clude

d be

daqu

iline,

or a

regi

men

whi

ch in

clude

d lin

ezol

id, o

r a re

gim

en w

ith n

eith

er b

edaq

uilin

e or

line

zolid

inclu

ded.

The

initi

al in

tent

ion

of th

e G

DG

was

to

asse

ss th

e in

terv

entio

n re

gim

en a

gain

st a

ll th

ree

com

paris

on g

roup

s; ho

wev

er, d

urin

g th

eir d

elib

erat

ions

the

pane

l agr

eed

that

the

judg

emen

ts sh

ould

be

base

d on

the

com

paris

on g

roup

w

ho re

ceive

d be

daqu

iline

and

linez

olid

as p

art o

f the

ir re

gim

en, b

ecau

se th

ese

patie

nts m

ost c

lose

ly re

sem

bled

pat

ient

s who

wou

ld re

ceive

cur

rent

ly re

com

men

ded

long

er re

gim

ens

com

pose

d of

med

icine

s fro

m G

roup

s A–C

. How

ever

, a d

irect

com

paris

on o

f BPa

L w

ith a

ll-or

al lo

nger

regi

men

s con

stru

cted

acc

ordi

ng to

the

mos

t rec

ent W

HO

reco

mm

enda

tions

issu

ed in

M

ay 2

019

was

not

pos

sible

, bec

ause

thes

e re

gim

ens m

ight

hav

e be

en in

use

onl

y sin

ce m

id-2

019,

and

trea

tmen

t out

com

es fo

r the

se p

atie

nts a

re n

ot y

et a

vaila

ble.

Addi

tiona

l dat

a re

view

ed b

y th

e G

DG

rele

vant

to th

is PI

CO q

uest

ion

wer

e a

cost

–effe

ctiv

enes

s an

alys

is, a

stu

dy o

n th

e ac

cept

abilit

y an

d lik

elih

ood

of im

plem

enta

tion

of th

e BP

aL re

gim

en,

mod

elle

d ph

arm

acok

inet

ic da

ta b

ased

on

the

deve

lopm

ent o

f a p

harm

acok

inet

ic–to

xicod

ynam

ic m

odel

, and

a s

umm

ary

revi

ew o

f pre

clini

cal a

nd e

arly

clin

ical d

ata

on p

reto

man

id. T

he

cost

–effe

ctiv

enes

s an

alys

is, a

ccep

tabi

lity

stud

y, an

d m

odel

led

phar

mac

okin

etic

stud

ies

wer

e co

nduc

ted

as p

art o

f the

Nix-

TB s

tudy

and

wer

e sp

onso

red

by th

e TB

Allia

nce.

The

GD

G c

onsid

ered

the

desir

able

effe

ct o

f tre

atm

ent s

ucce

ss, w

hich

was

hig

her i

n th

e in

terv

entio

n gr

oup

whe

n co

mpa

red

with

the

com

para

tor,

for a

ll fo

ur tr

eatm

ent o

utco

mes

that

w

ere

asse

ssed

. Ove

rall,

whe

n co

mpa

ring

treat

men

t suc

cess

ver

sus

failu

re/r

ecur

renc

e, th

e tre

atm

ent s

ucce

ss ra

te in

the

Nix-

TB s

tudy

was

97.

0% c

ompa

red

with

91.

7% in

the

com

para

tor

grou

p (re

sulti

ng in

6 m

ore

outc

omes

of t

reat

men

t suc

cess

per

100

pat

ient

s). F

or th

e co

mpa

rison

of t

reat

men

t suc

cess

ver

sus

deat

h, tr

eatm

ent s

ucce

ss w

as 9

3.2%

in th

e N

ix-TB

stu

dy

com

pare

d w

ith 9

1.9%

in th

e co

mpa

rato

r gro

up (r

esul

ting

in 1

mor

e ou

tcom

e of

trea

tmen

t suc

cess

per

100

pat

ient

s). F

or th

e co

mpa

rison

s of

trea

tmen

t suc

cess

ver

sus

failu

re/r

ecur

renc

e/de

ath

and

treat

men

t suc

cess

ver

sus

all u

nfav

oura

ble

outc

omes

com

bine

d (i.

e. fa

ilure

/rel

apse

/dea

th a

nd lo

ss to

follo

w-u

p), t

he p

ropo

rtio

ns o

f pat

ient

s w

ith tr

eatm

ent s

ucce

ss in

the

inte

rven

tion

and

com

para

tor g

roup

s w

ere

90.5

% v

ersu

s 84

.8%

(6 m

ore

outc

omes

of t

reat

men

t suc

cess

per

100

pat

ient

s) a

nd 8

8.9%

ver

sus

82.2

% (2

mor

e ou

tcom

es o

f tre

atm

ent

succ

ess

per 1

00 p

atie

nts)

, res

pect

ivel

y. O

n th

e ba

sis o

f the

se fi

gure

s, th

e pr

imar

y an

alys

is yi

elde

d ad

just

ed o

dds

ratio

s (a

ORs

) of 3

.3 fo

r tre

atm

ent s

ucce

ss (v

ersu

s th

e co

mbi

ned

outc

ome

of fa

ilure

and

recu

rrenc

e; 9

5% C

I: 0.

8–13

.7),

1.0

for s

ucce

ss v

ersu

s de

ath

(95%

CI:

0.1–

8.2)

, 1.8

for s

ucce

ss v

ersu

s fa

ilure

/rel

apse

/dea

th (9

5% C

I: 0.

7–4.

4), a

nd 1

.2 fo

r suc

cess

ver

sus

all u

nfav

oura

ble

outc

omes

(95%

CI:

0.5–

3.1)

, with

a m

ean

dura

tion

of fo

llow

-up

of 2

4 m

onth

s (ra

nge,

21–

25.5

mon

ths)

, whe

n BP

aL w

as c

ompa

red

with

long

er re

gim

ens

cont

aini

ng

beda

quilin

e an

d lin

ezol

id. T

he G

DG

con

sider

ed ra

tes

of lo

ss to

follo

w-u

p to

be

a de

sirab

le e

ffect

; the

pro

port

ion

of p

atie

nts

who

wer

e lo

st to

follo

w-u

p w

as lo

wer

in th

e in

terv

entio

n (B

PaL)

gro

up (1

.8%

) tha

n in

the

com

paris

on g

roup

(3.1

%);

how

ever

, thi

s di

ffere

nce

was

not

con

sider

ed b

y th

e pa

nel t

o be

larg

e. T

he p

anel

also

con

sider

ed a

sho

rten

ed d

urat

ion

of

treat

men

t and

less

dru

g ex

posu

re to

be

desir

able

effe

cts

of th

e in

terv

entio

n, a

nd n

oted

that

thes

e w

ere

both

com

pone

nts

of th

e ov

eral

l bur

den

of a

giv

en M

DR/

RR-T

B tre

atm

ent

regi

men

, whi

ch m

ay n

ot b

e w

holly

refle

cted

in ra

tes

of lo

ss to

follo

w-u

p al

one.

Spe

cifie

d su

bgro

up a

naly

ses

wer

e un

able

to b

e un

dert

aken

bec

ause

of l

imita

tions

in th

e sa

mpl

e siz

e.

12

Lase

rson

KF,

Thor

pe L

E, L

eim

ane

V, W

eyer

K, M

itnick

CD,

Rie

kstin

a V

et a

l. Sp

eakin

g th

e sa

me

lang

uage

: tre

atm

ent o

utco

me

defin

ition

s for

mul

tidru

g-re

sista

nt tu

berc

ulos

is. In

t J Tu

berc

Lun

g D

is. 2

005;

9(6)

:640

–5.

and

Def

initi

ons

and

repo

rtin

g fra

mew

ork

for t

uber

culo

sis –

201

3 re

visio

n (u

pdat

ed D

ecem

ber 2

014)

[WH

O/H

TM/T

B/20

13.2

]. G

enev

a, S

witz

erla

nd: W

orld

Hea

lth O

rgan

izat

ion;

201

3 (h

ttps:/

/app

s.who

.int/

iris/

bits

tream

/han

dle/

1066

5/79

199/

9789

2415

0534

5_en

g.pd

f?se

quen

ce=1

, acc

esse

d 20

Mar

ch 2

020)

.


The

BPaL

regi

men

was

also

ass

ocia

ted

with

a h

igh

rate

of a

dver

se e

vent

s, co

nsid

ered

to b

e re

late

d to

the

stud

y dr

ugs,

whi

ch w

as a

con

cern

for G

DG

mem

bers

. Of t

he 1

09 p

atie

nts

in

the

Nix-

TB s

tudy

, 28

(25.

7%) e

xper

ienc

ed a

t lea

st o

ne s

erio

us a

dver

se e

vent

. Thi

s in

clude

d 1

deat

h (0

.9%

) rel

ated

to a

cute

hae

mor

rhag

ic pa

ncre

atiti

s, 27

(25%

) oth

er s

erio

us a

dver

se

even

ts in

cludi

ng h

ospi

taliz

atio

ns a

nd li

fe-t

hrea

teni

ng e

vent

s, an

d 2

(1.8

%) a

dver

se e

vent

s th

at re

sulte

d in

per

siste

nt o

r sig

nific

ant d

isabi

lity

or in

capa

city.

Fifty

-thr

ee p

artic

ipan

ts (4

9%)

expe

rienc

ed a

t lea

st o

ne G

rade

3–4

adv

erse

eve

nt c

onsid

ered

to b

e re

late

d to

the

stud

y dr

ugs,

com

prisi

ng 2

5 w

ith p

erip

hera

l neu

ropa

thy

(reso

lved

in 1

1), 1

6 w

ith in

crea

sed

hepa

tic

trans

amin

ases

(res

olve

d in

13)

, 9 w

ith h

aem

atol

ogica

l adv

erse

eve

nts

(reso

lved

in a

ll), 8

who

had

incr

ease

d pa

ncre

atic

enzy

mes

(res

olve

d in

7),

and

2 w

ith o

ptic

neur

itis

(reso

lved

in

bot

h). T

his

led

to d

rug

disc

ontin

uatio

n of

all

thre

e dr

ugs

for 1

par

ticip

ant,

and

linez

olid

(ini

tial d

ose:

120

0 m

g/da

y) w

as d

iscon

tinue

d in

ano

ther

35

part

icipa

nts

(32%

). O

nly

18

part

icipa

nts

(17%

) com

plet

ed a

full

cour

se o

f lin

ezol

id a

t 120

0 m

g/da

y. Th

e G

DG

not

ed th

at it

is d

ifficu

lt to

com

pare

thes

e ad

vers

e ev

ent r

ates

with

oth

er s

tudi

es b

ecau

se o

f maj

or a

nd

impo

rtan

t diff

eren

ces

in a

scer

tain

men

t, as

sess

men

t, an

d re

port

ing

of a

dver

se e

vent

s. H

owev

er, i

n th

e IP

D s

tudi

es (w

here

90%

of p

artic

ipan

ts re

ceiv

ed a

line

zolid

dos

e of

≤60

0 m

g/da

y),

the

pool

ed ra

te o

f per

man

ent d

iscon

tinua

tion

of li

nezo

lid w

as 1

7.9%

, and

in th

e En

dTB

obse

rvat

iona

l stu

dy (w

here

all

patie

nts

rece

ived

≤60

0 m

g/da

y of

line

zolid

), th

e ra

te o

f lin

ezol

id

disc

ontin

uatio

n w

as 1

3.1%

. In

both

of t

hese

stu

dies

, >80

% o

f par

ticip

ants

rece

ived

a s

tart

ing

dose

of l

inez

olid

of 6

00 m

g/da

y. In

pre

limin

ary

anal

yses

of t

he E

ndTB

obs

erva

tiona

l stu

dy,

9 of

109

4 pa

rtici

pant

s (0

.8%

) die

d of

a p

ossib

ly o

r pro

babl

y dr

ug-r

elat

ed a

dver

se e

vent

, inc

ludi

ng 2

par

ticip

ants

with

sud

den

card

iac

deat

h; th

ese

patie

nts

wer

e re

ceiv

ing

beda

quilin

e,

clofa

zim

ine,

cap

reom

ycin

, and

p-a

min

osal

icylic

acid

(PAS

) and

had

hyp

okal

aem

ia.

Info

rmat

ion

pres

ente

d fro

m th

e in

depe

nden

t rev

iew

of t

he p

recli

nica

l dat

a an

d ea

rly-p

hase

clin

ical d

ata

high

light

ed th

at p

reto

man

id p

osse

sses

act

ivity

aga

inst

repl

icatin

g an

d no

nrep

licat

ing

bacil

li th

at is

bot

h co

ncen

tratio

n an

d do

se d

epen

dent

. A c

ompr

ehen

sive

desc

riptio

n of

the

safe

ty s

igna

ls w

as re

port

ed, m

any

of th

ese

signa

ls w

ere

obse

rved

at e

xpos

ures

th

at a

re h

ighe

r tha

n w

ould

be

used

in h

uman

s; ho

wev

er, s

afet

y sig

nals

of n

ote

inclu

de li

ver t

oxici

ties

(hyp

ertro

phy

of h

epat

ocyt

es, t

rans

amin

ase

elev

atio

n, a

nd in

crea

sed

liver

wei

ght,

obse

rved

at h

ighe

r dos

es in

rode

nts

and

low

er d

oses

in m

onke

ys) a

nd re

prod

uctiv

e to

xiciti

es in

mal

es o

bser

ved

in a

nim

al (m

urin

e an

d sim

ian)

mod

els,

whi

ch a

ppea

r to

be b

oth

time

and

dose

dep

ende

nt. T

hese

obs

erva

tions

in m

onke

ys m

ight

hav

e be

en a

ttrib

uted

to th

e ge

nera

l dec

line

of h

ealth

in th

ese

anim

als;

how

ever

, the

sam

e sig

nals

wer

e ob

serv

ed in

rode

nt

mod

els

with

som

e ev

iden

ce th

at th

ese

effe

cts

mig

ht b

e irr

ever

sible

. In

mou

se m

odel

s, th

ese

effe

cts

wer

e ob

serv

ed a

t exp

osur

es th

at w

ould

be

used

in h

uman

s. Re

prod

uctiv

e to

xiciti

es

wer

e al

so o

bser

ved

in fe

mal

es.

Addi

tiona

l inf

orm

atio

n on

adv

erse

eve

nts

pres

ente

d to

the

GD

G in

clude

d th

e re

sults

of a

pha

rmac

okin

etic–

toxic

odyn

amic

mod

el (S

avic

R, u

npub

lishe

d da

ta, U

nive

rsity

of C

alifo

rnia

Sa

n Fr

ancis

co, N

ovem

ber 2

019)

. On

the

basis

of t

hese

dat

a, it

was

con

clude

d th

at th

e ph

arm

acok

inet

ics re

late

d to

line

zolid

are

non

linea

r in

patie

nts

with

XD

R-TB

and

that

indi

vidu

al

linez

olid

con

cent

ratio

n tim

es a

re th

e be

st p

redi

ctor

of t

oxici

ty. H

ighe

r tox

icity

rate

s w

ere

obse

rved

at h

ighe

r tot

al d

aily

dos

es, w

ith c

ompa

rabl

e to

xicity

rate

s fo

r BID

and

QD

dos

ing

sche

dule

s. Th

e re

sults

of t

he m

odel

led

data

hig

hlig

hted

that

ana

emia

can

be

man

aged

by

close

ly m

onito

ring

chan

ges

in h

aem

oglo

bin

over

the

first

4 w

eeks

of t

reat

men

t (in

par

ticul

ar,

chan

ges

in h

aem

oglo

bin

that

repr

esen

t a >

10%

dec

reas

e fro

m b

asel

ine

shou

ld tr

igge

r a re

duct

ion

in th

e do

se o

f lin

ezol

id; h

aem

oglo

bin

leve

ls re

cove

r wel

l afte

r dos

e re

duct

ions

). Th

rom

bocy

tope

nia

was

pot

entia

lly n

ot a

maj

or c

once

rn. T

he s

tudy

inve

stig

ator

s re

com

men

ded

that

per

iphe

ral n

euro

path

y be

clo

sely

mon

itore

d, a

nd n

oted

that

the

mod

elle

d da

ta

show

ed th

at, w

hen

it di

d oc

cur,

it w

as re

vers

ible

for m

ost p

atie

nts,

with

in 3

mon

ths.


Subg

roup

con

side

ratio

nsCh

ildre

n. C

hild

ren

(age

d 0–

13 y

ears

) wer

e ex

clude

d fro

m th

e N

ix-TB

stu

dy; t

here

fore

, no

anal

ysis

spec

ific

to th

is su

bgro

up o

f pat

ient

s co

uld

be p

erfo

rmed

. It i

s re

com

men

ded

that

ch

ildre

n w

ith p

ulm

onar

y M

DR/

RR-T

B w

ith a

dditi

onal

resis

tanc

e to

fluo

roqu

inol

ones

be

give

n th

e sa

me

cons

ider

atio

n fo

r lon

ger t

reat

men

t reg

imen

s as

adu

lts, t

o in

clude

com

pone

nts

with

a s

afet

y pr

ofile

that

is b

ette

r est

ablis

hed.

Bed

aqui

line

is cu

rrent

ly re

com

men

ded

only

for c

hild

ren

aged

6 y

ears

or o

lder

. It i

s ac

know

ledg

ed th

at a

dditi

onal

dat

a on

the

use

of B

PaL

in

child

ren,

whe

n el

igib

le, w

ould

be

usef

ul; t

his

may

be

a fe

atur

e of

car

eful

ly p

lann

ed a

nd m

onito

red

futu

re re

sear

ch.

PLH

IV: P

LHIV

repr

esen

ted

half

of th

ose

enro

lled

in th

e N

ix-TB

stu

dy; h

owev

er, i

t was

impo

ssib

le to

per

form

any

adj

uste

d st

ratif

ied

anal

yses

for P

LHIV

bec

ause

of t

he s

ampl

e siz

e.

PLH

IV w

ere

elig

ible

to e

nrol

in th

e N

ix-TB

stu

dy if

they

had

a C

D4

coun

t of >

50 c

ells/

µL a

nd if

they

wer

e us

ing

perm

itted

ant

iretro

vira

l med

icatio

ns.13

It is

impo

rtan

t to

note

dru

g–dr

ug

inte

ract

ions

whe

n ad

min

ister

ing

TB a

nd H

IV m

edica

tions

in c

ombi

natio

n, in

cludi

ng th

e do

cum

ente

d in

tera

ctio

ns b

etw

een

beda

quilin

e an

d ef

avire

nz.14

Efa

vire

nz a

lso re

duce

s pr

etom

anid

ex

posu

res

signi

fican

tly; t

here

fore

, an

alte

rnat

ive

antir

etro

vira

l age

nt s

houl

d be

con

sider

ed if

pre

tom

anid

or t

he B

PaL

regi

men

is to

be

used

.15 R

egim

ens

inclu

ding

zid

ovud

ine

shou

ld b

e us

ed w

ith s

pecia

l cau

tion

beca

use

zido

vudi

ne a

nd li

nezo

lid m

ay b

oth

caus

e pe

riphe

ral n

erve

toxic

ity a

nd a

re k

now

n to

hav

e m

yelo

supp

ress

ion

cros

s-to

xicity

. Pr

egna

nt a

nd la

ctat

ing

wom

en w

ere

exclu

ded

from

the

Nix-

TB s

tudy

; the

refo

re, n

o an

alys

is sp

ecifi

c to

this

subg

roup

of p

atie

nts

coul

d be

per

form

ed. F

or s

uch

patie

nts,

it is

reco

mm

ende

d th

at a

long

er re

gim

en b

e in

divi

dual

ized

to in

clude

com

pone

nts

with

a s

afet

y pr

ofile

that

is b

ette

r est

ablis

hed.

Whe

n th

is is

the

case

, the

out

com

es o

f tre

atm

ent a

nd

preg

nanc

y (in

cludi

ng in

fant

cha

ract

erist

ics),

and

post

part

um s

urve

illanc

e fo

r con

geni

tal a

nom

alie

s, sh

ould

be

docu

men

ted

to h

elp

info

rm fu

ture

reco

mm

enda

tions

for M

DR-

TB tr

eatm

ent

durin

g pr

egna

ncy.

The

use

of b

edaq

uilin

e in

pre

gnan

cy h

as b

een

show

n to

be

asso

ciate

d w

ith in

fant

s bo

rn w

ith a

low

er m

ean

birt

h w

eigh

t, w

hen

com

pare

d w

ith in

fant

s w

hose

mot

hers

w

ho d

id n

ot ta

ke b

edaq

uilin

e; h

owev

er, t

his

did

not a

ppea

r to

be a

clin

ically

sig

nific

ant f

indi

ng w

hen

infa

nts

wer

e fo

llow

ed u

p ov

er ti

me.

Bre

astfe

edin

g is

not r

ecom

men

ded

for w

omen

ta

king

BPaL

.16

Extr

apul

mon

ary

TB: P

artic

ipan

ts w

ith e

xtra

pulm

onar

y TB

wer

e ex

clude

d fro

m th

e N

ix-TB

stu

dy; t

here

fore

, no

anal

ysis

spec

ific

to th

is su

bgro

up o

f pat

ient

s co

uld

be p

erfo

rmed

. The

W

HO

reco

mm

enda

tions

for l

onge

r MD

R-TB

regi

men

s ap

ply

to p

atie

nts

with

ext

rapu

lmon

ary

dise

ase,

inclu

ding

thos

e w

ith T

B m

enin

gitis

. The

re a

re fe

w d

ata

on th

e ce

ntra

l ner

vous

sy

stem

pen

etra

tion

of b

edaq

uilin

e or

pre

tom

anid

.Pa

tient

s w

ith v

ery

limite

d tr

eatm

ent o

ptio

ns: I

n so

me

inst

ance

s, pa

tient

s w

ill ha

ve e

xten

sive

drug

resis

tanc

e pr

ofile

s th

at m

ay m

ake

it di

fficu

lt (o

r im

poss

ible

) to

cons

truct

a re

gim

en

base

d on

exis

ting

WH

O re

com

men

datio

ns. I

n su

ch s

ituat

ions

, the

pat

ient

’s lif

e m

ay b

e en

dang

ered

. The

refo

re, f

or in

divi

dual

pat

ient

s fo

r who

m th

e de

sign

of a

n ef

fect

ive

regi

men

ba

sed

on e

xistin

g re

com

men

datio

ns is

not

pos

sible

,17 th

e BP

aL re

gim

en m

ay b

e co

nsid

ered

a la

st re

sort

und

er p

reva

iling

ethi

cal s

tand

ards

. For

suc

h pa

tient

s, th

e us

e of

BPa

L sh

ould

be

acco

mpa

nied

by

indi

vidu

al p

atie

nt in

form

ed c

onse

nt, a

dequ

ate

coun

sellin

g on

the

pote

ntia

l ben

efits

and

har

ms,

and

activ

e m

onito

ring

and

man

agem

ent o

f adv

erse

eve

nts.

Patie

nts

shou

ld a

lso b

e ad

vise

d th

at re

prod

uctiv

e to

xiciti

es h

ave

been

obs

erve

d in

ani

mal

stu

dies

, and

that

the

pote

ntia

l effe

cts

on h

uman

mal

e fe

rtilit

y ha

ve n

ot b

een

adeq

uate

ly e

valu

ated

at

this

time.

13

The

perm

itted

ant

iretro

viral

trea

tmen

ts w

ere

as fo

llow

s: (1

) nev

irapi

ne in

com

bina

tion

with

any

NRT

Is; (2

) lop

inav

ir/rit

onav

ir in

com

bina

tion

with

any

NRT

Is; (3

) ten

ofov

ir/la

mivu

dine

/aba

cavir

(if n

orm

al re

nal f

unct

ion)

; (4

) trip

le N

RTI t

hera

py c

onsis

ting

of z

idov

udin

e, la

miv

udin

e, a

nd a

baca

vir (

notin

g th

e in

crea

sed

risk

of p

erip

hera

l ner

ve to

xicity

with

zid

ovud

ine

and

linez

olid

); an

d (5

) ral

tegr

avir

in c

ombi

natio

n w

ith N

RTIs.

14

HIV

dru

g in

tera

ctio

ns [w

ebsit

e]. L

iver

pool

, Uni

ted

King

dom

Uni

vers

ity o

f Liv

erpo

ol 2

020

(http

s://w

ww.

hiv-

drug

inte

ract

ions

.org

/che

cker

, acc

esse

d 11

Mar

ch 2

020)

.15

D

rug

appr

oval

pac

kage

: Pre

tom

anid

[web

site]

. Mar

yland

, Uni

ted

Stat

es o

f Am

erica

: U.S

. Foo

d an

d D

rug

Adm

inist

ratio

n; 2

019

(http

s://w

ww.

acce

ssda

ta.fd

a.go

v/dr

ugsa

tfda_

docs

/nda

/201

9/21

2862

Orig

1s00

0TO

C.cf

m, a

cces

sed

28 F

ebru

ary

2020

).16

D

rug

appr

oval

pac

kage

: Pre

tom

anid

[web

site]

. Mar

yland

, Uni

ted

Stat

es o

f Am

erica

: U.S

. Foo

d an

d D

rug

Adm

inist

ratio

n; 2

019

(http

s://w

ww.

acce

ssda

ta.fd

a.go

v/dr

ugsa

tfda_

docs

/nda

/201

9/21

2862

Orig

1s00

0TO

C.cf

m, a

cces

sed

28 F

ebru

ary

2020

).17

Us

ually

this

grou

p of

pat

ient

s w

ould

inclu

de th

ose

with

an

exte

nsiv

e dr

ug re

sista

nce

prof

ile w

ho h

ave

very

lim

ited

treat

men

t opt

ions

as

part

of a

long

er tr

eatm

ent r

egim

en.


Impl

emen

tatio

n co

nsid

erat

ions

Giv

en th

e pa

ucity

of e

vide

nce

on th

e us

e of

BPa

L, a

nd th

e co

ncer

ns m

entio

ned

abov

e, m

embe

rs o

f the

GD

G s

ugge

sted

that

its

use

shou

ld b

e co

nditi

onal

upo

n im

plem

enta

tion

in

the

cont

ext o

f ope

ratio

nal r

esea

rch

only.

The

GD

G e

mph

asiz

ed th

at, d

espi

te th

e pr

omisi

ng tr

eatm

ent s

ucce

ss ra

tes

obse

rved

in th

e N

ix-TB

stu

dy, t

he re

gim

en m

ay n

ot b

e co

nsid

ered

fo

r pro

gram

mat

ic us

e w

orld

wid

e un

til a

dditi

onal

evi

denc

e on

effi

cacy

and

saf

ety

has

been

gen

erat

ed. T

he G

DG

mem

bers

em

phas

ized

the

need

for t

his

rese

arch

to ta

ke th

e fo

rm o

f ra

ndom

ized

, con

trolle

d tri

als

as w

ell a

s ob

serv

atio

nal s

tudi

es. G

iven

the

cond

ition

ality

of t

his

reco

mm

enda

tion

in th

e co

ntex

t of a

dditi

onal

rese

arch

, cer

tain

sta

ndar

ds a

nd p

rincip

les

are

prer

equi

sites

for t

he im

plem

enta

tion

of B

PaL.

Fur

ther

, the

GD

G e

mph

asiz

ed th

at in

any

ope

ratio

nal r

esea

rch

stud

y in

volv

ing

BPaL

, the

prin

ciple

s of

goo

d cli

nica

l pra

ctice

sho

uld

appl

y.O

vera

ll, to

repr

oduc

e th

e tre

atm

ent s

ucce

ss ra

tes

obse

rved

in th

e N

ix-TB

stu

dy, a

ll ef

fort

s ne

ed to

be

mad

e to

car

eful

ly s

elec

t elig

ible

pat

ient

s an

d th

en, o

nce

they

are

enr

olle

d, to

pr

ovid

e ef

fect

ive

patie

nt s

uppo

rt to

ena

ble

adhe

renc

e to

trea

tmen

t, as

wel

l as

close

mon

itorin

g fo

r adv

erse

eve

nts,

resp

onse

to tr

eatm

ent,

and

emer

ging

dru

g re

sista

nce.

All

effo

rts

shou

ld b

e m

ade

to d

o th

e fo

llow

ing:

• En

sure

pro

per p

atie

nt in

clusio

n (u

se is

not

adv

ised

in p

regn

ant a

nd la

ctat

ing

wom

en a

nd in

chi

ldre

n, n

otin

g th

e ot

her i

nclu

sion

and

exclu

sion

crite

ria o

f the

Nix-

TB s

tudy

). Al

thou

gh

DST

is a

n im

port

ant c

ompo

nent

of p

atie

nt s

elec

tion

for t

he B

PaL

regi

men

(des

crib

ed b

elow

), an

othe

r key

impl

emen

tatio

n co

nsid

erat

ion

is pr

ior T

B tre

atm

ent h

istor

y. Pa

tient

s ar

e el

igib

le fo

r the

BPa

L re

gim

en o

nly

if th

ey h

ave

not r

ecei

ved

beda

quilin

e or

line

zolid

for 2

wee

ks o

r mor

e pr

evio

usly,

and

this

was

an

elig

ibilit

y cr

iterio

n of

the

Nix-

TB s

tudy

. Giv

en

that

the

curre

nt W

HO

reco

mm

enda

tion

for l

onge

r tre

atm

ent r

egim

ens

for M

DR/

RR-T

B in

clude

s be

daqu

iline

and

linez

olid

as

prio

rity

med

icine

s in

Gro

up A

, som

e pa

tient

s w

ho

have

pre

viou

sly s

tart

ed tr

eatm

ent w

ith a

long

er M

DR/

RR-T

B re

gim

en m

ay in

fact

be

inel

igib

le fo

r BPa

L sh

ould

they

late

r dev

elop

fluo

roqu

inol

one

resis

tanc

e. T

his

reaf

firm

s pr

evio

us

stat

emen

ts b

y W

HO

on

the

need

to c

aref

ully

sel

ect e

ligib

le p

atie

nts

for l

onge

r or s

hort

er M

DR/

RR-T

B tre

atm

ent r

egim

ens,

and

then

, onc

e pa

tient

s ar

e re

ceiv

ing

a re

gim

en, t

o en

sure

pa

tient

sup

port

and

clo

se m

onito

ring

and

follo

w-u

p, in

cludi

ng m

onito

ring

for t

reat

men

t fai

lure

and

rela

pse,

and

em

ergi

ng d

rug

resis

tanc

e, w

ith D

ST p

erfo

rmed

whe

n in

dica

ted.

If

resis

tanc

e is

susp

ecte

d du

ring

treat

men

t and

DST

is n

ot a

vaila

ble,

the

stra

ins

shou

ld b

e co

nser

ved

and

refe

rred

to a

WH

O s

upra

natio

nal T

B re

fere

nce

labo

rato

ry fo

r fur

ther

test

ing.

Ea

ch o

pera

tiona

l res

earc

h pr

otoc

ol o

n th

e us

e of

BPa

L in

a g

iven

set

ting

will

need

to in

clude

det

aile

d in

clusio

n an

d ex

clusio

n cr

iteria

.•

Obt

ain

signe

d pa

tient

info

rmed

con

sent

afte

r det

aile

d ex

plan

atio

ns o

n th

e no

vel n

atur

e of

the

regi

men

and

pre

tom

anid

, inc

ludi

ng th

e ris

ks a

nd b

enef

its o

f the

regi

men

. The

GD

G

mem

bers

thou

ght t

hat a

lthou

gh in

divi

dual

pat

ient

info

rmed

con

sent

is n

eces

sary

, it s

houl

d no

t be

over

ly b

urde

nsom

e fo

r pat

ient

s; th

eref

ore,

con

sent

form

s sh

ould

be

adap

ted,

co

ntex

tual

ized

, stre

amlin

ed a

nd p

rovi

ded

in th

e lo

cal l

angu

age(

s) s

o th

at th

ey a

re e

asy

for p

atie

nts

to u

nder

stan

d. N

ever

thel

ess,

the

GD

G a

lso n

oted

that

pat

ient

s sh

ould

be

fully

in

form

ed a

bout

the

regi

men

, giv

en th

at it

also

inclu

des

a ne

w c

ompo

und,

pre

tom

anid

. As

part

of t

he in

form

ed c

onse

nt p

roce

ss, p

atie

nts

shou

ld b

e of

fere

d su

fficie

nt in

form

atio

n on

po

tent

ial a

dver

se e

vent

s, in

cludi

ng lo

w b

lood

cel

l cou

nts

(e.g

. ana

emia

, thr

ombo

cyto

peni

a, n

eutro

peni

a), l

iver

toxic

ities

, and

per

iphe

ral a

nd o

ptic

neur

opat

hy. P

atie

nts

shou

ld a

lso

be a

dvise

d th

at re

prod

uctiv

e to

xiciti

es h

ave

been

obs

erve

d in

ani

mal

stu

dies

and

that

the

pote

ntia

l effe

cts

on h

uman

mal

e fe

rtilit

y ha

ve n

ot b

een

adeq

uate

ly e

valu

ated

at t

his

time.

Pa

tient

s sh

ould

also

be

info

rmed

that

pre

tom

anid

is e

xcre

ted

in b

reas

t milk

, and

its

safe

ty in

infa

nts

and

child

ren

has

not b

een

adeq

uate

ly e

valu

ated

.18 A

med

icatio

n gu

ide

is av

aila

ble

as p

art o

f the

pre

tom

anid

pro

duct

labe

l tha

t may

be

used

whe

n in

form

ing

patie

nts

abou

t the

BPa

L re

gim

en a

s pa

rt o

f a re

sear

ch s

tudy

.•

Trea

tmen

t mus

t be

adm

inist

ered

und

er c

lose

ly m

onito

red

cond

ition

s, to

ena

ble

optim

al d

rug

effe

ctiv

enes

s an

d sa

fety

, and

to m

onito

r for

the

acqu

isitio

n of

em

ergi

ng d

rug

resis

tanc

e, s

houl

d it

arise

. Giv

en th

at th

e re

gim

en is

sho

rter

, tha

t it i

nclu

des

a ne

w c

ompo

und

(pre

tom

anid

), an

d th

at it

s im

plem

enta

tion

is in

the

cont

ext o

f res

earc

h, it

may

be

espe

cially

impo

rtan

t tha

t clin

ical p

rogr

ess

is m

onito

red

afte

r com

plet

ion

of tr

eatm

ent,

to e

nsur

e re

laps

e fre

e cu

re. O

ther

des

ign

feat

ures

of t

he N

ix-TB

stu

dy h

ave

impl

icatio

ns fo

r its

im

plem

enta

tion

unde

r ope

ratio

nal r

esea

rch

cond

ition

s. In

the

Nix-

TB s

tudy

, all

med

icatio

ns w

ere

adm

inist

ered

with

food

thro

ugho

ut, a

nd s

tudy

med

icatio

ns w

ere

supe

rvise

d ac

cord

ing

to lo

cal s

ite p

ract

ices,

as a

form

of p

atie

nt s

uppo

rt. P

reve

ntin

g tre

atm

ent i

nter

rupt

ion

is im

port

ant f

or in

crea

sing

the

likel

ihoo

d of

trea

tmen

t suc

cess

. Mea

sure

s to

sup

port

pat

ient

ad

here

nce,

eith

er b

y fa

cilita

ting

patie

nt v

isits

to h

ealth

car

e fa

ciliti

es o

r hom

e vi

sits

by h

ealth

car

e st

aff,

or b

y us

ing

digi

tal t

echn

olog

ies

for d

aily

com

mun

icatio

n, m

ay b

e im

port

ant f

or

rete

ntio

n of

pat

ient

s in

trea

tmen

t, ev

en th

ough

the

regi

men

is c

ompa

rativ

ely

shor

t.19 W

HO

reco

mm

enda

tions

on

the

care

and

sup

port

of p

atie

nts

with

MD

R/RR

-TB

are

prov

ided

in th

e W

HO

con

solid

ated

gui

delin

es o

n dr

ug-r

esist

ant T

B tre

atm

ent.20

• Ac

tive

phar

mac

ovig

ilanc

e an

d pr

oper

man

agem

ent o

f adv

erse

dru

g re

actio

ns a

nd p

reve

ntio

n of

com

plica

tions

from

dru

g–dr

ug in

tera

ctio

ns. T

he n

atio

nal T

B pr

ogra

mm

e sh

ould

act

ively

mon

itor d

rug

safe

ty to

ens

ure

prop

er p

atie

nt c

are,

to re

port

any

adv

erse

dru

g re

actio

ns to

the

resp

onsib

le d

rug

safe

ty a

utho

rity

in th

e co

untr

y, an

d to

info

rm n

atio

nal a

nd g

loba

l pol

icy.

18

Dru

g ap

prov

al p

acka

ge: P

reto

man

id [w

ebsit

e]. M

aryla

nd, U

nite

d St

ates

of A

mer

ica: U

.S. F

ood

and

Dru

g Ad

min

istra

tion;

201

9 (h

ttps:/

/ww

w.ac

cess

data

.fda.

gov/

drug

satfd

a_do

cs/n

da/2

019/

2128

62O

rig1s

000T

OC.

cfm

, acc

esse

d 28

Feb

ruar

y 20

20).

19

Gui

delin

es fo

r tre

atm

ent o

f dru

g-su

scep

tible

tube

rcul

osis

and

patie

nt c

are,

201

7 up

date

(WH

O/H

TM/T

B/20

17.0

5). G

enev

a, S

witz

erla

nd: W

orld

Hea

lth O

rgan

izat

ion;

201

7 (h

ttps:/

/app

s.who

.int/

iris/

bits

tream

/han

dle/

1066

5/25

5052

/978

9241

5500

00-e

ng.p

df?s

eque

nce=

1, a

cces

sed

20 M

arch

202

0).

20

WH

O c

onso

lidat

ed g

uide

lines

on

drug

resis

tant

tube

rcul

osis

treat

men

t. G

enev

a, S

witz

erla

nd: W

orld

Hea

lth O

rgan

izat

ion;

201

9 (h

ttps:/

/app

s.who

.int/

iris/

bits

tream

/han

dle/

1066

5/31

1389

/978

9241

5505

29-e

ng.

pdf?

ua=1

, acc

esse

d 20

Mar

ch 2

020)

.


The

impl

emen

tatio

n of

the

BPaL

regi

men

in th

e co

ntex

t of o

pera

tiona

l res

earc

h im

plie

s th

at:

• a

stud

y pr

otoc

ol h

as b

een

deve

lope

d by

app

ropr

iate

ly s

kille

d an

d ex

perie

nced

rese

arch

ers;

• th

is re

sear

ch p

roto

col i

s su

bmitt

ed to

a n

atio

nal e

thics

boa

rd o

r oth

er e

thica

l app

rova

l com

mitt

ees;

• th

ere

are

pre-

spec

ified

inclu

sion

and

exclu

sion

crite

ria in

pla

ce (n

otin

g th

e cr

iteria

use

d fo

r the

Nix-

TB s

tudy

);21

• th

ere

is an

app

ropr

iate

sch

edul

e of

saf

ety

mon

itorin

g an

d re

port

ing

in p

lace

, inc

ludi

ng a

ctiv

e dr

ug s

afet

y m

onito

ring

(aD

SM) –

usu

ally

ove

rsee

n by

a d

ata

safe

ty m

onito

ring

boar

d or

sim

ilar i

ndep

ende

nt re

sear

ch g

over

nanc

e co

mm

ittee

);•

ther

e is

a pr

edef

ined

sch

edul

e of

clin

ical a

nd m

icrob

iolo

gica

l mon

itorin

g in

pla

ce, p

refe

rabl

y in

cludi

ng fo

llow

-up

afte

r com

plet

ion

of tr

eatm

ent;

• in

divi

dual

pat

ient

info

rmed

con

sent

is o

btai

ned;

• pa

tient

sup

port

is p

rovi

ded;

and

• st

anda

rdiz

ed re

port

ing

and

reco

rdin

g is

used

, inc

ludi

ng fo

r adv

erse

eve

nts.

Revi

ew o

f tre

atm

ent a

nd m

anag

emen

t pro

toco

ls by

an

inde

pend

ent g

roup

of e

xper

ts in

clin

ical m

anag

emen

t and

pub

lic h

ealth

, suc

h as

the

natio

nal M

DR-

TB a

dviso

ry g

roup

, is

reco

mm

ende

d.D

rug-

susc

eptib

ility

test

ing

is an

impo

rtan

t im

plem

enta

tion

cons

ider

atio

n th

at w

ill ne

ed fu

rthe

r enh

ance

men

t in

man

y co

untri

es, g

iven

the

incr

easin

g po

tent

ial u

se o

f bed

aqui

line

and

linez

olid

(eve

n fo

r lon

ger r

egim

ens

for M

DR/

RR-T

B) a

nd th

e in

clusio

n of

new

med

icine

s –

such

as

pret

oman

id –

in M

DR-

TB tr

eatm

ent r

egim

ens.

Base

line

DST

will

conf

irm e

ligib

ility

for

the

BPaL

regi

men

; the

refo

re, t

he e

stab

lishm

ent a

nd s

treng

then

ing

of d

rug-

susc

eptib

ility

test

ing

serv

ices

will

be a

vita

l im

plem

enta

tion

cons

ider

atio

n. In

pat

ient

s w

ith b

acte

riolo

gica

lly

conf

irmed

MD

R/RR

-TB,

22 th

e M

TBD

Rsl a

ssay

may

be

used

as

the

initi

al te

st, i

n pr

efer

ence

to c

ultu

re a

nd p

heno

typi

c D

ST, t

o de

tect

resis

tanc

e to

fluo

roqu

inol

ones

(con

ditio

nal

reco

mm

enda

tion;

cer

tain

ty o

f evi

denc

e fo

r dire

ct te

stin

g of

spu

tum

from

low

to m

oder

ate.

23 In

set

tings

in w

hich

labo

rato

ry c

apac

ity fo

r DST

to fl

uoro

quin

olon

es is

not

yet

ava

ilabl

e, o

r ca

nnot

be

acce

ssed

, it w

ill be

diff

icult

to c

arry

out

ope

ratio

nal r

esea

rch

on B

PaL.

If te

stin

g fo

r sus

cept

ibilit

y to

bed

aqui

line

or li

nezo

lid is

ava

ilabl

e, it

is h

ighl

y de

sirab

le th

at th

is is

also

ca

rrie

d ou

t at b

asel

ine;

how

ever

, thi

s ne

ed n

ot b

e a

prer

equi

site

for t

reat

men

t ini

tiatio

n, n

or n

eed

it be

so

in th

e ab

senc

e of

cul

ture

con

vers

ion

durin

g tre

atm

ent.

DST

for p

reto

man

id is

no

t yet

ava

ilabl

e. C

urre

ntly,

ther

e is

limite

d ca

pacit

y gl

obal

ly to

car

ry o

ut D

ST fo

r bed

aqui

line

and

linez

olid

; how

ever

, lab

orat

ory

capa

city

shou

ld b

e st

reng

then

ed in

this

area

as

thes

e m

edici

nes

and

regi

men

s be

com

e m

ore

wid

ely

used

. Nat

iona

l and

refe

renc

e la

bora

torie

s w

ill ne

ed to

hav

e th

e m

edici

ne p

owde

rs a

vaila

ble

to e

nabl

e D

ST to

be

carr

ied

out a

nd w

ill ne

ed d

ata

on th

e m

inim

um in

hibi

tory

con

cent

ratio

n (M

IC) d

istrib

utio

n of

all

Myc

obac

teriu

m tu

berc

ulos

is lin

eage

s th

at a

re c

ircul

atin

g gl

obal

ly. If

resis

tanc

e to

any

of t

he c

ompo

nent

m

edici

nes

in th

e BP

aL re

gim

en is

det

ecte

d, th

e pa

tient

sho

uld

com

men

ce tr

eatm

ent w

ith a

long

er M

DR-

TB re

gim

en. W

HO

Sup

rana

tiona

l Ref

eren

ce L

abor

ator

y N

etw

ork

is av

aila

ble

to

supp

ort n

atio

nal T

B re

fere

nce

labo

rato

ries

in p

erfo

rmin

g qu

ality

-ass

ured

DST

. A W

HO

tech

nica

l con

sulta

tion

in 2

017

esta

blish

ed c

ritica

l con

cent

ratio

ns fo

r DST

for t

he fl

uoro

quin

olon

es,

beda

quilin

e, d

elam

anid

, clo

fazi

min

e an

d lin

ezol

id.24

Met

hods

for t

estin

g pr

etom

anid

sus

cept

ibilit

y ar

e cu

rrent

ly u

nder

dev

elop

men

t.

21

The

prot

ocol

for t

he N

ix-TB

stu

dy is

ava

ilabl

e at

: http

s://c

linica

ltria

ls.go

v/ct

2/sh

ow/N

CT02

3337

9922

M

DR/

RR-T

B is

usua

lly c

onfir

med

by

rapi

d m

olec

ular

test

s tha

t det

ect r

esist

ance

to ri

fam

picin

and

M. t

uber

culo

sis. C

urre

nt W

HO

reco

mm

enda

tions

stat

e th

at th

e Xp

ert M

TB/R

IF a

ssay

shou

ld b

e us

ed ra

ther

than

co

nven

tiona

l micr

osco

py, c

ultu

re, a

nd D

ST a

s th

e in

itial

dia

gnos

tic te

st in

adu

lts s

uspe

cted

of h

avin

g M

DR-

TB o

r HIV

-ass

ocia

ted

TB (s

trong

reco

mm

enda

tion;

hig

h-qu

ality

evi

denc

e). T

he X

pert

MTB

/RIF

ass

ay

shou

ld b

e us

ed r

athe

r th

an c

onve

ntio

nal m

icros

copy

, cul

ture

, and

DST

as

the

initi

al d

iagn

ostic

test

in c

hild

ren

susp

ecte

d of

hav

ing

MD

R-TB

or

HIV

-ass

ocia

ted

TB (s

trong

reco

mm

enda

tion;

ver

y lo

w-q

ualit

y ev

iden

ce) –

Aut

omat

ed re

al-t

ime

nucle

ic ac

id a

mpl

ifica

tion

tech

nolo

gy fo

r rap

id a

nd s

imul

tane

ous

dete

ctio

n of

tube

rcul

osis

and

rifam

picin

resis

tanc

e: X

pert

MTB

/RIF

ass

ay fo

r the

dia

gnos

is of

pul

mon

ary

and

extra

pulm

onar

y TB

in a

dults

and

chi

ldre

n (W

HO

/HTM

/TB/

2013

.16)

. Gen

eva,

Sw

itzer

land

: Wor

ld H

ealth

Org

aniz

atio

n; 2

013

(http

s://a

pps.w

ho.in

t/iri

s/bi

tstre

am/h

andl

e/10

665/

1124

72/9

7892

4150

6335

_eng

.pd

f?se

quen

ce=1

, acc

esse

d 20

Mar

ch 2

020)

. A re

cent

WH

O ra

pid

com

mun

icatio

n re

info

rced

the

high

dia

gnos

tic a

ccur

acy

and

impr

oved

pat

ient

out

com

es o

f rap

id m

olec

ular

dia

gnos

tic te

sts s

uch

as X

pert

MTB

/RI

F, Xp

ert M

TB/R

IF U

ltra,

and

Tru

eNat

– R

apid

com

mun

icatio

n: m

olec

ular

ass

ays

as in

itial

test

s fo

r the

dia

gnos

is of

tube

rcul

osis

and

rifam

picin

resis

tanc

e. G

enev

a, S

witz

erla

nd W

orld

Hea

lth O

rgan

izat

ion

2020

(h

ttps:/

/app

s.who

.int/

iris/

bits

tream

/han

dle/

1066

5/33

0395

/978

9240

0003

39-e

ng.p

df, a

cces

sed

20 M

arch

202

0).

23

The

use

of m

olec

ular

line

pro

be a

ssay

s fo

r the

det

ectio

n of

resis

tanc

e to

sec

ond-

line

anti-

tube

rcul

osis

drug

s: po

licy

guid

ance

[WH

O/H

TM/T

B/20

16.0

7]. G

enev

a, S

witz

erla

nd: W

orld

Hea

lth O

rgan

izat

ion;

201

6 (h

ttps:/

/app

s.who

.int/

iris/

bits

tream

/han

dle/

1066

5/24

6131

/978

9241

5105

61-e

ng.p

df?s

eque

nce=

1, a

cces

sed

20 M

arch

202

0).

24

Auto

mat

ed re

al-t

ime

nucle

ic ac

id a

mpl

ifica

tion

tech

nolo

gy fo

r rap

id a

nd si

mul

tane

ous d

etec

tion

of tu

berc

ulos

is an

d rif

ampi

cin re

sista

nce:

Xpe

rt M

TB/R

IF a

ssay

for t

he d

iagn

osis

of p

ulm

onar

y an

d ex

trapu

lmon

ary

TB in

adu

lts a

nd c

hild

ren

(WH

O/H

TM/T

B/20

13.1

6). G

enev

a, S

witz

erla

nd: W

orld

Hea

lth O

rgan

izat

ion;

201

3 (h

ttps:/

/app

s.who

.int/

iris/

bits

tream

/han

dle/

1066

5/11

2472

/978

9241

5063

35_e

ng.p

df?s

eque

nce=

1,

acce

ssed

20

Mar

ch 2

020)

.


Dos

ing

of li

nezo

lid: T

he li

nezo

lid d

osag

e us

ed in

the

Nix-

TB s

tudy

was

120

0 m

g/da

y. In

itial

ly, a

ll st

udy

part

icipa

nts

rece

ived

600

mg

of li

nezo

lid B

D b

ecau

se th

at w

as th

e ap

prov

ed d

ose

used

to tr

eat b

acte

rial i

nfec

tions

for u

p to

28

days

at t

he ti

me

the

stud

y co

mm

ence

d. H

owev

er, i

n M

ay 2

018,

the

prot

ocol

was

cha

nged

to a

dos

ing

of 1

200

mg

OD.

Acc

ordi

ng to

the

prot

ocol

, dos

e re

duct

ion

to 6

00 m

g da

ily a

nd fu

rthe

r to

300

mg

daily

or t

empo

rary

ces

satio

n of

line

zolid

was

per

mitt

ed fo

r up

to 3

5 co

nsec

utiv

e da

ys, f

or a

ny k

now

n lin

ezol

id a

dver

se

reac

tions

of m

yelo

supp

ress

ion,

per

iphe

ral n

euro

path

y an

d op

tic n

euro

path

y. If

toxic

ity p

rohi

bite

d fu

rthe

r tre

atm

ent w

ith li

nezo

lid, t

hen

patie

nts

coul

d co

ntin

ue to

take

bed

aqui

line

and

pret

oman

id, p

rovi

ded

that

they

had

rece

ived

the

1200

mg/

day

dose

for a

t lea

st th

e fir

st 4

con

secu

tive

wee

ks, w

ere

sput

um s

mea

r-neg

ativ

e an

d w

ere

resp

ondi

ng to

trea

tmen

t as

indi

cate

d by

clin

ical m

onito

ring

and

follo

w-u

p. M

issed

dos

es o

f lin

ezol

id w

ere

not m

ade

up d

urin

g th

e N

ix-TB

stu

dy, a

nd d

ose

mod

ifica

tions

for b

edaq

uilin

e an

d pr

etom

anid

wer

e no

t al

low

ed. O

vera

ll, 18

pat

ient

s (1

7.3%

) in

the

Nix-

TB s

tudy

com

plet

ed a

full

cour

se o

f lin

ezol

id a

t the

120

0-m

g do

se, 3

8 (3

6.5%

) com

plet

ed w

ith a

600

-mg

dose

, 16

(15.

4%) c

ompl

eted

with

a

300-

mg

dose

, and

32

(30.

7%) s

topp

ed li

nezo

lid e

arly

bec

ause

of a

n ad

vers

e ev

ent.

In v

iew

of t

he e

xper

ienc

e of

the

Nix-

TB s

tudy

, it m

ay b

e ne

cess

ary

to m

odify

the

dose

of l

inez

olid

du

ring

treat

men

t on

the

basis

of a

dver

se e

vent

s, hi

ghlig

htin

g th

e im

port

ance

of c

lose

mon

itorin

g, p

atie

nt fo

llow

-up

and

aDSM

. Add

ition

al s

tudi

es –

suc

h as

the

ZeN

ix st

udy

(TB

Allia

nce)

–

are

unde

rway

to a

sses

s th

e op

timal

dos

ing

and

dura

tion

of li

nezo

lid fo

r the

trea

tmen

t of d

rug-

resis

tant

TB;

how

ever

, the

resu

lts o

f the

se s

tudi

es a

re n

ot y

et a

vaila

ble

for r

evie

w. To

da

te, t

he B

PaL

regi

men

has

bee

n st

udie

d as

a s

tand

ardi

zed

cour

se o

f tre

atm

ent.

Mod

ifica

tion

of th

e re

gim

en th

roug

h ea

rly d

iscon

tinua

tion

or re

plac

emen

t of a

ny o

f the

com

pone

nt

med

icine

s m

ay re

sult

in p

oor t

reat

men

t out

com

es. T

he p

reto

man

id p

rodu

ct la

bel r

ecom

men

ds th

at if

eith

er b

edaq

uilin

e or

pre

tom

anid

tabl

ets

are

disc

ontin

ued,

the

entir

e BP

aL re

gim

en

shou

ld a

lso b

e di

scon

tinue

d. If

line

zolid

is p

erm

anen

tly d

iscon

tinue

d du

ring

the

initi

al 4

con

secu

tive

wee

ks o

f tre

atm

ent,

then

bed

aqui

line

and

pret

oman

id s

houl

d al

so b

e di

scon

tinue

d.

If lin

ezol

id is

disc

ontin

ued

afte

r the

initi

al 4

wee

ks o

f con

secu

tive

treat

men

t, cli

nicia

ns s

houl

d co

ntin

ue a

dmin

ister

ing

beda

quilin

e an

d pr

etom

anid

, con

siste

nt w

ith th

e N

ix-TB

stu

dy

prot

ocol

. In

the

Nix-

TB s

tudy

, it w

as n

eces

sary

for p

atie

nts

to c

ompl

ete

6 m

onth

s of

the

regi

men

(i.e

. 26

wee

ks o

f pre

scrib

ed d

oses

) with

in 8

mon

ths,

and

for t

hose

who

had

trea

tmen

t ex

tend

ed, i

t was

nec

essa

ry fo

r pat

ient

s to

com

plet

e 9

mon

ths

of tr

eatm

ent (

i.e. 3

9 w

eeks

of p

resc

ribed

dos

es) w

ithin

12

mon

ths.

Patie

nts

who

rem

aine

d cu

lture

pos

itive

or w

ho re

vert

ed

to b

eing

cul

ture

pos

itive

bet

wee

n m

onth

s 4

and

6, a

nd w

hose

clin

ical c

ondi

tion

sugg

este

d th

ey m

ight

hav

e on

goin

g TB

infe

ctio

n, h

ad tr

eatm

ent e

xten

ded

to a

tota

l of 9

mon

ths.

Mon

itorin

g an

d ev

alua

tion

Patie

nts

who

rece

ive

BPaL

(or a

ny s

hort

er re

gim

en fo

r the

trea

tmen

t of M

DR/

RR-T

B) n

eed

to b

e te

sted

at b

asel

ine

and

then

mon

itore

d du

ring

treat

men

t usin

g sc

hedu

les

of re

leva

nt

clini

cal a

nd la

bora

tory

test

ing.

Acc

ordi

ng to

the

prod

uct l

abel

for p

reto

man

id, b

asel

ine

asse

ssm

ents

bef

ore

initi

atio

n of

the

BPaL

regi

men

inclu

de a

sses

smen

ts fo

r sym

ptom

s an

d sig

ns

of li

ver d

iseas

e (e

.g. f

atig

ue, a

nore

xia, n

ause

a, ja

undi

ce, d

ark

urin

e, li

ver t

ende

rnes

s an

d he

pato

meg

aly)

and

the

cond

uct o

f lab

orat

ory

test

s (a

lani

ne a

min

otra

nsfe

rase

[ALT

], as

part

ate

amin

otra

nsfe

rase

[AST

], al

kalin

e ph

osph

atas

e, a

nd b

ilirub

in, c

ompl

ete

bloo

d co

unt a

nd s

erum

pot

assiu

m, c

alciu

m, a

nd m

agne

sium

, whi

ch s

houl

d be

cor

rect

ed if

abn

orm

al).

Trea

ting

clini

cians

sho

uld

also

obt

ain

an e

lect

roca

rdio

gram

bef

ore

initi

atio

n of

trea

tmen

t. Th

e ba

selin

e m

onito

ring

sche

dule

of t

he N

ix-TB

stu

dy w

as m

uch

mor

e co

mpr

ehen

sive

than

this,

and

in

clude

d a

thor

ough

bas

elin

e cli

nica

l ass

essm

ent,

follo

wed

by

a sc

hedu

le o

f wee

kly p

atie

nt m

onito

ring

until

wee

k 20

and

then

mon

itorin

g ev

ery

4 to

6 w

eeks

ther

eafte

r, pa

rtly

dep

ende

nt

on w

heth

er th

e pa

tient

had

trea

tmen

t for

6 m

onth

s in

tota

l or w

heth

er tr

eatm

ent w

as e

xten

ded

by a

noth

er 3

mon

ths

(to 9

mon

ths

in to

tal).

Giv

en th

at th

e BP

aL re

gim

en is

new

and

is b

eing

impl

emen

ted

unde

r ope

ratio

nal r

esea

rch

cond

ition

s, it

is al

so im

port

ant t

o fo

llow

up

with

pat

ient

s af

ter t

he c

ompl

etio

n of

trea

tmen

t for

po

ssib

le re

laps

e. In

the

Nix-

TB s

tudy

, mon

itorin

g af

ter c

ompl

etio

n of

trea

tmen

t was

car

ried

out m

onth

ly fo

r mon

ths

1 to

3, a

nd th

en e

very

3 m

onth

s th

erea

fter.

Follo

w-u

p af

ter t

reat

men

t co

mpl

etio

n w

as fo

r a to

tal o

f 24

mon

ths;

how

ever

, at t

he ti

me

of d

ata

anal

ysis,

abo

ut h

alf o

f the

pat

ient

s ha

d be

en fo

llow

ed u

p fo

r thi

s pe

riod.

The

ana

lysis

of t

he N

ix-TB

stu

dy d

ata

indi

cate

d th

at th

ere

was

trea

tmen

t fai

lure

or r

ecur

renc

e in

3 p

atie

nts

(2.8

% o

f pat

ient

s ov

eral

l), ta

king

into

acc

ount

the

perio

d of

pos

t tre

atm

ent c

ompl

etio

n fo

llow

-up.

Det

aile

d sc

hedu

les

of b

asel

ine

and

follo

w-u

p m

onito

ring,

inclu

ding

pos

t tre

atm

ent c

ompl

etio

n, s

houl

d be

dev

elop

ed fo

r any

BPa

L op

erat

iona

l res

earc

h pr

otoc

ol, w

ith s

tand

ardi

zed

mea

sure

s fo

r rec

ordi

ng a

dver

se e

vent

s. Th

e W

HO

fram

ewor

k fo

r aD

SM n

eeds

to b

e ap

plie

d to

pat

ient

s re

ceiv

ing

any

type

of M

DR-

TB re

gim

en, t

o en

sure

app

ropr

iate

act

ion

and

an

acce

ptab

le le

vel o

f mon

itorin

g fo

r and

pro

mpt

resp

onse

to a

dver

se e

vent

s –

alon

gsid

e m

onito

ring

for t

reat

men

t out

com

es, i

nclu

ding

ear

ly m

onito

ring

for t

reat

men

t fai

lure

. Add

ition

al

evid

ence

gen

erat

ed o

n ad

vers

e ev

ents

will

be im

port

ant f

or b

uild

ing

the

evid

ence

bas

e on

the

safe

ty o

f the

BPa

L re

gim

en in

var

ied

setti

ngs.

Mon

itorin

g of

cha

nges

in d

osin

g an

d du

ratio

n of

line

zolid

in p

artic

ular

(whe

n ne

eded

) will

also

be

impo

rtan

t for

info

rmin

g th

e fu

ture

evi

denc

e ba

se o

n th

e w

ider

use

of t

he B

PaL

regi

men

and

the

tole

rabi

lity

of li

nezo

lid in

th

is re

gim

en.


Rese

arch

prio

ritie

s•

Rese

arch

on

the

use

of B

PaL

to c

ompa

re e

ffica

cy, s

afet

y an

d to

lera

bilit

y to

oth

er a

ll-or

al re

gim

ens.

• D

ata

from

oth

er re

gion

s an

d co

untri

es (b

eyon

d So

uth

Afric

a).

• D

escr

iptio

n of

the

mec

hani

sm a

nd m

olec

ular

mar

kers

of p

reto

man

id re

sista

nce.

Sur

veilla

nce

for t

he d

evel

opm

ent o

f res

istan

ce, w

ith a

dequ

ate

cons

ider

atio

n pa

id to

the

impa

ct o

f se

lect

ed m

utat

ions

. •

Doc

umen

ting

of th

e fu

ll ad

vers

e ef

fect

pro

file

of p

reto

man

id, a

nd th

e fre

quen

cy o

f rel

evan

t adv

erse

effe

cts,

with

a fo

cus

on h

epat

otox

icity

and

repr

oduc

tive

toxic

ity in

hum

ans.

Repr

oduc

tive

toxic

ities

of p

reto

man

id h

ave

been

sig

nalle

d in

ani

mal

stu

dies

but

pot

entia

l effe

cts

of th

is m

edici

ne o

n hu

man

fert

ility

have

not

bee

n ad

equa

tely

eva

luat

ed a

nd re

quire

ap

prop

riate

rese

arch

. •

Expl

orin

g th

e re

lativ

e ef

ficac

y (a

nd a

dded

val

ue in

mul

tidru

g re

gim

ens)

of p

reto

man

id a

nd d

elam

anid

.•

Rese

arch

on

optim

al d

ose

and

dura

tion

of li

nezo

lid u

se in

dru

g-re

sista

nt T

B re

gim

ens

(ZeN

ix st

udy)

.

AFB:

acid

-fas

t bac

illus;

ART:

ant

iretro

vira

l the

rapy

; BID

: Tw

ice a

day

[dos

ing]

; BPa

L: b

edaq

uilin

e, p

reto

man

id a

nd lin

ezol

id; C

I: co

nfid

ence

inte

rval

; GD

F: G

loba

l Dru

g Fa

cility

; GD

G: G

uide

line

Dev

elop

men

t Gro

up; H

IV:

hum

an im

mun

odef

icien

cy v

irus;

IPD

: ind

ivid

ual p

atie

nt d

ata;

KN

CV: K

NCV

Tube

rcul

osis

Foun

datio

n; M

DR-

TB: m

ultid

rug-

resis

tant

tube

rcul

osis;

MD

R/RR

-TB:

mul

tidru

g- o

r rifa

mpi

cin-r

esist

ant t

uber

culo

sis; M

DR-

TB:

mul

tidru

g-re

sista

nt tu

berc

ulos

is; M

IC: m

inim

um in

hibi

tory

con

cent

ratio

n; N

RTI:

nucle

osid

e re

vers

e-tra

nscr

ipta

se in

hibi

tors

; PLH

IV: p

eopl

e liv

ing

with

hum

an im

mun

odef

icien

cy v

irus;

PICO

: pat

ient

s, in

terv

entio

n,

com

para

tor a

nd o

utco

mes

(que

stio

ns);

QD

: onc

e a

day

(dos

ing)

; TB:

tube

rcul

osis;

WH

O: W

orld

Hea

lth O

rgan

izat

ion;

XD

R-TB

: ext

ensiv

ely

drug

-res

istan

t tub

ercu

losis

.


A4.2 WHO treatment guidelines for isoniazid-resistant tuberculosis, 2018Refer to Annex 6: GRADE evidence-to-decision tables in the WHO treatment guidelines for isoniazid-resistant tuberculosis (https://www.who.int/tb/publications/2018/WHO_treatment_guidelines_ isoniazid_resistant_TB_Online_GRADE_tables_Annexes.pdf, accessed 2 March 2019).

A4.3 WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2018 updateRefer to Annex 9: GRADE evidence-to-decision tables in the WHO treatment guidelines for multidrug-and rifampicin-resistant tuberculosis, 2018 update (https://www.who.int/tb/areas-of-work/drug-resistant-tb/ Annexes_8–10.pdf, accessed 2 March 2019).

A4.4 Guidelines for the programmatic management of drug-resistant tuberculosis, 2011 updateRefer to Annex 2: GRADE glossary and summary of evidence tables (questions 6 and 7) in the Guidelines for the programmatic management of drug-resistant tuberculosis, 2011 update (https://apps.who. int/iris/bitstream/handle/10665/70677/WHO_HTM_TB_2011.6b_eng.pdf, accessed 2 March 2019), where the content of the evidence-to-decision process was summarized in the remarks relating to each recommendation.

A4.5 WHO treatment guidelines for drug-resistant tuberculosis, 2016 updateRefer to Annex 5: Evidence-to-decision tables (question 4) in the WHO treatment guidelines for drug- resistant tuberculosis, 2016 update (https://apps.who.int/iris/bitstream/handle/10665/250125/ 9789241549639-webannexes-eng.pdf, accessed 2 March 2019).

A4.6 Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 updateRefer to Annex 4: Evidence-to-decision tables (questions 10 and 11) in the Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update (https://www.who.int/tb/publications/2017/ dstb_guidance_2017/en/, accessed 2 March 2019)






Annex 5: Summaries of unpublished data

A5.1 WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2020 updateA5.1.1: Summary review for the GDG of preclinical and early clinicl data on pretomanid for use in MDR and XDR-TB: CPMT Project No.: 19010 By Professor Susan M Abdel-Rahman

Overview:

Pretomanid (Pa) was granted approval by the U.S. FDA in August 2019 to be used as part of a bedaquiline, pretomanid, linezolid (BPaL) regimen. This document summarizes a broader report to WHO detailing background information on Pa including pre-clinical dat and early phase clinical safety and efficacy.

Chemistry:

Pa represents a class of nitroimidazopyrans arising from the naturally occurring nitroimidazole, azomycin, and its synthetic derivative metronidazole. It bears structural similarity to the nitroimidazooxazole, delamanid.[1–4]

Putative mechanisms of action for Pa include; 1) reductive activation to reactive nitro radical anion intermediates, 2) nitric oxide release, 3) ketomycolic acid depletion, and 4) toxic methylglyoxal accumulation.[1, 5–7] The cofactor F420 mediated redox system is integral to the activity of Pa and sequence variations in MTb proteins that are involved with the synthesis, oxidation or reduction of this cofactor are linked to resistance. These include Ddn (Rv3547), Fgd (Rv0407), fbiA (Rv3261), fbiB (Rv3262), fbiC (Rv1173), and fbiD (Rv2983).[1, 8–14] With limited exception, these proteins are not required for the growth/survival of MTb and their disruption does not limit mycobacterial fitness.[15–19]

The frequency of spontaneous Pa resistance in vitro (10–5 to 10–7) is influenced by the concentration to which the isolates are exposed and the starting mycobacterial inoculum. Estimates are greater than that of rifampin but comparable to other agents including isoniazid, ethambutol, and pyrazinamide.[20] Spontaneous resistance rates in vivo are variable (~10–3–10–5) and increase in direct proportion with dose; however, they drop in combination with INH.[13, 21–23]

Cross resistance to other antimycobacterial agents is rare with the exception of delamanid for which it is common but incomplete.[24] Cross resistance has also been documented with the more recently discovered nitrofuranylamides and 5-nitrothiophenes which share structural features with Pa and delamanid.[25,26]


Microbiology:

MIC for Pa against drug-susceptible, monoresistant, MDR, and XDR isolates of MTb (0.005–0.48 μg/mL) suggest that resistance phenotype has limited impact on Pa activity.[24] MICs against MTb increase in low oxygen conditions and in the presence of human albumin/serum.[24, 27–28] Pa demonstrates activity against other species in the Mycobacterium tuberculosis complex including M. bovis, M. africanum, and M. pinnipedii (MIC range <0.0312 to 0.125 μg/mL);however, there is little to no activity in other mycobacterial and non-mycobacterial species.[24]

In vitro, Pa appears to exhibit both concentration- and time-dependent bactericidal activity.[24] Intracellular potency appears comparable to INH and inferior to delamanid and rifampin, though intracellular to extracellular ratios vary by drug and incubation condition.[29–31]

Murine models support a dose-response relationship for Pa with a minimum effective dose of 12.5 mg/kg and a minimum bactericidal dose of 100 mg/kg. At this dose, CFU reductions in the lung and spleen comparable to INH (25 mg/kg), gatifloxacin (100 mg/kg) and moxifloxacin (100 mg/kg).[1, 21, 32]. Monotherapy with Pa at 50 mg/kg fails to achieve a sterile cure, though combinations with bedaquiline and an oxazolidinone achieve CFU reductions that are a full order of magnitude lower than achieved with Pa alone.[26, 33–35] The combination PaMZ is similarly effective in the guinea pig model.[1, 36] Dose fractionation studies in these animal models suggest that %T>MIC demonstrates the strongest association with CFU count reduction.[37]

In humans, 14-day single-dose studies suggest no appreciable increase in EBA above 200 mg.[38–39] When administered in combination, EBA observed in regimens containing Pa did not appear inferior to combinations without this agent. Pa-based regimens also outperformed standard HRZE treatment regimens in select studies, though none of the combinations tested reflect the FDA approved BPaL regimen.[40–43]

Pharmacology/Toxicology:

Information relevant to understanding the disposition of Pa and its drug-interaction potential derives largely from the CDER review [44] and are summarized as follows:

• Absolute bioavailability in non-human primate is less than 50%• Protein binding ranges from 86.3 to 86.5% with a low potential for partitioning into red blood cells.• Pa undergoes biotransformation by multiple P450 and non-P450 pathways with CYP3A4 the only

relevant P450 accounting for up to 20% the drugs metabolism. • In vitro studies demonstrate the potential for Pa to inhibit CYP3A4/5, though at concentrations

in excess of those observed with routine dosing. Recorded IC50 values suggest DDI mediated via other P450 isoforms is unlikely.

• The potential for pretomanid to induce CYP3A4 appears to be negligible.• Pa does not appear to be a substrate for transporters evaluated to date; however, it does inhibit

the renal tubular uptake transporter OAT3 at clinically relevant concentrations. • Clinically relevant in vivo DDI observed in humans are limited to a drop in Pa exposure when

co-administered with CYP3A inducers (e.g. rifampin, efavirenz, lopinavir/ritonavir).[45–48] • Pa does appear to increase in moxifloxacin exposures in rats; however, the mechanism and relevance

to humans is unclear.• Drug-food interactions are marked by an increase in Pa exposures (Cmax and AUC) when

co-administered with a high-fat meal. The relative increase in bioavailability gets disproportionately larger with increasing dose.[49]

• Cardiac toxicity mediated by hERG inhibition (IC50 was 17.3 μM) is not likely to be relevant at labeled doses.

• Carcinogenicity and mutagenicity risk also appear low.[24, 44] However, safety signals in animals have been observed in various organ systems the most relevant of which is hepatotoxicity at labeled


doses.[24, 44] Testicular toxicity has also been observed at lower exposures and the uncertain human implications have lead the FDA to require additional post-marketing studies.

Clinical Pharmacokinetics:

In healthy volunteers, Pa concentrations peak between 4–5 hours post-dose with a less-than proportional relationship between dose and exposure through 600 to 1000 mg after which point increasing dose produces no corresponding increase in exposure.[50–51] Mean Pa half-life ranges from 15–20 hours explaining a doubling in the extent of exposure at steady state.[50]

Efficacy/Safety:

Nix-TB [24]: This non-comparative study of BPaL in 109 individuals reported favorable outcomes in 89%, 91% and 92% of their ITT, MITT, and PP populations respectively. No appreciable differences in response were observed as a function of HIV status, linezolid regimen (BID vs. QD), age, gender, race, cavitation, or time to positivity at baseline. All participants (100%) experienced at least 1 treatment emergent adverse event (TEAE), 99% of which were considered related to study regimen. The most frequently reported AE can be identified in the clinicaltrials.gov URL referenced above. Those most likely associated with Pa based on preclinical data include: dermatitis/eczema (53.2%), non-infective gastrointestinal upset (48.6%), hepatic disorder (38.5%), headache (29.4%), lens disorder (13.8%), severe cutaneous reaction (6.4%), and convulsions (1.8%). There were 8 deaths in the trial 7 of which led to premature discontinuation of the study and TEAE in an additional 5 patients that led to treatment discontinuation.

STAND [52]: In this trial of PaMZ, the rate of unfavorable outcomes for the primary measure exceeded those of the standard HRZE treatment group. At the point of analysis, the Pa containing regimens failed non-inferiority criterion prompting early discontinuation of the trial. Note that this was preceded by a clinical hold from the FDA owing to 3 hepatotoxicity associated deaths. TEAE rates ranged from 87–94% in the Pa containing arms compared with 91% in standard treatment arm. The only SAE observed in more than 1 individual across all pretomanid containing regimens include increases in ALT/AST and seizures. Additional AE observed with more than a 2-fold higher rate in the Pa groups (vs. HRZE) were gastrointestinal (nausea, vomiting, diarrhea) and pulmonary (pleuritic pain, hemoptysis, URI).

ZeNix [53]: In this ongoing trial of BPaL, 83.6% of 61 participants have experienced at least one TEAE, 55.7% of which were considered related to study drug. The most frequently reported AE parallel those reported in Nix-TB. To date, TEAE have led to permanent discontinuation in 2 participants.

Early Clinical Trials [38–43]: In the 14-day EBA monotherapy studies, reported SAE were restricted to complications of the underlying disease (pneumonia, pneumothorax, hemoptysis). The only non-serious AE experienced by more than one individual across all treatment arms was nausea, vomiting, headache, pruritis, rash, and iron deficiency anemia. In the 8-week BA studies, TEAE rates approximated those of the efficacy studies described above. When the regimens are broadly combined, and non-serious AE are evaluated against the standard HRZE regimen, neurologic and hepatic disturbances appeared to be more prevalent in the Pa containing regimens. Early clinical studies also identified a relationship between trough Pa concentrations and an increase in circulating serum creatinine levels which resolved after discontinuation of the drug.[50] Subsequent exploratory studies suggests that these changes are likely the result of inhibition of creatinine secretion at the level of the renal proximal tubule.[51]

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A5.1.2: Model-based projections of costs and cost effectiveness of changes in MDR/RR-TB regimensBy Dr Emily A Kendall, MD PhD

Background:

Changes in recommended MDR/RR-TB treatment are likely to have economic consequences, through their effects on drug costs, drug delivery (for example, injections), safety monitoring requirements, numbers of follow-up visits, or (via changes in treatment outcomes) the number of TB patients who will require treatment in the future. Changes to recommended regimens might be cost-saving under common conditions, or might result in cost increases and potential access concerns that need to be weighed against clinical advantages. We developed a model to estimate the costs and cost-effectiveness of three potential changes to recommended treatments for MDR/RR TB.

Methods:

A single decision analytic modeling framework was developed to evaluate multiple regimen comparisons that were under consideration by the Guidelines Development Group (GDG). For PICO question 1, the costs and effectiveness of a shorter (9–12 month), all-oral, bedaquiline-containing regimen (modeled as based on South African guidelines) were compared to two types of currently recommended MDR/RR-TB regimens: (a) a longer (18–20 month), bedaquiline-containing oral regimen (modeled as consisting of WHO class A and B drugs bedaquiline, linezolid, levofloxacin, clofazimine, and terizidone), or (b) a 9–12 month, injectable-containing regimen (modeled as evaluated in STREAM). For PICO 3 (use of bedaquiline for longer than 6 months in longer oral regimens), use of bedaquiline for 6 months in the 18–20 month regimen described above was compared to use for the duration of treatment. For PICO 4 (concurrent use of delamanid and bedaquiline), use of delamanid was modeled in two ways: (a) as an addition to the 18–20 month oral regimen (thus potentially increasing efficacy while adding cost) or (b) as a replacement for linezolid (with main goal to reduce toxicity).

Each pair of regimens was compared in a population of adult patients with MDR/RR (not pre-XDR/XDR) pulmonary TB. Modeled differences in TB outcomes between regimens (differences in relapse/failure, mortality, and loss to follow up) were based on the statistical analyses of individual patient data performed for the GDG by Drs. J Campbell and R Menzies. Differences in cost, in 2019 US dollars, were evaluated from a health system perspective, accounting for resources required to manage current and future TB (including drugs, office visits and hospitalizations, safety monitoring, recurrences and secondary cases) and adverse events. Future non-TB health care costs (e.g. of ART) incurred as a result of preventing deaths were excluded. Serious adverse event risks were estimated per drug-month using data from a global surveillance project. Differences in effectiveness, in disability-adjusted life years (DALYs) averted, accounted for estimated morbidity and mortality during and after treatment (with disability weights13 for TB disease, drug side effects, treatment burden, and health status, and with 3%/year discounting of DALYs and costs). Primary analyses were based in South Africa, and sensitivity analyses explored the range of health care costs, drug costs, and HIV co-prevalence expected across low- and middle-income countries.


Results:

PICO 1: A shorter, all-oral, bedaquiline-containing regimen was projected to be cost-saving relative to either comparator regimen: by nearly $3,000 per patient when compared to a longer, all-oral regimen, and by $1,000 per patient when compared to a short, injectable-containing regimen (both in South Africa). Compared to the longer oral regimen, the majority of the resource savings associated with the shorter all-oral regimen were due to reduced costs of drugs, but savings were also projected in costs of health care delivery, adverse events, and future retreatments and secondary cases. Compared to the short, injectable-containing regimen, the shorter all-oral regimen did not reduce drug costs, but it provided similar projected resources savings in other categories. The shorter all-oral regimen was also projected to be more effective than either comparator.

In sensitivity analyses, the resource savings of the shorter all-oral regimen relative to a longer all-oral regimen appeared extremely robust to country setting and underlying assumptions. The greatest variations in (cost savings) were seen with a two-fold decrease or increase in drug costs (cost savings $2000 and $4600, respectively) and with a two-fold decrease or increase in all non-drug healthcare costs (cost savings $2300 and $4000). The resource savings of the shorter all-oral regimen relative to the shorter injectable-containing regimen were nearly as robust, with the shorter all-oral regimen ceasing to be cost-saving (but remaining cost-effective, at < $400 per DALY averted) only when we assumed a large (four-fold) isolated increase in the cost of the drug bedaquiline.

PICO 3: Extending the duration of bedaquiline treatment, from six months to the full 18–20 month duration of a longer all-oral regimen, was expected to add approximately $500 per patient to health system costs (at current drug prices). Cost-effectiveness depended heavily on the magnitude of the clinical benefit of extending treatment, and a sufficiently large benefit to achieve cost-effectiveness when used for all patients could not be observed in available data. If patients could be identified who would derive a clinically meaningful efficacy benefit (e.g. odds ratio of 0.6 for treatment success), then extending the duration of bedaquiline might be cost effective for those patients, at an estimated incremental cost effectiveness ratio in South Africa of $1,200 per DALY averted.

PICO 4: Current high delamanid prices made cost-effectiveness difficult to achieve, whether delamanid was considered for inclusion in MDR/RR-TB treatment regimens in order to enhance efficacy (analysis a) or to prevent toxicity from another drug through substitution (assuming no significant loss of efficacy, analysis b). When adding delamanid to an otherwise-optimized longer all-oral regimen that already contained bedaquiline, the best-case incremental cost effectiveness ratio was $2,000 per DALY averted in South Africa, at the most optimistic data-consistent estimate of the efficacy benefit that delamanid might provide to patients. Data also supported an outcome of additional cost with no benefit, if true efficacy gains were minimal. When delamanid replaced a more toxic drug (e.g. linezolid) without changing regimen efficacy, then at current drug prices, the most optimistic incremental cost effectiveness ratio achievable in sensitivity analyses was $16,000 per DALY averted; this required assuming a serious adverse event rate of 0.7%/month for the drug that was replaced by delamanid (at the high end of the uncertainty range supported by data for linezolid), and high acute DALY impact per serious adverse event (0.4 DALYs each, similar to one full year with symptomatic active TB), and a high management cost of $17,000 per averted serious adverse event.

Conclusions:

A 9–12 all-oral regimen was projected to be both cost-saving and effective, relative to either a longer all-oral regimen or a shorter injectable-containing regimen, and cost savings were robust to setting-dependent variables and parameter uncertainty.

On the other hand, extending the duration of bedaquiline or adding delamanid within longer MDR/RR-TB regimens added substantial cost, and these changes were unlikely to be cost-effective at current prices when implemented for all patients, because of the relatively small effectiveness benefits


expected. However, moderate cost effectiveness was possible when used for select patients for whom effective regimens could not otherwise be composed.

A5.1.3: Patient perspectives on DR-TB treatment: a summary report prepared for the November 2019 WHO GDG Meeting

Introduction

Patient values and preferences for treatment, and perspectives on treatment acceptability, feasibility and equity are key to the World Health Organization’s Evidence to Decision framework for drug-resistant tuberculosis (DR-TB) treatment interventions. A qualitative study was undertaken to illuminate patient perspectives and inform discussions for a November 2019 Guidelines Development Group (GDG) meeting for updated DR-TB treatment guidelines. A summary of the study is provided here.

Methods

Private in-depth interviews were held with persons who had received M/XDR-TB treatment in or after 2012, and were at least 18 years old and not receiving any form of TB treatment at the time of the study. They were recruited by referral from non-governmental organizations, as well as former patients with public profiles, from high DR-TB burden countries. Representation was sought from women, men, and people who had received newer or repurposed drugs for DR-TB. Interviews were conducted by phone in English, Russian, Mandarin or Spanish, and audio-recorded. Interview topics included: experiences with DR-TB treatment; preferences for treatment regimens; and the real or perceived acceptability of newer regimens, including perspectives on access and delivery. Recordings were transcribed, translated and identifiers removed. Data were thematically analyzed using OneNote to develop insights on patient values and preferences (characteristics, concerns and expectations of treatment that are considered to be most important); acceptability (appropriateness of treatment based on anticipated or experienced physical, cognitive and emotional effects); feasibility (practical considerations related to taking treatment); and equity (perceived or potential impacts on health and social inequalities). Ethics approval was granted by the Office of Research Ethics, York University, Canada.

Findings

Sixteen participants (44% female) of median age 29.5 years (range 22–64) were interviewed over two weeks in Oct 2019, from Africa (4), Asia (5), Eastern Europe (5) and South America (2). Nine (56%) participants began treatment for MDR-TB and 7 (44%) for pre-XDR or XDR-TB between 2011 to 2017. All had received longer regimens, from 1.5 up to 3 years. Most (96%) participants had experience with a second-line injectable and 40% with at least one of the new or repurposed drugs. One participant received bedaquiline as first-line therapy. Two participants were treated when they were adolescents. Few participants reported a co-morbidity: HIV (1), diabetes (2), chronic kidney illness (1).

Participants’ acceptability and preferences for DR-TB treatment were rooted in the following core values: minimal disruption to normal life and independence during treatment, and full physical and mental recovery post treatment. A short, injection-free regimen with few to no side effects and a low pill burden was considered to be the most acceptable treatment for DR-TB. Barring the fulfillment of all these characteristics, a regimen with least side effects was prioritized, as side effects were considered to be the most disruptive aspect of treatment. This was followed by a shorter regimen, no injections, and fewer pills, in that order.

Side effects that tended to resolve themselves over the course of a day or over the course of treatment (nausea, mild vomiting, body aches and pains, fatigue, and ringing in the ears) were disliked but tolerated. By contrast, severe and persistent vomiting, intense mental health effects ( severe depression including suicidal ideation, and severe anxiety including delusional thoughts), and any side effect that


could result in organ or sensory damage (hearing or vision loss, major damage to organs such as the kidney or heart, jaundice, and severe neuropathy or burning) were all considered unacceptable, even if they were short-term and reversible. Severe mental health problems and any loss of hearing and vision were described as the worst side effects. Skin pigmentation and injection pain were highly undesirable; they were accepted in the short-term only if there was no other treatment choice.

There were caveats and nuances to participants’ priorities, as well as important differences in acceptability, based on personal experiences with treatment, and the environment and context in which DR-TB care was received. Consequently, informed patient choice was considered a highly valuable component of the treatment decision-making process. Other elements valued by participants and considered crucial to acceptability of DR-TB treatment regimens were tight monitoring of serious adverse events, mental health counselling and support, ability to receive treatment in one’s own community (e.g., decentralized care), and universal access to new drugs and regimens.

These values and preferences have implications for the feasibility of new DR-TB treatment interventions. Some patient values may conflict due to feasibility challenges, for example if treatment monitoring cannot be reasonably provided in the community. Feasibility issues give way to equity considerations if patient preferences are not upheld across all communities, or place certain populations at a disadvantage, such as those living in remote or rural locations where provision of new drugs or treatment monitoring may be difficult.

Study attributes and limitations

Open ended in-depth inquiry was key to uncovering the dynamic subjectivity of patient values and preferences. Saturation was likely not achieved with regards to the perspective of people with co-morbidities, permanent clinical sequalae, and experience with shorter, non-injectable regimens as first-line treatment. The sample was enriched by the voices of several participants who were TB peer educators and patient advocates and brought the experience of current patients into their narratives.

Conclusion

The study, rooted in the recent lived experience of people who were treated for DR-TB in a number of high burden countries, illuminates novel insights into patients’ core values, ranked preferences, and comparative risk perceptions and acceptability related to DR-TB treatment. Insights gained may inform patient-centred treatment guidelines for DR-TB.

Acknowledgements

The study was conducted by Amrita Daftary and Stephanie Law in preparation for the WHO GDG for updated DR-TB treatment in November 2019. AD is based at the School of Global Health & Dahdaleh Institute of Global Health Research, York University, Canada, and appointed to the Centre for the AIDS Programme of Research in South Africa (CAPRISA). SL is postdoctoral fellow at the Department of Global Health and Social Medicine, Harvard Medical School, Boston, USA. The researchers wish to acknowledge and sincerely thank the people who participated in this study, as well as referring organizations and persons.


Annex 6: Statistical analysis plans

A6.1 WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2020 updateA6.1.1: PICO question 1: In MDR/RR-TB patients, does an all-oral treatment regimen lasting 9-12 months safely improve outcomes when compared with other regimens conforming to WHO guidelines?

Effectiveness of an all-oral MDR/RR-TB regimen lasting 9–12 months in South Africa: Statistical Analysis Plan (draft)Prepared by Jonathon Campbell & Dick Menzies, McGill University: April 15, 2020

Overarching PICO Question (PICO 1)

In MDR/RR-TB patients, does an all-oral, bedaquiline-containing regimen lasting 9–12 months safely improve outcomes when compared with other regimens conforming to current WHO guidelines?

Population Intervention Comparator Outcomes

MDR/RR-TB patientsa. without additional drug

resistanceb. with additional drug resistance

patterns (for FLDs and/or SLDs; if specific mutation data is available in dataset).

c. with FQ resistanced. with severe disease

(i.e. cavitary disease on radiography or SS+)

e. previously treated with 2nd line drugs or not

f. children (0–14y) / adults (adolescents 10–19y if available)

g. persons with HIV (+/- ARVs)h. pregnant womeni. with extrapulmonary diseasej. with comorbidities (e.g.

diabetes mellitus; malnutrition; mental disorders)

– An all-oral shorter regimen of 9–12 months duration including bedaquiline

1. Shorter regimen recommended by WHO

2. Old longer regimens without new drugs in the IPD dataset

3. Longer regimens with new TB drugs from the IPD dataset

4. Longer regimens with use of new drugs from the EndTB dataset.

• Successful completion of treatment (or lack of successful completion)

• Bacteriological cure by end of treatment

• Adherence to treatment (or treatment interruption due to non-adherence)

• Treatment failure or relapse

• Survival (or death)• Adverse reactions from anti-TB medicines

• Acquisition (amplification) of drug resistance

• Relapse free cure


Research Questions

Primary – intervention and comparator populations from South Africa data

1. Relative to the WHO recommended short-regimen lasting 9–12 months, does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes?

2. Relative to a regimen lasting ≥18 months without the use of new TB drugs (e.g. does not contain bedaquiline, linezolid, delamanid, or carbapenems), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes?

3. Relative to a regimen lasting ≥18 months with new TB drugs (e.g. contains bedaquiline), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes?

Secondary – intervention population from South Africa data, and comparator populations are from IPDinMDR – 2019 or the EndTB observational study

1. Relative to people in the IPDinMDR – 2019 data set receiving a regimen lasting ≥18 months without the use of new TB drugs (e.g. does not contain bedaquiline, linezolid, delamanid, or carbapenems), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes?

2. Relative to people in the IPDinMDR – 2019 data set receiving a regimen lasting ≥18 months with new TB drugs (e.g. contains bedaquiline), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes?

3. Relative to people in the EndTB data set receiving a regimen lasting ≥18 months with bedaquiline and/or delamanid (for a maximum of 6-months), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes?

Background and Rationale

The use of shorter (9–12 months) regimens, in particular the new all-oral regimens for MDR/RR-TB, is presumed to have more benefits as compared to longer regimens lasting ≥18 months; as well as to other shorter injectable-containing regimens. Primarily, the shorter duration puts a lower burden on patients and reduces the direct and indirect costs (both to the patient and the healthcare system) associated with treatment since MDR/RR-TB treatment is usually delivered through directly observed therapy. Secondly, injectable-agents are among the most toxic drugs used for MDR/RR-TB, have poor efficacy against TB and can lead to irreversible adverse events. While treatment & care delivery for TB25, including patients with drug-resistant TB can be community-based, usually injection-containing regimens must be administered at health facilities, adding travel and waiting time to the discomfort and inconvenience, and potentially contributing to poor treatment adherence in some cases. Thus, there are several advantages to a shorter all-oral regimen if they are as effective as regimens that (a) last longer and/or (b) contain an injectable.

To date, shorter regimens have only been recommended for individuals who have not been exposed to second-line TB drugs (i.e. are new patients or have only received first-line TB drugs) and whose TB isolates have proven susceptibility to fluoroquinolones and second-line injectables. Given the nature of programmatic data, this latter criterion often simplifies to “not proven resistant” – i.e., their drug susceptibility test result is ‘susceptible’ or ‘not performed’ for these two classes of drugs, although in ideal settings, drug susceptibility results would be available. However, generally this means that patients with MDR/RR-TB that qualify for a shorter regimen are much less “complex”, than patients with MDR -TB with additional resistance patterns26 and XDR-TB, or that have been previously treated with second-line TB drugs. This makes comparisons of treatment of these two groups at very high-risk

25 Treatment & care delivery for TB is used in this context to refer to the administration of “Directly Observed Therapy [DOT]”.26 MDR -TB with additional resistance patterns refers to MDR-TB cases which present MDR-TB plus resistance to fluoroquinolones (MDR-

TB+FQ) or additional resistance to injectable agents (MDR-TB+SLI). This term does NOT mean MDR with resistance to PZA, EMB, Ethionamide Cycloserine or other similar and commonly used second-line drugs.


of bias. Thus, for the purposes of this PICO question, we will exclude patients from all data sources (detailed below in Section 3.1) who have been exposed to second line drugs previously or who are MDR-TB with additional resistance to a second-line injectable and/or a fluoroquinolone. The number of patients excluded will be quantified, but are expected to be minimal, with only 4% and 1.5% of patients treated with a short regimen in South Africa previously receiving second-line drugs and having MDR -TB with additional resistance patterns or XDR, respectively, in a prior analysis of 2014–2015 data.

Within South Africa, over 10,000 people initiate MDR/RR-TB treatment each year. Both shorter (9–12 months) and longer (≥18 months) regimens have been used and, over the last 2–3 years, there has been a transition from the WHO recommended short, injectable-containing regimen, to one that has replaced the injectable with bedaquiline. Thus, the data from South Africa presents a unique opportunity to compare patient important outcomes with four different types of regimens27 delivered concurrently in the same settings, by the same providers, faced with the same health system resources and constraints. The comparisons within the South Africa data set are thus considered the primary analysis.

In addition to comparison within South Africa, use of patients from the IPDinMDR – 2019 database and/or from the EndTB observational study allow comparisons between settings and patients with different characteristics. If findings are similar, we can be more confident in their generalizability. Due to many potentially confounding differences between health systems and patients with MDR/RR-TB, within South Africa, and other settings, the comparisons between South African cohorts and other cohorts will be considered secondary.

Data Sources

South Africa

All data for MDR/RR-TB patients who initiated treatment within South Africa is housed within the Electronic Drug Resistant TB register (EDRWeb). This register includes information such as age, sex, facility of treatment, previous treatment history, HIV co-infection, ART use, every drug received during treatment, individual culture and smear results during treatment, drug-resistance testing (both genotypic and phenotypic), regimen type (short or long), and end-of-treatment outcomes.

We plan to use data from every individual in South Africa who initiated any short-regimen between Jan 1 and Dec 31, 2017 (N=3772) and data from every individual in South Africa who initiated a “long”-regimen in Q1 and Q2 2017 (Jan 1 to June 30, 2017) (N=3722). We selected the year 2017 for the short, injectable-free regimen as this was the first year this short-regimen had been widely used throughout the country. As well, regardless of the date a person started treatment that year, every individual should have at least 6 months of post treatment follow-up for possible relapse (data extraction for relapse is being performed in August 2019). We selected the first two quarters of 2017 (1 January to 30 June) for the long regimen as these patients would be receiving treatment concurrently with the short regimen patients and 95% of patients initiating therapy within this interval should have had an end of treatment outcome by 31 December 2018, allowing at least 6 months of follow-up for possible relapse. There may be concerns regarding selection of individuals to a short or long regimen when both were systematically offered in 2017. To examine this, we will also compare outcomes with the BDQ short regimen received in 2017 with outcomes among patients who received the conventional (long) regimen in 2016 for a second comparison. In 2016 only 213 of 13,193 (1.6%) persons starting RR/MDR-TB treatment received a short regimen, suggesting that selection bias should have been minimal in 2016, compared to 2017.

As many of the regimens being compared are significantly different in duration, accounting for relapse and death non-differentially presents a challenge. For example deaths during treatment may occur up to 18 or even 24 months after initiation of a conventional ‘long’ regimen, but only up to 12 months with

27 All-oral 9–12 month regimen; WHO recommended 9–12 month regimen; Longer regimen without new drugs; Longer regimen with new drugs.


the short regimen. Therefore, death in Months 12–24 will be counted as ‘deaths during TB treatment’ with the long regimen, even if unrelated to TB, whereas they would not be classified as such with the short regimen. Similarly, a patient could have culture reversion at month 15 of a long regimen and be classified as a treatment failure, but such a late reversion would not detected with the short regimen (unless relapse was carefully measured). In both situations, knowledge of post-treatment relapse and death outcomes is crucial to minimize differential outcome ascertainment. We plan to detect relapses within EDRWeb by cross-matching all names of those treated in 2016 and 2017 with EDRWeb to ascertain if any patients who are classified as treatment success are subsequently restarted on MDR/RR treatment. We will detect these relapses by probabilistically matching patients within EDRWeb. However, as deaths following treatment completion are not recorded with EDRWeb (treatment must be initiated to be entered in this system), we will link all patients who started treatment in Jan 1 to June 30 2017, and those who started the short regimen from July 1 to Dec 31 2017 and successfully completed treatment with the South African MRC using their South Africa ID number to see if death occurred after treatment completion. Information about the South Africa ID within EDRWeb is ~90% complete, so we expect this should result in a fairly complete capture of deaths post-treatment.

IPDinMDR – 2019

In 2018 an IPD was assembled of 53 data sets from 40 countries/regions containing records for more than 13,000 patients with MDR-TB. This IPD-2018 data set was analyzed to answer a number of PICO questions developed by a WHO MDR-TB guidelines development group (GdG). These guidelines have since been published. This IPD-2018 itself was based on an IPD data set assembled in 2016–17 to answer questions of a GdG of the CDC/ATS/IDSA/ERS. These guidelines have not yet been published, but the analyses that informed this set of guidelines were published in the Lancet in Sept 2018. This database contains records of~150 patients from the EndTB study, who will be removed and updated with the more complete data set (see below). Further, the IPD-2018 contains about 3,500 records from South Africa, which we will exclude for the purposes of the secondary analyses.

Within this iteration of the IPD – 2019, we anticipate adding data from a public call executed by the WHO, however at the time of writing we are unsure of the type, number, and treatment regimens of patients who might be added.

EndTB Observational Study

The EndTB observational study includes 1094 patients with MDR-TB who were treated with bedaquiline- and/or delamanid-containing long regimens between 1 April 2015 and 31 March 2017 in 17 countries28. They were followed as part of an observational study – executed by three institutions – PIH, MSF and IRD. There is comprehensive data capture on all important variables within the data set, including detailed information on treatment associated adverse events.

Considerations for the IPDinMDR – 2019 and EndTB Observational Study Data Sets

Within the IPDinMDR – 2019 and EndTB data sets, there are important differences when compared to the South Africa cohorts from 2016 and 2017 that willl be analyzed. Firstly, these data sets contain patients treated from 2000–2017. We will only include patients initiating treatment from 1 January 2013 onwards to ensure comparability with the patients treated in 2016 and 2017 in South Africa. Further, it is important to compare patients treated in similar resource settings. The primary analysis will include patients treated in all settings, and in sensitivity analyses we will restrict the comparators to patients treated in other World Bank classified upper-middle-income countries, as is this is the category South Africa belongs to. We will quantify how many patients this represents and compare them to those we included from both studies.

28 Armenia, Bangladesh, Belarus, Democratic People’s Republic of Korea (DPRK), Ethiopia, Georgia, Haiti, Indonesia, Kazakhstan, Kenya, Kyrgyzstan, Lesotho, Myanmar, Pakistan, Peru, South Africa and Vietnam; (http://endtb.org/about)


Defining Regimens

As the treatment trajectory of MDR/RR-TB represents the complex interaction of patient, provider and health system capacities and constraints, there may be deviations from intended durations of therapy and number of drugs used. We will examine descriptively the distribution of treatment duration for all persons who received long or short regimens, as well as the distribution of treatment duration for persons with successful treatment who received a long or a short regimen. Based on these descriptive analyses, we will select cut-points (ideally using inter-modal points) that appear to best define the duration of treatment that can be called ‘short’ and ‘long’ (e.g. how far before or after the ‘planned’ duration of ‘short’ treatment do we accept as still meeting the definition of a short regimen to include in this analysis?).

Therefore, we propose to establish criteria to classify people within regimen types. For data from South Africa, we plan to classify people who received a long-regimen as those who: (i) were classified as receiving a long-regimen within EDRWeb; (ii) had treatment duration not exceeding 24 months; (iii) received ≥4 TB drugs (any drugs, regardless of susceptibility for this definition) during treatment, regardless of whether they were effective and; (iv) if given an outcome of cure or complete, had a treatment duration ≥17.5 months. For data from IPDinMDR – 2019 and the EndTB data set, all patients received a long regimen, therefore we will include people conforming to criteria (ii), (iii), and (iv).

We plan to classify people who received a short-regimen as those who: (i) were classified as received a short-regimen within EDRWeb; (ii) had a treatment duration not exceeding 12 months; (iii) received ≥6 drugs during treatment and; (iv) if given an outcome of cure or complete, had a treatment duration ≥8.5 months. These duration cut-points are subject to change pending the distribution of treatment durations we find. The short regimen target duration is 9 months, but a 3-month (33%) extension is permissible by PICO definition, similarly, a long regimen target duration is 18 months, so the equivalent extension permissible is 24 months. Further, for the minimum treatment durations for success in the 2018 MDR Guideline Update, the 17.5 month cut-point for the long-regimen was used. A similar two-week period should be used for the short-regimen, which may reflect simply differences in dispensation of prescriptions (e.g. 36 weeks of meds vs. 270 days) or deviations in timing of visits and pills dispensed. We will describe any patients excluded because their treatment duration does not fall within these limits.

Regimen Classifications

Intervention Regimen

All-Oral Short Bedaquiline-Containing Regimen: The intervention in each analysis will be individuals who receive a short regimen (lasting 9–12 months) who did not receive any injectable during treatment and received bedaquiline.

Comparator Regimens

1. WHO Recommended Short-Regimen: The first comparator is the WHO recommended short-regimen, which consists of pyrazinamide, ethambutol, moxifloxacin/levofloxacin, and clofazimine given for 9–11 months with high-dose isoniazid, amikacin (if given kanamycin or capreomycin – these will be included), and ethionamide or prothionamide given in the first 4–6 months of treatment.

2. Long Regimen Without New TB Drugs: The second comparator is a long regimen given for a duration of 18–20 months, which does not contain one of the new TB drugs: bedaquiline, delamanid, linezolid, clofazimine, or carbapenems. The target duration of the regimen may not be reached due to treatment non-response, death, or loss to follow-up. Hence, we refer to long regimens as those intended to be given for ≥18 months in our analysis plan.

3. Long Regimen Containing New TB Drugs: The third comparator is a long regimen given for a duration of 18–20 months, which contains at least one of the new TB drugs: bedaquiline,


delamanid, linezolid, clofazimine, or carbapenems. The target duration of the regimen may not be reached due to treatment non-response, death, or loss to follow-up. Hence, we refer to long regimens as those intended to be given for ≥18 months in our analysis plan.

Regimens Excluded from Analysis

a. Short-Regimen without Bedaquiline and Not Conforming to WHO Recommendations: It is possible patients are treated with a regimen lasting 9–12 months that does not conform to the WHO recommended regimen and does not contain bedaquiline. Individuals receiving a regimen falling into this category will be classified uniquely. We will compare characteristics and outcomes of these patients to others receiving a short regimen descriptively, but they will be excluded from analysis.

b. Short-Regimen with Bedaquiline and an Injectable: It is possible patients began a short-regimen with an injectable, only to have it stopped and replaced with bedaquiline. Individuals receiving a regimen falling into this category will be classified uniquely. We will compare characteristics and outcomes of these patients to others receiving a short regimen descriptively, but they will be excluded from analysis.

Analysis of Outcomes

The PICO lists eight distinct outcomes: (i) Successful completion of treatment, (ii) Bacteriological cure by end of treatment, (iii) Adherence to treatment (or treatment interruption due to non-adherence)29; (iv) Treatment failure or relapse, (v) Death during treatment, (vi) Adverse reactions from anti-TB medicines, (vii) Acquisition (amplification) of drug resistance, and (viii) Sustained bacteriological cure at least 6 months after successful treatment

We will combine failure and relapse, and also combine completion and cure as success. We will estimate odds of relapse free treatment success vs several combinations of poor outcomes, and also examine loss to follow-up (LTFU) vs other outcomes – as summarized below. Adverse reactions from anti-TB medicines, and acquisition of drug resistance during treatment can NOT be analyzed using South Africa data as this information is not routinely captured in South Africa’s EDRWeb.

Comparisons analyzed:

1. Relapse free treatment success (cure + treatment completion) up to 24* months post treatment initiation vs. failure/relapse

2. Relapse free treatment success (cure + treatment completion) up to 24* months post treatment initiation vs. failure/relapse and death during treatment.

3. Relapse free treatment success (cure + treatment completion) up to 24* months post treatment initiation vs. all other outcomes (fail/relapse, death, and loss to FU).

4. Lost to follow-up during treatment vs. all other outcomes.

* The follow-up periods were selected as this will give follow-up times that are comparable for both regimens. A key consideration is that the first patient in our analysis initiates treatment in January 2017 and follow-up ends in June 2019 (30 months elapsing from the time of the first patient recruited until follow-up ends). This time elapsed necessarily shrinks as the year progresses. Thus, setting a limit of 24 months post-treatment initiation for follow-up, and censoring events occurring beyond this period, maximizes the study population for comparison. As this limitation necessarily excludes all patients initiating treatment beyond June 2017, we will conduct sensitivity analyses, examining outcomes 18-months post treatment initiation and 21-months post treatment initiation. Therefore, we will have three comparisons described in the table below:

29 This correlates with loss to follow-up


Months of Follow-up Post-Treatment Initiation

Dates of Patients Included Receiving Short Regimen

Dates of Patients Included Receiving Long Regimen

18 months January to December 2017 January to June 2017

21 months January to September 2017 January to June 2017

24 months January to June 2017 January to June 2017

Outcomes are clinician defined within South Africa and from our experience largely reflect Laserson (WHO 2005) criteria; this is how the majority of outcomes have been defined in IPDinMDR – 2019 (44/53 studies). Within EndTB, outcomes are coded as per WHO 2013 outcomes, however we will also create outcomes based on microbiologic data to align with WHO 2005 for comparability.

Summary of Approach for Each Research Question

We will conduct all main analyses described in sections 5.1.1, 5.2.1, and 5.3.1 using the concurrent long regimen controls (from Q1 and Q2 2017) and the historical long regimen controls (from all of 2016). These estimates will be shown separately. We will only conduct sensitivity analyses in these sections on the concurrent long regimen controls. For the outcomes described in section 4.0, we will conduct sensitivity analyses examining outcomes up to 18-months and 21-months post-treatment initiation in addition to those at 24 months post-treatment initiation.

Overall Descriptive Analysis

Before analysis of each research question, we will conduct a descriptive analysis for each of the reference and exposure group (detailed below), looking at key characteristics including: age (continuous and 0–14 vs. 14+ and 10–19 vs. 19+), sex, previous treatment history (drugs received and outcome), baseline acid-fast bacilli smear result, number of drugs received during treatment, total number and type of drugs resistant to (not double-counting ‘similar ’ drugs of ethionamide/prothionamide and cycloserine/terizidone, for example), presence of specific drugs in the regimens (e.g. bedaquiline, linezolid, clofazimine, moxifloxacin/levofloxacin, delamanid), and province of treatment. This will help clarify if there are systematic differences between the people who received each regimen, possible differences in where each regimen was used, and provincial differences in overall treatment outcomes. The information elicited from this analysis will be used to inform further variables for matching and/or adjustment described below – for example, addition of a random-effect for province of treatment (or exact matching within the province). Thus, within the approach for each question, the listed variables are an a priori list for inclusion, but may be modified based on data completeness and availability, and further sensitivity analyses including/excluding other variables may be developed based on the results of the descriptive analyses.

The descriptive analysis is also intended to determine how many individuals would be excluded due to regimen composition. We will see if there are any important differences between those included and excluded from analysis.

Primary Analysis (within South Africa only)

Primary Analysis Question 1

Relative to the WHO recommended short-regimen lasting 9–12 months, does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes?

Intervention: All-Oral Short Bedaquiline-Containing Regimen 9–12 months in duration Comparator: WHO Recommended Short-Regimen


Approach

Our approach will be to use a combination of exact matching and propensity score-based matching on several covariates to create two groups that are as comparable as possible, and thereby minimize bias and confounding. Between the intervention and comparator groups, we will perform exact matching on HIV co-infection/ART-use, previous TB treatment history (a 2 level variable – never and prior 1st line [recall, all people who previously received 2nd line TB treatment will be excluded]), and total number of drugs the strain was resistant to – this latter covariate is key to ensure the groups are comparable with regard to the full resistance patterns. We will further perform propensity score-based matching on age, sex, and baseline sputum AFB smear result. This matching process will be conducted with replacement using a caliper distance of 0.02 during the propensity score-based matching. We will examine the distribution of the matched covariates within the intervention and comparator groups to assess the fidelity of the matching process.

For each outcome described in section 4.0, within our ‘matched’ population we will conduct logistic regression using mixed-models including random-intercepts for each matched ‘pair ’ and, depending on what we find for the descriptive analysis, for province of treatment. We will not include random-slopes as our experience is that there are significant model convergence issues when these random-effects are included. The logistic regression analysis will calculate adjusted odds ratios and associated 95% confidence intervals. We will further conduct binomial regression, using only fixed effects, on the matched population to calculate adjusted risk differences and their associated 95% confidence intervals.


Relative to a regimen lasting ≥18 months without the use of new TB drugs (e.g. does not contain bedaquiline, linezolid, delamanid, or carbapenems), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes?

Intervention: All-Oral Short Bedaquiline-Containing Regimen 9–12 months in duration Comparator: Long Regimen Without New TB Drugs

Approach

We will utilize the same approach described in section 5.1.1 to compare outcomes among people receiving the intervention and comparator regimens.


Relative to a regimen lasting ≥18 months with new TB drugs (e.g. contains bedaquiline), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes?

Intervention: All-Oral Short Bedaquiline-Containing Regimen 9–12 months in duration Comparator: Long Regimen Containing New TB Drugs

Approach

We will utilize the same approach described in section 5.1.1 to compare outcomes among people receiving the intervention and comparator regimens.

If there are enough patients, we will conduct sensitivity analyses within sub-groups defined by use of specific drugs, or combinations of drugs. For example, the sub-group of patients who received, or did not receive linezolid, or delamanid, or bedaquiline, or carbapenems, as part of a long regimen. If any of the subgroup analyses result in <100 patients being included in the analysis population, we will not conduct analyses. We will further conduct a sensitivity analysis repeating the approach in section 5.1.1 for other new or repurposed drugs: delamanid, linezolid, and carbapenems.


Secondary Analysis (Comparing to IPDinMDR – 2019 or EndTB Data Sets)

Secondary Analysis Question 1

Relative to people in the IPDinMDR – 2019 data set receiving a regimen lasting ≥18 months without the use of new TB drugs (e.g. does not contain bedaquiline, linezolid, delamanid, or carbapenems), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes?

Intervention: All-Oral Short Bedaquiline-Containing Regimen 9–12 months in duration Comparator: Long Regimen Without New TB Drugs

Approach

We will utilize the same approach as described in section 5.1.1 to compare outcomes among people receiving the intervention and comparator regimens. Recall that we will only include people from the IPDinMDR – 2019 data set who began treatment from the year 2013 onward and who were treated in an upper-middle income country. We will conduct a sensitivity analysis relaxing the criteria for country-level income and report the outcomes.


Relative to people in the IPDinMDR – 2019 data set receiving a regimen lasting ≥18 months with new TB drugs (e.g. contains bedaquiline), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes?


Approach

We will utilize the same approach as described in section 5.1.1 to compare outcomes among people receiving the intervention and comparator regimens. Recall that we will only include people from the IPDinMDR – 2019 data set who began treatment from the year 2013 onward and who were treated in an upper-middle income country. We will conduct a sensitivity analysis relaxing the criteria for country-level income and report the outcomes.

If there are enough patients, we will conduct further sensitivity analyses within sub-groups defined by use of specific drugs, or combinations of drugs. For example, the sub-group of patients who received, or did not receive linezolid, or clofazimine, or delamanid, or bedaquiline, or carbapenems, as part of a long regimen. If any of the subgroup analyses result in <100 patients being included in the analysis population, we will not conduct analyses. We will further conduct a sensitivity analysis repeating the approach in section 5.1.1 for other new or repurposed drugs: delamanid, linezolid, and carbapenems.


Relative to people in the EndTB data set receiving a regimen lasting ≥18 months with bedaquiline and/or delamanid (for a maximum of 6-months), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes?


Approach

We will utilize the same approach as described in section 5.1.1 to compare outcomes among people receiving the intervention and comparator regimens. Recall that we will only include people from the EndTB observational study data set who began treatment from the year 2013 onward and who


were treated in an upper-middle income country. We will conduct a sensitivity analysis relaxing the criteria for country-level income and report the outcomes.

As all patients in EndTB observational study data set received bedaquiline and/or delamanid, we will conduct further sensitivity analyses within sub-groups defined by use of these specific drugs. These will include patients who received, or did not receive, bedaquiline, or delamanid, or both bedaquiline and delamanid. If any of the subgroup analyses result in <100 patients being included in the analysis population, we will not conduct analyses.

Limitations

Within the South Africa cohorts, drug resistance testing is reflexive and generally relies solely on genotypic drug resistance tests: Xpert MTB/RIF for rifampicin and line probe assays for isoniazid and rifampicin (GenoType MTBDRplus) and fluoroquinolones and second-line injectables (GenoType MTBDRsl). Because of this, resistance to drugs commonly used in short regimens (pyrazinamide, clofazimine, ethambutol, and ethionamide/prothionamide) is likely not available for most patients. As we are matching patients exactly on previous treatment history and pre-XDR/XDR phenotypes are excluded (as they would not be eligible for a short-regimen), we expect these unknown resistances to be similar between the groups being compared.

We do not have chest radiographic results at baseline which may have influenced a clinician’s decision to treat patient with a short or long regimen. Hence this must be considered an unmeasured confounder.

Adverse events and acquisition (or amplification) of drug resistance are not reported in the South Africa cohorts, so analyses of these important outcomes are not possible.

Co-morbidities of diabetes, mental health disorders, and others are not routinely captured within EDRWeb, so the potential impact of these disorders on treatment outcomes cannot be analyzed. Extrapulmonary TB is not included in the IPDinMDR – 2019 data set and represents only 2% of patients receiving a short regimen in a previous extract of EDRWeb, so they cannot be analyzed as a subgroup as well. However bacteriologic confirmation of cure or failure/relapse is rarely obtained, which makes analysis of these outcomes more subject to observer bias. And, in drug sensitive TB results of RCT in pulmonary TB have been successfully applied to treatment of extra-pulmonary TB.


A6.1.2: PICO question 2: In XDR-TB patients or patients who are treatment intolerant or with non-responsive MDR-TB, does a treatment regimen lasting 6-9 months composed of bedaquiline, pretomanid and linezolid safely improve outcomes when compared with other regimens conforming to WHO guidelines?

Comparative analysis of outcomes and safety between current XDR-TB treatments and a new regimen of bedaquiline, pretomanid, and linezolid.

Statistical Analysis Plan, Draft. Prepared by Dick Menzies, Nicholas Winters and Jonathon Campbell, McGill University.

PICO Question (WHO):

In XDR-TB patients or patients who are treatment intolerant or with non-responsive MDR-TB, does a treatment regimen lasting 6–9 months composed of bedaquiline, pretomanid and linezolid safely improve outcomes when compared with other regimens conforming to current WHO guidelines?


XDR/TB patients or and/ or those who are treatment intolerant or with non-responsive MDR-TB:a. with additional drug resistance patternsb. with severe disease (i.e. cavitary disease on radiography or SS+)c. previously treated with 2nd line drugs or not persons with HIV (+/- ARVs)d. adults (adolescents 10–19y if available)e. With comorbidities (e.g. diabetes mellitus; malnutrition; mental disorders)

– Nix-TB trial regimen containing bedaquiline, pretomanid and linezolid given for 6 to 9 months

– Using matched controls from the individual patient dataset (*current WHO recommendations)[1]





• Survival (or death)• Adverse reactions from anti-TB medicines


Research Questions:

1. Do patients receiving BPaL have the same or better outcomes 24 months post treatment start compared to patients receiving non-pretomanid regimens containing BDQ/LZD, with total duration of treatment of 24 months (within an allowed range of 22.5 to 25.5 months)

2. Do patients receiving BPaL have the same or better outcomes 18 months post treatment start compared to patients receiving non-pretomanid regimens containing BDQ/LZD for with total duration of treatment of 18 months (within an allowed range of 17 to 19 months – see Page 6)


3. What is the occurrence of Grade 3–5 adverse events (AE), serious AE, and AE resulting in permanent discontinuation of at least one of the three component drugs of the Nix-TB regimen. (This is descriptive only, and ideally these rates of AE would be compared to rates with a WHO recommended BDQ/LZD containing regimen, but the comparator would have to come from a data set with equally careful and thorough ascertainment of treatment associated AEs.)

Rationale:

Despite global advances in controlling Tuberculosis (TB), this remains one of the most important communicable diseases in the world, accounting for an estimated 10 million cases and 1.6 million deaths in 2017 [WHO TB Report 2018]. Treatment of drug sensitive TB is highly effective in randomized controlled trials, however, treatment is much less effective for drug resistant strains of TB, particularly multidrug resistant TB (MDR-TB), defined as TB that is resistant to both rifampicin (Rif ) and Isoniazid (INH). As TB strains become more resistant, the treatment is increasingly difficult. MDR-TB patients with additional resistance to at least one fluoroquinolone and one second-line injectable, termed extensively drug resistant TB (XDR-TB), are an increasing public health concern. There were an estimated 600,000 cases of MDR-TB in 2016, of which approximately 6.2% were XDR-TB [WHO TB report 2018].

Currently, for treatment of XDR-TB the WHO recommends the use of at least five drugs in the intensive phase and four in the continuation phase, with durations ranging from 18–24 months. In the XDR-TB patients notified to the WHO in 2015, only 34% completed treatment and 26% died. These poor outcomes are in large part due to a lack of novel drugs, as well as lengthy treatment duration and frequent drug toxicity that result in low adherence. In order to combat XDR-TB and prevent possible devastating epidemics, new drugs as well as shorter regimens that increase the likelihood of adherence are needed.

A novel, all-oral, treatment regimen consisting of bedaquiline, pretomanid and linezolid (BPaL) for 6 months has been assessed in an open-label trial. However, the trial had no comparison group. To adequately assess the efficacy and safety of this new regimen in the context of current XDR-TB treatment, it is essential to compare outcomes in NIX-TB trial patients with similar patients who received different regimens. To do this we plan to use an individual patient dataset, contributed over the past 3 years by more than 55 centres. This data now includes more than 13,000 patients with MDR and more than 3,000 patients with pre-XDR and XDR TB.

Data Sources:

Intervention group: the Nix-TB study was a one arm, phase 3, open labeled trial assessing the safety and efficacy of BPaL in patients > 14 years of age with confirmed sputum culture-positive XDR-TB or treatment intolerant/non-responsive MDR-TB. The trial was conducted between 2014 and 2019 in South Africa. The data from this trial that will be used in our analyses includes, but is not limited to: age, sex, race, medical history (BMI, diabetes, alcohol), TB treatment history, AFB smear microscopy results, Gene Xpert results, HIV and ART use, chest x-ray results, sputum culture result, patient reported severity of TB symptoms and health status, hematology/CBC/FBC, clinical chemistry, urinalysis, DST results (phenotypic), adverse events (AE) and serious AE based on DMID severity scale.

Control or comparison group: Patients included in an individual patient data meta-analysis (IPD-MA) study, that included MDR/XDR-TB patients from 53 studies/centres in 40 countries. The included patients began treatment between 1993 and 2016, but we will select patients treated after BDQ was approved for treatment of MDR-TB in 2013 (of the XDR or pre-XDR patients there were 1007 on Bdq and 956 on Lzd). These patients will be matched to patients in the Nix-TB trial, on the basis of patients’ characteristics, DST, drugs used, and other factors that will affect treatment propensity (described in detail below).


Regimens:

Intervention: The Nix-TB regimen consists of bedaquiline (Bdq, at a 400 mg once daily for 2 weeks then 200 mg 3 times per week), pretomanid (200 mg once daily) and linezolid (Lzd, at a daily dose of 1200 mg/day) for 6–9 months (9 months if sputum culture positive at 4 months). These patients were followed for up to 24 months after treatment end.

Comparison (control): 4 comparator regimens will be assessed. Patients receiving regimens for up to 25.5 months (Q1) or 19.0 months (Q2) that contained:

Bdq plus Lzd plus other anti-TB drugs, Bdq plus others, Lzd plus others, Neither Bdq nor Lzd, but other drugs.

No patients in the IPD received pretomanid. In the Nix-TB trial there are treatment start and stop dates, and in the MDR IPD we have precise total/planned treatment duration until outcome. Thus, analyses will be conducted comparing patients in both regimens from time of treatment start to outcome or end of the specified analytical duration.

The regimens used in the IPD-MA for XDR-TB are significantly longer than the 6–9mo BPaL regimen in the Nix-TB study. This will present difficulties in comparing end-of-treatment outcomes, particularly failure and death. Patients treated with the conventional longer regimens have a much longer time during which they could die (of TB or other causes) or fail. Patients treated with conventional 18 or 24 months regimens may have sputum culture conversion at 6 months, but later revert to culture positivity. If treatment had been only 6 months, they would have been considered a ‘cure’, and then a relapse. Similarly, if a patient dies in the 15th month of conventional XDR treatment, that is, by definition a ‘death during treatment’ whereas if the regimen had been only 6 or 9 months, this would not have been a death during treatment. It is therefore necessary to assess outcomes from treatment start to a specified duration of time where after any events that occur in the comparator groups are censored, as diagramed below (Tx = treatment). Therefore in our analyses of treatment outcomes, all relapses or deaths (regardless of cause) occurring post-treatment in NIX-TB patients, up to 25.5 months (Question 1) or up to 19.0 months (Question 2) post treatment start, will be considered to have the outcomes of failure/relapse, or death and considered equivalent to “during treatment” failure or deaths with conventional regimens.

Tx start

Comparator Tx end

6months 18months 24months

BPaL Tx end

Duration used in analysis

Question 1

BPaL

Comparator

BPaL

Comparator

Tx start

ComparatorTx end

6months 18months 24months

BPaL Tx end

Duration used in analysis

Question 2

Censored (excluded)


Outcome Definitions:

The PICO lists seven distinct outcomes: (i) Successful completion of treatment, (ii) Bacteriological cure by end of treatment, (iii) Adherence to treatment (or treatment interruption due to non-adherence); (iv) Treatment failure or relapse, (v) Death during treatment, (vi) Adverse reactions from anti-TB medicines, and, (vii) Acquisition (amplification) of drug resistance

In the analyses, we will combine failure and relapse, and also combine completion and cure as success. We will estimate odds of relapse free treatment success vs several combinations of poor outcomes, and also examine LTFU vs other outcomes – as summarized below.

Adverse reactions from anti-TB medicines, and Acquisition of drug resistance during treatment can NOT be analyzed using the IPD data as this information is not routinely captured in many data sets. These two outcomes were measured in the NixTB study carefully, so can be described. As discussed below a different source of comparator data would be ideal. This has been discussed and agreed upon in principle by investigators with the EndTB and the Alliance, and is now described briefly in the sensitivity analyses.

The outcomes are defined in the Nix-TB protocol as follows:

Bacteriologic failure: during the treatment period = failure to attain culture conversion to negative; bacteriologic relapse: during the follow-up period = failure to maintain culture conversion to negative status in culture, with culture conversion to positive status with a Mycobacterium tuberculosis (M.tb.) strain that is genetically identical to the infecting strain at baseline;

Clinical failure: a change from protocol-specified TB treatment due to treatment failure, retreatment for TB during follow up, or TB-related death.

In the IPD cohorts treatment outcomes were defined according to the WHO guidelines, summarized below:

WHO 2005 (Laserson) Outcome Definitions (44/53 studies in our IPD used these definitions or definitions based on bacteriologic criteria)

Outcome Definition

Cure Completed treatment according to program protocol and has at least five consecutive negative cultures from samples collected at least 30 days apart in the final 12 months of treatment. If only one positive culture is reported during that time, and there is no concomitant clinical evidence of deterioration, a patient may still be considered cured, provided that this positive culture is followed by a minimum of three consecutive negative cultures taken at least 30 days apart.

Complete Completed treatment according to program protocol but does not meet the definition for cure because of lack of bacteriological results (i.e. fewer than five cultures were performed in the final 12 months of treatment).

Failure Treatment will be considered to have failed if two or more of the five cultures recorded in the final 12 months of therapy are positive, or if any one of the final three cultures is positive. (Treatment will also be considered to have failed if a clinical decision has been made to terminate treatment early because of poor clinical or radiological response or adverse events).

Death A patient who dies for any reason during the course of MDR/RR-TB treatment

Lost to Follow-up A patient whose treatment was interrupted for two or more consecutive months for any reason without medical approval.


WHO 2013 Outcome Definitions: 9/53 studies in our IPD used these definitions

Outcome Definition

Cure Treatment completed as recommended by the national policy without evidence of failure AND three or more consecutive cultures taken at least 30 days apart are negative after the intensive phase (or Month 8 if no intensive phase).

Complete Treatment completed as recommended by the national policy without evidence of failure BUT no record that three or more consecutive cultures taken at least 30 days apart are negative after the intensive phase (or Month 8 if no intensive phase).

Failure Treatment terminated or need for permanent regimen change of at least two anti-TB drugs because of: (1) lack of conversion by the end of the intensive phase, or (2) bacteriological reversion in the continuation phase after conversion to negative, or (3) evidence of additional acquired resistance to fluoroquinolones or second-line injectable drugs, or (4) adverse drug reactions.

Death A patient who dies for any reason during the course of treatment

Lost to Follow-up A patient whose treatment was interrupted for 2 consecutive months or more.

For our analysis, we will use different outcome definitions for patients in the Nix-TB trial from patients in the IPD-2019. For Nix-TB, the detailed clinical and microbiologic data will be used to verify the investigator defined end-of-treatment outcomes. Assuming they match their definition outlined in their protocol, we will use their investigator defined end-of-treatment outcomes, plus account for relapse during up to 18 months of post-treatment follow-up. For the EOT outcomes in the IPD-2019, we will use the investigator defined outcomes as well. In the data set we have now, 44/53 data sets used 2005 WHO guidelines to define these outcomes, and 9/53 stated they used WHO2013, but all data sets contained sufficient information to verify that almost all patients met microbiologic outcome definitions (ie fit WHO2005). Therefore we have already redefined the outcomes of the nine studies that used the 2013 guidelines to conform to the 2005 WHO criteria. In summary, within the IPD-2019 data set, we will verify investigator defined outcomes, reclassify if applicable to meet microbiologic criteria (WHO 2005 criteria) and compare these end-of treatment outcomes in the analysis to the NixTB investigator defined outcomes (including relapse as above). The coding of all information from the Nix-TB study will be verified with Alliance staff, and all discordant outcomes will also be verified manually (ie if a specific patient is classified as having treatment success in the original data set but does not meet that definition using the data we have – this will be manually checked)

Analytic approach:

Descriptive statistics:

Treatment outcomes: as described above, the treatment outcomes assigned to patients in the NixTB trial will be reclassified (potentially) according to WHO 2005 definitions, using the detailed clinical and microbiological information available from the Alliance. The concordance of these outcome swill be verified as a first step. Any discordance will be verified manually and the data and programming may also be verified with the Alliance.

Duration: As the treatment trajectory of MDR/RR-TB represents the complex interaction of patient, provider and health system capacities and constraints, there may be deviations from intended durations of therapy and number of drugs used. In the IPD data, we will examine descriptively the


distribution of treatment duration for persons with successful treatment who received one of the four comparator regimens. Based on these descriptive analyses, we will select cut-points (ideally using inter-modal points) that appear to best define the duration of treatment that can be called ‘18 months’ and ’24 months’ (e.g. how far before or after the exact duration of 18 or 24 months do we accept as still meeting the definition of a regimen of 18 or 24 months to include in this analysis?). A second issue is the planned duration in persons who die, or are lost to follow-up (‘default’), or fail and therapy is stopped early. These patients will not have an actual treatment duration of 18 or 24 months, but of course must be included in the analyses to avoid bias. To identify persons with these outcomes we will use the planned duration (listed in many data sets). In some data sets planned duration is not given. In these we will examine the frequency distribution of duration in those patients treated successfully at the same centres. If this is unimodal, then the mode will be considered the planned duration. If this is a more complex distribution then we will predict the duration based on key predictors of duration (age, extent of resistance, extent of disease and specific drugs used) at that centre.

Patient populations Before analysis of each research question, we will conduct a descriptive analysis for the BPal and four comparator groups (detailed below), looking at key characteristics including: age (continuous and 0–14 vs. 14+ and 10–19 vs. 19+), sex, previous treatment history (drugs received and outcome), baseline acid-fast bacilli smear result, number of drugs received during treatment, total number and type of drugs resistant to (not double-counting ‘similar ’ drugs of ethionamide/prothionamide and cycloserine/terizidone, for example), presence of specific drugs in the regimens (e.g. bedaquiline, linezolid, clofazimine, moxifloxacin/levofloxacin, delamanid), and country of treatment. This will help clarify if there are systematic differences between the people who received each regimen, and possible differences in characteristics and outcomes where each regimen was used. The information elicited from this analysis will be used to inform further variables for matching and/or adjustment described below, and addition of a random-effect for country of treatment (or exact matching by country). Thus, within the approach for each question, the listed variables are an a priori list for inclusion, but may be modified based on data completeness and availability, and further sensitivity analyses including/excluding other variables may be developed based on the results of the descriptive analyses. The descriptive analysis is also intended to determine how many individuals would be included, and excluded due to regimen composition. In addition, for non-Nix-TB patients we will include the number of drugs received during treatment and presence of specific drugs in the regimens (e.g. Bdq, Lzd, clofazimine, moxifloxacin/levofloxacin, delamanid).

Comparing efficacy of regimens::

Q1: Do patients receiving BPaL have the same or better outcomes 24 months post treatment start compared to patients receiving one of 4 comparator non-pretomanid containing regimens, with total duration of treatment of 24 months (within an allowed range of 22.5 to 25.5 months). These four comparators are: (1) Bdq+Lzd+others, (2) Bdq+others, (3) Lzd+others, and (4) neither Bdq or Lzd containing regimens.

Comparisons:

1. Relapse free treatment success (defined as cure or treatment completion) vs. bacteriological/clinical failure or relapse.

2. Relapse free treatment success vs. death

3. Relapse free treatment success vs. clinical/bacteriological failure or relapse, or death.

4. Relapse free treatment success vs. clinical/bacteriological failure or death or relapse or lost to follow-up/default.

Our approach will use a combination of exact matching and propensity score-based matching on several covariates to select comparator groups from the IPD-MA that are as comparable as possible to the patients who received BPal, and thereby minimize bias and confounding. All patient matching


will be performed by an algorithm in our statistical software that will randomly select from the best patient matches. This algorithm will not include outcome. The variables used for exact matching will depend on the distribution of characteristics in the Nix-TB data and will be finalized once we are able to explore this in detail. For exact matching, we anticipate matching on two variables we consider critical: (1) XDR vs non-responsive/intolerant MDR-TB; and, (2) HIV infection and ART-use. Once we have matched on these two critical variables, we intend to further match exactly, if possible, based on the following important variables: (3) number of drugs to which the patient’s isolate is resistant, and, (4) previous FLD/SLD use, and if the data allows, also (5) disease severity (indicated by one of: AFB smear, cavitary and/or Bilateral disease),. These variables will ensure that patients with clinical profiles which predict their treatment outcomes will be compared. There may be issues with identifying patients in the IPD cohort who have non-responsive/intolerant MDR-TB. If so, we will select IPD patients who have previous SLD use. In addition, we will match patients based on PS, calculated using age, sex, and remaining variables of the three important variables listed above which could not be used for exact matching (AFB smear, Cavitation, number of drugs resistant to, etc). We will allow a calliper distance equal to 0.2 of the standard deviation of the logit of the propensity score. Matching will be done with replacement. If no potential matches fall within the calliper distance, the next closest match to 0.2 of the standard deviation will be selected. We will assess the success of matching by assessing the balance of confounders between the two groups. Additionally, we will determine how many patients were matched more than once to different patients in Nix-TB. This will indicate the need for consideration of methods to control for the effects of independence and increased variance on model fit, from having multiple matches.

The power of this analysis is limited by the small number of patients in the NixTB study. To enhance power, we will match up to 4 controls from the IPD to each Nix-TB patient, depending on whether there are sufficient numbers of suitable matches to each NixTB patient (Four is considered the optimal number to enhance power, after which little added power is gained by matching further controls).

For each outcome, we will conduct logistic regression using mixed-models including random-intercepts for each matched ‘pair ’ and, depending on what we find for the descriptive analysis, for country of treatment. We will not include random-slopes as our experience is that there are significant convergence issues when these random-effects are also included. Outcomes will be dichotomous (i.e. the outcome occurred during the specified analysis duration = 1 vs. the outcome not occurring = 0). The logistic regression analysis will calculate adjusted odds ratios and associated 95% confidence intervals. We will further conduct binomial regression, using fixed effects, on the ‘matched’ group to calculate adjusted risk differences and their associated 95% confidence intervals.

For post-treatment relapse, we will first determine in which data sets of IPD-2019 this outcome was assessed. Then we will obtain information from the study authors on the methods of ascertainment, the intensity of follow-up visits, and the duration of follow-up. This will give us an idea of the comparability of this outcome with that of the NixTB study. In addition duration of follow-up and timimg of relapse may not be available for all individuals or centres. Therefore we will present cumulative incidence of relapse in each study as the proportion of patients relapsing out of the total number of patients that succssfully completed treatment.

This analysis will be repeated for each of the four comparisons listed above.

Q2: Do patients receiving BPaL have the same or better outcomes 18 months post treatment start compared to patients receiving non-pretomanid regimens containing BDQ/LZD for with total duration of treatment of 18 months (within an allowed range of 17 to 19 months)

We will use the same methods outlined in Q1, except that duration used in the analyses will be 18 months, and any event occurring in post treatment follow-up of the BPal group after this period will be censored.


Q3: Descriptive analysis of the occurrence of Grade 3–5 adverse events (AE), serious AE, and AE resulting in permanent discontinuation of at least one of the three component drugs of the Nix-TB regimen. Three separate but related outcomes.

We will describe the occurrence of any of the secondary outcomes listed above to present results on the safety related measures recorded in the Nix-TB data. Permanent discontinuation of each component drug of the BPaL regimen will be analysed, and the stoppage of one drug but continuation of the others will be considered a drug associated AE for the drug that was stopped. In addition, we will also investigate the effects of dose reduction. We will use proportions or mean (standard deviations) where appropriate. This will not be compared to any of the comparator groups in our IPD listed above.

Comparator: As noted earlier, this safety analysis is limited by the lack of an adequate comparator population, as AE’s were not ascertained with the same methods in the IPD-MA studies. Ideally these rates of AE would be compared to rates with a WHO recommended BDQ/LZD containing regimen, but the comparator would have to come from a data set with equally careful and thorough ascertainment of treatment associated AEs. The only data set to which we have access with comparable methods of systematically assessing AEs is the EndTB data set. We suggest that the AEs’ reported – in patients who received one of the 4 types of regimens listed above in the EndTb study, would be compared with the AEs reported in NixTB. Note that this suggestion would require the agreement of the EndTB investigators as well as the Alliance)

Sensitivity analyses:

We will conduct the same analyses outlined in Q1 and 2 using different subpopulations of patients to select comparators:

(1) Match patients in the Nix-TB trial to patients in IPD-2019, using ONLY South African cohorts. By limiting to South African cohorts, we will match to patients from the same region, which may account for unique characteristics of the patient populations.

(2) Match patients in the Nix-TB trial to patients who received treatment ONLY in high income countries. This may result in a better match on the basis of resources available for follow-up.

(3) Limit comparisons to patients from studies where relapse was ascertained for at least 6 months of follow-up post treatment end. We will contact authors from these studies to obtain any additional information re definition and methods for ascertainment for relapse.

(4) to compare AE between Nix-TB and a suitable comparator group, we need to ensure we have patient populations that are comparable, but also that AE are ascertained in a similar way. In the IPD-2019 we did not have systematic methods to detect, define, investigate manage or report AEs. Thus, we will match patients in the Nix-TB trial to those from the EndTB data, as AE were collected and documented with similar intensity of monitoring to Nix-TB.

Limitations:

There may have been substantial selection bias into the Nix-TB trial, as there was no randomization. Hence participation could have been influenced by physician selection of patients judged better able to tolerate the regimen, or that were sicker, with fewer treatment options (i.e. selection bias could go either way). There is also the potential for bias in the comparison of patients in NixTB with the IPD patients due to differences in loss to follow up. We can lessen, but not eliminate the impact of these biases, by exact and propensity score matching patients in the Nix-TB study to patients in the MDR IPD. This matching should result in patient groups that are balanced with respect to measured confounding factors, which should enhance clinical utility of the results. There may also be limitations in achieving four exact matches on all variables for each NixTB patient. This is why we have listed variables in order of their importance, and PS matching on the same variables will be used if exact


matching cannot be achieved. In addition, we will use PS matching with a wider caliper distance to achieve matching, if necessary.

Additionally, as noted above, the data on safety is limited in our IPD, and so we will be unable to compare the secondary safety outcomes between patients in NixTB and the IPD.

Relapse was not measured systematically in most studies included in the IPD-2019. Hence this may have been under-estimated. As well for patients treated for 24 months, they finish treatment at the same time as post treatment follow-up ends for the NIXTB patients. So to include post-treatment follow-up will bias results as different lengths of Follow-up can lead to differences in outcomes due to other events. Relapse can be measured for 6 months if treatment is only 18 months, but early relapse rates tend to be highest – so this may overestimate cumulative relapse rates.

Sept 6, 2019


A6.1.3: PICO questions 3: In MDR/RR-TB patients, does a treatment regimen containing bedaquiline for more than six months safely improve outcomes when compared with bedaquiline for up to six months as part of longer regimens otherwise conforming to WHO guidelines? and 4: In MDR/RR-TB patients, does concurrent use of bedaquiline and delamanid safely improve outcomes when compared with other treatment regimen options otherwise conforming to WHO guidelines?

Statistical Analysis Plan (draft) for PICO 3 & 4 using the EndTB observational study and the IPD2019 data: prepared by Dick Menzies & Jonathon Campbell, McGill University: Sept. 6, 2019

WHO Guidelines group – PICO questions

Question 3. In MDR/RR-TB patients, does treatment with bedaquiline for more than six months safely improve outcomes when compared with treatment up to six months as part of regimens otherwise conforming to current WHO guidelines?

Population Intervention Comparator Outcome

MDR/RR-TB patients:a. Simple MDR-TB (no additional resistance, risk factors)-b. with additional drug resistance patterns, but not XDRc. with XDR-TBd. with severe disease (i.e. cavitary disease on radiography or SS+)e. previously treated with 2nd line drugs or notf. children (0–14y) / adults (adolescents 10–19y if available)g. persons with HIV (+/- ARVs)h. pregnant womeni. people with diabetes mellitus j. extrapulmonary diseasek. malnutrition

- Use of bedaquiline as part of the treatment regimen beyond six months of treatment

- A regimen containing bedaquiline for six months of treatment only





• Survival (or death)• Adverse events with anti-TB medicines



(PICO 3) Effectiveness of prolongation of bedaquiline beyond 24 weeks:

Three specific questions – related to use of different information sources

1. Relative to bedaquiline (BDQ) use for 24 weeks (6 months), does prolongation of bedaquiline beyond 24 weeks (within properly designed regimens) result in improved treatment outcomes for patients with RR-TB in the EndTB observational study?

2. In the IPD-2019 data set, are treatment outcomes improved in patients who take more than 6 months of BDQ compared to BDQ for 6 months, and to no BDQ?

3. In the combined IPD-2019 and EndTB data sets, are treatment outcomes improved in patients who take more than 6 months of BDQ compared to BDQ for 6 months, and to no BDQ?

Five Outcomes of interest for the Proposed Analyses:

End of treatment:

1. Relapse free treatment success (or simply success, if relapse not assessed) vs fail/relapse

2. Relapse free treatment success (or simply success if relapse not assessed) vs fail/relapse/death

3. Relapse free treatment success (or simply success if relapse not assessed) vs death alone

4. Relapse free treatment success (or simply success if relapse not assessed) vs fail/relapse/death/LTFU (i.e. good vs all bad combined)

During therapy:

5. Adverse events (AE) – defined as serious AEs that resulted in permanent discontinuation of that medication.

• This information is available in considerable detail in the EndTB data following the MSF severity scale – definitions provided at the end of the document. It is less consistently available [~8000 patients in 30 datasets] and defined as grade 3–5 or serious AE that resulted in permanent discontinuation of that medication and may be differentially ascertained in the IPD2019. This may confound comparisons of AE rates – particularly for drugs that are used more, or less in the two datasets.

• If permission granted from all parties, we will also compare AE in EndTB data set with AE detected in NixTB study. These two studies had more comparable intensity of AE detection, although different definitions, and methods for AE.

N.B. Adherence (as % doses taken or other measure) is available in the EndTB data set, but not the IPD2019. Thus, this will only be described for the EndTB data set.

DATA SETS to be used in PICO 3 analyses:

IPD2019

In 2018 an IPD was assembled of 53 data sets from 40 countries/regions containing records for 13,000 patients with MDR-TB. This IPD-2018 data set was analyzed to answer a number of PICO questions developed by a WHO MDR-TB guidelines development group (GdG). These guidelines have since been published. This IPD-2018 was itself was based on an IPD data set assembled in 2016–17 to answer questions of a GdG of the CDC/ATS/IDSA/ERS. These guidelines have not yet been published, but the analyses that informed this set of guidelines were published in the Lancet in Sept 2018.

Hence the IPD-2019 represents an update of the IPD-2018. We anticipate adding data from one national surveillance programs – in South Africa. We will delete the previous records of patients treated in the EndTB observational study, that were included in the IPD-2018, to avoid duplication and overlap with the new data set from EndTB. We may also add two other data sets – provided in response to a public call for data contributions.


EndTB:

1094 patients with MDR-TB were treated with bedaquiline- and/or delamanid-containing regimens between 1 April 2015 and 31 March 2017. They were followed as part of an observational study – executed by three NGO’s – PIH, MSF and IRD.

Rationale

Why the question of optimal duration of BDQ is challenging.

There are several important potential sources of bias in analysis of duration of therapy in observational studies. We note 2 examples here:

i) Patients who live longer on RR-TB treatment can be treated longer with bedaquiline. Simply comparing the outcomes among people who survive to receive the longer treatment to those who didn’t receive the longer treatment can result in an overestimate of the benefits of the longer treatment. This bias is called “immortal time bias”.

ii) Bedaquiline prolongation varied by patient factors and by country and time. Bedaquiline was prolonged most often in patients with baseline and on-treatment risk factors for poor outcome, i.e., patients whose initial response to treatment was poor, whose regimens without bedaquiline were considered weak, or whose resistance profile or treatment-emergent toxicities limited treatment options. Simply comparing the outcomes among people who got prolonged bedaquiline to those who did not could underestimate the benefits of prolonged bedaquiline. This bias is called (time-varying) confounding by indication.

In the EndTB study, across countries and over time, the use of prolonged bedaquiline varied. Some countries prolonged bedaquiline in nearly all patients, while in other countries, bedaquiline prolongation was not permitted by national guidance. At other sites, bedaquiline prolongation became more common over time as clinicians became more comfortable with the drug.

It’s important to acknowledge the focus on bedaquiline (and delamanid) duration is exceptional, as other drugs (i.e. linezolid) have analogous issues in that people can receive them longer if they don’t experience treatment-limiting toxicity, which in linezolid’s case is ~1 in 5 people. Thus, while the analysis approach that we propose attempts to minimize many sources of bias, we acknowledge it may not be possible to manage all biases.

Defining ‘margins’ in duration analyses:

Since start dates and end-dates of specific drugs are available in the EndTB dataset the duration can be defined to the precise number of days. But, in reality, the precise duration depends on timing of visits, and events such as missed visits, cancelled clinics, holidays or even just bad weather can result in variation of up to a month around the time when a specific drug is stopped. Hence we will first define a frequency distribution of duration for BDQ, in order to define the optimal cut-points for each duration. As an example, from recent analysis of one data set – the frequency of actual duration in days of one drug is plotted (see Annex 1). This plot shows a large number of persons with duration centred around 6 months, but we would conclude that for our purposes “6 months” duration should include patients with duration of 150 to 200 days.

Therefore, in this SAP when we refer to duration of “24 weeks”, or “36 weeks”, or “52 weeks” we mean N weeks + NN weeks, with the value of NN to be determined from the initial descriptive analysis.

Challenges in comparing results using the EndTB data, and the IPD2019 data:

There are several important potential differences between the patient populations, treatment, and other factors between these two sources of individual patient data.


i) The EndTB study was conducted by agencies and at centres with different patient populations, as well as resources and clinical expertise, from those in the IPD-2019. The IPD-2019 contains data from a greater variety of settings including samples of patients included in national MDR surveillance systems. Hence outcomes may be different in the IPD data-set – independent of measured clinical and treatment characteristics due to unmeasured confounding. While for some datasets in the IPD there may also be differences in outcomes, we will quantify differences between the IPD and EndTB descriptively. As we have done in the past, mixed models will be used to account for heterogeneity between datasets.

ii) There is a perception that the EndTB sites have more complicated patients who have comorbidities and other challenges (homelessness, hx of incarceration, IV drug and alcohol use) that make developing an effective regimen especially difficult;

iii) the extent and quality of data, particularly on-treatment, longitudinal observations; follow-up for recurrent disease (ie for relapse);

iv) methods for collection and reporting of safety data;

v) extent of prolongation of Bdq;

vi) In the EndTB data set all patients received DLM or BDQ or both. But none got neither of these drugs – in contrast to large numbers of patients in the IPD data set who received neither. If DLM is very effective, this could substantially affect comparisons of the no BDQ group in the IPD2019 cohort to the no BDQ group in the EndTB data set since all these patients received DLM. We will, therefore, control for exposure to DLM in all analyses.

vii) overall willingness to use Bdq/Dlm;

viii) outcome classification.

Some of these differences are sources of variability within the IPD as well (e.g., bdq use, outcome classification, safety, etc). However, the IPD2019 data set includes data from over 13,000 patients, treated in 53 studies in 40 countries/regions. The diversity of patients, disease, providers, and treatments provides an excellent opportunity to compare and contrast treatment related covariates in very different settings and should result in more generalizable findings.

The results from Questions 1 and 2 will see if the effect of bedaquiline use beyond six-months is similar in EndTB and the IPD, after accounting for numerous possible confounders. Any confounding effect of DLM will be managed by controlling for delamanid in all analyses. The analysis for Question 3 will analyze the benefit of BDQ for 6 months, vs longer vs a group that did not receive BDQ while adjusting for use of delamanid as well as the data source or study (ie EndTB or IPD2019) and other covariates. In other words, in this analysis the reference group (comparator) will be the group who received BDQ for 6 months. While the IPD2019 data set has important limitations, compared to the EndTB data set, we believe there are important advantages of conducting the analyses of BDQ duration using both the IPD2019 data set and the EndTB dataset. These advantages include the greater diversity of settings and patients in which this question can be addressed – enhancing the generalizability of results. As well the diversity of settings increases the likelihood of diversity in patients receiving longer duration of BDQ – potentially reducing unmeasured confounding relative to actual differences in detectable treatment benefits. Finally, this should increase the number of patients who received any single regimen/combination of medications/duration of BDQ, so simply enhancing power.


Overview of the analyses for the three specific Questions (end of treatment outcomes)

Q1: Relative to bedaquiline (BDQ) cessation at 24 weeks, does prolongation of bedaquiline result in improved treatment outcomes for patients with RR-TB in the EndTB observational study?

Comparator: use of bedaquiline for 24 weeks in EndTB

Intervention: use of bedaquiline for >24 weeks in EndTB

Sensitivity analysis comparator: use of bedaquiline for 24–36 weeks in EndTB

Sensitivity analysis Intervention: use of bedaquiline for >36 weeks in EndTB

Defining a Time Cut-Off for Bedaquiline Use

As discussed above, it seems likely that BDQ use will not be precisely 24 weeks in many patients, due to the vagaries of dates of visits, drug supply, delays in starting, or stopping, or missed doses. We want to know, as best as we can, if 6 months, or 9 months is planned – what, in reality is the duration? If we restricted analysis to those who got exactly 180 or 270 days – we would have about 20 people. So, we need to account for some variation in actual duration. Hence, we propose to examine the frequency distribution of duration of BDQ to attempt to find ‘inter-modal’ cut-points that best discriminate patients treated with BDQ for ’24 weeks’, or 36 weeks, or 52 weeks. ONLY TO DEFINE THIS CUT-POINT, we will exclude patients who died or were lost to follow-up to ensure that the population assessed are only those who could have received the drug to this point. This will also be done for the sensitivity analysis population. It should be recognized that any selected timepoint will necessarily dichotomize some patients who received only a few days difference of bedaquiline treatment, however by selecting the inter-modal points, this problem should be minimized. The rest of this plan below is written assuming 24 weeks is selected but will be adjusted based on our findings here and may represent a range (e.g., 20–26 weeks of bedaquiline).

Step 1: Descriptive Analysis of the Population Subgroups

We will then undertake descriptive analysis to characterize those who did not receive BDQ, those who received BDQ for at least one month, but <6 months, and those who received at least 24 weeks – divided into two groups: (BDQ for 24 weeks; and BDQ for >24 weeks). We will also sub-divide the group with BDQ for >24 weeks into persons who were treated with BDQ for 24–36 weeks, and those who received BDQ for >36 weeks. The description will include: site where treated, baseline/pre-treatment characteristics: sex, age, HIV and ART treatment, other comorbidities, prior TB treatment, AFB smear, CXR results, DST results (both in terms of resistance patterns and total number of drugs resistant to), year of starting treatment, and number of likely effective drugs used initially. Consideration of the total number of drugs resistant warrants further explanation. It is possible that for drugs with DST that is perceived to be unreliable (e.g. cycloserine, PAS), in the event they were found susceptible, they were reinforced, or in the event they were found resistant, the drug was used anyways. Likewise, there may be reasons some drugs had DST done on them, perhaps due to previous exposure or a regimen was failing. Thus, for these reasons it is important to consider the total number of drugs a patient is resistant to, as well, the more drugs a person is resistant to, the more limited treatment options are, and the more probable it is that bedaquiline is extended. So, we plan to adjust for this covariate in statistical analysis. Because of this, we propose to count the number of drugs individuals are resistant to drugs other than fluoroquinolones and second-line injectables (which will be accounted for in the composite resistance pattern of MDR, pre-XDR, and XDR) – we will assume cross-resistance to similar drugs (e.g. ethionamide and prothionamide or cycloserine and terizidone, or amikacin and kanamycin – unless there is DST for both drugs). There are also sensitivity analyses surrounding this, detailed in the appropriate section below. We are also interested in events during treatment that would affect clinical decisions at the time points of interest – meaning at 6, 9 and 12 months. These would include: culture and DST results indicating any newly detected drug resistance from cultures


of samples collected prior to the end of week 16 (we assume that at the time of the 6-months evaluation, that cultures and DST would be available only for samples collected prior to weeks 16 and 12 respectively. We would examine AFB smear and CXR results from 24 weeks, as well as number of drugs permanently stopped due to intolerance / AEs up to 24 weeks – all of which information would be available at the 6-month evaluation and could be indications for extension of BDQ. This descriptive analysis will be further stratified by site to determine if there are unique site characteristics. We will further describe exact resistance patterns of all drugs (Resistant, Susceptible, Not Done/Unknown) to see how common testing was and prevalent resistances were when testing was done. We will repeat the descriptive analysis using appropriate time-points for the proposed sensitivity analysis.

Step 2: Exploring the use of delamanid – descriptively

In the same way as bedaquiline, we will descriptively examine the characteristics of people who received delamanid (no BDQ) or did not receive delamanid, and compare those to patients who received DLM and BDQ and to patients who received BDQ alone. One issue that will be explored is whether delamanid was used from the start, or introduced after, since many patients received DLM after several months of therapy. This raises the possibility of indication bias, since those who had DLM added are likely to have been responding poorly, but on the other hand, also immortal time bias since patients had to survive longer to have a chance of later introduction of delamanid. (This is where separate analyses of failure, and death may be especially helpful). Thus we will describe median (IQR) time of delamanid start after treatment start and also how many started within 0–3 months, 4–6 months, 7–9 months, or 9+ months after treatment start. We will also look at these characteristics by site, as policies regarding use may vary between sites, and could be an important potential determinant of use. We will examine whether characteristics of patients was ‘balanced’ between the treatment groups as defined above. Even if there is no evidence of substantial confounding of patient characteristics with DLM use, we will consider delamanid as a unique drug given and adjust for its use in the multivariable analyses described below (like LZD or later generation FQN, for example).

Step 3: Analysis of duration of BDQ

To assess the benefit of bedaquiline extension beyond 24 weeks, we plan two analytical methods and will compare the results. We will do this for each of the four outcomes defined above each method will be repeated for sensitivity analysis.

Method 1: Exact and Propensity score matching. Patient characteristics at baseline that are missing will be imputed using multivariate imputation via chained equations. Note – exposure and outcome data will never be imputed. We will match persons who received bedaquiline for 24 weeks to those who received it longer using a combination of exact and propensity score based matching for covariates that are likely to influence treatment extension at week 24. These covariates include: Baseline characteristics: Resistance to FQ or SLI, total Number of drugs resistant to, AFB smear, Cavitation on CXR, HIV-coinfection and ART use, previous treatment history (first-line drugs only or also second-line), age and sex. During-treatment characteristics: culture status at 12 and 16 weeks (ie culture conversion or non-conversion), number of acquired/new resistances at 16 weeks (0, 1, or 2+), cumulative number of drugs stopped due to adverse events at week 24 (0,1 or 2+), radiologic findings at week 24, treatment at Week 24 including use of receipt of fluoroquinolone, linezolid, and delamanid and number of other likely effective medications. As we have done in past analyses, we attempt to match exactly on as many covariates as possible (recognizing that within the EndTB data set this may be challenging), and propensity score match on the remainder. The covariates selected for exact matching are those with strongest association with the outcomes of interest for that analysis. We will propensity score match on the remaining covariates listed above. We again will consider clustering by site and further adjustment by year of treatment start and/or country level income. We will estimate adjusted odds ratios and associated 95% CI. For each analysis, the matched groups will be examined in standard reports looking at the improvement (or not) in balance of characteristics between the two groups from the matching algorithm.


Method 2: Survival Analysis using inverse probability of treatment weighting (IPTW) and inverse probability of censor weighting (IPCW). The survival analysis will begin with everyone included in the analysis population who received treatment with bedaquiline for at least six months (i.e., baseline=month 6). We will examine exposure in two ways. (1) Dichotomous: received only six-months of BDQ vs. received more than six-months of BDQ; (2) Continuous: treating months of BDQ beyond six as a continuous variable. The outcome of interest will be failure/relapse/death (composite). We will treat loss to follow-up as a censoring event. We will include patient time until the end of follow-up for relapse. We will construct a baseline patient profile based on what would be clinically known at month 6, including time-fixed covariates of age, sex, previous treatment history, etc. From here, we will update information each month for patients that is time-varying: receipt of concomitant drugs (type and number), number of AE requiring drugs to be stopped, culture status, radiologic findings. Using these time-fixed and time-varying covariates, we will estimate the IPCW for the population (i.e., for LTFU). We will also estimate the IPTW based on timing of BDQ stop (i.e, for people stopping BDQ at month 6, IPTW will be estimated for all time points; for people continuing to receive BDQ beyond month 6, IPTW will be estimated until the time of BDQ stop, then considered constant). We will then run a survival analysis, clustering by patients and centre and incorporating the calculated IPCW and IPTW weights. This analysis will be run for both dichotomous and continuous outcome. For the continuous outcome, please see sensitivity analyses where we consider the benefit of bedaquiline to be non-linear and we describe alternate analytic methods to be explored (e.g. g-formula).

Q2: In IPD-2019 data set, are treatment outcomes improved in patients who take more than 6 months of BDQ compared to no BDQ and BDQ for 6 months?

Exposure 1: No use of Bedaquiline (defined as <30 days) in IPD2019

Reference (comparator) 1: Use of bedaquiline for 24 weeks in IPD2019 (exact duration based on descriptive analysis as in Q1).

Exposure 2: Use of bedaquiline for >24 weeks in IPD2019 (exact duration based on descriptive analysis as in Q1).

We propose three analyses: No BDQ to 24 weeks, and 24 weeks to BDQ to >24 weeks, plus a combined – where BDQ use is a 3-level categorical variable (none, 24 weeks, and >24 weeks). Since this is all within IPD2019 – We propose to match patients exactly on the baseline characteristics of fluoroquinolone and second line injectable resistance, HIV co-infection and ART use, and country-level income (using World Bank categories). We will match patients further using propensity score matching on age, sex, previous TB treatment (first line and second line drugs), extent of disease (AFB smear and/or cavitation on CXR), use of linezolid, use of fluoroquinolones, use of delamanid, BMI (dichotomized as underweight or not), and number of other effective drugs used in the initial regimen. Because of limitations of lack of detailed information about changes and events during therapy, we cannot include these variables in this analysis.

Q3: In the combined IPD-2019 and EndTB data sets, are treatment outcomes improved in patients who take more than 6 months of BDQ compared to no BDQ and BDQ for 6 months?

Exposure 1: No use of Bedaquiline (defined as <30 days) in IPD2019

Reference (comparator) 1: Use of bedaquiline for 24 weeks in IPD2019 (exact duration considered 24 weeks based on descriptive analysis as in Q1).

Exposure 2: Use of bedaquiline for >24 weeks EndTB and in IPD2019

In the analysis strategy deployed, the “exposure” will be BDQ use for 24 weeks or >24 weeks, as treatment in the combined data set of EndTB and IPD2019. The comparator will be BDQ use for <30


days in IPD2019. Our analytic approach will follow the same approach as described in Q2 comparing the reference to exposure 1 and exposure 2, and when comparing exposure 1 to exposure 2.

Outcome 5: Analysis of adverse events:

The analysis plan for adverse events is made somewhat difficult by the fact that we are not yet certain of the data available from the EndTB study. In the IPD2019 we have information on type of adverse events, and the drug considered responsible by the treating team, as well as whether that drug was permanently stopped – in 30 studies with >8000 patients. We did not have much information on the severity of the AE (i.e. few studies provided information on the Grade), so the analysis was simply the cumulative percent of patients who received at least 1 month of the drug, and the drug was stopped permanently because of an AE, as well as type of AE in most of these studies. Using this we calculated a proportion stopping each drug in each study.

We propose to try three approaches to analyze the occurrence of AE. First, we will perform standard aggregate data meta-analysis for proportions. The estimated proportion of patients within each cohort in whom each specific drug was stopped permanently (out of all patients in the cohort receiving that drug) because of an AE ( AE incidence) . Then AE proportion for each drug from each cohort will be estimated using generalized linear mixed model with random effects at cohort level using the “metaprop” function within R package “meta”, then pooled using standard aggregate data random effects meta-analysis. To address the PICO question, we will sub-divide each cohort into ‘comparator = 6 months BDQ’ and ‘intervention = BDQ longer’. This analysis will be conducted without adjustment for confounders, then we will assess the relationship of covariates (especially age, sex, HIV status, and extent of disease indicators) to AE, and repeat the analysis with adjustment for these confounders.

Second, we can perform an arm-based network meta-analysis using the “nma.ab.bin” function within R package “pcnetmeta” (ref ). In this approach, drugs not used in a study or cohort will be considered as missing at random. The use of a multivariate Bayesian mixed model allows estimation of the population averaged treatment specific event proportions. This model will account for the correlation between different treatments within each cohort as compared to the above approach that estimated drug-specific event proportions based solely on cohorts that used the particular drug. Absolute risk of AE for each drug will be estimated using a random effects model within the Bayesian framework, and the median value with 95% credible interval and mean value with standard deviation reported.

A third approach is to use a ranking-based non-parametric method, as this should more accurately assess the relative toxicity of shorter and longer BDQ vs other drugs in different studies (i.e. if comparing AE in IPD2019 and EndTB. In the first step, within each cohort the drugs used were ranked in the order of observed AE incidence of each drug, from one to N (representing the total number of distinct drugs prescribed). If more than one drug was stopped, they received a proportion of a point (e.g. if two drugs stopped 0.5, if three drugs stopped 0.33, etc.) Note that ‘incidence’ refers to cumulative incidence in the IPD2019 – as we may not have adequate information on drug duration, so we have used the proportion who stopped among those who received the drug for at least 1 month. If two or more drugs had the same AE incidence in a study, the drugs were assigned tied ranks. Next, the raw ranks were adjusted by the maximum distinct number of drugs of all cohorts. In a third step, the unweighted average rank for each drug was calculated across all cohorts using the drug, with equal weight ascribed to each cohort. The weighted average rank for each drug will be estimated in the same way except a weight will be assigned for each cohort based on the number of patients using the drug in that cohort; however, cohorts with large sample size will have a dominant influence on the average ranks; therefore, the unweighted ranking will be considered the primary approach. For this PICO, we will assess the ranking of BDQ in those who received BDQ for 6 months (reference or comparator), vs more than 6 months. A change in ranking would imply greater or lesser AE in the intervention group. An improved AE ranking might suggest selection – since those who tolerate a drug are more likely to continue it.


Limitations (PICO 3 analysis)

As noted above, patients may receive prolonged bedaquiline, because they were sicker, or had fewer treatment options (AE, or more resistance ). Indeed, information from the investigators indicates that all EndTB countries initiated BDQ use in the patients with the worst MDRTB and the least treatment options – many after prior treatment failures. Early in the EndTB project, countries were very conservative to use BDQ therefore it was included only when cases were desperate and late in the treatment. Second, across countries and over time, the use of prolonged bedaquiline may have varied. However, this is in fact an advantage, as some differences in bedaquiline prescription and duration may have had less to do with patient characteristics, and more to do with local policy, physicians’ beliefs, and BDQ availability – creating a quasi-experimental situation – with less confounding due to patient characteristics. We will use two methods to control for confounding; however, we will not be able to completely control all possible confounding, especially unmeasured confounding. But we expect that if unmeasured confounding is related to indication, then this will act to underestimate the benefit of bedaquiline if sicker patients or those with fewer effective drugs are more likely to receive prolonged bedaquiline.

Potential Sensitivity analyses

1. Analyses repeated but accounting for missed doses (due to non-adherence) from the 24 weeks of initial bedaquiline exposure in EndTB.

2. Assess time to loss-to FU/dropout/default, inpatients who take no BDQ, 6 months BDQ and >6 months BDQ. Compare time to LTFU in EndTB and IPD2019 in same sub-groups based on BDQ duration.

3. Examine whether the effect of prolongation depends on specific other drugs used in the treatment regimen (eg, Dlm, clofazimine, PZA or cycloserine).

4. Assess whether Bdq prolongation is more effective than no Bdq prolongation in patients with an indication for prolongation, i.e., patients whose regimen would be compromised if Bdq were withdrawn (resistance, toxicity, culture positivity, etc). It’s very possible that Bdq prolongation is not helpful in patients who don’t need it after 6 months. Including these patients in an analysis of effectiveness of Bdq prolongation could underestimate the contribution of prolongation. To analyze the effect of prolongation in those who need prolongation would require establishing the risk group based on patient characteristics after 6 months of Bdq, not only those at baseline.

5. For Question 1, Method 2: We will consider modelling time non-linearly using a spline or by including a second quadratic term for duration. Further, we will also use g-formula to calculate the expected probabilities of our outcome, which would reduce biases introduced due to people surviving longer can receive bedaquiline longer. Finally, we will consider LTFU an outcome, and not a censoring event, since LTFU may be due to undetected, clinically important reasons of long duration and/or toxicity.

6. For Question 1: We will not consider the number of drugs a person is resistant to, but instead consider drugs with perceived unreliable DST (notably E, Z, PAS, Eto/Pto, Cs/Trd) as (a) susceptible regardless of result and (b) resistant regardless of result.

7. For AE: Compare frequency of specific drug related AE in EndTB and NixTB studies.

Adverse Event Definitions in EndTB

EndTB AEs are classified using severity grades 1–5 according to the MSF severity scale. They use the commonly-accepted (ICH-GCP among others) criteria to classify events as serious: results in death; is life-threatening (places the subject at immediate risk of death from the event as it occurred); results in inpatient hospitalization or prolongation of existing hospitalization; results in a persistent or significant disability/incapacity; results in a congenital anomaly/birth defect; or is otherwise medically significant: based upon appropriate medical judgment, may jeopardize the subject’s health and may require medical or surgical intervention to prevent one of the other outcomes listed in this definition.

http://endtb.org/sites/default/files/2016-12/PV-TB-D12%20-%20TB%20Severity%20Grading%20Scale_version%205.0_14Nov2016.xls


Question 4. In MDR/RR-TB patients, does concomitant use of bedaquiline and delamanid safely improve outcomes when compared with other treatment options in regimens otherwise conforming to current WHO guidelines?


MDR/RR-TB patients a. with additional drug resistance patternsb. with XDR-TBc. with severe disease (i.e. cavitary disease on radiography or SS+)d. previously treated with 2nd line drugs or note. children (0–14y) / adults (adolescents 10–19y if available)f. persons with HIV (+/- ARVs)g. pregnant womenh. people with diabetes mellitus i. extrapulmonary diseasej. malnutrition

– Concomitant use of bedaquiline and delamanid, given for six months of treatment

– A regimen without concomitant use of bedaquiline and delamanid for six months of treatment





• Survival (or death)• Adverse events with anti-TB medicines


(PICO 4) Adding Delamanid to bedaquiline: specific questions

1. In the EndTB data set are treatment outcomes improved with concomitant use of BDQ and DLM compared to use of BDQ without DLM (in addition to other components of an adequate MDR regimen)?

2. In the combined IPD-2019 and EndTB data sets, are treatment outcomes improved with concomitant use of BDQ and DLM compared to use of other treatment options?

Challenges in this analysis:

In the EndTB study, DLM use varied between sites, and may have been started at beginning, or given later in therapy, even given as ‘salvage therapy’. If added later, DLM may have been added because of local or individual preference/protocol, or based on response to therapy to that point. Hence, we will begin this analysis with a careful descriptive analysis (as described above as Step 2 for PICO 3) – comparing those who received DLM to those who did not – separately within the EndTB data set. We will also perform the same descriptive analyses for the IPD2019 (where same problems likely applied). This will include an assessment of timing of DLM start, and duration of use.

Study population/data sources (PICO 4):

IPD-2019.

In 2018 an IPD was assembled of 53 data sets from 40 countries/regions containing records for 13,000 patients with MDR-TB. This IPD-2018 data set was analyzed to answer a number of PICO questions developed by a WHO MDR-TB guidelines development group (GdG). These guidelines have since been published. This IPD-2018 was itself was based on an IPD data set assembled in 2016–17 to answer questions of a GdG of the CDC/ATS/IDSA/ERS. These guidelines have not yet been published, but the analyses that informed this set of guidelines were published in the Lancet in Sept 2018.


Hence the IPD-2019 represents an update of the IPD-2018. We anticipate adding data from one national surveillance programs – in South Africa. We will delete the previous records of patients treated in the EndTB observational study, that were included in the IPD-2018, to avoid duplication and overlap with the new data set from EndTB. We may also add two other data sets – provided in response to a public call for data contributions.

EndTB:

1094 patients with MDR-TB were treated with bedaquiline- and/or delamanid-containing regimens between 1 April 2015 and 31 March 2017. They were followed as part of an observational study – executed by three NGO’s – PIH, MSF and IRD.

Approach

As with PICO 3, the approach here will have the same outcomes. We will again observe the distribution of ‘duration’ for people receiving BDQ and DLM to define cut-points to call the duration six-months. We will perform the same descriptive analyses described in Question 1 of PICO 3 for the intervention population receiving BDQ and DLM to six months and perform the same statistical analyses comparing it to the comparator populations of (1) people who received only Bdq; (2) people who received only Dlm; (3) people who received BDQ and Dlm for <6 months and; (4) people who received BDQ and Dlm for more than 6 months. We will limit analyses within EndTB as this data set is the only one with enough detail to adequate control for the numerous time-varying confounders that may influence which patients fell into the intervention group or one of the four comparator groups.

Limitations – PICO 4

Many of the same limitations apply to PICO 4 as PICO 3, except that in addition there were fewer patients treated – in IPD2019 or end-TB data sets – limiting ability to match on key confounding covariates and limiting power as well to detect small benefits (or harms). In addition, there may have been even greater selection biases (and immortal time bias) affecting estimates of effect of DLM on outcomes.

A6.2 WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2018 updateRefer to Annex 10: Summaries of unpublished data and analysis plans used for the recommendations in the WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2018 update (https://www.who.int/tb/areas-of-work/drug-resistant-tb/Annexes_8-10.pdf, accessed 2 March 2019).

A6.3 Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 updateRefer to Annex 5: Reports of the systematic reviews (reports on systematic reviews for: adherence interventions in tuberculosis treatment and decentralized treatment and care for multidrug-resistant tuberculosis patients) in the Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update (https://www.who.int/tb/publications/2017/dstb_guidance_2017/en/, accessed 2 March 2019). The systematic reviews have subsequently been published (37,38)

who consolidated guidelines on tuberculosis · 2020. 6. 24. · who consolidated guidelines on...

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