the public health approach to reduce the burden of...
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The public health approach to reduce the burden of advanced HIV disease:
WHO recommendations
Po-Lin Chan/Nathan FordWorld Health Organisation
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Background and rationale
• A significant proportion of patients continue to present with advanced HIV disease
• People starting ART with advanced HIV disease have high mortality particularly in first six months following ART initiation
• Major causes of death include co-infections such as TB, severe bacterial infections, cryptococcal meningitis
• WHO guidelines include individual recommendations for diagnosis, prophylaxis and treatment
• Recent studies have assessed the potential for an enhanced package of interventions to reduce mortality/morbidity
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Why are people still dying from HIV?
7,5
19,5
1,91
0
5
10
15
20
25
2011 2012 2013 2014 2015 2016
Number on ART
Number of deaths
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For adults and adolescents, and children older than five years, advanced HIV disease is defined as CD4 cell count <200cells/mm3 or WHO stage 3 or 4 event.
Includes both ART naïve individuals and those who interrupt treatment and return to care
All children younger than five years old with HIV are considered as having advanced HIV disease.
WHO definition of advanced HIV disease
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IeDEA-COHERE: Results based on 951 855 adults from 55 countries after imputation of missing dataDoes not include “re-starters” after interruption
In 2015,37% of people
starting ART did so at CD4 cell count <200 cells/mm3
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Carmona S et al, CID 2018
IeDEA and COHERE, CID 2017
Proportion presenting with low CD4 cell count has not changed
Persistent challenge of advanced HIV disease
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Causes of mortality
Ford et al, Lancet HIV 2016
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Need to target the right OI..
Osler et al, CID 2018
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Packaged interventions for reducing mortality among patients with advanced
HIV disease
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Key study characteristics
REALITY(enhanced prophylaxis)
REMSTART(enhanced OI screening &
adherence)
Study countries Kenya, Malawi, Uganda, Zimbabwe Tanzania, Zambia
Sample size and design study 1805 individuals (open label) 1999 individuals (open label)
Eligibility criteria and population CD4 < 100 ( PLHIV ≥ 5 yrs old) CD4 < 200 (PLHIV ≥ 18 yrs old)
Main outcome Mortality reduction at 6 and 12 mo Mortality reduction at 12 mo
Rapid ART initiation✓
CrAg screening test✓
Adherence support visits x 4 weeks✓
CTX/isoniazid/B6 daily x 12 weeks ✓ ✓
Fluconazole 100mg daily x 12 weeks✓ ✓
Azithromycin 500 mg daily x 5 days✓ ✓
Albendazole 400 mg x single dose ✓ ✓
Costing analysis✓ ✓
Cost effectiveness analysis✓
1 TB screening with GenXpert at baseline included in both arms of the study , re-screening at 6 weeks in intervention arm :TB cases only asssessed in interventiongroup2 ART intensification (RAL) x 4 weeks and food supplementation x 12 weeks, not included a s part of the PICO question but assessed in the factorial analysis and discounted.
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Outcomes
• 28% reduced death• Improved adherence
at 6 months• 27% reduced death• Reductions in
incident morbidity• Reductions in
hospitalization
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BEN
EFIT
S &
HA
RM
S
BENEFITS HARMS• Reduced all-cause mortality • Potential for antimicrobial resistance
-azithromycin
• Reduced incident morbidity• New TB disease• New cryptococcal disease
• Potential for antifungal resistance -fluconazole 100mg
• Reduced (or unchanged) new hospitalisations
• Potential increased absolute cost to health services
• Simplified package consistent with public health approach
• Simplified package may reduce attention to other important comorbidities/co-infections
• Promotes increased attention to advanced disease
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A package of interventions including screening, treatment and/or prophylaxis for major opportunistic infections, rapid ART initiation* and intensified adherence support interventions should be offered to everyone presenting with advanced HIV disease.
Strong recommendation, moderate-quality evidence
WHO Recommendation
* linked recommendation
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WHO, 2017
Package of care for people with advanced HIV disease
Diagnosis Prophylaxis ART initiation Adapted adherence support
XPERT MTB/RIF as first test for TB
Cotrimoxazoleprophylaxis
Rapid ART initiation
Tailoredcounselling to support adherence
LF-LAM for TB diagnosis among peoplewith signs and symptoms
TB preventive treatment
Defer if clinicalsymptomssuggest TB or cryptoccalmeningitis
Cryptococcalantigen screening
Fluconazolepre-emptive therapy
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WHO, 2017
INH/B6/CTX scored FDC, Half doses if <12 years
Diagnosis Prophylaxis ART initiation Adapted adherence support
XPERT MTB/RIF as first test for TB
Cotrimoxazoleprophylaxis
Rapid ART initiation
Tailoredcounselling to support adherence
LF-LAM for TB diagnosis among people with signs and symptoms
TB preventive treatment
Defer if clinicalsymptomssuggest TB or cryptoccalmeningitis
Cryptococcalantigen screening
Fluconazolepre-emptive therapy
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- Diagnosis- Prevention and screening- Treatment (1 week Ampho B + Flucytosine)- (non) use of corticosteroids- Timing of ART
Shorter induction treatment = better outcomes
WHO guidelines for cryptococcal disease
WHO 2018; Molloy et al, NEJM 15 March 2018
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• The role of presumptive treatment in managing TB, Pneumocystis jirovecii pneumonia, severe bacterial infections and cryptococcal disease should be considered in settings in which access to diagnostic tests is limited and people present with typical signs and symptoms (especially when accompanied by clinical signs indicating severe illness)
• The WHO algorithm for managing people with HIV who are suspected of having TB and are seriously ill incorporates presumptive treatment of TB, bacterial infections and Pneumocystis jirovecii pneumonia into the care pathway
Considerations
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Advanced HIV disease: a renewed focus
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Guideline Development Group
Co-chairs: Alexandra Calmy (Hôpitaux Universitaires de Genève, Switzerland) and Graeme Meintjes (University of Cape Town, South Africa).
Eduardo Arathoon (Asociacion de Salud Integral, Guatemala), Patricia Asero (International Community of Women Living with HIV, Kenya), Rosa Bologna (Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Argentina), Mohamed Chakroun(Fattouma Bourguiba Teaching Hospital, Tunisia), Lucia Chambal (Ministry of Health, Mozambique), Tom Chiller (MycoticDisease Branch, United States Centers for Disease Control and Prevention, USA), Francesca Conradie (University of the Witwatersrand, South Africa), Serge Eholie (Centre Hospitalier Universitaire de Treichville, Côte d’Ivoire), Lisa Frigati(Tygerberg Hospital and Stellenbosch University, South Africa), Diana Gibb (Medical Research Council, United Kingdom), Eric Goemaere (Médecins Sans Frontières, South Africa), Nelesh Govender (University of the Witwatersrand and National Institute for Communicable Diseases, South Africa), Alison Grant (London School of Hygiene and Tropical Medicine, United Kingdom), Nagalingeswaran Kumarasamy (YRGCARE, India), David Lalloo (Liverpool School of Tropical Medicine, United Kingdom), Thuy Le (Oxford University Clinical Research Unit, Viet Nam), Emilio Letang (Barcelona Institute for Global Health and Ifakara Health Institute, Spain), Dorothy Mbori-Ngacha (UNICEF, Kenya), Sayoki Mfinanga (Muhimbili Medical Research Centre, National Institute for Medical Research, United Republic of Tanzania), Mathieu Nacher (Université de Guyane, French Guiana), Muhayimpundu Ribakare (Rwanda Biomedical Centre, Rwanda), Kenly Sikwese (African Community Advisory Board, Zambia), Nini Tun (Medical Action Myanmar, Myanmar), Jose E. Vidal (Instituto de Infectologia Emílio Ribas and Universidade de São Paulo, Brazil)
External Review Group
Xavier Anglaret (Inserm – French National Institute of Health and Medical Research, France), Moherndran Archary (King Edward VIII Hospital, South Africa) Moses Bateganya (United States Centers for Disease Control and Prevention, USA), David Boulware (University of Minnesota, Uganda), Sergio Carmona (National Health Laboratory Services, South Africa) Marcelo Freitas (ICAP, Mozambique), Beatriz Grinstejn (Fundação Oswaldo Cruz, Brazil), Joseph Jarvis (London School of Hygiene and Tropical Medicine, United Kingdom and Botswana Harvard AIDS Institute Partnership, Botswana), David Meya(Makerere University, Kampala, Uganda), Eyerusalem Negussie (Ministry of Health, Ethiopia), Daniel O’Brien (BarwonHealth, Australia), Heather Paulin (United States Centers for Disease Control and Prevention, USA), Andy Prendergast (Queen Mary University of London, United Kingdom), George Siberry (Office for the US Global AIDS Coordinator, USA), and Evy Yunihastuti (Faculty of Medicine, Universitas Indonesia, Indonesia)
WHO
Nathan Ford and Marco Vitoria (HIV Department, WHO) coordinated the overall guideline development process with support from Chantal Migone (HIV Department, WHO), under the leadership of Meg Doherty and Gottfried Hirnschall(HIV Department, WHO). Helen Bygrave (independent consultant, United Kingdom) wrote the guideline document withNathan Ford
Acknowledgements