DIAGNOSIS & MANAGEMENT OF TB IN RNTCP

DR. RAJESH N.SOLANKI MD, FNCCP

PROFESSOR,DEPARTMENT OF TB & CHEST DISEASES,B.J.MEDICAL COLLEGE & CIVIL HOSPITAL,

AHMEDABAD.

NODAL OFFICER-STATE DOTS PLUS COMMITTEE, GUJARATMember, National DOTS Plus Committee, GOI

Member, National Air Borne Infection Control Committee, GOI

DIAGNOSTIC APPROACH

• Constitutional or generalized symptoms due to tuberculous toxemia: Low grade evening rise fever, anorexia, weight loss (slow & progressive), digestive disturbances, night sweats, fatiguability, weakness etc.

• Pulmonary : Cough w or w/o Expectoration, shortness of breath, hemoptysis, chest pain.

• Extra-pulmonary : Symptoms and signs as per affected system.

CARDINAL SYMPTOM: Cough for 2 weeks or more

BACTERIOLOGICAL DIAGNOSIS1) SMEAR - Examination

2) FNAC – from Lymph nodes, Abscesses

3) Biopsy - Incisional or Excisional biopsy

Biopsy is more reliable.

Radiological Diagnosis

• Difficult to interpret active or inactive lesions

• Atypical presentation of HIV-TB co-infection

• Inter and intra observer variation

• Co-morbid respiratory illness

• Expert radiologists always demand for

clinical, bacteriological and serological

correlation.

TB of organs other than lungs confirmed by bacteriological

Or

Histopathological confirmation

Or

Radiological evidence

Or

Strong clinical evidence

Extra pulmonary TB

How to Diagnose EPTB

• Clinical Evaluation

• Radiological

• Histo-pathological

• Bacteriological

• Serological

• Biochemical Markers

Diagnosis of Paediatric TB

• TB suspected if, the child has– Fever and/or

cough for more than three weeks

– With or without weight loss or no weight gain

– History of contact with a suspected or diagnosed case of active TB in the last two years

DIAGNOSTIC METHODS (LABORATORY ASPECTS)

• SOLID CULTURE: L J MEDIA, “Gold Standard” for Culture

• LIQUID CULTURE: BACTEC, “Gold Standard” for DST

• MOLECULAR TECHNIQUE: PCR BASED

• MICROSCOPIC OBSEVATION OF DRUG SUSCEPTIBILITY (MODS)

• ADDITIONAL MODELITIES

-SEROLOGICAL MARKERS -GAMMA INTERFERRON -PIEZO ELECTRIC SENSOR -HRCT AND CECT

• A number of rapid assays have been developed where rifampicin resistance is used for presumptive diagnosis for MDR-TB.

The rapid tests have decreased the time for diagnosing MDR-TB - L-J culture : 3-4 months - MGIT {currently the gold-standard for (DST)} : 3 to 4 weeks - FAST Plaque-Response : 2 days - Nucleic acid amplification technology : 8 hours or less - GenoType® MDRTB plus - INNO-LIPA Rif. TB

• Three tests have proven efficacy and are commercially available, 1. INNO-LIPA Rif.TB kit (Innogenetics, Zwijndrecht, Belgium), 2. Geno Type® MDRTB plus assay (Hain’s Life science, GMBH,

Germany). 3. FAST Plaque-Response test (Biotec Ltd, UK).

RAPID DIAGNOSIS

Reducing diagnostic delay in RNTCP DOTS-Plus

Projected time to DST results by assay

0 20 40 60 80

LJ culture/DST

MGITculture/DST

MODS directDST

Molecular DST

Days

Specimen collection/delivery (7d)

Processing (1d)

Initial culture

DST

Return results (3d)

The new rapid assays have proven efficacy under controlled laboratory conditions, but available information about effectiveness under programmatic settings is on going at various places

Information from the programmatic implementation of the test is required to

-confirm the performance of the test in these settings,

-Indicate how the test may be best applied and confirm the benefits (including financial) from implementation,

-Identify constraints on implementation.

RAPID DIAGNOSIS

Projects in Pipeline – FIND (India)Product Sites

Evaluation1. Cellestis St. John’s Research Institute,

Bangalore

2. Cepheid & Capilia TB Hinduja Hospital, Mumbai

3. Eiken LAMP assay JALMA Institute, Agra

Demonstration1. MGIT DST & MTB Speciation by Capilia

LRS Institute, Delhi; STDC Ahmedabad; STDC Hyderabad

2. HAIN’S TEST- MTBDR plus STDC Ahmedabad; STDC Hyderabad; SMS Medical College, Jaipur; GHTM Thambaram; AIIMS; TRC Chennai

3. LED Fluorescence microscope CMC Vellore; other sites to be identified

• M.tb grows rapidly in liquid culture

– 15 days to obtain growth in liquid

• Inhibitors need to be added to reduce growth of commensals

• Liquid culture is more sensitive than solid culture

• BSL level III and it requires Negative pressure system

MGIT 960 uses fluorochrome tubes, which glow on depletion of oxygen, whereas MB/BacT detects CO2 production

MGIT 960 approved by US FDA for culture & DST

Liquid culture (approved by WHO 2007)

MOLECULAR DIAGNOSIS

• REAL TIME PCR

• MULTIPLEX PCR WITH ADDED ADVANTAGE (LPA- HAIN’S TEST)

• TRANSCRIPTION MEDIATED AMPLIFICATION

• DETECTION BY SEQUENCING

MTBDR plus assay (Line Probe Assay)

• Multiplex PCR DNA strip assay.

• It is designed to detect mutant conferring H and R resistance.

• Result within 8 hours.

• rpo B, kat G and inh A.

• For effectiveness and utility (EP), Confirmation of accuracy (DP) required.

DNA EXTRACTION

Master-Mix (Pre PCR) room

Amplification

Hybridization

GeneXpertGeneXpert

Automated Sample Prep, Automated Sample Prep,

Amplification and DetectionAmplification and Detection

<120 minutes

High tech in low tech settings: XpertHigh tech in low tech settings: XpertTMTM MTB MTB

A technology platform:A technology platform:

TB & Rif ResistanceTB & Rif Resistance

Potential for HIV viral Potential for HIV viral loadload

Potential for …Potential for …

Challenges downstream:Meeting the target price

2008 2009 2010

DevelopmentDemonstration

in 15 microscopy centers AccessSTAGEvaluation in 5 trial sites

MTB / Rif-resistance test

Major advantages in workflow

• fully automated with 1-step external sample prep. • time-to-result 1 1/2 h (walk away test)• throughput: up to 16 tests / module / run• no bio-safety cabinet• closed system (no contamination risk)

Performance

• specific for MTB• sensitivity similar to culture• detection of rif-resistance via rpoB gene

cartridgeMTB

Integrated automated NAAT: Cepheid

TRANSCRIPTION MEDIATED AMPLIFICATION

• It is based on RNA amplification.

• Very rapid

• Highly sensitive

• Further studies required for smear negative cases & Extra Pulmonary TB

• Not recommended for the non-respiratory specimens.

Methods

(N=139)

Respiratory Sp.

(N=94)

Non-Resp. SP

(N=45)

L J method

Positive 64 (68%) 28 (62%)

Negative 30 (32%) 17 (38%)

TB-BACTEC

Positive 74 (79%) 29 (64%)

Negative 20 (21%) 16 (36%)

TMA

Positive 75 (80%) 27 (60%)

Negative 19 (20%) 18 (40%)

Phage Assay (n=84) Resp. Sp. (44) Non-Resp. Sp. (40)

Positive 32 (73%) 25 (63%)

Negative 12 (27%) 15 (37%)

Results of Different Methods –P D Hinduja National Hospital and Medical Research Centre, Mumbai

SERO DIAGNOSISSEROLOGY

Antibody detection ( IgG, IgM, IgA )Antigen detection Immune complex Assays

METHODS

RadioimmunoassayEnzyme link Immuno Sorbant Assay.Agglutination Test Immunodiffusion Test.Monoclonal Antibodies

SEROLOGY: TB

• IDEAL:INFECTION Vs DISEASE• SENSITIVITY: Variable (30% to 65%)• SPECIFICITY : Variable (20% to 48%)• Can not asses Diseases Severity• No values in MONITORING & PROGNOSIS• CLINICAL INTERPRETATION: PUO with sero-positive

value ??• No proper study suggestive of cut of value –pos/neg• Only supportive value in Initial Diagnosis in NSN or EP

TB

BIOCHEMICAL MARKERS

• Fluid/Pus Analysis :- pleural, pericardial, ascitic, CSF, Synovial, Abscess

- Protein level - Glucose level - TC and DC - ADA - LDH - Fluid smear for AFB and Culture

• TUBERCULINE TEST: up to 40% adults are infected with TB infection,

GAMMA INTERFERON

• LTBI – It detects accurately latent Tuberculosis infection with high sensitivity and specificity.

• The Tb specific antigens, early secretary antigenic target 6(ESAT6) and culture filtrate protein 10 (CFP10), encoded by genes located within the region of difference segment of the M. tuberculosis genome are specific to TB.

GAMMA INTERFERON • It detects CMI response to TB infection.• TB specific antigen stimulates T-cells within a

patient's whole blood sample• If previously exposed to M.Tuberculosis T-cells

will secrete the cytokine interferon-gamma into the plasma

• Measured by ELISA to indicate the likelihood of TB infection. ( Value > 0.35 IU/ml)

GAMMA INTERFERON

• Useful in HIV infected individuals, childhood TB and Extra Pulmonary TB.

LIMITATIONS

• Storage time : < 16 hours and temperature 220c +/- 50c

• M. kansasii, M. marinum and M.szulgai infections may show positivity.

MODS ASSAY FOR DIAGONOSIS OF TB

• Microscopic Observation Drug Susceptibility (MODS) culture for the diagnosis and direct detection of MDR-TB.

• It is faster and more sensitive than gold standard techniques.

• It is inexpensive and more appropriate for the countries with limited resources.

• A disadvantage is that requirement of inverted microscope which is not routinely available.

PIEZOELECTRIC IMMUNOSENSOR

• A piezoelectric immunosensor was developed for detecting M.tuberculosis.

• It is based on modified protein A and its specific binding with the antibodies.

• It is rapid, sensitive, specific and inexpensive and can be easily set up in every public-health laboratory.

• This sensor was stable and reusable.• The study for immunosensor was carried out at

Hunan university, Changhsa; results were good.

Fengjiao He et al. ;2002:China

Symptoms

Smear - 60%

LJ - 40d

LED +10% LAMP+25% Xpert +40%

AG/AB

SensitivitySensitivity

Time to responseTime to response

Point of carePoint of care

Molecular

MGIT 15d MTBDR+ 1d

Enose

FIND deliverables for 3 levels of the FIND deliverables for 3 levels of the health systemhealth system

Management of Tuberculosis Before 1940s Sanatorium based treatment

and surgery ( collapse therapy )

1940-60s Anti-TB drugs like SM, INH, PAS and TZN

1960-70s Conventional/Standard Chemotherapy

up to 2 years

1972 – 92 Short course chemotherapy

(6-9 months)

1993-2005 RNTCP Based on DOTS Strategy

2006 STOP TB STRATEGY and ISTC based on

on DOTS & DOTS-Plus.

The Revised National Tuberculosis

Program or RNTCP, is an

application of the principles of

DOTS to the Indian context

The 5 components of DOTS

TB Register

Political & admin. commitment

Diagnosis by microscopy

Adequate supply of the right drugs

Directly observed treatment

Accountability

Science of DOTSScience of DOTS

Diagnosis of TB primarily based on

sputum microscopy

Domiciliary treatment

Short course chemotherapy

Intermittent chemotherapy

Directly observed treatment

Drug action on TB bacillary population

Extra-cellularrapidly

multiplying 108

Dormant

Extra-cellular slowly

multiplying <105

Intra- and extra-cellular, acidic

environment<105

INH

RIF

PZA

No drug

RIF

SM

EMB

PAS

No drugs

Scientific basis of intermittent chemotherapy

Organism multiplication time (TB) is 18 hrs

24 hours maintenance of MIC

not necessary.

Achievement of serum peak levels of

all drugs simultaneously is essential.

Lag period exhibited by mycobacteria

Suitability and Science for Intermittent use

• In vitro experiments have shown that when tubercle bacilli are exposed to a drug for a short-time (6-24 hrs.) and after careful removal of the drug, are transferred to a drug-free medium, the surviving bacilli may grow again after an interval of several days.

• This interval is called “Lag period”.

Growth of M TB during & after exposure to H

Log Viable Units of

M TB

Lag phase

Days

INH added

INH washed

References:• Dickinson JM, Mitchison DA. In vitro studies on the choice of drugs for intermittent chemotherapy of

tuberculosis. Tubercle, 1966, 47: 370–380.• Canetti G, Grumbach F, Grosset J. Long-term, two-stage chemotherapy of advanced experimental

murine tuberculosis with intermittent regimes during the second stage. Tubercle,1963, 44:236–240.

Lag in growth of M. Tuberculosis after temporary exposure to drugs

* Depending on the pH of the medium (6.2 - 5.5)

Ref. : K.T. Toman, WHO 1997

Why not once or twice a week?

The risk of adverse effects increases with the length of the interval of intermittency. Thus, if treatment is taken only once a week, toxicity is high.

- Toman’s Tuberculosis (WHO, 2002)

Treatment RegimensTreatment Regimens

Cat I New smear–positive; seriously ill smear negative; seriously ill extra-pulmonary

2(HRZE)3/

4(HR)3

Cat II Previously treated smear–positive (relapse, failure, treatment after default)

2(HRZES)3/

1(HRZE)3/

5(HRE)3

Cat III New smear–negative and extra-pulmonary, not seriously ill

2(HRZ)3/

4(HR)3

“Extension of CAT I or CAT II in CP can be decided by Concerned Specialists”

Drug Dosages of Anti TB Drugs

DRUGS DOSAGES FORMULATION

Inj. SM. 750 mg 1 vial

Tab. INH 600 mg 300 mg*2 tablet

Cap. RMP. 450 mg 1 Capsule

Tab. EMB. 1200 mg 600 mg*2 tablet

Tab. PZA. 1500 mg 750 mg*2 tablet

Paediatric Patient Wise Boxes

6 – 10 kg would require

11 – 17 kg would require

18 – 25 kg would require

26 – 30 kg would require

PC 13

PC 14

PC 13 PC 14

PC 14 PC 14

+

+

Drug Dosages of Anti TB Drugs: Paediatric

Drugs PC 13 PC 14 No. of Tablets

Pyrazinamide Tablet 250 mg 500 mg 1 Tablet

Ethambutol Tablet 200 mg

400 mg 1 Tablet

Isoniazid Tablet 75 mg 150 mg 1 Tablet

Rifampicin Tablet 75 mg

150 mg 1 Tablet

Directly Observed Treatment

Treatment observer must be accessible and acceptable to the patient and accountable to the health system

Directly Observed Treatment(DOT) vs DOTS

Directly observed treatment (DOT) is one

element of the DOTS strategy

An observer watches and helps the patient

swallow the tablets

Direct observation ensures treatment for the

entire course with the right drugs

in the right doses

at the right intervals

During the intensive phase of treatment each and every dose of medicine is to be taken under direct observation of the PHW or community volunteer; During Continuation phase, one of the three weekly doses should be directly observed

Management of MDR TB in RNTCP

MDR-TB: DIAGNOSTIC APPROACH

• MDR-TB is a lab diagnosis, NOT a clinical one

• Quality assured laboratory facility for culture and DST must be available

• In Clinical practise, patient is failing to respond after optimum duration of first line ATT, Always the possibility of MDR TB Suspect rather than a MDR TB case

• Not all CAT II “failures” are MDR-TB cases i.e. a ”chronic” case is not always MDR-TB

When To Suspect DR TB?• CLINICALLY :

If patient has taken first line ATT for more than 5 month and shows no improvement or worsening of clinical signs and symptoms

It should be investigated completely to rule out other etiology

And if a case of Treatment Failure, by doing Culture & DST (Pus/Fluid or Tissue Specimens) one can know that patient is Mono, Poly, MDR TB or XDR TB (Laboratory Diagnosis)

DRUG RESISTANT TB

• MDR-TB suspects

– Category II cases who remain smear positive after 4

months of treatment or later

– Failures of Cat I,II and III

– Contacts of MDR-TB who found as smear positive TB in

diagnosis• MDR-TB is defined as resistance to isoniazid and rifampicin, with

or without resistance to other anti-TB drugs.

• XDR-TB is defined as resistance to at least Isoniazid and Rifampicin (i.e. MDR-TB) plus resistance to any of the fluoroquinolones and any one of the second-line injectable drugs (amikacin, kanamycin, or capreomycin).

•51

MDR TB Suspect identified and sample sent to laboratory for

diagnosis

Patient diagnosed as MDR TB

Patient discharged to home district for daily ambulatory DOT

Patient flow under DOTS Plus

Patient referred to DOTS PLUS Site for evaluation and initiation

of treatment

Follow up Protocol• Smear and Culture monthly during IP and Quarterly during CP• Physical evaluation monthly during IP and Quarterly during CP• KFT and other investigations at regular intervals

MDR Suspect

•Cat I and III failures•Cat II who remain smear + at 4 months or later• Smear + contacts of MDR cases

MDR-TB and DOTS-Plus

– Rational treatment design (evidence-based) - Standardized Treatment regimens (STR)

– Treatment regimen – • Include at least 4 drugs• Include an injectable in IP• Include at least 3 most active drugs in CP• have an IP of at least 6-9 and CP of 18 months

– Daily regimens - Directly observed therapy (DOT) ensuring long-term adherence

– Initial hospitalization for Pre-treatment Evaluation & initiation of Treatment – Monitoring and Management of adverse reactions– Adequate human resources

DOTS Plus Site – Gujarat

DOTS Plus Site •Tertiary care Centre•Dedicated inpatient facility•Trained Staff available•Facilities for pre-Rx assessment & management of adverse reactions •1 per 10 million population

However, one treatment strategy does not fit for all

Standardized treatment

Empiric treatment

Individualized treatment

Standardized treatment followed by

individualized treatment

No DST done (or DST only done to confirm MDR-TB). All

patients in a patient group or category get the same regimen.

Regimen is designed based on patient history and DST.

Initially all patients in a certain group get the same regimen

and it is then adjusted when DST results become available.

No DST done (or DST only done to confirm MDR-TB). Each regimen is individually designed based on patient history.

Empiric treatment followed by

individualized treatment

Each regimen is individually designed based on patient

history and then adjusted when DST results become available.

Treatment Strategies

Grouping of Anti TB Agents

Grouping Drugs

Group 1: First-line oral anti-TB

agents

Isoniazid (H); Rifampicin (R); Ethambutol (E); Pirazinamide (Z)

Group 2: Injectable anti-TB agents

Streptomycin (S); Kanamycin (Km); Amikacin (Am); Capreomycin (Cm); Viomycin (Vm).

Group 3: Flouroquinolones

Ciprofloxacin (Cfx); Ofloxacin (Ofx); Levofloxacin (Lvx); Moxifloxacin (Mfx); Gatifloxacin (Gfx)

Group 4: Oral second-line anti-TB

agents

Ethionamide (Eto); Prothionamide (Pto); Cycloserine (Cs); Terizadone (Trd);

para-aminosalycilic acid (PAS);

Group 5: Agents with Unclear role

in Treatment of DR TB

Clofazimine(cfz); Clarithromycin(Clr) Amoxacillin/Clavulanate(amx/clv);

Thioacetazone(Thz); High Dose INH; Imipenem/Cilastatin(Ipm/Cln); Linezolide(lzd);

MDR TB:RNTCP Category IV Regimen

RNTCP is using a Standardised Treatment Regimen

(STR) for the treatment of MDR-TB cases under the

programme by daily DOT.

REGIMEN: 6 (9) Km Ofx Eto Cs Z E /

18 Ofx Eto Cs E

Na PAS is a substitute drug for any one Bactericidal Na PAS is a substitute drug for any one Bactericidal (Km, Oflo, Ethio, PZA) or Two bacteriostatic drugs (Km, Oflo, Ethio, PZA) or Two bacteriostatic drugs (Cys, EMB) in case of ADRs (Cys, EMB) in case of ADRs

Drug Dosages and Formulation CAT IV

Drugs 16-25 Kgs 26-45 Kgs >45 Kgs

Kanamycin

Ofloxacin

Ethionamide

Ethambutol

Pyrazinamide

Cycloserine

Na PAS

500 mg

400 mg

375 mg

400 mg

500 mg

250 mg

5gm

500 mg

600 mg

500 mg

800 mg

1250 mg

500 mg

10 gm

750 mg

800 mg

750 mg

1000 mg

1500 mg

750 mg

12 gm

Treatment regimen

• Standardized regimen- Cat IV– Intensive phase (6-9 months)

• Km, Ofx*, Cs, Eto, Z, E

– Continuation phase (18 months)• Ofx*, Cs, Eto, E

– PAS is used a substitute drug

– Three weight bands – • 16-25 Kg ; 26-45 Kg and >45 Kg

• Patients who remain culture + after 6 months of Rx are subjected to SLDST (Km and Ofx) – If found to be XDR will be started on Cat V regimen

– Cm, Mx, Lzd, Amoxy-clav, Clofazimine, High H, PAS, Clarithromycin & Thiacetazone

3 monthly drug box

XDR TB: Drug Dosages & Formulation CAT V

Drugs ≤45 Kgs >45 Kgs

Capreomycin

INH

Moxifloxacin

PAS

Linezolide

Co- AmoxyClav

Clofazamine

750 mg

600 mg

400 mg

10 gm

600 mg

1250 mg BID

200 mg

1000 mg

900 mg

400 mg

12 gm

600 mg

1250 mg BID

200 mg

Clarithromycin 500 mg BID 500 mg BID

Thiacetazone 150 mg 150 mg

CASE REPORT

• A female patient 28 year, residing at Navsari, Gujarat, after her marriage on Immigration, she went to New Zealand.

• She became chest symptomatic in January 2007 and her induced sputum was smear negative.

• After all investigation, RUL infiltrate on CXR, in early March induced sputum showed culture positive TB and she was diagnosed as XDR-TB

MYCOBACTERIAL INVESTIGATIONS

SPECIMEN / SITE: Induced Sputum STAINED FILM : No acid fast bacilli seen. CULTURE (1) Growth of Mycobacterium tuberculosis **

This isolate of M. tuberculosis complex is resistant to INH at a concentration of 0.1 and 0.4 mcg/ml.

• (1) (1) Streptomycin R Isoniazid R Rifampicin R Ethambutol R Pyrazinamide S Ciprofloxacin R Clofazimine R Rifabutin S Capreomycin R Prothionamide S Amikacin R Cycloserine S P-aminosalicylic acid R Moxifloxacin R • R = Resistant S = Sensitive I = Intermediate • (1) Growth of Mycobacterium tuberculosis**

• Mycobacterium tuberculosis causes a NOTIFIABLE DISEASE please notify the Medical Officer of Health by telephone (09) 623-4600 OR Fax (09) 630-7431

• For notifications outside the Auckland region, • please contact your local Medical Officer of Health. • COMMENT Moxifloxacin MIC >0.2mg/L • Signed out by : SANDIE NEWTON on 3 Apr 07 9:16

CASE REPORT CONT.

• She was put on Cys, Pth, Rifabutin and PZA at Auckland hospital.

• After 4 months, she came to India and DTO and my self got reference from concerned authority.

• Feed back was given by us and she was on Pth, PZA and Rifabutin as she developed Cys toxicity.

• Letter on Dr. Cathy gave us reports after reconfirmation on five subculture turned out to be only H resistance and not a XDR-TB.

CULTURE SENSITIVITY OF Miss. SABAH, 13 yrs. F LAB-A LAB-B LAB-C LAB-DSTM. S R MS RRIF. S R R INTINH. R R R SETM. S S S SPZA. R R R

AWTTHIA. S R -- SPAS. S S MS S KANA. -- -- MS --CYCLO. S -- S --ETHIO. -- R R SCIPRO. -- -- -- SSPAR -- S S SCLOFA. -- R S --

R Prasad Lucknow

Treatment Challenges……. • Long duration, Toxic, expensive treatment

– 2000 $ per patient course (1.5 Lacs rupees)

• Daily ambulatory DOT

– 6-9 months of injectables

• Availability of DOTS Plus sites (1 per 10 million population)

• Extensive training, supervision and monitoring needed at all levels

• Ensuring treatment adherence

• Ensuring timely follow up

•

Global Policy: MDR-TB and XDR-TB

1. Strengthen basic TB and HIV/AIDS control, to avoid creation of MDR-TB and XDR-TB

2. Scale-up programmatic management of MDR-TB and XDR-TB

3. Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB

4. Expand MDR-TB and XDR-TB surveillance 5. Introduce infection control, especially in high

HIV prevalence settings6. Strengthen advocacy, communication and

social mobilization (e.g., Response Plan)7. Pursue resource mobilization at global,

regional and country levels8. Promote research and development into new

diagnostics, drugs and vaccines

Is DOTS Essential?Is DOTS Essential?

DOTS is not the final answer

There will be a better way!

BUT

DOTS is the BEST strategy for controlling

TB that we have

BUT

The most contentious part of DOTS is DO