World Health Organization

1. "The international experience of DOTS-Plus and the Green Light Committee mechanism" Dr Ernesto JaramilloMedical Officer, WHO/HTM/STB/THD World Health Organization WHO/STB/THD

2. DOTS-Plus The strategy designed to manage MDR-TB using second-line anti-TB drugs within the DOTS strategy in low- and middle-income countries. DISCLAIMER: DOTS-Plus means DOTS first WHO/STB/THD

3. The ‘Green Light Committee’ mechanism of the Stop TB Partnership The mechanism of WHO and its partners of the Stop TB Partnership to enabling access to second-line anti-TB drugs in low- and middle-income countries to treat multidrug resistant tuberculosis under programmatic conditions and following specific guidelines (Guidelines for implementing DOTS-Plus projects for the management of MDR-TB). WHO/STB/THD

4. The ‘Green Light Committee’ mechanism of the Stop TB Partnership • DOTS-Plus and the GLC mechanism: a comprehensive response to… • Evidence that basic DOTS was not enough to control TB and MDR-TB • Global widespread misuse of second-line TB drugs • Failure of the market of second-line TB drugs • Lack of policy to manage and control MDR-TB WHO/STB/THD

5. A market failure: management of MDR-TB before the creation of the GLC mechanism Situation on low and middle income countries High Cost of Treatment Lack of Drug Demand Insufficient response to demand Lack of Policy Lack of evidence on feasibility and cost-effectiveness WHO/STB/THD

6. Response to MDR-TB by linking concepts ACCESS Price & quality RATIONAL USE OF DRUGS GLC mechanism POLICY FOR TB CONTROL WHO/STB/THD

7. Advantages of applying to the WHO GLC mechanism • Access to quality-assured drugs following international accepted standards (including WHO) • Access to low-cost drugs • Access to a continuous drug supply, essential for treatment success • Access to technical assistance to ensure rational drug use WHO/STB/THD

8. Advantages of applying to the WHO GLC mechanism • Access to an external monitoring mechanism • Increased rational use of drugs • Creation of wide evidence base for national policy development • Ensures consolidation of DOTS as the strategy to control TB WHO/STB/THD

9. Scaling-up of DOTS-Plus through the GLC mechanism April 2005 – 33 projects WHO/STB/THD

10. Scaling-up of DOTS-Plus through the GLC mechanism 10, 939 WHO/STB/THD

11. The GLC has contributed to a paradigm shift in the management of MDR-TB 34 projects 28 countries 10,939 patients Source: WHO 2002 GLC-approved DOTS-Plus projects Applications under review by the GLC Countries preparing application WHO/STB/THD

12. The ‘Green Light Committee’ mechanism • …has contributed to demonstrate that: • Market of SLDs can be increased and be rationally handled • DOTS-Plus is feasible, effective and cost-effective • Integration of DOTS-Plus into regular DOTS is feasible and strengthens regular DOTS programmes WHO/STB/THD

13. DOTS-Plus and the ‘Green Light Committee’ mechanism: a learning experience for all! • …by creatively sailing in non-chartered waters, the Working Group on DOTS-Plus and its subgroups have contributed to demonstrate that: • Market of SLDs can be increased and be rationally handled • DOTS-Plus is feasible, effective and cost-effective • Integration of DOTS-Plus into regular DOTS is feasible and strengthens regular DOTS programmes WHO/STB/THD

14. Increasing rational use of second-line TB drugs 2002 Worldwide sales of two second-line TB drugs by country by a single manufacturerCapreomycin Cycloserin WHO/STB/THD

15. Increased size and quality of the market of second-line anti-TB drugs • Eli Lilly transfer of technology and effects on supply • Increasing production capacity in some manufacturers • Investments in some manufacturers to meet quality standards WHO/STB/THD

16. Main components of a DOTS-Plus project • Plan(who will do what, when, how, where?) • Locating the project in the NTP structure • Case finding strategy • Treatment regimen • Drug management (including procurement plan) WHO/STB/THD

17. Main components of a DOTS-Plus project • Role of hospital vs ambulatory treatment • Management of adverse reactions • Data collection and analysis • Laboratory functions • Training of health care workers WHO/STB/THD

18. Main components of a DOTS-Plus project • Role of hospital vs ambulatory treatment • Management of adverse reactions • Data collection and analysis • Laboratory functions • Training of health care workers WHO/STB/THD

19. Lessons learned: main barriers to implement DOTS-Plus • Poor integration of the MDR-TB activities in the NTP • Lack of drug registration of quality-assured drugs • Poor understanding of drug side effects, its prevention and management • Poor TB laboratory capacity and/or performance (no quality control system in place, lack of quality assurance for performing DST for first-line TB drugs) WHO/STB/THD

20. Lessons learned: main barriers to implement DOTS-Plus • Lack of experience in managing second-line drugs to treat MDR-TB under programmatic conditions • Inadequate facilities to hospitalize and/or treat MDR-TB patients • Absence of social support measures to facilitate adherence to treatment WHO/STB/THD

21. Lessons learned: different ways to implement a single framework • MDR-TB burden does not determine the decision to implement DOTS-Plus: from Latvia to Lebanon • Country-wide DOTS coverage does not determine the decision to implement DOTS-Plus: from Peru to the Philippines • High cost of treatment does not prevent to treat MDR-TB: from El Salvador to Estonia WHO/STB/THD

22. Lessons learned: different ways to implement a single framework • Flexibility to adapt DOTS-Plus to local resources: • Control of infection risk: from Estonia to Bolivia • Social support: from Peru to Latvia • Implementer: from Haiti to Honduras • Treatment strategy: from Mexico to Malawi • Delivery of treatment: from Nepal to Nicaragua WHO/STB/THD

23. Lessons learned: DOTS-Plus preparation takes time! DOTS-Plus does not necessarily mean MDR-TB diagnosis and treatment in all regions and all districts from the very beginning ! Slow steps should be taken in order to pilot, adjust and expand a rational and feasible capacity to manage drug resistant TB WHO/STB/THD

24. Lessons learned: DOTS-Plus preparation takes time! • Stepwise implementation of DOTS-Plus includes: • Assessment of drug resistance situation (DRS data, risk groups, laboratory capacity, SLD use ) • Relevance of DOTS-Plus in the context of TB control • From pilot phase to country-wide expansion: many scenarios, good to start to with national/provincial centres of excellence WHO/STB/THD

25. Preliminary results of DOTS-Plus projects • More than 5,000 patients have been enrolled and 3,100 have completed treatment • MDR-TB among new cases in projects assessed range from 1.5-17.1% • 57% of the MDR-TB cases treated are resistant to all first line-drugs and also to second-line anti-TB drugs • Treatment success rates range from 61-82% • Only 2% of patients have stopped treatment due to adverse events WHO/STB/THD

26. Adverse events (1) Data in 924 patients from Estonia, Latvia, Russia and Philippines show that only 2% (17patients) have stopped treatment due to side effects WHO/STB/THD

27. Adverse events (1) WHO/STB/THD

28. Adverse events (2) • Adverse events are manageable in the treatment of MDR-TB in resource-limited settings provided that standard management strategies are applied including: • altering dosages when appropriate • ancillary drugs to treat adverse events • discontinuation of some drugs if indicated • special training on adverse events to second-line drugs • standard protocols for registration WHO/STB/THD

29. Profile of MDR-TB patients WHO/STB/THD

30. Drug resistance pattern of cases WHO/STB/THD

31. Standardized treatment No DST done (or DST only done to confirm MDR-TB). All patients in a patient group or category get the same regimen. Empiric treatment No DST done (or DST only done to confirm MDR-TB). Each regimen is individually designed based on patient history. Individualized treatment Regimen is designed based on patient history and DST. Standardized treatmentfollowed by individualized treatment Initially all patients in a certain group get the same regimen and it is then adjusted when DST results become available. Empiric treatmentfollowed by individualized treatment Each regimen is individually designed based on patient history and then adjusted when DST results become available. Lessons learned: one treatment strategy does not fit all WHO/STB/THD

32. Evidence of feasibility and effectiveness of DOTS-Plus: Treatment outcomes in some DOTS-Plus sites WHO/STB/THD

33. Evidence of cost-effectiveness:Cost per patient treated under DOTS-plus projects by major line item (health system perspective, 2003 US$) WHO/STB/THD

34. Evidence of cost-effectiveness of DOTS-plus projects Examples of general benchmarks to compare cost-effectiveness: • ≤ GNI per capita • ≤ 1-3 times GDP per capita [WHR, 2002]. • ≤ US$ 565-847 per DALY averted (2003 US$ prices), estimated "limited care" component of essential health package for middle income countries [World Bank, 1993]. WHO/STB/THD

35. Costs, effects, cost-effectiveness of DOTS-Plus in the Philippines Cost per DALY averted • < per capita Gross National Income (GNI) (~US$1000) • ~ level (US$200 in 2002 prices) considered "attractive" investment in low-income countries by World Bank in 1993 • < 3x per capita GNI (Commission on Macroeconomics and Health, WHO, 2001) WHO/STB/THD

36. Preliminary results of DOTS-Plus projects Strengthened DOTS: quality, consolidation and expansion Training of human resources for management of drug resistant TB Laboratory capacity strengthened Size and quality of market of second-line TB drugs Commitment of GFATM to fund management of MDR-TB WHO/STB/THD

37. Preliminary results of DOTS-Plus projects • DOTS-Plus is creating, fixing and strengthening DOTS • Makes DOTS the default option to control TB: Moldova • Ensures political commitment: Estonia • Strengthen laboratory capacity: Peru • Contributes to a comprehensive TB control policy: the Philippines • Highlights the importance of drug management in TB control: all • Improves the skills of health care workers: Latvia • Improves understanding of local TB and MDR-TB epidemiology: all WHO/STB/THD

38. DOTS-Plus framework 1. Sustained Political commitment 2. Diagnosis of MDR-TB through quality-assured culture and drug susceptibility testing (DST). 3. Appropriate treatment strategies that utilize second line drugs under proper management conditions. 4. Uninterrupted supply of quality assured reserve antituberculosis drugs. 5. Recording and reporting system designed for DOTS-Plus programs WHO/STB/THD

39. Framework Component 1:Sustained Political commitment • Long term investment of resources (human and financial) • Addressing the factors leading to the emergence of MDR-TB • A well functioning DOTS program !! • Procurement of quality-assured drugs and legislation to assure rational use • Effective coordination between community, local governments, and international agencies WHO/STB/THD

40. Framework Component 2:Diagnosis of MDR-TB through quality-assured culture and drug susceptibility testing (DST) • Proper triage of patients into susceptibility testing and the DOTS-Plus component of the DOTS program. • Some programs can do drug susceptibility testing for all patients • Most programs will use DST strategies that target MDR risk groups (failures, chronics) • Some enrol patients based on representative DRS data (Nepal) • But, all programs need access to quality assured drug smear microscopy, culture and susceptibility testing WHO/STB/THD

41. Framework Component 3:Appropriate treatment strategies that utilize second-line drugs under proper management conditions • Appropriate regimens • Directly observed therapy (DOT) throughout • Monitoring and early management of side effects • Adequate human resources (both quantity and quality) WHO/STB/THD

42. Framework Component 3:Appropriate treatment strategies that utilize second-line drugs under proper management conditions(continued) • Monitoring and management of side effects • Management algorithms provided in guidelines • Ability to refer when indicated • Active monitoring (clinical ! and laboratory) • Ancillary medicines at no cost to patient WHO/STB/THD

43. Framework Component 4:Uninterrupted supply of quality assured second-line anti-tuberculosis drugs • Many challenges of drug procurement • Individualized regimens are frequently being adjusted (due to side-effects, drug susceptibility testing results, and lack of treatment response) • Short shelf life (18 – 36 months) • Global production of quality-assured drugs is limited • Drug registration may be lengthy and costly WHO/STB/THD

44. Framework Component 5:Recording and reporting system designed for DOTS-Plus programs • Enables • patient registration • monitoring (including culture, DST, laboratory tests…etc) • interim indicators • final outcome analysis • comparison of different cohorts WHO/STB/THD