1. World Health Organization
"The international experience of DOTS-Plus and the Green Light Committee mechanism" Dr Ernesto Jaramillo Medical Officer, WHO/HTM/STB/THD
World Health Organization
April 2005
WHO/STB/THD

2. DISCLAIMER: DOTS-Plus means DOTS first
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
April 2005
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).
April 2005
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
April 2005
WHO/STB/THD

5. Situation on low and middle income countries
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
April 2005
WHO/STB/THD

6. Response to MDR-TB by linking concepts
ACCESS
Price & quality
RATIONAL USE OF DRUGS
GLC
mechanism
POLICY FOR TB CONTROL
April 2005
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
April 2005
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
April 2005
WHO/STB/THD

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

10. Scaling-up of DOTS-Plus through the GLC mechanism
10, 939
April 2005
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
April 2005
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
April 2005
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
April 2005
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 manufacturer Capreomycin Cycloserin
April 2005
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
April 2005
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)
April 2005
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
April 2005
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
April 2005
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)
April 2005
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
April 2005
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
April 2005
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
April 2005
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
April 2005
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
April 2005
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 %
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
April 2005
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
April 2005
WHO/STB/THD

27. Adverse events (1)
April 2005
WHO/STB/THD

28. Adverse events (2) altering dosages when appropriate
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
April 2005
WHO/STB/THD

29. Profile of MDR-TB patients
April 2005
WHO/STB/THD

30. Drug resistance pattern of cases
April 2005
WHO/STB/THD

31. Lessons learned: one treatment strategy does not fit 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
Each regimen is individually designed based on patient
history and then adjusted when DST results become available.
April 2005
WHO/STB/THD

32. Evidence of feasibility and effectiveness of DOTS-Plus: Treatment outcomes in some DOTS-Plus sites
April 2005
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$)
April 2005
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$ per DALY averted (2003 US$ prices), estimated "limited care" component of essential health package for middle income countries [World Bank, 1993].
April 2005
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)
April 2005
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
April 2005
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
April 2005
WHO/STB/THD

38. 1. Sustained Political commitment
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
April 2005
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
April 2005
WHO/STB/THD

40. Some programs can do drug susceptibility testing for all patients
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
April 2005
WHO/STB/THD

41. Directly observed therapy (DOT) throughout
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)
April 2005
WHO/STB/THD

42. Monitoring and management of side effects
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
April 2005
WHO/STB/THD

43. Many challenges of drug procurement
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
April 2005
WHO/STB/THD

44. monitoring (including culture, DST, laboratory tests…etc)
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
April 2005
WHO/STB/THD