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

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

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

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

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

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

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

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

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

Scaling-up of DOTS-Plus through the GLC mechanism 10, 939 April 2005 WHO/STB/THD

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 April 2005 WHO/STB/THD

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

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

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

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

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

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

Evidence of feasibility and effectiveness of DOTS-Plus: Treatment outcomes in some DOTS-Plus sites April 2005 WHO/STB/THD

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

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]. April 2005 WHO/STB/THD

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

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

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

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

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

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

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

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

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

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