Transcript DOTS-Plus and the

"The international experience of DOTS-Plus and
the Green Light Committee mechanism"
Dr Ernesto Jaramillo
Medical Officer, WHO/HTM/STB/THD
April 2005
World Health Organization
WHO/STB/THD
1
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
April 2005
WHO/STB/THD
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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 middleincome 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
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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 MDRTB
– 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
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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
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WHO/STB/THD
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Response to MDR-TB by linking concepts
ACCESS
Price & quality
GLC
RATIONAL
USE OF
DRUGS
mechanism
POLICY
FOR TB
CONTROL
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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
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WHO/STB/THD
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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
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WHO/STB/THD
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Scaling-up of DOTS-Plus through the GLC mechanism
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April 2005 – 33 projects
Projects approved
30
25
20
15
10
5
0
2000
April 2005
2001
2002
2003
WHO/STB/THD
2004
2005
9
Scaling-up of DOTS-Plus through the GLC mechanism
12000
Number of patients being enrolled on treatment
10, 939
10000
8000
6000
4000
2000
0
2000
April 2005
2001
2002
2003
WHO/STB/THD
2004
2005
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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
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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
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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
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Increasing rational use of second-line TB drugs
2002 Worldwide sales of two second-line TB drugs by country by a single manufacturer
Capreomycin
23%
Other
33%
WHO
Cycloserin
WHO
49%
Other
Russia
17%
KAZ
Kazahkstan
WHO
RUS
Other
Other
27%
RUS
April 2005
31%
WHO
20%
RUS
WHO/STB/THD
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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
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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
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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
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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
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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
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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
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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 MDRTB: from El Salvador to Estonia
April 2005
WHO/STB/THD
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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
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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
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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
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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
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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
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WHO/STB/THD
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Adverse events (1)
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WHO/STB/THD
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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
April 2005
WHO/STB/THD
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Profile of MDR-TB patients
100%
80%
60%
Patients treated before
with 2nd line drugs
Patients treated before
with 1st line drugs
40%
New cases
20%
0%
Estonia
April 2005
Latvia
Orel
Philippines
WHO/STB/THD
Tomsk
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Drug resistance pattern of cases
100%
80%
Patients resistant to HRES and
second-line drugs
60%
Patients resistant to HRES
40%
Patients resistant to HR only
20%
April 2005
Tomsk
Philippines
Peru
Orel
Latvia
Estonia
0%
WHO/STB/THD
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Lessons learned: one treatment strategy
does not fit all
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 treatment
Initially all patients in a certain group get the same regimen
and it is then adjusted when DST results become available.
followed by
individualized treatment
Empiric treatment followed by
individualized treatment
April 2005
Each regimen is individually designed based on patient
history and then adjusted when DST results become available.
WHO/STB/THD
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Evidence of feasibility and effectiveness of DOTS-Plus:
Treatment outcomes in some DOTS-Plus sites
100%
8
28
80%
21
10
12
14
8
4
12
12
Failed
15
Defaulted
60%
12
Died
40%
76
61
59
Cured
48
20%
0%
Estonia
April 2005
Peru
Philippines
WHO/STB/THD
Russia-Tomsk
32
Evidence of cost-effectiveness:
Cost per patient treated under DOTS-plus projects by
major line item (health system perspective, 2003 US$)
12000
10319
10000
9020
US$
8000
6000
3432
4000
2544
2000
0
Estonia
Peru
Philippines
Russia-Tomsk
Drugs
Hospitalization
DOT visits
Sputum smears, cultures, DST and X-rays
Training
Programme and data management
Food parcels
Adverse events
Other
April 2005
WHO/STB/THD
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Evidence of cost-effectiveness of DOTSplus projects
Mean cost per DALY averted (2003 US$)
1200
Examples of general
benchmarks to compare
cost-effectiveness:
1135
1000
• ≤ GNI per capita
• ≤ 1-3 times GDP per capita
800
556
600
• ≤ US$ 565-847 per DALY
400
225
183
200
0
Estonia
GNI per capita
(2003 US$)
April 2005
[WHR, 2002].
Peru
Philippines
Russia-Tomsk
Estonia
Peru
Philippines
Russia-Tomsk
4960
2150
1080
2610
WHO/STB/THD
averted (2003 US$ prices),
estimated "limited care"
component of essential
health package for middle
income countries [World
Bank, 1993].
34
Costs, effects, cost-effectiveness of DOTS-Plus in the
Philippines
600000
Total costs
10000
8000
400000
Patient
Health system
300000
200000
100000
Number
US$
500000
DALYs lost
6000
4000
2000
0
0
DOTS-plus
No DOTS-plus
DOTS plus
No DOTS plus
US$
Cost per DALY averted
450
400
350
300
250
200
150
100
50
0
Cost per DALY averted
242
179
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
Health system
perspective
April 2005
<
Societal
perspective
<
3x per capita GNI (Commission on
Macroeconomics and Health, WHO, 2001)
WHO/STB/THD
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Preliminary results of DOTS-Plus projects
Strengthened
Training
of human resources for management of drug resistant TB
Laboratory
Size
capacity strengthened
and quality of market of second-line TB drugs
Commitment
April 2005
DOTS: quality, consolidation and expansion
of GFATM to fund management of MDR-TB
WHO/STB/THD
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Preliminary results of DOTS-Plus projects
 DOTS-Plus
is creating, fixing and
strengthening DOTS
–
–
–
–
–
–
–
April 2005
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
37
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
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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
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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
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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
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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
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Framework Component 4:
Uninterrupted supply of quality assured second-line antituberculosis 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
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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
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