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

April 2005 WHO/STB/THD 1World Health Organization

"The international experience of DOTS-Plus and "The international experience of DOTS-Plus and the Green Light Committee mechanism" the Green Light Committee mechanism"

Dr Ernesto JaramilloDr Ernesto JaramilloMedical Officer, WHO/HTM/STB/THD Medical Officer, WHO/HTM/STB/THD

April 2005 WHO/STB/THD 2

DOTS-PlusDOTS-Plus

The strategy designed to manage MDR-TB using

second-line anti-TB drugs within the DOTS strategystrategy in

low- and middle-income countries.

DISCLAIMER: DOTS-Plus means DOTS firstDISCLAIMER: DOTS-Plus means DOTS first


The ‘Green Light Committee’ mechanism of the The ‘Green Light Committee’ mechanism of the Stop TB PartnershipStop 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).


The ‘Green Light Committee’ mechanism of the The ‘Green Light Committee’ mechanism of the Stop TB PartnershipStop 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


A market failure: management of MDR-TB before A market failure: management of MDR-TB before the creation of the GLC mechanism the creation of the GLC mechanism

High Cost of Treatment

Insufficient response to demand

Lack of evidence on feasibility and cost-effectiveness

Lack of Policy

Lack of Drug Demand

Situation on low and middle income countries


Response to MDR-TB by linking conceptsResponse to MDR-TB by linking concepts

GLCGLCmechanismmechanism

ACCESSACCESSPrice & qualityPrice & quality

RATIONAL RATIONAL USE OF USE OF DRUGSDRUGS

POLICY POLICY FOR TB FOR TB

CONTROLCONTROL


Advantages of applying to the WHO GLC mechanismAdvantages 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


Advantages of applying to the WHO GLC mechanismAdvantages 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


0

5

10

15

20

25

30

35

2000 2001 2002 2003 2004 2005

Projects approved April 2005 – 33 projects

Scaling-up of DOTS-Plus through the GLC mechanism


0

2000

4000

6000

8000

10000

12000

2000 2001 2002 2003 2004 2005

Number of patients being enrolled on treatment 10, 939

Scaling-up of DOTS-Plus through the GLC mechanism


The GLCThe GLC has contributed to a paradigm shift has contributed to a paradigm shift in the management of MDR-TBin the management of MDR-TB

Source: WHO 2002

Applications under review by the GLCApplications under review by the GLC

GLC-approved DOTS-Plus projectsGLC-approved DOTS-Plus projects

Countries preparing applicationCountries preparing application

34 projects

28 countries

10,939 patients


The ‘Green Light Committee’ mechanismThe ‘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


DOTS-Plus and the ‘Green Light DOTS-Plus and the ‘Green Light Committee’ mechanism: a learning Committee’ mechanism: a learning

experience for all!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


2002 Worldwide sales of two second-line TB drugs by country by a single manufacturer2002 Worldwide sales of two second-line TB drugs by country by a single manufacturer

Capreomycin Capreomycin Cycloserin Cycloserin

20% RUS

31% WHO

49% Other

WHO

RUS

Other

33% WHO

27% RUS

17% KAZ

23% Other

WHO

Russia

Kazahkstan

Other

Increasing rational use of second-line TB drugs


Increased size and quality of the market of Increased size and quality of the market of second-line anti-TB drugssecond-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


Main components of a DOTS-Plus projectMain 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)



Role of hospital vs ambulatory treatment

Management of adverse reactions

Data collection and analysis

Laboratory functions

Training of health care workers



Role of hospital vs ambulatory treatment

Management of adverse reactions

Data collection and analysis

Laboratory functions

Training of health care workers


Lessons learned: main barriers to implement Lessons learned: main barriers to implement DOTS-Plus 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)


Lessons learned: main barriers to implement Lessons learned: main barriers to implement DOTS-Plus 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


Lessons learned: different ways to implement Lessons learned: different ways to implement a single frameworka 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


Lessons learned: different ways to implement Lessons learned: different ways to implement a single frameworka 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


Lessons learned: DOTS-Plus Lessons learned: DOTS-Plus preparation takes time!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


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

Lessons learned: DOTS-Plus Lessons learned: DOTS-Plus preparation takes time!preparation takes time!


Preliminary results of DOTS-Plus projectsPreliminary 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


Adverse events (1)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





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


Profile of MDR-TB patientsProfile of MDR-TB patients

0%

20%

40%

60%

80%

100%

Estonia Latvia Orel Philippines Tomsk

Patients treated beforewith 2nd line drugs

Patients treated beforewith 1st line drugs

New cases


Drug resistance pattern of casesDrug resistance pattern of cases

0%

20%

40%

60%

80%

100%

Esto

nia

La

tvia

Ore

l

Pe

ru

Ph

ilip

pin

es

To

msk

Patients resistant to HRES andsecond-line drugs

Patients resistant to HRES

Patients resistant to HR only


Lessons learned: one treatment strategy Lessons learned: one treatment strategy does not fit alldoes 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

individualized treatment

Each regimen is individually designed based on patient

history and then adjusted when DST results become available.


Evidence of feasibility and effectiveness of DOTS-Plus: Evidence of feasibility and effectiveness of DOTS-Plus: Treatment outcomes in some DOTS-Plus sitesTreatment outcomes in some DOTS-Plus sites

59

48

61

76

12

12

15

421

12

14 8

8

28

10 12

0%

20%

40%

60%

80%

100%

Estonia Peru Philippines Russia-Tomsk

Failed

Defaulted

Died

Cured


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

0

2000

4000

6000

8000

10000

12000


US

$

Drugs Hospitalization DOT visits

Sputum smears, cultures, DST and X-rays Training Programme and data management

Food parcels Adverse events Other

9020

3432

2544

10319


Evidence of cost-effectiveness of DOTS-Evidence of cost-effectiveness of DOTS-plus projectsplus 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].

0

200

400

600

800

1000

1200


Mean

co

st

per

DA

LY

avert

ed

(2003 U

S$)

1135

183225

556

Estonia Peru Philippines Russia-TomskGNI per capita (2003 US$)

4960 2150 1080 2610


Costs, effects, cost-effectiveness of DOTS-Plus in the Costs, effects, cost-effectiveness of DOTS-Plus in the PhilippinesPhilippines

Total costs

0

100000

200000

300000

400000

500000

600000

DOTS-plus No DOTS-plus

US

$

Patient

Health system

DALYs lost

0

2000

4000

6000

8000

10000

DOTS plus No DOTS plus

Nu

mb

er

Cost per DALY averted

179242

050

100150200250300350400450

Health systemperspective

Societalperspective

US

$

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)



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



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


DOTS-Plus frameworkDOTS-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


Framework Component 1:Framework Component 1:

Sustained Political commitmentSustained 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


Framework Component 2:Framework Component 2: Diagnosis of MDR-TB through quality-assured culture and drug Diagnosis of MDR-TB through quality-assured culture and drug

susceptibility testing (DST)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


Framework Component 3:Framework Component 3: Appropriate treatment strategies that utilize second-line drugs under Appropriate treatment strategies that utilize second-line drugs under

proper management conditionsproper management conditions

Appropriate regimens Directly observed therapy (DOT) throughout Monitoring and early management of side

effects Adequate human resources (both quantity and

quality)


Framework Component 3:Framework Component 3: Appropriate treatment strategies that utilize second-line drugs under Appropriate treatment strategies that utilize second-line drugs under

proper management conditionsproper management conditions (continued)(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


Framework Component 4:Framework Component 4: Uninterrupted supply of quality assured second-line anti-Uninterrupted supply of quality assured second-line anti-

tuberculosis drugstuberculosis 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


Framework Component 5:Framework Component 5: Recording and reporting system designed for DOTS-Plus Recording and reporting system designed for DOTS-Plus

programsprograms

Enables – patient registration– monitoring (including culture, DST, laboratory

tests…etc)– interim indicators – final outcome analysis– comparison of different cohorts

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

Documents

glc mechanism slide

tb control slide

whostbthd dotsplus strategy

dots strategy

control mdrtb slide

tb source

consolidation of dots

basic dots