PROGRAMMATIC OPERATIONAL RESEARCH

DEVELOPMENT OF MALAWI’ S POLICY ON

COTRIMOXAZOLEPREVENTIVE

THERAPY

R. Zachariah / AD Harries Contacts: adharries@theunion.org, zachariah@internet.lu

COTRIMOXAZOLE PREVENTIVE THERAPY (CPT)

Useful against:-

• Pneumocystis carinii pneumonia

• Toxoplasma encephalitis

• Isospora belli diarrhoea

• Some bacteria and enterobacteria

• Nocardiosis

• Falciparum malaria

CPT in HIV-positive patients in the West:

used in those with CD4 <200• Reduces risk of PCP

• Reduces mortality in those who get PCP

• Reduces risk of toxoplasmosis

• Reduces risk of isosporiasis

• Reduces risk of bacterial infections on daily treatment

COTRIMOXAZOLE PROPHYLAXIS

Advantages

• Cheap• Widely available• Easy to administer

Disadvantages

• Side effects• Drug resistance• Lack of efficacy?

CPT in new HIV+ve TB patients in Cote d’Ivoire

760 HIV-positive smear+ve TB patients

on short course chemotherapy

one month later - CPT or placebo

CPT associated with

48% lower mortality

44% lower hospitalisation rate (Wiktor et al Lancet 1999;353: 1469)

UNAIDS 2000 PROVISIONAL RECOMMENDATIONS

CPT be used in adults and children living with AIDS in Africa as part of minimum package

of care

Ethical implications

• Unethical to conduct further randomised controlled clinical trials on CPT efficacy in HIV-positive TB patients

• UNAIDS- funded Blantyre COM RCT trial on CPT was stopped after recruiting 37 patients

Malawi MOH Meeting in 2000 (1)

• CPT may not have the same efficacy in Malawi as Cote d’Ivoire because different resistance patterns and different spectrum of HIV-related illness

• Malawi not prepared to adopt WHO – guidelines on CPT as policy because no evidence of effect and may be dangerous (SP in malaria)

Malawi MOH Meeting in 2000(2)

• Strong endorsement for district operational research

• Operational research studies run in Thyolo and Karonga districts on CPT in HIV+ve TB patients

AIM OF DISTRICT STUDIESin Thyolo and Karonga

To determine the feasibility and effectiveness of “VCT and CPT” in

reducing case fatality in a cohort of TB patients registered under routine

programme conditions

[Zachariah et al, AIDS 2003 – Thyolo study]

[Mwaungulu et al, Bulletin WHO 2004 – Karonga study]

STUDY PROTOCOLS

• TB patients registered in DTO office

• TB treatment - standardised regimens

• All patients referred to VCT unit

• HIV testing with patient consent

• Post-test counselling

• HIV+ve patients offered CPT

STUDY PROTOCOLS

CPT:

• offered if no contraindication

• dose 960 mg daily –split AM and PM

• started as soon as HIV result known

• side effects monitored clinically

• continued indefinitely unless side effects

ANALYSIS: Historical comparison

• VCT+CPT group: the cohort offered VCT and CPT and registered during a full one year period

• Control group: the cohort not on CPT and registered the previous year during a full one year period

Comparison of mortality at the end of treatment between the two groups

REGISTERED TB CASES

Thyolo

VCT-CPT 1061

Control 925

Karonga

VCT-CPT 362

Control 355

Interventions in TB patients

Thyolo

(1061 patients)

Karonga

(362 patients)

HIV tested 91% 73%

HIV-positive 69% 51%

Started CPT 94% 96%

START OF CPT

• In Thyolo, HIV-positive patients were started on CPT a median of 4 days after registration

• In Karonga, HIV-positive patients were started on CPT a median of 8 days after registration

REACTIONS TO CPT

Thyolo:

No. on CPT 693

No. reactions 14 (2%)

Karonga:

No. on CPT 153

No. reactions 8 (5%)

Reactions were all dermatological - no deathsReactions were all dermatological - no deaths

Case fatality: all TB types

Thyolo:

VCT-CPT 28%

Control 36%

p < 0.001

Karonga:

VCT-CPT 29%

Control 37%

p < 0.001

Number of TB patients that needed treatment with “VCT and CPT” to prevent

one death = 12in both Thyolo and Karonga

“estimated cost to prevent one death = USD$100”

CONCLUSION

• In the two district based studies, the “package of VCT and CTX” given to patients at or shortly after registration was associated with a significant reduction in case fatality.

• The drug was safe with minimal side effects

MOH POLICY MEETING

• Meeting on October 1st 2002 with MOH:

• Stakeholders included NTP, NAC, COM, PROTEST, MSF-Luxembourg, Thyolo, Karonga, Lighthouse Project, Wellcome Trust, WHO, Directors of central hospitals

POLICY RECOMMENDATIONS for TB PATIENTS (1)

• HTC + CPT continues in Thyolo, Karonga and Lilongwe

• Expand HTC + CPT to other districts in a phased manner in accordance with 3-Year TB-HIV plan

• Undertake further operational research on the best ways to deliver this package

POLICY RECOMMENDATIONS for TB PATIENTS (2)

• NTP will take responsibility for CPT procurement and delivery to patients while on TB treatment, but not after

• NTP will work with partners on conducting a proper RCT (never done)

• NTP will explore how best CPT can be continued after TB treatment is completed and how CPT can be given to other patients

POLICY RECOMMENDATIONS for TB PATIENTS (3)

• NTP will keep up to date with new data from the region and act accordingly

• There is not enough evidence to support widespread use of CPT for HIV-positive patients without TB

HIV Testing and CPT in TB patients in Malawi: progress

MALAWI 2003 2004 2005 2006 2007

TB patients 26,836 26,136 26,019 26,659 25,767

HIV tested 15% 26% 47% 66% 83%

HIV positive 69% 72% 69% 66% 69%

Started CPT 87% 97% 92% 98% 97%

Progress: 2003-2007

HIV testing and CPT in TB patients in Malawi - Progress 2003-2007

0102030405060708090

100

2003 2004 2005 2006 2007

Year

Perc

enta

ge

HIV tested

HIV-positive

Started CPT

Prior to 2002…..

• ELISA based – tests batched; delays in results

• HIV testing for public health benefit (VCT)

• No useful interventions for HIV-positive patients

• No data on how many people tested per year

2002: the rapid HIV test

National TB treatment outcomes in new smear-positive PTB

Year Treatment Success Death Other

2002 71% 19% 10%

2003 70% 19% 11%

2004 71% 16% 13%

2005 74% 15% 11%

2006 79% 13% 8%

Trend in treatment outcomes Malawi: 2002-2006

Trend in TB treatment outcomes 2002-2006, Malawi

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100

2002 2003 2004 2005 2006

Year

Perc

enta

ge

Deaths

Treatment success

Other

The “New Evidence” from Africa: 2003 - 2005

New evidence in adults and children on

the safety and efficacy of CPT

• Mermin et al, Lancet 2004 (Uganda)• Chintu et al, Lancet 2004 (Zambia)• Grimwade et al, AIDS 2005 (South

Africa)

Summary of New Evidence: CPT in HIV+ve adults and children

• 25-46% reduction in mortality

• Reduction in frequency of hospital visits

• Improvement in weight gain

• Reversal of decline in CD4 counts

• Reversal in rise of viral loads

• Efficacy seen even in areas with high bacterial resistance to Cotrimoxazole

Meeting convened in February 2005 to review Malawi CPT

policyProcess:

• Meeting of 30 national experts

• Recommendations produced

• Endorsed by the Secretary for Health

• Endorsed by the MOH directors of services

CPT Policy - 2005

Who should get CPT:

Adults:• All symptomatic HIV+ve adults (Stage 2,3,4)• HIV+ve adults with CD4 count of 500 or less• Pregnant women with the above after 1st Trimester

Children:• All children born to HIV+ve mothers• All HIV+ve children, regardless of symptoms

CONCLUSION

…Operational research is only useful if it “delivers the goods”..

• Did it change policy and practice ?

• Did the research improve program performance ?