PROGRAMMATIC OPERATIONAL RESEARCH DEVELOPMENT OF MALAWI’ S POLICY ON COTRIMOXAZOLE PREVENTIVE THERAPY R. Zachariah / AD Harries Contacts:

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 STUDIES in 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-CPT1061 Control925 Karonga VCT-CPT362 Control355

Interventions in TB patients Thyolo (1061 patients) Karonga (362 patients) HIV tested91%73% HIV-positive69%51% Started CPT94%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 deaths

Case fatality: all TB types Thyolo: VCT-CPT 28% Control 36% p < Karonga: VCT-CPT 29% Control 37% p < 0.001

Number of TB patients that needed treatment with “VCT and CPT” to prevent one death = 12 in 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 TB patients26,83626,13626,01926,65925,767 HIV tested15%26%47%66%83% HIV positive69%72%69%66%69% Started CPT87%97%92%98%97%

Progress:

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 YearTreatment SuccessDeathOther %19%10% %19%11% %16%13% %15%11% %13%8%

Trend in treatment outcomes Malawi:

The “New Evidence” from Africa: 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 policy Process: Meeting of 30 national experts Recommendations produced Endorsed by the Secretary for Health Endorsed by the MOH directors of services

CPT Policy

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 1 st 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 ?