Cryptococcal meningitis (CM) is a leading cause of death in AIDS patients in the developing world,responsible for up to 500,000 deaths each year in sub-Saharan Africa alone. In Uganda,cryptococcosis accounts for 30% of mortality in AIDS patients after starting ART. Many of thesecases of CM may be preventable. Routine screening for sub-clinical infection, using a simple bloodtest (cryptococcal antigen or CRAG) in patients presenting to ART programmes, can identify whichpatients are at risk of developing CM. If identified, these persons could be given 'pre-emptive' anti-fungal treatment to prevent development of overt meningitis and death.Our research team has demonstrated in a study of 311 persons with advanced HIV-infection inKampala, Uganda, that such a screen and treat strategy would be highly cost-effective, at anestimated $21 per quality-adjusted life year (QALY) saved. We know that ART alone is insufficientto prevent the development of CM in patients with sub-clinical infection, and antifungal therapy isrequired. Yet, the optimal pre-emptive anti-fungal treatment dose and duration necessary to preventCM in patients with sub-clinical infection have yet to be established.We propose to investigate how practical and effective CRAG screening and targeted pre-emptivefluconazole treatment would be in the operational setting of patients entering ART treatmentprogrammes in Kampala City Council clinics in Uganda. In addition, a new point-of-care CRAGscreening test will be evaluated in parallel with the currently used test. In the planned study, 1000patients will be screened for cryptococcal antigenemia prior to starting ART. Those with a positiveresult will receive pre-emptive short course oral fluconazole therapy to treat sub-clinicalcryptococcosis and determine if this is effective at preventing CM. All patients will then be started onstandard ART and followed for 6 months to determine their overall outcome and incidence of clinicalCM compared to historical cohort controls. The cost-effectiveness of the intervention with pre-emptive fluconazole therapy will be analyzed. The results of this operational research would bewidely applicable to other regions in sub-Saharan Africa and could lead to improved public policiesto prevent CM.

Public Health Relevance

Cryptococcal meningitis, a fungal infection around the brain, is a leading cause of death due to AIDS in Africa and is potentially detectable during an asymptomatic pre-clinical phase. High dose oral anti-fungal therapy (fluconazole) can improve survival after ART initiation.

National Institute of Health (NIH)
Coordinating Office of Global Health (COGH)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZGH1-SRC (99))
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Infectious Diseases Institute
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