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 these cases of CM may be preventable. Routine screening for sub-clinical infection, using a simple blood test (cryptococcal antigen or CRAG) in patients presenting to ART programmes, can identify which patients 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 in Kampala, Uganda, that such a screen and treat strategy would be highly cost-effective, at an estimated $21 per quality-adjusted life year (QALY) saved. We know that ART alone is insufficient to prevent the development of CM in patients with sub-clinical infection, and antifungal therapy is required. Yet, the optimal pre-emptive anti-fungal treatment dose and duration necessary to prevent CM in patients with sub-clinical infection have yet to be established. We propose to investigate how practical and effective CRAG screening and targeted pre-emptive fluconazole treatment would be in the operational setting of patients entering ART treatment programmes in Kampala City Council clinics in Uganda. In addition, a new point-of-care CRAG screening test will be evaluated in parallel with the currently used test. In the planned study, 1000 patients will be screened for cryptococcal antigenemia prior to starting ART. Those with a positive result will receive pre-emptive short course oral fluconazole therapy to treat sub-clinical cryptococcosis and determine if this is effective at preventing CM. All patients will then be started on standard ART and followed for 6 months to determine their overall outcome and incidence of clinical CM 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 be widely applicable to other regions in sub-Saharan Africa and could lead to improved public policies to 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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