Edward Mpoza, MBChB, MMed
Nominated From: University of Minnesota
Research Site: Uganda
Research Area: Infectious Disease
Primary Mentor: Radha Rajasingham
Preventing AIDS-related cryptococcal meningitis: comparison of a 24-Week Fluconazole Regimen compared to a 10-Week regimen in asymptomatic antigenemia
HIV-associated cryptococcal meningitis (CM) is the leading cause of adult meningitis in Sub-Saharan Africa with an annual incidence of about 720,000 cases and accounts for 15%–20% of AIDS-attributable mortality (1-2). Asymptomatic cryptococcal antigenemia (CrAg) can be detected in the blood weeks prior to onset of meningitis, and is an independent predictor of mortality (3-4). The prevalence of asymptomatic CrAg in HIV patients with CD4 counts less than 100 cells/mcl in Uganda is 8.8%(5). A public health strategy to reduce mortality is to screen people entering HIV care with a CD4 <100 cells/mcl for CrAg in serum. Those who are asymptomatic CrAg positive (+) can be preemptively treated with oral fluconazole to prevent meningitis and death(5). This CrAg screening strategy has been validated in a randomized controlled trial of 2,000 HIV-infected persons in Uganda, where CrAg screening plus adherence counseling resulted in a 28% survival benefit compared to standard of care(6). This strategy is now recommended by the World Health Organization (WHO). The current WHO recommended treatment for asymptomatic CrAg+ patients is fluconazole 800mg for 2 weeks then 400mg for 8 weeks. However, the optimal dose and duration of fluconazole are based largely on expert opinion. Among patients with CM, after induction and consolidation therapy, a maintenance regimen of fluconazole 200mg daily is recommended until the patient has reconstituted their immune system, typically for more than 1 year. It is unknown whether asymptomatic CrAg+ patients require subsequent maintenance fluconazole. Consequently, different countries have adopted different strategies (7). In Uganda, current guidelines recommend the initial 10 weeks of fluconazole as pre-emptive therapy whereas in South Africa, HIV guidelines recommend continuing maintenance fluconazole (200mg daily) for 6 months. Unpublished data from Uganda show a high 6 months all-cause mortality rate and ongoing incidence of CM among those receiving pre-emptive fluconazole therapy for only 10 weeks. In the upcoming year, new Ugandan guidelines will recommend a 24-week fluconazole pre-emptive regimen such that fluconazole will be administered at a dose of 200mg daily for 14 additional weeks following the initial 10 weeks of pre-emptive therapy. There is a critical need to identify treatment strategies to maximize survival in asymptomatic CrAg+ persons. A public health strategy to reduce AIDS-related mortality is to screen at risk persons, using CrAg testing in the blood, followed by targeted preemptive antifungal therapy for those who test CrAg positive.(8) Despite a survival benefit with CrAg screening, the current standard of care treatment is inadequate, as asymptomatic CrAg positive persons still have a 2-fold worse survival compared with CrAg negative persons.(9) In 2011, the WHO recommended CrAg screening in those with a CD4 count <100/µL, followed by fluconazole preemptive therapy for asymptomatic CrAg+ persons (conditional recommendation based on low quality evidence).(10) Studies to evaluate the optimal treatment, dosing, and duration of preemptive therapy are critically needed. Uganda has recently changed their guidelines from a 10-week fluconazole preemptive therapy regimen to a 24 week fluconazole regimen. It is not known whether this 24 week regimen has any survival benefit or decreases meningitis incidence compared to the 10 week regimen in the management of asymptomatic cryptococcal antigenemia. The overall objective of this proposal is to determine the survival benefit of 24 weeks of fluconazole pre-emptive therapy compared to 10 weeks fluconazole pre-emptive therapy in asymptomatic CrAg+ patients in HIV clinics in Uganda. My central hypothesis is that the longer duration of fluconazole preemptive therapy will significantly improve survival and reduce cryptococcal meningitis in this patient population.
This study will examine optimal dosing and duration of fluconazole pre-emptive therapy for HIV-infected people with asymptomatic cryptococcal infection (cryptococcal antigen (CrAg) positive in serum). While cryptococcal meningitis is a devastating and important cause of meningitis, the incidence in the US is too low to conduct the study in the US. This study will be conducted in Uganda where the prevalence of cryptococcal meningitis is much higher. Besides contributing to improved care of cryptococcal meningitis in Uganda, it would significantly contribute to more effective treatment of cryptococcal meningitis treatment in the US and could potentially inform national and international HIV recommendations.
Aim 1: To determine the 6-month survival benefit of 24 weeks of fluconazole pre-emptive therapy compared to 10 weeks fluconazole pre-emptive therapy in asymptomatic CrAg+ patients at HIV clinics in Uganda
Aim 2: To evaluate the incidence of cryptococcal meningitis at 6 months among patients with asymptomatic cryptococcal antigenemia receiving a 24 weeks of fluconazole pre-emptive therapy compared to a 10-week fluconazole regimen
- Dr. David Meya, College of Health Sciences, Makerere University, Uganda
- Dr. Radha Rajasingham, Department of Medicine, Division of Infectious Diseases and International Medicine, University of Minnesota
- Dr. Joshua Rhein, Department of Medicine, Division of Infectious Diseases and International Medicine, University of Minnesota
- Dr. Abdu Musubire, Makerere University, Uganda
- Dr. Andrew Kambugu, Infectious Diseases Institute, College of Health Sciences, Makerere University, Uganda