Cryptococcal Meningitis is a common infection in people with AIDS. The purpose of this study is to help find out if a new treatment for Cryptococcal Meningitis using high doses of oral fluconazole is a safe and effective alternative to the existing treatment using Intra-Venous amphotericin B. This study is being done to see if taking fluconazole alone at a dose of 1200 mg per day, 1600 mg per day, or 2000 mg per day is tolerable, safe, and effective for the treatment of Cryptococcal Meningitis for up to 10 weeks. Fluconazole is a drug that is taken by mouth that is approved throughout the world and in Kenya by the Pharmacy and Poisons Board in doses up to 400 mg per day for the treatment of Cryptococcal Meningitis. Currently, fluconazole is given alone mainly for people with mild cases of Cryptococcal Meningitis. Doses higher than 400 mg per day have not been approved by the U.S. Food and Drug Administration. The study will also collect information about treating Cryptococcal Meningitis with amphotericin B (alone or with another drug, either flucytosine or fluconazole). Amphotericin B is a drug that must be given to you through a vein in your arm. The study was planned in two stages whereby stage 1 was Dose escalation and stage 2 dose validation.

The Kericho Site will recruit between 20-30 HIV-1 infected males and females 18 years and above presenting with their first episode of cryptococcal meningitis in those who are on antiretroviral therapy or in those who have not initiated ART. Kericho site recruited 13 participants in stage 1 and will recruit up to 15 participants in stage 2

Cryptococcal meningitis [CM] is the commonest complication of the central nervous system [CNS] accounting for many AIDS associated deaths in Kenya and other parts of the developing world .The preferred regimen of CM treatment is the two week induction with intravenous amphotericin B infusions followed by a course oral fluconazole. The administration of ampho-B in resource poor setting poses a challenge due to its requisite safety monitoring and prohibitive cost and therefore the use fluconazole as a single oral agent is quite desirable.
This study is randomized, open label clinical trial being carried out in over 10 sites worldwide by the AIDS Clinical Trials Group (ACTG).The overall aim of the study is to establish a Maximum Tolerable Dose [MTD] of fluconazole which can be safely and effectively used as a single oral agent in the management of AIDS associated cryptococcal meningitis.
The study will be conducted in two stages ; Stage 1, Dose Escalation, up to three induction doses of fluconazole will be tested in sequentially enrolled cohorts. At this stage, safety will be evaluated i.e the maximum tolerable dose of fluconazole will be determined.
Stage 2, Dose Validation, induction doses of fluconazole that were found to be safe in Stage 1 will be tested against Amphotericin B for efficacy in simultaneously enrolled cohorts. This comparison aims to identify the lower dose of fluconazole with the highest efficacy. This will also serve as a pilot for a larger phase III efficacy trial and obtain additional AE reports in a larger study population.
The Kericho Site will recruit between 20-30 HIV-1 infected males and females 18 years and above presenting with their first episode of cryptococcal meningitis who have not received ART within 30 days prior to study entry.
Recruitment will primarily be done through the Kericho District Hospital HIV clinic. All enrolled participants will be followed up for 24 weeks. Due to the nature of the study (pauses between doses in Stage 1 and to confirm efficacy prior to initiating Stage 2), it is difficult to estimate the duration of accrual on this study. However it is anticipated that accrual may be completed approximately 1 year after all eligible sites are able to begin enrolling.