ACTG Study Findings Suggest Need to Update WHO Treatment Guidelines for Cryptococcol Meningitis

Cryptococcal meningitis (CM) remains one of the most common and serious opportunistic infections in people living with HIV in southern Africa. Understanding the best therapy for this infection is critically important. In some settings, fluconazole, which can be given orally, can be an exceptionally important medication. A5225 tested using high doses of fluconazole in the initial treatment of CM and compared this to amphotericin B deoxycholate (0.7 – 1 mg/kg per day) therapy. Giving 1200 mg of fluconazole was associated with increased mortality in an early stage of the study and that dose was stopped. The two highest doses of fluconazole (1600 and 2000 mg daily) were safe and well tolerated. The time it took the two doses to clear cryptococcus in the spinal fluid was similar but not as rapid as amphotericin.

WHO guidelines now recommend a single high dose of liposomal amphotericin B coupled with 14 days of flucytosine and fluconazole for the initial treatment of CM. However, where amphotericin is not available, fluconazole (1200 mg daily) plus flucytosine for 14 days is recommended for initial treatment. The data from this study suggest that higher doses of fluconazole with flucytosine should be considered.

Lalloo, U. G., Komarow, L., Aberg, J. A., Clifford, D. B., Hogg, E., McKhann, A., Bukuru, A., Lagat, D., Pillay, S., Mave, V., Supparatpinyo, K., Samaneka, W., Langat, D., Ticona, E., Badal-Faesen, S., Larsen, R. A., & ACTG A5225 Team (2023). Higher Dose Oral Fluconazole for the Treatment of AIDS-related Cryptococcal Meningitis (HIFLAC)-report of A5225, a multicentre, phase I/II, two-stage, dose-finding, safety, tolerability and efficacy randomised, amphotericin B-controlled trial of the AIDS Clinical Trials Group. PloS one, 18(2), e0281580.