Single high-dose liposomal amphotericin based regimen for treatment of HIV-associated Cryptococcal Meningitis: results of the phase-3 Ambition-cm Randomised Trial


BACKGROUND: Cryptococcal meningitis (CM) is a leading cause of HIV-related mortality. Based on phase-II study data showing that a single high-dose of 10mg/kg liposomal amphotericin-B (AmBisome, Gilead Sciences Inc) was non-inferior to 14 days of standard dosing in clearing Cryptococcus from the cerebrospinal fluid we performed a phase-III randomised controlled non-inferiority trial to examine the impact of a single high-dose of AmBisome in averting all-cause mortality from CM.
METHODS: HIV-positive adults with a first episode of CM in Botswana, Malawi, South Africa, Uganda and Zimbabwe were randomised to induction therapy of either (i) single, high-dose AmBisome (10mg/kg) given with 14 days of flucytosine 100mg/kg/day and fluconazole 1200mg/day (AmBisome) or (ii) 7 daily doses of amphotericin B deoxycholate (1mg/kg) plus 7 days of flucytosine 100mg/kg/day, followed by 7 days of fluconazole 1200mg/day (control). All participants received consolidation therapy of fluconazole 800mg/day for eight weeks. The primary endpoint was all-cause mortality at 10 weeks with the trial powered to show non-inferiority with a 10% margin.
RESULTS: We randomised 844 participants from January 2018 to February 2021. 60.2% were men, with median age of 37 years, median CD4 of 27 cells/mm2, and 28.5% had abnormal mental status; 30 participants met early withdrawal exclusion criteria, leaving 814 in the intention-to-treat (ITT) population. None were lost to follow-up. In the primary ITT analysis 10-week mortality was 24.82% (101/407) in the AmBisome arm and 28.75% (117/407) in the control arm. The difference in mortality between the AmBisome arm and control arm was -3.93%, with the upper limit of the 1-sided 95%CI for the difference being 1.17%, well below the pre-specified 10% non-inferiority margin. The single high-dose AmBisome treatment was well tolerated.

CONCLUSIONS: Single high-dose AmBisome on a backbone of flucytosine and fluconazole was non-inferior to the current WHO recommended standard of care for HIV-associated cryptococcal meningitis.