Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis

Abstract

Background: Cryptococcal meningitis is a leading cause of human immunodeficiency virus (HIV)-related death in sub-Saharan Africa. Whether a treatment regimen that includes a single high dose of liposomal amphotericin B would be efficacious is not known.

Methods: In this phase 3 randomized, controlled, noninferiority trial conducted in five African countries, we assigned HIV-positive adults with cryptococcal meningitis in a 1:1 ratio to receive either a single high dose of liposomal amphotericin B (10 mg per kilogram of body weight) on day 1 plus 14 days of flucytosine (100 mg per kilogram per day) and fluconazole (1200 mg per day) or the current World Health Organization-recommended treatment, which includes amphotericin B deoxycholate (1 mg per kilogram per day) plus flucytosine (100 mg per kilogram per day) for 7 days, followed by fluconazole (1200 mg per day) for 7 days (control). The primary end point was death from any cause at 10 weeks; the trial was powered to show noninferiority at a 10-percentage-point margin.

Results: A total of 844 participants underwent randomization; 814 were included in the intention-to-treat population. At 10 weeks, deaths were reported in 101 participants (24.8%; 95% confidence interval [CI], 20.7 to 29.3) in the liposomal amphotericin B group and 117 (28.7%; 95% CI, 24.4 to 33.4) in the control group (difference, -3.9 percentage points); the upper boundary of the one-sided 95% confidence interval was 1.2 percentage points (within the noninferiority margin; P<0.001 for noninferiority). Fungal clearance from cerebrospinal fluid was -0.40 log₁₀ colony-forming units (CFU) per milliliter per day in the liposomal amphotericin B group and -0.42 log₁₀ CFU per milliliter per day in the control group. Fewer participants had grade 3 or 4 adverse events in the liposomal amphotericin B group than in the control group (50.0% vs. 62.3%).

Conclusions: Single-dose liposomal amphotericin B combined with flucytosine and fluconazole was noninferior to the WHO-recommended treatment for HIV-associated cryptococcal meningitis and was associated with fewer adverse events. (Funded by the European and Developing Countries Clinical Trials Partnership and others; Ambition ISRCTN number, ISRCTN72509687.).

Figure 1. Screening, randomization, and analysis populations (CONSORT).

Participants may have had more than one reason for exclusion. AmB denotes amphotericin B deoxycholate, HIV human immunodeficiency virus, and L-AmB liposomal amphotericin. *Two participants in the AmBisome group received at least one dose of amphotericin B deoxycholate and three participants in the control group received high dose fluconazole during the first week of induction therapy.

Figure 2. All-cause mortality.

Panel A shows the cumulative all-cause mortality by week 10 according to treatment strategy in the intention-to-treat population. Panel B shows a non-inferiority graph for differences in all-cause mortality at 10 weeks. The mean difference in 10-week mortality risk (absolute percentage difference) between the AmBisome and control arms and the two-sided 90% confidence intervals in both unadjusted and adjusted intention-to-treat and per-protocol analyses are shown. The dashed line indicated the prespecified 10% non-inferiority margin. Adjusted analysis adjusting for pre-specified baseline covariates of: site, age, sex, Glasgow Coma Scale, CD4 count, cerebrospinal fluid colony forming units/mL, HIV therapy status, hemoglobin, and CSF opening pressure.

Figure 2. All-cause mortality.

Panel A shows the cumulative all-cause mortality by week 10 according to treatment strategy in the intention-to-treat population. Panel B shows a non-inferiority graph for differences in all-cause mortality at 10 weeks. The mean difference in 10-week mortality risk (absolute percentage difference) between the AmBisome and control arms and the two-sided 90% confidence intervals in both unadjusted and adjusted intention-to-treat and per-protocol analyses are shown. The dashed line indicated the prespecified 10% non-inferiority margin. Adjusted analysis adjusting for pre-specified baseline covariates of: site, age, sex, Glasgow Coma Scale, CD4 count, cerebrospinal fluid colony forming units/mL, HIV therapy status, hemoglobin, and CSF opening pressure.