1. Single-dose liposomal amphotericin B followed by flucytosine and fluconazole was non-inferior in the treatment of cryptococcal meningitis in HIV-positive adults, compared to standard therapy, which includes amphotericin B deoxycholate.
2. The liposomal amphotericin B regimen was associated with fewer adverse events.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Cryptococcal meningitis is death in regions with high human immunodeficiency virus (HIV) prevalence, such as sub-Saharan Africa. The World Health Organization (WHO) recommends a standard therapy consisting of amphotericin B deoxycholate plus flucytosine, followed by fluconazole. The main barriers of this regimen include the toxicity of amphotericin B deoxycholate and the logistical challenges of its intravenous administration in resource-limited countries. Liposomal amphotericin B can be given at a higher single dose with potentially fewer adverse events and higher brain penetration. The current phase 3 trial evaluated the efficacy and safety of a novel regimen utilizing a single dose of liposomal amphotericin B followed by flucytosine and fluconazole, against the WHO-recommended regimen as control. The novel regimen was found to be non-inferior to the control group in cryptococcal clearance from cerebrospinal fluid (CSF) and mortality in the participants. Nonetheless, the liposomal regimen was associated with fewer high-grade adverse events than the control group. These results provided evidence for the potential of liposomal amphotericin B in treating cryptococcal meningitis while relying on fewer resources and shorter hospital stays in advanced HIV patients.
In-Depth [randomized controlled trial]: The current study was a phase 3 open-label, randomized, controlled, noninferiority trial. It was conducted in 5 African nations, to compare the efficacy and safety of a novel regimen utilizing single-dose liposomal amphotericin B against a WHO-recommended control to treat cryptococcal meningitis in HIV-positive patients. Overall, 814 participants were included in the intention-to-treat analysis. HIV-positive adults who had a diagnosed episode of cryptococcal meningitis were recruited from 8 hospitals. Exclusion criteria included having previously received more than two doses of fluconazole or amphotericin B, pregnancy or breastfeeding, history of adverse reaction to study drugs, elevated alanine aminotransferase, leukopenia, and thrombocytopenia. The control group was given the WHO-recommended regimen of 1 week of amphotericin B deoxycholate (1mg/kg/day) plus flucytosine (100mg/kg/day), followed by 1 week of fluconazole (1200mg/day). The intervention group was given a single dose of liposomal amphotericin B (10mg/kg), followed by 14 days of flucytosine (100mg/kg/day) and fluconazole (1200mg/day). Participants were randomized 1:1 to each group and all were treated in hospital for at least 7 days. Afterward, all patients received fluconazole at 800mg/day for 8 weeks, then 200mg/day. Concurrent antiretroviral therapy was provided for HIV management. The primary endpoint was death from any cause at 10 weeks following randomization. Secondary endpoints included death from any cause at 2 weeks, 4 weeks, and 16 weeks, and fungal clearance rates. The noninferiority margin was specified as 10 percentage points for the upper boundary of the one-sided 95% confidence interval (CI) of the absolute difference in mortality rates. At 10 weeks, the mortality rate was 24.8% for the intervention group (95% CI, 20.7 to 29.3) and 28.7% (95% CI, 24.4 to 33.4) for the control group. Hence, the upper boundary of the one-sided 95% CI was 1.2%, which was within the noninferiority margin (P<0.001). Similar observations were made for mortality at 2, 4, and 16 weeks. Fungal clearance rate assessed from cerebrospinal fluid was -0.40 log10 colony-forming units (CFU)/mL/day for the intervention and -0.42 log10 CFU/mL/day for the control. Within the first 21 days of treatment, 50.0% of the liposomal amphotericin B group developed grade 3 or 4 adverse events, whereas 62.3% of the control group developed these events (P<0.001). Specifically, life-threatening (Grade 4) adverse events were significantly less prevalent in the intervention group (21.7%) than in the control (30.1%) (P=0.005). Other pertinent high-grade adverse events such as anemia, creatinine elevation, and thrombophlebitis were also less prevalent in the intervention group. Overall, these results showed that the regimen with liposomal amphotericin B had non-inferior efficacy in treating cryptococcal meningitis, compared to the standard WHO-recommended therapy, while also exhibiting a more favorable safety profile. Furthermore, despite the standardized 7-day inpatient monitoring in the study, there was a potential for liposomal amphotericin B to shorten hospital stay in real-world use as well.
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