Comparison of Early Fungicidal Activity and Mortality Between Daily Liposomal Amphotericin B and Daily Amphotericin B Deoxycholate for Cryptococcal Meningitis

Abstract

Background: Limited data exist on the antifungal activity of daily liposomal amphotericin B with flucytosine induction regimens for cryptococcal meningitis, which are recommended in high-income countries. Liposomal amphotericin B monotherapy at 3 mg/kg previously failed to meet noninferiority criteria compared to amphotericin B deoxycholate in its registrational clinical trial. We aimed to compare the quantitative antifungal activity and mortality between daily amphotericin B deoxycholate and daily liposomal amphotericin B among persons with human immunodeficiency virus (HIV)-related cryptococcal meningitis receiving adjunctive flucytosine 100 mg/kg/day.

Methods: We analyzed data from 3 clinical studies involving participants with HIV-associated cryptococcal meningitis receiving either daily liposomal amphotericin B at 3 mg/kg/day with flucytosine (n = 94) or amphotericin B deoxycholate at 0.7-1.0 mg/kg/day with flucytosine (n = 404) as induction therapy. We compared participant baseline characteristics, cerebrospinal fluid (CSF) early fungicidal activity (EFA), and 10-week mortality.

Results: We included 498 participants in this analysis, of whom 201 had available EFA data (n = 46 liposomal amphotericin B; n = 155 amphotericin B deoxycholate). Overall, there is no statistical evidence that the antifungal activity of liposomal amphotericin B (mean EFA, 0.495 [95% confidence interval {CI}, .355-.634] log10 colony-forming units [CFU]/mL/day) differ from amphotericin B deoxycholate (mean EFA, 0.402 [95% CI, .360-.445] log10 CFU/mL) (P = .13). Mortality at 10 weeks trended lower for liposomal amphotericin B (28.2%) versus amphotericin B deoxycholate (34.6%) but was not statistically different when adjusting for baseline characteristics (adjusted hazard ratio, 0.74 [95% CI, .44-1.25]; P = .26).

Conclusions: Daily liposomal amphotericin B induction demonstrated a similar rate of CSF fungal clearance and 10-week mortality as amphotericin B deoxycholate when combined with flucytosine for the treatment of HIV-associated cryptococcal meningitis.

Trial registration: ClinicalTrials.gov NCT04031833.

Keywords: HIV; amphotericin B deoxycholate; antifungal; cryptococcal meningitis; liposomal amphotericin B.

Figure 1.

Spaghetti plots demonstrating individual participant early fungicidal activity by amphotericin group. Figure 1 demonstrates early fungicidal activity of the cerebrospinal fluid (CSF) clearance rate of Cryptococcus yeasts over time. The spaghetti plots display individual participants' CSF quantitative culture data presented as log₁₀ colony-forming units/mL (y-axis) over time (x-axis). The black line represents the group mean. Abbreviations: AMBITION, AMBIsome Therapy Induction OptimisatioN; EnACT, Encochleated oral Amphotericin for Cryptococcal meningitis Trial.

Figure 2.

Kaplan-Meier curve for 10-week survival for persons with human immunodeficiency virus–associated cryptococcal meningitis. Figure 2 demonstrates cumulative survival probability over 10 weeks of induction and consolidation therapy. Overall, mortality at 10 weeks did not statistically differ in participants receiving daily liposomal amphotericin B (28.2% [95% confidence interval {CI}, 16.1%–38.5%]) versus those receiving daily amphotericin B deoxycholate (34.6% [95% CI, 29.3%–39.5%]) (absolute difference, 6.4%; log-rank P = .089; Peto-Peto P = .055). Supplementary Figure 3 demonstrates the same Kaplan-Meier curve with at-risk and event tables included.