Simpler Antifungal Course Works for Cryptococcal Meningitis in Africa

A single high-dose course of liposomal amphotericin B as part of a three-drug antifungal treatment regimen was non-inferior to the current WHO-backed antifungal drug regimen for cryptococcal meningitis in people living with HIV, according to a phase III trial.

In an intention-to-treat (ITT) analysis of 814 patients, 101 deaths were reported in the intervention group (24.8%, 95% CI 20.7-29.3) and 117 in the control group (28.7%, 95% CI 24.4-33.4) at 10 weeks, which met criteria for non-inferiority, reported Joseph Jarvis, MBBS, PhD, of the London School of Hygiene & Tropical Medicine, and colleagues in the Ambition Study Group.

Moreover, significantly fewer participants reported grade 3/4 adverse events (AEs) in the intervention group versus controls (50% vs 62%, P<0.01 respectively), they wrote in the New England Journal of Medicine.

Cryptococcal meningitis is the second leading cause of HIV-related death worldwide, with most of those deaths occurring in sub-Saharan Africa, the authors wrote. Current World Health Organization (WHO) guidelines recommend 2 weeks of amphotericin B deoxycholate-based regimen, which not only has poor efficacy with fluconazole, but "high incidence of toxic effects." The 2018 updates to WHO guidelines recommend a 1-week regimen of this drug with antibiotic flucytosine in resource-limited settings, but this too produces serious AEs such as "anemia, kidney impairment and electrolyte abnormalities."

They touted the benefits of liposomal amphotericin B, since it can be given at higher doses due to a lower incidence of drug-related "toxic effects," has a long-half life, and "effectively penetrates brain tissue." The drug also showed potential in phase II trials.

An accompanying editorial by Mahomed-Yunus Moosa, MD, PhD, and Richard Lessells, PhD, of University of KwaZulu-Natal in Durban, South Africa, praised the trial design as "exemplary," with results generalizable to everyday clinical practice.

They hypothesized about the "potential for this treatment regimen to improve outcomes in high-burden settings, where weak health systems contribute to the high mortality," given the fact that the regimen contains a one-time intravenous infusion.

This "will cut back the need for hands-on nursing care, reduce the incidence of complications from continued intravenous access, and eliminate missed doses," the editorialists wrote. "This strategy also opens the possibility for shorter hospital stays for some patients, which would relieve overburdened inpatient services."

For the current study done from January 2018 to February 2021, adults in five African countries living with HIV and cryptococcal meningitis were randomized 1:1 to receive one of two drug protocols:

• Intervention: A single high dose of liposomal amphotericin B (10 mg/per kg body weight) on day 1, plus 14 days of flucytosine and fluconazole
• Control: Amphotericin B deoxycholate plus flucytosine for 7 days, followed by fluconazole for 7 days

Overall, 407 of each group were included in the ITT. Median age of both groups was 37 years, 60% of participants were men, and a little less than two-thirds had previously been on antiretroviral therapy.

The per protocol analysis also met prespecified non-inferiority margins, as 95 of 388 participants died in the intervention group (24.5%, 95% CI 20.3-29.1) and 113 of 396 died in the control group (28.5%, 95% CI 24.1-33.3). Results of mortality analyses at 2, 4, and 16 weeks were similar, the authors noted. Mean rate of fungal clearance from cerebrospinal fluid over 14 days was also similar between groups.

Examining safety, significantly fewer potentially life-threatening AEs occurred in the intervention group (21.7% vs 30.1% of controls, P=0.005), while significantly more participants in the control group developed grade 3/4 anemia (39.1% vs 13.3% in the intervention group, P<0.001).

Limitations to the data included the open-label nature of the trial, and that "clinical care of critically ill participants with advanced HIV disease was complex," the study authors noted.

"Because this clinical trial...was conducted in a range of health care settings across five countries in southern and eastern Africa with no loss to follow-up, our results are likely to be generalizable to other African settings with a high prevalence of HIV," they stated.

Jarvis and colleagues also pointed out that the liposomal amphotericin B regimen could lead to a shorter length of stay at the hospital. "For the evaluation of safety in this trial, our protocol required that all participants be hospitalized for a 7-day period of inpatient monitoring," they explained. "However, when scaled-up in real-world situations, earlier discharge will probably be possible for some patients."

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