April 01, 2022
4 minute read
Disclosures: Boulware reports receiving grants from EDCTP and NIHR and other support from Gilead Sciences during the study. Jarvis reports receiving grants from EDCTP and NIHR during the study. Lessells and Moosa do not report any relevant financial information. Please see the study for relevant financial information from all other authors.
A large study in five African countries has identified an easier, less toxic treatment for HIV-associated cryptococcal meningitis that includes a single high dose of liposomal amphotericin B.
Experts said the regimen will simplify treatment guidelines and could improve outcomes in high-burden areas.
Joseph N. Jarvis, MRCP, PhD, a researcher from the London School of Hygiene & Tropical Medicine and colleagues from the Ambition Study Group conducted the Phase 3 randomized controlled non-inferiority trial in eight hospitals in Botswana, Malawi, South Africa, Uganda and in Zimbabwe.
“Cryptococcal meningitis is the most common cause of meningitis in adults in areas with a high prevalence of [HIV] and is the second leading cause of HIV-related death globally, with the majority of deaths occurring in sub-Saharan Africa,” Jarvis and colleagues wrote.
According to the authors, conventional antifungal regimens have not been very effective against cryptococcal meningitis and are frequently associated with toxic effects.
The WHO updated its treatment guidelines in 2018 to recommend the use of a shorter one-week course of amphotericin B deoxycholate and flucytosine in resource-limited settings. “However,” wrote Jarvis and colleagues, “even 1 week of treatment with amphotericin B deoxycholate is associated with anemia, renal failure, and electrolyte abnormalities, and administration and monitoring of intravenous amphotericin for 7 days pose logistical challenges in many clinical settings”.
On the other hand, liposomal amphotericin B “is potentially well suited for use in short-course induction treatments of cryptococcal meningitis because it can be administered at higher doses due to a lower incidence of ‘drug-induced toxic effects, has a long tissue half-life and effectively penetrates brain tissue,’ they wrote.
For their study, Jarvis and colleagues recruited 814 HIV-positive adults aged 18 or older who had a first episode of cryptococcal meningitis and randomly assigned them from January 2018 to February 2021 in a 1:1 ratio to receive the one of two regimes:
- an experimental regimen comprising a single dose (10 mg per kilogram body weight) of liposomal amphotericin B plus 14 days of flucytosine (100 mg per kilogram per day) and fluconazole (1200 mg per day), or
- the WHO-recommended regimen of 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) on days 8-14 .
The study did not lose any participants to follow-up.
“After the 2-week induction period, all participants received fluconazole at a dose of 800 mg daily for 8 weeks, then at a dose of 200 mg daily thereafter,” explained Jarvis and colleagues. . “Antiretroviral therapy was initiated, reinitiated, or switched to new antiretroviral therapy with a different agent during weeks 4 to 6 and was chosen according to national guidelines.”
Death from any cause at 10 weeks – the primary endpoint of the study – occurred in 24.8% of participants who received the experimental regimen (95% CI, 20.7% at 29.3%) and 28.7% of participants in the control group (95% CI, 24.4% to 33.4%) – an absolute difference of 3.9 percentage points, according to an unadjusted analysis.
The 95% confidence interval for this difference (10.0 to 2.2) crossed zero. However, an analysis adjusted for covariates associated with cryptococcal mortality showed a difference of 5.7 percentage points in favor of the experimental treatment, with a 95% confidence interval that did not cross zero (11.4 to 0, 04).
In addition, the mean rate of fungal clearance from cerebrospinal fluid over 14 days – one of the secondary endpoints – was 0.40 logten colony forming units (CFU) per milliliter per day in the experimental treatment group and 0.42 logten CFU per milliliter per day in the control group. The researchers also noted that fewer participants in the experimental treatment arm had grade 3 or 4 adverse events than in the standard treatment group, 50.0% versus 62.3%.
On Twitter, David BoulwareMD, MPH, professor of medicine in the division of infectious diseases and international medicine at the University of Minnesota Medical School, said it was the largest randomized controlled trial ever of cryptococcal meningitis.
“This is a major trial that will change international treatment guidelines for cryptococcal meningitis, which is the most common cause of meningitis in Africa,” Boulware, who participated in the study, told Healio. “Furthermore, the observed success in this trial opens up this single dose as a possibility for other fungal infections.”
“Important Clinical Implications”
The findings have “important clinical implications,” according to Mahomed-Yunus S. Moosa, MBChB, PhD, and Richard J. Lessells, MBChB, PhD, from the University of KwaZulu-Natal in Durban, South Africa.
In an editorial that accompanied the study, Moosa and Lessells noted that there was a lower incidence of anemia and thrombophlebitis leading to antibiotic therapy in participants who received liposomal amphotericin B.
The treatment also has the benefit of requiring only a single intravenous infusion, “which will reduce the need for hands-on nursing care, reduce the incidence of complications from continued intravenous access, and eliminate missed doses, which are all too common.” .with daily administration of amphotericin B,” they wrote. It could also result in shorter hospital stays, relieving “overburdened inpatient wards.”
“There is clear potential for the liposomal amphotericin B regimen proposed by Jarvis and colleagues to simplify management and improve outcomes of cryptococcal meningitis in high-burden settings,” Moosa and Lessells wrote. “Improving outcomes for cryptococcal meningitis has long been hampered by limited access to leading antifungal drugs. To take full advantage of the proposed regimen, multiple actors must now come together to ensure sustained access to liposomal amphotericin B and other antifungal agents where they are most needed.
They described the “design and conduct” of the study as “exemplary”.
“The fact that no participants were lost is testament to the high quality clinical trial systems that have been integrated into hospitals in several African countries by this research group,” they wrote. “The trial population reflects the patients we see in daily clinical practice, which gives us confidence in the generalizability of the results. This regimen has the potential to improve outcomes in high-burden settings, where weak health systems contribute to high mortality.
Moosa M-YS, Lessells RJ. N Engl J Med. 2022;doi:10.1056/NEJMe2201150.