Study finds easier, less toxic regimen for HIV-associated cryptococcal meningitis
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A large study conducted in five African countries identified an easier and 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 areas with a high burden of the disease.
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 noninferiority trial at eight hospitals in Botswana, Malawi, South Africa, Uganda and Zimbabwe.
“Cryptococcal meningitis is the most frequent cause of adult meningitis in areas with a high prevalence of [HIV] and is the second leading cause of HIV-related death worldwide, 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.
WHO updated its treatment guidelines in 2018 to recommend using a shorter 1-week course of amphotericin B deoxycholate and flucytosine in resource-limited settings. “However,” Jarvis and colleagues wrote, “even 1 week of treatment with amphotericin B deoxycholate is associated with anemia, kidney impairment, and electrolyte abnormalities, and administering and monitoring intravenous amphotericin for 7 days poses logistic 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 given at higher doses owing to a lower incidence of drug-induced toxic effects, has a long tissue half-life, and effectively penetrates into brain tissue,” they wrote.
‘Major trial’
For their study, Jarvis and colleagues enrolled 814 adults aged 18 years or older with HIV who had a first episode of cryptococcal meningitis and randomly assigned them from January 2018 through February 2021 in a 1:1 ratio to receive one of two regimens:
- an experimental regimen that included a single dose (10 mg per kilogram of body weight) of liposomal amphotericin B plus 14 days of flucytosine (100 mg per kilogram per day) and fluconazole (1,200 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 (1,200 mg per day) on days 8 through 14.
The study did not lose any participants to follow-up.
“After the 2-week induction period, all the participants received fluconazole at a dose of 800 mg per day for 8 weeks and then at a dose of 200 mg per day thereafter,” Jarvis and colleagues explained. “Antiretroviral therapy was initiated, reinitiated, or switched to a new antiretroviral therapy with a different agent during weeks 4 to 6 and was chosen in accordance with national guidelines.”
Death from any cause at 10 weeks — the study’s primary end point — occurred in 24.8% of the participants who received the experimental regimen (95% CI, 20.7% to 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 that difference (10.0 to 2.2) crossed zero. However, an analysis that was adjusted for covariates associated with cryptococcal mortality showed a 5.7 percentage point difference in favor of the experimental treatment, with a 95% confidence interval that did not cross zero (11.4 to 0.04).
Additionally, the mean rate of fungal clearance from cerebrospinal fluid over 14 days — one of the secondary end points — was 0.40 log10 colony-forming units (CFU) per milliliter per day in the experimental treatment group and 0.42 log10 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% vs. 62.3%.
On Twitter, David Boulware, MD, 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 of cryptococcal meningitis ever conducted.
“This is a major trial that will change the international treatment guidelines for cryptococcal meningitis, which is the most common cause of meningitis in Africa,” Boulware, who was involved in the study, told Healio. “Additionally, the success observed in this trial opens up this one-time dosing as a possibility for other fungal infections.”
‘Important clinical implications’
The results 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 among participants who received liposomal amphotericin B.
The treatment also has the advantage of requiring only a one-time IV infusion, “which will cut back 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 lead to shorter hospital stays, too, relieving “overburdened inpatient services.”
“There is clear potential for the liposomal amphotericin B-based regimen proposed by Jarvis and colleagues to simplify management and improve outcomes of cryptococcal meningitis in high-burden settings,” Moosa and Lessells wrote. “An improvement in the outcomes from cryptococcal meningitis has for a long time been hampered by poor access to key antifungal drugs. To realize the full benefits of the proposed regimen, multiple actors need to now come together to ensure sustainable access to liposomal amphotericin B and other antifungal agents where they are most needed.”
They praised the “design and conduct” of the study as “exemplary.”
“The fact that not a single participant was lost to follow-up is a testament to the high-quality clinical trial systems that have been embedded in hospitals across several African countries by this research group,” they wrote. “The trial population reflects the patients we see in everyday clinical practice, which gives us confidence in the generalizability of the findings. There is potential for this treatment regimen to improve outcomes in high-burden settings, where weak health systems contribute to the high mortality.”
References:
Jarvis JN, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2111904.
Moosa M-YS, Lessells RJ. N Engl J Med. 2022;doi:10 .1056/NEJMe2201150.
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