New regimens better for HIV-associated cryptococcal meningitis

In resource-limited settings, a shorter 1-week course of amphotericin B plus flucytosine is the most effective option for induction therapy in patients with HIV-associated cryptococcal meningitis, according to findings from a phase 3 trial published in The New England Journal of Medicine.

Results from the Advancing Cryptococcal Meningitis Treatment for Africa (ACTA) trial also suggested that an oral combination of fluconazole plus flucytosine is an effective and sustainable option in places where amphotericin B is unavailable or cannot be administered safely, Síle F. Molloy, PhD, epidemiologist and international project manager for cryptococcal meningitis treatment trials at the Centre for Global Health, St. George’s University of London, and colleagues said.

Experts have estimated that cryptococcal meningitis kills more than 180,000 people globally each year, most in sub-Saharan Africa, and is responsible for 15% of AIDS-related deaths. ACTA was conducted from 2013 to 2016 at nine sites in four sub-Saharan African countries — Cameroon, Malawi, Tanzania and Zambia — to test new treatment strategies for HIV-related cryptococcal meningitis.

Molloy and colleagues sought therapies that were more sustainable than the standard 2 weeks of amphotericin B plus flucytosine, which is not available in most of Africa, and more effective than monotherapy with fluconazole, which is easier to obtain and widely used but associated with slower rates of fungal clearance and high rates of mortality, they said.

Based on findings from the trial, WHO issued new guidelines recommending a 1-week course of amphotericin B and flucytosine as the preferred induction regimen for adults, adolescents and children living with HIV. If amphotericin B is unavailable, the agency recommends combination flucytosine and fluconazole as an alternative regimen. According to the new guidelines, which were published just this month, these regimens can potentially reduce mortality by half compared with using fluconazole monotherapy.

But WHO also noted that flucytosine is not registered and largely unavailable in resource-limited settings, especially sub-Saharan Africa, where the ACTA trial took place.

“The cost of registration in many countries is an additional disincentive to using flucytosine. Advocacy is required to reduce the cost of flucytosine and simplify drug registration procedures,” the agency said.

In the trial, Molloy and colleagues randomly assigned 721 participants aged 18 years and older to receive either a 2-week oral regimen of fluconazole (1,200 mg per day) plus flucytosine (100 mg per kilogram of body weight per day) or 1 or 2 weeks of amphotericin B (1 mg per kilogram per day). Patients in the amphotericin B groups were also randomly assigned to receive either fluconazole or flucytosine as a partner drug.

Among the 678 patients who were eligible for inclusion in the intent-to-treat analyses, mortality was similar across all three groups at 2 weeks (18.2%, 21.9% and 21.4% for the oral regimen, 1 week of amphotericin B and 2 weeks of amphotericin B, respectively) and 10 weeks (35.1%, 36.2% and 39.7%, respectively).

According to Molloy and colleagues, flucytosine was the superior partner drug for amphotericin B. It was associated with a lower mortality rate than fluconazole — 31.1% vs. 45%, with an HR for death at 10 weeks of 0.62 (95% CI, 0.45 to 0.84; P = .002). The researchers said patients who received 1 week of amphotericin B plus flucytosine had a 24.2% mortality rate at 10 weeks (95% CI, 16.2 to 32.1) — the lowest of the group.

“Despite the fact that patients in resource-limited settings have access to ART, the incidence of cryptococcal meningitis is not decreasing in many centers,” Molloy and colleagues wrote. “Widespread availability of generic flucytosine is urgently needed as an essential part of global programs to reduce HIV-related mortality, as is continued investigation into new drug therapies. Efforts by international agencies to make flucytosine available are gaining momentum.” – by Gerard Gallagher

References:

Molloy SF, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1710922.

WHO. Guidelines for managing advanced HIV disease and rapid initiation of antiretroviral therapy. 2018. http://www.who.int/hiv/pub/guidelines/advanced-HIV-disease/en/. Accessed March 16, 2018.

Disclosures: Molloy reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.