Amphotericin and Flucytosine Safe, Effective for HIV-Associated Cryptococcal Meningitis

One-week amphotericin plus flucytosine was found to have comparable efficacy and safety profiles as the standard of care, 2-weeks amphotericin-based therapy, for treatment of HIV-associated cryptococcal meningitis in African patients.

The findings of the ACTA trial (Advancing Cryptococcal Meningitis Treatment for Africa) presented at the 9th International AIDS Society (IAS) Conference on HIV Science held in Paris, France, found 1-week amphotericin (AmB) plus flucytosine to be non-inferior to 2-week AmB-based therapy for treatment of HIV-associated cryptococcal meningitis (CM) in African patients. This treatment combination had the lowest 10-week mortality (24%) compared with 2 alternative treatment strategies

“The ACTA trial, with Chief Investigator Tom Harrison, is the largest trial for the treatment of cryptococcal meningitis to date, recruiting 721 patients from centers in Zambia, Malawi, Tanzania and Cameroon,” said Síle Molloy, PhD, trial manager, St George’s University of London, United Kingdom, in an email interview with Infectious Disease Advisor.

“The trial showed that two alternative treatment regimens were as good, or better, than the recommended WHO [World Health Organization] gold standard,” explained Dr Molloy, and emphasized the study’s importance by noting the grim statistics associated with CM, “Cryptococcal meningitis kills over 100,000 patients with HIV in Africa every year, accounting for 15% of all HIV-related deaths. In routine hospital settings 70% of patients with this infection will die, a death rate higher than that seen with the Ebola virus.”

The open label, phase 3, randomized, controlled, non-inferiority trial compared the safety, efficacy, and sustainability of 2 new treatment strategies against the standard of care treatment for CM, 2-weeks AmB plus flucytosine. A total of 721 study participants were randomly assigned to one of three treatment arms: oral fluconazole (1200 mg/day) plus flucytosine (100 mg/kg/day) for 2 weeks; 1-week AmB (1 mg/kg/day) plus fluconazole (1200 mg/day) or flucytosine (100 mg/kg/day) in a 1:1 ratio, and 2-weeks AmB (1 mg/kd/day) plus fluconazole (1200 mg/day) or flucytosine (100 mg/kg/day) in a 1:1 ratio, for 14 days. Fluconazole and flucytosine were compared as adjunctive treatments in the AmB arms. Antiretroviral therapy was started at 4 weeks and patient follow-up was continued up to 10 weeks.

“When a combined oral therapy of flucytosine and fluconazole (which is less toxic than the gold standard, is easier to administer, and is cheaper than the gold standard) was given during this trial the death rate was reduced by half, to 35%, a similar death rate to that seen in patients given the WHO recommended gold standard therapy (38%),” said Dr Molloy.

“When patients were given a shorter course of 1 week of AmB treatment and flucytosine (which is cheaper, easier to administer, and is less toxic than the gold standard) the death rate was further reduced to just 24%,” she added.

Mortality, assessed at 2 and 10 weeks, in the oral, 1-week, and 2-week AmB treatment groups was 18%, 22%, 21%, and 35%, 36%, 40%, respectively. Overall, the 1-week AmB plus flucytosine treatment regimen was associated with better survival compared with all other AmB treatment arms. Furthermore, flucytosine was found to be superior to fluconazole as adjunctive treatment with AmB (hazard ratio [HR] 95%CI: 1.62 [1.19-2.20], P =.002).

The greatest number of adverse events was reported in the 2-week AmB group (154), compared with the 1-week AmB (128) and oral (129) groups. Anemia, neutropenia, and hypokalemia were most frequently reported in all 3 treatment groups.

“We therefore advocate that centers in Africa should give 1 week of amphotericin B plus flucytosine as first line induction therapy for the treatment of HIV-associated cryptococcal meningitis,” stressed Dr Molloy and added, “If amphotericin B is not available, or cannot be administered safely, oral combination of fluconazole plus flucytosine provides an effective and sustainable alternative.”

Dr Molloy is hopeful that the findings of the ACTA trial will have long-term impacts on treatment of cryptococcosis in Africa.

“As flucytosine is a key component of both new, effective regimens, but is not available across Africa (due to acute market failure), we are calling for cheap generic manufacture and widespread availability to address this inequality and help to save tens of thousands of lives each year across Africa,” she concluded.

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Molloy S, Kanyama C, Heyderman R, et al; ACTA trial study team. A randomized controlled trial for the treatment of HIV-associated cryptococcal meningitis in Africa: oral fluconazole plus flucytosine or one week amphotericin-based therapy vs two weeks amphotericin-based therapy. The ACTA Trial. Presented at: IAS 2017; July 23-26, 2017; Paris, France; Oral Abstract MOAX0201LB.