Antifungal Combination Treatment for Cryptococcal Meningitis in HIV

Both 1-week amphotericin B/flucytosine and 2-week fluconazole/flucytosine regimens may be effective as induction therapies for cryptococcal meningitis in resource-limited settings, according to a study published in the New England Journal of Medicine.

Cryptococcal meningitis accounts for 10% to 20% of all HIV-related deaths in a year; treatment in resource-limited settings is challenging. At this time, the standard 2-week amphotericin B regimen is unsustainable in Africa because of required monitoring, and the fluconazole monotherapy is not as effective.

A phase 3 trial (Advancing Cryptococcal Meningitis Treatment for Africa [ACTA]; Current Controlled Trials identifier: 1SRCTN45035509) compared efficacy and sustainability of 5 potential HIV-associated cryptococcal meningitis therapies between January 2013 and November 2016. 

Overall, 678 HIV-seropositive and cryptococcal meningitis-positive adults (≥18 years old) were included from 9 African centers. The following patients were excluded: those who had previously received >1 dose of amphotericin B, had >1 treatment dose (1200 mg), had >7 low doses (200 mg) of fluconazole within 2 weeks of screening, or who were pregnant/lactating.

The 5 treatment combinations included fluconazole (1200 mg/day) plus flucytosine (100 mg/kg body weight/day) orally for 2 weeks, amphotericin B (1 mg/kg/day) and either flucytosine or fluconazole intravenously for 1 week followed by 1 week of fluconazole, and amphotericin B and either flucytosine or fluconazole intravenously for 2 weeks.

All-cause mortality at 2 weeks was the primary end point to compare experimental treatments with standard 2-week amphotericin B therapy; all-cause mortality at 10 weeks was the primary endpoint to compare amphotericin B partner drugs. Secondary endpoints included 2-, 4-, and 10-week all-cause mortality; infection clearance rate; and grade 3 and 4 adverse effects.

As an amphotericin B partner drug, flucytosine was superior to fluconazole (10-week hazard ratio for death, 0.62; P =.002), which may be a result of more prolonged postantibiotic properties than fluconazole, in addition to rapid fungicidal activity.

The 1-week amphotericin B/flucytosine group had the lowest 10-week mortality, at 24.2%, which was significantly lower for than any other amphotericin B-inclusive regimen group. Compared with the 1-week amphotericin B/flucytosine group, the hazard ratios for death by 10 weeks were 1.56, 2.54, and 1.97 in the oral, 1-week, and 2-week fluconazole-inclusive groups, respectively. The oral regimen group had the slowest clearance rate of infection.

Reflective of the severe immunosuppression of patients, clinical adverse events were frequent among all regimens. Overall, the oral regimen showed less adverse effects than the 1-week and 2-week groups. Grade 4 anemia was seen in 0.9%, 4.9%, and 8.8% of patients in the oral regimen, 1-week regimens, and 2-week regimens, respectively. Grade 4 neutropenia was recorded in 0.9% and 3.2% of patients in 1-week and 2-week flucytosine-inclusive regimens, respectively, and in 1.3% of patients in flucytosine-free regimens.

Results reflect a needed balance between clearance rate of infection and drug-related adverse effects. The study authors concluded that although 1 week of amphotericin B/flucytosine was the most effective induction therapy for patients with HIV-associated cryptococcal meningitis, “in the absence of availability of amphotericin B, or in conditions which amphotericin B cannot be administered safely, the oral combination of fluconazole plus flucytosine provides an effective and sustainable alternative.”

Reference

Molloy SF, Kanyama C, Heyderman RS, et al; ACTA trial study team. Antifungal combinations for treatment of cryptococcal meningitis in Africa [published online March 15, 2018]. N Engl J Med. 2018;378:1004-1017.