Flucytosine plus fluconazole is noninferior to amphotericin B in treating cryptococcal meningitis

1. Treatment of cryptococcal meningitis with two weeks of flucytosine and fluconazole was noninferior to two weeks of amphotericin B.

2. Addition of flucytosine to amphotericin B was superior to amphotericin B plus fluconazole.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Cryptococcal meningitis accounts for a significant burden of morbidity and mortality in HIV-infected adults. Although current treatments for this opportunistic infection are effective, there is a need for efficacious treatment regimens that are more widely available. The gold standard induction therapy, two weeks of amphotericin B and flucytosine, is not available at most African clinical centers. This noninferiority clinical trial sought to assess the efficacy of combined oral flucytosine and fluconazole compared to amphotericin B among HIV-seropositive adults with cryptococcal meningitis, and determine what is an optimal drug to add to amphotericin B treatment regimens. Mortality at two weeks after treatment initiation was the primary outcome. The combination of flucytosine and fluconazole for two weeks was noninferior to two weeks of amphotericin B therapy. Addition of flucytosine to amphotericin B resulted in superior mortality outcomes relative to fluconazole add-on therapy. The most effective regimen tested was one week of amphotericin B plus flucytosine. Adverse events, including anemia and kidney injury, were most common with two weeks of amphotericin B. These results support efforts to increase accessibility of flucytosine in regions with a high burden of HIV infection.

A major strength of this study is its multicenter, randomized design. Results were consistent across both multivariable adjusted and sensitivity analyses. The use of daily intravenous normal saline and potassium and magnesium supplementation for those treated with amphotericin B might preclude generalizability of the efficacy and safety of amphotericin B treatment regimens.

Click to read the study, published in NEJM

Relevant Reading: Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis.

In-Depth [randomized controlled trial]: This was a phase three, open-label randomized controlled trial that enrolled patients from nine African centers. Inclusion criteria included HIV-seropositive status, a diagnosis of cryptococcal meningitis supported by either India ink staining or Cryptococcal antigen assay, and lack of multiple prior exposures to study drugs. The treatment arms included: i) two weeks of oral fluconazole and flucytosine, ii) one week of amphotericin B with either flucytosine or fluconazole, and iii) two weeks of amphotericin B with either flucytosine or fluconazole. The primary outcome was mortality at two weeks. Secondary outcomes included mortality at four and ten weeks, as well as rate of CSF fungal clearance.

The absolute rates of mortality at two weeks in the treatment arms were similar, with the 95% confidence intervals for difference in rates of mortality overlapping zero and meeting criteria for noninferiority (rate of mortality at two weeks: oral-regimen 18.2% (41/225); 1-week amphotericin B 21.9% (49/224); 2-week amphotericin B 21.4% (49/229)). When added to amphotericin B, flucytosine was associated with a lower risk of death relative to fluconazole (hazard ratio for death at 10 weeks [HR], 0.62; 95% confidence interval [CI], 0.45 to 0.84; p = 0.002). The rate of clearance of infection in cerebrospinal fluid was faster in the amphotericin B groups compared to the oral-regimen group, and was maximized with flucytosine add-on therapy. Grade 4 anemia developed in 8.8% of patients in the 2-week amphotericin B group compared to 0.9% in the oral-regimen group. Similar trends were seen in rates of kidney injury.

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