Cryptococcal meningitis associated with HIV infection causes more than 600,000 deaths each year worldwide. Treatment has changed little in 20 years, and there are no imminent new anticryptococcal agents. The use of adjuvant glucocorticoids reduces mortality among patients with other forms of meningitis in some populations, but their use is untested in patients with cryptococcal meningitis.
In this double-blind, randomized, placebo-controlled trial, we recruited adult patients with HIV-associated cryptococcal meningitis in Vietnam, Thailand, Indonesia, Laos, Uganda, and Malawi. Diagnosis of crytococcal meningitis was based on clinical syndrome consistent with cryptococcal meningitis, and microbiologic confirmation of disease, as indicated by one or more of the following test results: positive India ink staining of CSF, culture of cryptococcus species from CSF or blood, or cryptococcal antigen detected in CSF on cryptococcal antigen lateral flow assay.
All the patients received either dexamethasone or placebo for 6 weeks, along with combination antifungal therapy with amphotericin B and fluconazole. Dexamethasone was given intravenous : 0.3 mg per kilogram of body weight per day during the first week and 0.2 mg per kilogram per day during the second week, followed by oral administration of 0.1 mg per kilogram per day during the third week, 3 mg per day during the fourth week, 2 mg per day during the fifth week, and 1 mg per day during the sixth week. Amphotericin B deoxycholate was administered at a dose of 1 mg per kilogram per day and fluconazole at a dose of 800 mg per day for 2 weeks, followed by consolidation therapy (800 mg of fluconazole per day for 8 weeks) and then maintenance therapy (200 mg of fluconazole per day). The protocol initially recommended starting antiretroviral therapy 2 to 4 weeks after the initiation of antifungal treatment, updated to 5 weeks later on. The primary outcome was survival until 10 weeks after randomization.
The trial was stopped for safety reasons after the enrollment of 451 patients. Mortality was 47% in the dexamethasone group and 41% in the placebo group by 10 weeks (hazard ratio in the dexamethasone group, 1.11; 95% confidence interval [CI], 0.84 to 1.47; P = 0.45) and 57% and 49%, respectively, by 6 months (hazard ratio, 1.18; 95% CI, 0.91 to 1.53; P = 0.20). The percentage of patients with disability at 10 weeks was higher in the dexamethasone group than in the placebo group, with 13% versus 25% having a prespecified good outcome (odds ratio, 0.42; 95% CI, 0.25 to 0.69; P<0.001). Clinical adverse events were more common in the dexamethasone group than in the placebo group (667 vs. 494 events, p = 0.01), with more patients in the dexamethasone group having grade 3 or 4 infection (48 vs. 25 patients, p = 0.003), renal events (22 vs. 7, p = 0.004), and cardiac events (8 vs. 0, p = 0.004). Fungal clearance in cerebrospinal fluid was slower in the dexamethasone group. Results were consistent across Asian and African sites.
In conclusion, dexamethasone did not reduce mortality among patients with HIV-associated cryptococcal meningitis and was associated with more adverse events and disability than was placebo.
previous item
