Dexamethasone not reducing mortality in cryptococcal meningitis

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For patients with HIV-associated cryptococcal meningitis, dexamethasone does not reduce mortality compared with placebo, according to a study. According to an Infectious Disease Advisor report, Dr Justin Beardsley, from the Oxford University Clinical Research Unit in the UK, and colleagues recruited adult patients with HIV-associated cryptococcal meningitis in Vietnam, Thailand, Indonesia, Laos, Uganda, and Malawi. Participants were randomised to dexamethasone or placebo for six weeks, with combination antifungal therapy with amphotericin B and fluconazole.

After enrolment of 451 patients the trial was stopped for safety reasons. The researchers found that by 10 weeks, mortality was 47% and 41% in the dexamethasone and placebo groups, respectively (hazard ratio in the dexamethasone group, 1.11; 95% confidence interval, 0.84 to 1.47); by six months, mortality was 57% and 49%, respectively (hazard ratio, 1.18; 95% confidence interval, 0.91 to 1.53).

At 10 weeks, the percentage of patients with disability was higher in the dexamethasone versus the placebo group (13% and 25% with a pre-specified good outcome, respectively; odds ratio, 0.42; 95% confidence interval, 0.25 to 0.69). Compared with the placebo group, the dexamethasone group more frequently had clinical adverse events (667 versus 494 events; P = 0.01)

“Dexamethasone did not reduce mortality among patients with HIV-associated cryptococcal meningitis and was associated with more adverse events and disability than was placebo,” the authors write.

Summary
Background
Cryptococcal meningitis associated with human immunodeficiency virus (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.
Methods
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. All the patients received either dexamethasone or placebo for 6 weeks, along with combination antifungal therapy with amphotericin B and fluconazole.
Results
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.
Conclusions
Dexamethasone did not reduce mortality among patients with HIV-associated cryptococcal meningitis and was associated with more adverse events and disability than was placebo.

Infectious Disease Advisor material
New England Journal of Medicine article summary


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