COMMENTARY

A Negative Trial for HIV-Associated Cryptococcal Meningitis

Laurie L. Barclay, MD

Disclosures

March 01, 2016

Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis

Beardsley J, Wolbers M, Kibengo FM, et al, for the CryptoDex Investigators
N Engl J Med. 2016;374:542-554

Study Summary

Each year, cryptococcal meningitis in patients with HIV infection causes more than 600,000 deaths worldwide. With no new anticryptococcal agents on the horizon and little change in standard treatment over the past two decades, adjuvant glucocorticoid therapy is in widespread use. This intervention has been shown to lower mortality associated with other forms of meningitis but is untested in cryptococcal meningitis.[1,2,3]

This double-blind trial enrolled adults with HIV-associated cryptococcal meningitis in Vietnam, Thailand, Indonesia, Laos, Uganda, and Malawi. All patients received combination antifungal therapy of amphotericin B and fluconazole, and were randomly assigned to receive either 6 weeks of dexamethasone or placebo.

After enrollment of 451 patients, the trial was terminated prematurely due to safety concerns. Compared with the placebo group, the dexamethasone group had greater disability at 10 weeks, with prespecified good outcome of 13% in the dexamethasone group vs 25% in the placebo group (odds ratio 0.42; 95% confidence interval [CI], 0.25-0.69; P<.001) and more clinical adverse events in the dexamethasone group (667 vs 494 events; P=.01). More patients in the dexamethasone group compared with the placebo group had grade 3 or 4 infection (48 vs 25 events; P=.003), renal events (22 vs 7 events; P=.004), and cardiac events (8 vs 0 events; P=.004). The dexamethasone group also had slower fungal clearance in cerebrospinal fluid.

The groups did not differ significantly in mortality, with 47% in the dexamethasone group vs 41% in the placebo group by 10 weeks (hazard ratio [HR] 1.11; 95% CI, 0.84-1.47; P=.45) and 57% in the dexamethasone group vs 49% in the placebo group by 6 months (HR 1.18; 95% CI, 0.91-1.53; P=.20). Findings were similar across Asian and African sites.

Viewpoint

Cryptococcomas with mass effect, acute respiratory distress syndrome, and immune reconstitution inflammatory syndrome were infrequent among participants and are indications for glucocorticoids according to current guidelines. Thus, this trial cannot exclude the possibility that dexamethasone would be helpful in such patients. In addition, 11% of all patients who were excluded from the study had already received glucocorticoids for central nervous system disease. Early trial termination lowered statistical power to show an effect of dexamethasone on the primary outcome of mortality at 10 weeks.

Despite these limitations, the findings suggest that, compared with placebo, dexamethasone did not improve survival among patients with HIV-associated cryptococcal meningitis and was associated with more disability and adverse events. Given the lack of effective adjunctive therapy, improving access to flucytosine and other effective antifungal treatments should be a global priority.

Abstract

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