Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis

Abstract

BACKGROUNDCryptococcal 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. METHODSIn 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. RESULTSThe 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. CONCLUSIONSDexamethasone did not reduce mortality among patients with HIV-associated cryptococcal meningitis and was associated with more adverse events and disability than was placebo.

Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa

“…Also supportive of the generalizability of the results was the finding that mortality in the 2-week amphotericin B-fluconazole group (41.3% at 10 weeks) was the same as that seen in the placebo group of the recent multicenter trial of adjunctive glucocorticoids in which the same antifungal regimen was used. 20 The results were consistent with those in animal models and in our phase 2 studies [10][11][12][13] and may reflect, at least in part, a balance between the rate of clearance of infection and the drug-related side effects. Flucytosine as the partner drug with amphotericin B was associated with more rapid clearance of infection than fluconazole and had a similar side-effect profile, as was previously shown in a study in Vietnam.…”

CD4 + T Cells Orchestrate Lethal Immune Pathology despite Fungal Clearance during Cryptococcus neoformans Meningoencephalitis

“…In these patients, treatment strategies must strike a balance between activation of antifungal T cell responses and limiting CNS damage due to inflammation. Although indiscriminate use of steroids is not universally justified for all cases of cryptococcal meningitis (54), including initial treatment of most HIV-infected patients where the immune response is generally poor and microbiological control has not been achieved (55), steroid therapy has been used with some success in refractory cases where elevated levels of IFN-␥, CNS T cell reactivity, and neuronal injury are predominate features of disease, such as in IRIS and PIIRS (6, 11, 27, 28, 32-34, 41, 42). However, a more complete understanding of immune pathogenesis is desperately needed to develop more precise and effective therapies.…”

The use of mannitol in HIV-infected patients with symptomatic cryptococcal meningitis

“…In our study, during the first 1 to 2 weeks, 1-2 mg dexamethasone was added to amphotericin B to reduce the infusion-related toxicities of amphotericin B. A recent study showed that dexamethasone is harmful in HIV-associated CM (24). Nevertheless, the dose of dexamethasone in our clinical practice was very small and the duration was relatively short, therefore in our opinion, the negative effects of dexamethasone were negligible.…”