Compared with placebo in adults living with HIV, adjunctive dexamethasone did not improve survival or any of several secondary outcomes of tuberculous meningitis, researchers report. “The mortality associated with tuberculous meningitis among HIV-positive persons remains unacceptably high, which emphasizes the global importance of enhanced detection and early treatment of HIV and tuberculosis,” conclude the authors.
In Vietnam and Indonesia, 520 HIV-positive adults with tuberculous meningitis were randomized to a double-blind 6-to-8-week tapering course of dexamethasone or placebo in addition to 12 months of antituberculosis chemotherapy. Based on a primary endpoint of death from any cause during the 12 months after randomization, the study showed the following: “The median age was 36 years; 255 of 520 participants (49.0%) had never received antiretroviral therapy, and 251 of 484 participants (51.9%) with available data had a baseline CD4 count of 50 cells per cubic millimeter or less. Six participants withdrew from the trial, and five were lost to follow-up. During the 12 months of follow-up, death occurred in 116 of 263 participants (44.1%) in the dexamethasone group and in 126 of 257 participants (49.0%) in the placebo group (hazard ratio, 0.85; 95% confidence interval, 0.66 to 1.10; P = 0.22). Prespecified analyses did not reveal a subgroup that clearly benefited from dexamethasone. The incidence of secondary end-point events, including cases of immune reconstitution inflammatory syndrome during the first 6 months, was similar in the two trial groups. The numbers of participants with at least one serious adverse event were similar in the dexamethasone group (192 of 263 participants [73.0%]) and the placebo group (194 of 257 participants [75.5%]) (P = 0.52).”
Editorial: “Despite the negative result, this trial sends an unequivocal message: a plateau has been reached with existing therapies in tuberculous meningitis,” editorialists write. “Different approaches are required. Attention to low-cost nontherapeutic interventions, such as improvements in basic supportive management and earlier provision of therapy through better diagnostics and pathways to care, may have large effects. Current trials are evaluating enhanced antituberculosis-drug regimens and aspirin (which has antiinflammatory effects at higher doses). The tuberculosis community should be open to developing and testing even bolder interventions, including rifamycin-free drug combinations designed specifically for tuberculous meningitis, delivered with the most promising novel candidates for host-directed therapy. Donovan and colleagues have shown progress can be made to reduce suffering from tuberculous meningitis, but there is still a long way to go.”