In the recent best-selling book and award-nominated movie, The Martian, astronaut and botanist Mark Watney is stranded alone on Mars. The story follows his attempts to defy certain death and, through creativity and scientific experimentation, use his limited resources to generate oxygen, grow food, and make it home to Earth. Recently the medical community has found itself in a similar, albeit less Oscar-worthy, situation: there are almost 1 million cases of HIV-associated cryptococcal meningitis per year, with high rates of associated death and morbidity. With limited treatment options and years until new therapies may be available, front-line clinicians have been challenged to think creatively.
In this week’s NEJM, Beardsley et al. report on a double-blinded, randomized and placebo-controlled trial that attempts to do just that. Inspired by prior studies demonstrating a clinical benefit of adjunctive steroids for acute bacterial meningitis and tuberculous meningitis, Beardsley et al. hypothesized that dexamethasone might benefit patients undergoing treatment for cryptococcal meningitis. Unfortunately, the study was stopped early when preliminary analysis raised concerns that dexamethasone use was associated with clinical harm.
Beginning in February 2013, study-sites in Indonesia, Laos, Thailand, Vietnam, Malawi, and Uganda enrolled adults with HIV, clinical concern for cryptococcal meningitis, and either (1) a positive CSF india ink stain, (2) a positive CSF or blood culture for Cryptococcus, or (3) a positive CSF cryptococcal antigen.
Two-hundred twenty-four patients were randomized to the dexamethasone group and 227 to the placebo group. In addition to 2 weeks of directly-observed intravenous amphotericin and fluconazole followed by 8 weeks of oral consolidation therapy, study participants received adjunctive dexamethasone or placebo for 6 weeks.
Following early study cessation at 22 months, subsequent data analysis did not reveal a significant difference in mortality between the groups at 10 weeks or 6 months, but did demonstrate several concerning findings among the secondary and safety outcomes. There was a significant association between dexamethasone therapy and decreased rates of CSF cryptococcal clearance (p<0.001) and increased rates of a composite of death or disability at 10 weeks and 6 months (p<0.001, p<0.002). Additionally, the dexamethasone group had significantly increased rates of clinical adverse events (p=0.01), including rates of AIDS-defining illnesses, infections, and gastrointestinal, renal/urinary and cardiac disorders.
The findings reported by Beardsley et al. provide evidence against the universal use of adjunctive dexamethasone in the treatment of HIV-associated cryptococcal meningitis. However, this is not the end of the story for those clinicians on a mission to find better ways to treat this serious infection. A brief review of clinicaltrials.gov revealed several ongoing studies of new approaches to therapy that utilize existing medications. Additionally, there is ongoing work to improve access to current evidence-based antifungals. Rather than discourage us, the results of Beardsley et al. reinforce the importance of pragmatic creativity in medicine. As protagonist Mark Watney says, “I guess you could call it a ‘failure,’ but I prefer the term ‘learning experience.’”