The Lack of Benefits of Dexamethasone in the Treatment of Tuberculous Meningitis

The addition of dexamethasone to the treatment for tuberculous (TB) meningitis in heavily immunosuppressed HIV-positive patients in low-resource settings did not significantly improve survival or provide any other measured benefits, according to a randomized controlled trial conducted in Vietnam and Indonesia. The trial involved 520 HIV-positive adults who received a year of chemotherapy for TB meningitis. The study found that there was no significant difference in mortality between those who received dexamethasone and those who received a placebo. The incidence of secondary endpoint events was similar in both groups.

The study, published in the New England Journal of Medicine, reported that 44.1% of the participants who received dexamethasone died during the 12-month follow-up period, while 49% of those who received placebo died. The hazard ratio for death in the dexamethasone group was 0.85, with a confidence interval of 0.66-1.10 and a p-value of 0.22, indicating that the difference was not statistically significant. The researchers also found that none of the subgroups from pre-specified analyses benefited from dexamethasone.

Treatment guidelines have recommended the use of glucocorticoids, such as dexamethasone, for all patients with TB meningitis, regardless of HIV status, based on a 2004 trial that showed improved survival in Vietnamese adults with TB meningitis who received dexamethasone. However, that trial only included 98 HIV-positive participants, and there has been no subsequent research on the use of steroids specifically in HIV-positive patients with TB meningitis. Moreover, other trials with HIV-positive patients who had different types of TB have found an increased risk of HIV-associated cancers from glucocorticoids.

The new findings suggest that the intracerebral inflammation in HIV-associated tuberculous meningitis may be different or that the mechanisms leading to death may differ in HIV-positive and HIV-negative individuals. This insight challenges the previous notion that glucocorticoids should be universally recommended for all patients with TB meningitis.

The findings of this study have more global, international implications, particularly for HIV-positive adults in the developing world. Patients in resource-rich countries, such as the United States, are typically better controlled and have less severe immune suppression. Therefore, the lack of benefit from dexamethasone in this study may not directly apply to these populations.

In an accompanying editorial, the authors proposed a more targeted approach to immune modulation with therapeutics other than glucocorticoids, such as tumor necrosis factor α blockers. They also suggested investigating other therapeutic targets in this population to improve outcomes.

While the study did not find a significant benefit from dexamethasone, it also did not find any excess harm from the use of glucocorticoids. Given the severity and high mortality of TB meningitis, the use of glucocorticoids may still be justified, even if there is only a modestly lower risk of death. The decision to use steroids should consider the patient’s HIV control and level of immune suppression. Patients with well-controlled HIV may still benefit from glucocorticoids, while those who are profoundly immunosuppressed may not.

Additionally, expanding programs like PEPFAR (the U.S. President’s Emergency Plan for AIDS Relief) that improve prevention and increase access to HIV therapy can significantly reduce the risk of TB meningitis. Addressing the problem of TB meningitis requires a comprehensive approach beyond the use of steroids. Further research and larger trials are needed to clarify the role of dexamethasone and explore other potential therapeutic options.

The study had several limitations. One was that a smaller true effect from dexamethasone may exist but was not identified due to the sample size or other factors. Additional trials with larger populations may help resolve this issue. Another limitation was that some participants received open-label glucocorticoids during treatment, which may have obscured outcome differences between the two groups. This highlights the need for better-controlled studies in the future.

The addition of dexamethasone to the treatment for TB meningitis did not significantly improve survival or provide any other measured benefits in heavily immunosuppressed HIV-positive patients. The findings of this study challenge previous recommendations and call for a more targeted approach to immune modulation in this population. While the decision to use glucocorticoids should be made on an individual basis, it is important to consider the patient’s HIV control and level of immune suppression. Further research is needed to explore alternative therapeutic options and improve outcomes for patients with TB meningitis.

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