By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC
Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH
SYNOPSIS: A randomized, placebo-controlled clinical trial in human immunodeficiency virus-positive adults with tuberculous meningitis found no benefit for adjunctive dexamethasone in survival or risk of neurologic immune reconstitution inflammatory syndrome (IRIS). Side effects were similar to placebo.
SOURCE: Donovan J, Bang ND, Imran D, et al. Adjunctive dexamethasone for tuberculous meningitis in HIV-positive adults. N Engl J Med 2023;389:1357-1367.
Although adjunctive corticosteroids are widely used in human immunodeficiency virus (HIV) patients with tuberculous (TB) meningitis, the evidence of their benefit is weak. For comparison, some studies have shown worse outcomes with steroids and HIV-associated cryptococcal meningitis. Steroid use also has been associated with an increased risk of cancer in patients with HIV. Therefore, Donovan and colleagues aimed to determine whether adjunctive dexamethasone would reduce mortality from HIV-associated TB meningitis.
The study was a randomized, double-blind, placebo-controlled trial conducted in Vietnam and Indonesia with HIV-positive adults aged 18 years or older. Patients were included who had a clinical diagnosis of TB meningitis and TB therapy was planned or started. Exclusion criteria were having another brain infection, receiving anti-TB therapy for more than six consecutive days prior to trial enrollment, receiving systemic steroids for more than three consecutive days prior to enrollment, or if systemic steroids were contraindicated. Patients were randomized 1:1 to either receive dexamethasone or placebo. All received standard-of-care anti-TB therapy and antiretroviral (ART) therapy. Clinical assessments were performed at baseline and on days 3, 7, 10, 14, 21, and 30, and then monthly until month 12.
The primary outcome was death from any cause during the 12 months after randomization. Development of neurologic immune reconstitution inflammatory syndrome (IRIS) during the first six months, HIV-associated cancer, need for shunt surgery, and serious adverse events were secondary outcomes.
There were 520 patients enrolled in the trial, of whom 263 received dexamethasone and 257 received placebo. The median age was 36 years (range, 30 to 41 years). Thirty-five percent (186/520) had newly diagnosed HIV. CD4 counts ≤ 50 cells/mm3 were observed in 251/484 (51.9%) patients. The most common anti-TB regimens were rifampin, isoniazid, pyrazinamide, and ethambutol. Multidrug resistance (MDR) was found in 16 patients, 10 in the dexamethasone group and six in the placebo group.
The primary endpoint of death occurred in 116/263 patients (44.1%) in the dexamethasone group and in 126/257 patients (49%) in the placebo group (hazard ratio, 0.85; 95% confidence interval [CI], 0.66 to 1.10; P = 0.22). Similar results were found after adjusting for disease severity. There was no benefit from dexamethasone discovered after subgroup analysis. Furthermore, the presence of MDR TB did not affect results from either the dexamethasone or placebo groups.
Secondary endpoints were comparable between the two groups. The rate of serious adverse events was similar between those who received dexamethasone (192/263, 73%) and placebo (194/257, 75%; P = 0.52). However, an increase in alanine transaminase (ALT) levels in the dexamethasone group (36/263, 13.7%) compared to the placebo group (20/257, 7.8%) was observed. One patient in the dexamethasone group required shunt surgery, and there were no reported HIV-related cancers. The rate of neurologic IRIS in the dexamethasone group and placebo group was 4.2% and 3.5%, respectively.
COMMENTARY
This was a well-conducted study with a clinically important endpoint (i.e., mortality) on a relatively neglected yet serious infection. Indeed, the mortality rate for HIV patients with TB meningitis is approximately 50%. Until this trial was conducted, only 98 HIV patients with TB meningitis had ever been enrolled in a clinical trial investigating the impact of steroids. A subsequent meta-analysis concluded that the role of steroids in HIV-positive patients with TB meningitis was uncertain. Even though the study by Donovan and colleagues reported a negative result, the finding that dexamethasone was not beneficial is significant. The impetus on researchers now should be to find novel approaches for treating HIV-associated TB meningitis that are effective, inexpensive, and able to be implemented in resource-limited settings. For example, trials are underway investigating the role of aspirin as adjunctive anti-inflammatory therapy.
Another interesting finding was that steroids did not reduce the incidence of neurologic IRIS. Previous studies showed steroids prevented IRIS in non-neurologic TB. In the current study, the dexamethasone dose usually was low by the time ART was started (median, 33 days after randomization). This may have lessened the ability of dexamethasone to prevent neurologic IRIS.
There were some limitations to the study. First, a majority of the patients (51.9%) had severe immunosuppression (CD4 count of ≤ 50 cells/mm3). Whether dexamethasone could be beneficial when the CD4 count is higher is unknown. Second, the study was conducted in two resource-limited countries and might not be generalizable to other higher-resource settings. Third, whether a larger clinical trial would show any benefits from steroids remains uncertain. However, the investigators chose meaningful primary and secondary outcomes, so finding other outcomes that are clinically relevant would be a challenge.
The study by Donovan and colleagues is a welcome advance that should impact clinical practice and future TB guidelines. While there are no obvious harms from steroids, there does not appear to be any clear benefit either. Given the high morbidity and mortality associated with TB meningitis in HIV patients, further pragmatic studies that aim to improve outcomes still are needed.
