High-Dose Rifampicin Shows No Survival Benefits in Tuberculous Meningitis: Clinical Implications

Radboud University Medical Center and international partners tested whether adding a higher oral rifampicin dose to standard four-drug therapy would reduce deaths in adults with tuberculous meningitis in the randomized high-dose rifampicin trial. The trial escalated rifampicin to as much as 35 mg/kg but found no survival advantage at six months—an important signal that greater central nervous system exposure alone does not reliably lower mortality in this disease.

The multicenter trial enrolled 499 adults across Indonesia, Uganda, and South Africa and prespecified six-month mortality as the primary endpoint, with follow-up through the early high-risk period and to six months.

Overall six-month mortality remained high: reported mortality rates were 44.6% in the high-dose arm versus 40.7% with standard dosing. That numerical difference did not reach statistical significance in the primary analysis, so the trial did not demonstrate a survival benefit from the increased rifampicin dose in this population.

The high-dose group showed a slightly higher point estimate for early deaths concentrated in the first weeks after diagnosis, and subgroup analyses suggested heterogeneity by clinical factors. Possible explanations include dose-related toxicity, variable blood–brain barrier pharmacokinetics that fail to increase effective intrathecal drug levels uniformly, or drug–drug interactions in patients with comorbidities such as HIV—none of which the trial proved. These safety signals and mechanistic uncertainties merit cautious interpretation and further focused study.

Key Takeaways:

• Randomized data from 499 adults show that higher-dose rifampicin (up to 35 mg/kg) did not reduce six-month mortality in tuberculous meningitis.
• Point estimates favored slightly higher mortality in the high-dose arm; causality is unclear and requires mechanistic investigation.
• Clinical practice should continue standard rifampicin dosing and prioritize guideline-concordant supportive care until further evidence justifies dose changes.