Trial of High-Dose Oral Rifampin in Adults with Tuberculous Meningitis

Abstract

Background: Tuberculous meningitis is often lethal, and many survivors have disabilities despite antimicrobial treatment and adjunctive glucocorticoid therapy. Standard-dose rifampin has limited central nervous system penetration. Whether high-dose rifampin could improve survival outcomes is unknown.

Methods: We performed a double-blind, randomized, placebo-controlled clinical trial involving adults with tuberculous meningitis in Indonesia, South Africa, and Uganda. We assigned persons with and those without human immunodeficiency virus (HIV) coinfection to receive standard daily isoniazid, rifampin (at a dose of 10 mg per kilogram of body weight), ethambutol, and pyrazinamide plus either additional rifampin (for a cumulative dose of 35 mg per kilogram; high-dose group) or matched placebo (standard-dose group) for 8 weeks; participants in both groups received standard therapy for the remainder of the 9-to-12-month treatment course. The primary outcome was 6-month mortality.

Results: A total of 499 participants were included in the intention-to-treat population (249 randomly assigned to the high-dose group and 250 to the standard-dose group), of whom 304 (60.9%) were persons living with HIV and 428 (85.8%) had definite or probable tuberculous meningitis. During 6 months of follow-up, 109 participants (Kaplan-Meier estimate, 44.6%) in the high-dose group and 100 participants (Kaplan-Meier estimate, 40.7%) in the standard-dose group died (hazard ratio, 1.17; 95% confidence interval, 0.89 to 1.54; P = 0.25). Among the participants who died within 6 months, the median time to death was 13 days (interquartile range, 4 to 39) in the high-dose group and 24 days (interquartile range, 6 to 56) in the standard-dose group. Drug-induced liver injury occurred in 8.0% of the participants in the high-dose group and in 4.4% of those in the standard-dose group, but no deaths from drug-induced liver injury occurred.

Conclusions: Among persons with tuberculous meningitis, no evidence of beneficial effect from high-dose rifampin was observed, and the potential for a harmful effect cannot be ruled out. (Funded by the U.K. Medical Research Council and others; ISRCTN Registry number, ISRCTN15668391.).

Figure 1. CONSORT Diagram

Overall, 529 participants were randomized of whom 29 met late exclusion criteria present at baseline and were administratively withdrawn. Table S1 in the Supplementary Appendix lists screening and enrollment by site. Table S2 in the Supplementary Appendix lists exclusion and late withdrawal criteria. One participant was discovered to have died in the period between informed consent and randomization, resulting in 499 participants included in the intent-to-treat analysis. Eight persons in each arm withdrew consent for the intervention.

Figure 2. Kaplan–Meier Curves for 6-month Survival by Treatment Group and Key Subgroups

The overall 6-month mortality estimated via Kaplan-Meier approach was 44.6% (95% CI: 37.9% to 50.5%) for the high-dose 35 mg per kilogram rifampicin group and 40.7% (95% CI 34.2% to 46.6%) for the standard-dose 10 mg per kilogram rifampicin group as displayed in Panel A (Hazard Ratio, 1.17; 95% confidence interval, 0.89 to 1.54; P = 0.25). Panel B displays the between-group differences in survival over time. In the first 21 days, the high-dose group had 68 deaths (Kaplan-Meier estimate: 27.6%, 95% CI: 21.8% to 33.0%) compared with 48 deaths (Kaplan-Meier estimate: 19.4%, 95% CI: 14.3% to 24.2%) in the standard-dose group. Eight participants in each group were censored before 6 months (range 1 to 162 days). Panels C display the outcomes by HIV status.

Figure 3. Forest Plot assessing treatment effect heterogeneity by baseline characteristics

Interactions between the treatment group and prespecified baseline subgroups were assessed to determine whether the treatment effect (hazard ratio of high-dose rifampicin vs standard-dose placebo for death) were dependent on those apriori identified baseline characteristics. Subgroups were generally consistent with the overall outcome, none showing the benefit of high-dose rifampicin. Figures S1 in the Supplementary Appendix display Kaplan-Meier curves by subgroups. HIV viral suppression was selected as a post-hoc subgroup, based on the antiretroviral therapy finding.

Figure 3. Forest Plot assessing treatment effect heterogeneity by baseline characteristics

Interactions between the treatment group and prespecified baseline subgroups were assessed to determine whether the treatment effect (hazard ratio of high-dose rifampicin vs standard-dose placebo for death) were dependent on those apriori identified baseline characteristics. Subgroups were generally consistent with the overall outcome, none showing the benefit of high-dose rifampicin. Figures S1 in the Supplementary Appendix display Kaplan-Meier curves by subgroups. HIV viral suppression was selected as a post-hoc subgroup, based on the antiretroviral therapy finding.

Figure 3. Forest Plot assessing treatment effect heterogeneity by baseline characteristics

Interactions between the treatment group and prespecified baseline subgroups were assessed to determine whether the treatment effect (hazard ratio of high-dose rifampicin vs standard-dose placebo for death) were dependent on those apriori identified baseline characteristics. Subgroups were generally consistent with the overall outcome, none showing the benefit of high-dose rifampicin. Figures S1 in the Supplementary Appendix display Kaplan-Meier curves by subgroups. HIV viral suppression was selected as a post-hoc subgroup, based on the antiretroviral therapy finding.