Efficacy and Safety of Daily Drug Regimens Containing High-Dose Versus Standard-Dose Rifampicin for Treating Pulmonary Tuberculosis: Systematic Review and Meta-Analysis

Abstract Rationale: Pulmonary tuberculosis (PTB) is currently managed with daily anti-tubercular treatment (ATT) containing rifampicin in a dose of 10 mg/kg/day. However, this dose is placed at the lower end of the drug exposure-response curve, and subtherapeutic drug levels are common. Few randomised controlled trials (RCTs) have evaluated high-dose rifampicin, but the benefit remains uncertain. We evaluated if higher daily rifampicin doses (15 mg/kg/day or greater) result in greater efficacy or harm. Methods: We searched PubMed, Embase, and the Cochrane CENTRAL databases for RCTs compared efficacy and/or safety of standard and high rifampicin doses for treating rifampicin-susceptible PTB. Our co-primary efficacy endpoints were proportion of patients with positive mycobacterial culture at end of intensive phase, and at end of treatment. The primary safety endpoint was incidence of severe hepatotoxicity. Secondary efficacy endpoints were proportion of patients with culture positivity at 1, 3, and 4 months. death, treatment failure, recurrence after treatment, and loss to follow-up. Secondary safety endpoints were incidence of any adverse event, serious adverse event, drug-related serious adverse event, any hepatotoxicity, and treatment interruption/discontinuation. Data were summarized using random effects inverse variance models to generate summary risk ratios (RR) and 95% confidence intervals (95%CI). The study protocol was prospectively registered with PROSPERO database (CRD42024510530). Results: We identified 5668 publications and selected 12 RCTs with 3230 participants (1310 administered standard-dose rifampicin and 1920 administered rifampicin between 15-35 mg/kg/day). All except three studies had low risk of bias. Those on high-dose rifampicin had significantly lower culture positivity at end of intensive phase (8 RCTs, summary RR 0.74, 95%CI 0.62-0.89), but not at end of treatment (4 RCTs, summary RR 0.52, 95%CI 0.23-1.15). There was significantly higher incidence of severe hepatotoxicity with high-dose rifampicin (7 RCTs, summary RR 2.06, 95% CI 1.15-3.68). All secondary efficacy outcomes were not significantly different between the two treatment strategies. Patients on high-dose rifampicin showed greater treatment interruption/discontinuation (4 RCTs, summary RR 1.89, 95%CI 1.09-3.28). Other secondary safety outcomes were similar between the two treatment strategies. Conclusion: Higher daily rifampicin doses accelerated sputum conversion by end of intensive of ATT, but severe hepatotoxicity remains a potential concern. Optimizing higher daily rifampicin doses for PTB can potentially improve outcomes and shorten ATT duration under programmatic settings.