Abstract
BACKGROUND: Tuberculosis (TB) remains a significant cause of mortality globally, yet first-line treatment has hardly changed for fifty years. The dose of rifampicin, the most important drug in this regimen, has been historically based on pragmatic cost- and risk-benefit considerations. Evidence suggests the current recommended dose (8-12 mg/kg) may not maximise the potential benefits of this drug. We sought to evaluate the efficacy and safety of higher doses of rifampicin in adults with presumed drug-susceptible TB. METHODS: In this systematic review we searched MEDLINE, EMBASE, CENTRAL and Global Health databases for randomised controlled trials up to 31 July 2024 of adults with presumed drug-susceptible TB receiving first-line treatment with an intervention of rifampicin doses higher than currently recommended. Meta-analyses were performed using random effects models where background regimens were the same. Risk ratio was used as the measure for treatment effect. Outcomes of interest related to efficacy and safety. FINDINGS: Of the 5441 total records identified by our searches, nineteen studies (6332 patients, 31.0% female) were eligible for the systematic review and twelve (3763 patients, 31.0% female) for meta-analysis. Rifampicin doses varied from 8 to 35 mg/kg and implementation of the intervention varied between trials. There was no evidence for increased efficacy with higher doses of rifampicin, however the majority of trials investigated minimally increased doses (up to 20 mg/kg). At higher doses (>20 mg/kg), there may be evidence of increased risk of drug-induced liver injury, albeit with no consistent dose-response relationship. INTERPRETATION: Evidence on the efficacy of higher doses of rifampicin in the first-line regimen for TB remains incomplete. While higher doses appear generally safe, the risk of drug-induced liver injury may be increased above doses of 20 mg/kg. Larger clinical trials reporting definitive outcomes are needed to determine whether dosing up to 40 mg/kg could safely improve treatment outcomes or reduce duration of first-line therapy. FUNDING: WHO, Wellcome Trust.