Efficacy and safety of daily drug regimens containing high-dose versus standard-dose rifampicin for treating pulmonary tuberculosis: Systematic review and meta-analysis.

Standard rifampicin doses used to treat pulmonary tuberculosis lie at the lower end of drug exposure-response curve. We evaluated if higher daily rifampicin doses result in greater efficacy or harm. We searched literature databases for randomized controlled trials comparing efficacy and/or safety of standard and high rifampicin doses (>=15 mg/kg/day) for treating pulmonary tuberculosis. Our co-primary efficacy endpoints were proportion of patients with positive mycobacterial culture at end of intensive phase and 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 adverse event (any, serious, and drug-related serious), hepatotoxicity, and treatment interruption/discontinuation. We generated summary risk ratios (RR) using random effects models. We identified 5668 publications and selected 12 studies with 3230 participants. Nine studies had low risk of bias. Those on high-dose rifampicin had significantly lower culture positivity at end of intensive phase (summary RR 0.74, 95%CI 0.62-0.89), but not at end of treatment (summary RR 0.52, 95%CI 0.23-1.15), as well as significantly higher incidence of severe hepatotoxicity (summary RR 2.06, 95% CI 1.15-3.68) and treatment interruption/discontinuation (summary RR 1.89, 95%CI 1.09-3.28). Other secondary efficacy and safety outcomes were similar between the two treatment strategies. We conclude that higher daily rifampicin doses accelerate sputum conversion by the end of intensive phase of ATT, but severe hepatotoxicity remains a potential concern.