Safety, Efficacy, and Pharmacokinetics of Daily Optimized Doses of Rifampicin for the Treatment of Tuberculosis: A Systematic Review and Bayesian Network Meta-Analysis

Background Higher than standard doses of rifampicin could improve the treatment outcome of drug-susceptible tuberculosis (TB) without compromising the safety of patients.Methods We performed a systematic review of prospective clinical studies including adults with pulmonary and extrapulmonary TB receiving rifampicin doses above 10 mg/kg/day. We extracted the data on overall adverse events (AE), hepatic AE, sputum culture conversion (SCC) at week 8, recurrence, mortality, and pharmacokinetics. We performed a Bayesian network meta-analysis (NMA) using a random-effects model.Results In 19 studies, 2033 out of 3654 participants received rifampicin doses higher than 10 mg/kg/day. The NMA showed an increased risk of overall and hepatic AE for the 40 mg/kg/day dose (risk ratio [RR] 4.8, 95% credibility interval [CrI]: 1.1, 25, and 15.00; 95% CrI: 1.1, 58.0, respectively), but no other doses, including 50 mg/kg/day showed such an increase. Increasing doses improved sputum culture conversion at week 8 (RR 1.3, 95% CrI: 1.1, 1.7 for SCC with 35 mg/kg/day).Conclusions Optimal doses of rifampicin may be between 25 and 35 mg/kg/day, but should be tailored at the individual or, at least, at the population level. The standard doses of rifampicin were established decades ago, limited by costs and availability. We systematically reviewed recent studies, which suggest rifampicin at 25-35 mg/kg/day is safe and improves early outcomes for adults with drug-susceptible tuberculosis (TB).