Efficacy & safety of high-dose rifampicin in pulmonary tuberculosis: A systematic review & meta-analysis

Background & objectives Evidence suggests that higher doses of rifampicin aid in faster culture conversion, but its effects on unfavourable outcomes are unclear. We aimed to synthesise evidence on the efficacy and safety of high-dose rifampicin (>15 mg/kg) containing anti-tuberculosis regimen compared to a regimen with standard dose of rifampicin in adults with pulmonary tuberculosis. Methods We searched for studies from MEDLINE, Embase, Web of Science, Google Scholar, and the Cochrane Library without geographical restriction. We included randomised controlled trials that evaluated high-dose rifampicin (>15 mg/kg for 8 wk) with a six-month duration. Our outcomes of interest were sputum conversion at eight wk, mortality, treatment failure at six months, Grade 3 and Grade 4 hepatotoxicity, and adverse events leading to treatment discontinuation. Two authors independently screened titles, abstracts, and full texts and extracted data. We performed a meta-analysis using the RevMan web software as per the Cochrane Handbook for Systematic Reviews of Interventions. Results Out of 3950 articles screened, we included nine for meta-analysis. High-dose rifampicin (≥15 mg/kg) showed little benefit compared to the standard dose for sputum conversion at eight wk [(83% vs. 78%, Relative risk (RR) 1.05 (95% confidence interval (CI): 1.0-1.09), Number needed to treat (NNT)-24)] and this benefit was higher as the rifampicin dose increased [20-30 mg RR: 1.07 (95% CI 1.02-1.14), NNT-17]; >30 mg RR: 1.12 (95% CI 1.04 -1.20) NNT-9]. However, treatment failure and mortality showed no benefit with high-dose rifampicin. Grade 3 and 4 hepatotoxicity and treatment discontinuation due to toxicity had a dose-response relationship and were significantly higher in the more than 30 mg/kg group [RR: 4.01 (95%CI 1.75-9.19), Number needed to harm -20]. Interpretation & conclusions High doses of rifampicin (≥15 mg/kg) increased the rate of sputum culture conversion after two months of the intensive phase. There was no difference in mortality and treatment failure between high-dose rifampicin and standard arms. In the subgroup analysis, the 20-30 mg/kg dose exhibited a beneficial effect in sputum conversion with no significant risk of hepatotoxicity and adverse drug reactions (ADR) leading to treatment discontinuation. This dose could be administered with close monitoring of adverse events and hepatotoxicity. There is an urgent need for adequately powered trials that assess long-term treatment outcomes, including recurrence.