1 Division of Infectious Diseases and9 Division of Global Health Equity, Brigham and Women's Hospital, Boston, Massachusetts2 Department of Global Health and Social Medicine, Harvard Medical School, Boston, Massachusetts3 Institute of Infection and Global Health and4 Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom5 Hospital Nacional Hipólito Unanue, Lima, Peru6 Hospital Nacional Sergio Bernales, Lima, Peru7 Partners in Health/Socios en Salud Sucursal Peru, Lima, Peru8 College of Pharmacy and Emerging Pathogens Institute, University of Florida, Gainesville, Florida; and10 Partners in Health, Boston, Massachusetts
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Rationale:We examined whether increased rifampin doses could shorten standard therapy for tuberculosis without increased toxicity.Objectives:To assess the differences across three daily oral doses of rifampin in change in elimination rate of Mycobacterium tuberculosis in sputum and frequency of rifampin-related adverse events.Methods:We conducted a blinded, randomized, controlled phase 2 clinical trial of 180 adults with new smear-positive pulmonary tuberculosis, susceptible to isoniazid and rifampin. We randomized 1:1:1 to rifampin at 10, 15, and 20 mg/kg/d during the intensive phase. We report the primary efficacy and safety endpoints: change in elimination rate of M. tuberculosis log10 colony-forming units and frequency of grade 2 or higher rifampin-related adverse events. We report efficacy by treatment arm and by primary (area under the plasma concentration-time curve [AUC]/minimum inhibitory concentration [MIC]) and secondary (AUC) pharmacokinetic exposure.Measurements and Main Results:Each 5-mg/kg/d increase in rifampin dose resulted in differences of −0.011 (95% confidence interval, −0.025 to +0.002; P = 0.230) and −0.022 (95% confidence interval, −0.046 to −0.002; P = 0.022) log10 cfu/ml/d in the modified intention-to-treat and per-protocol analyses, respectively. The elimination rate in the per-protocol population increased significantly with rifampin AUC0-6 (P = 0.011) but not with AUC0-6/MIC99.9 (P = 0.053). Grade 2 or higher rifampin-related adverse events occurred with similar frequency across the three treatment arms: 26, 31, and 23 participants (43.3%, 51.7%, and 38.3%, respectively) had at least one event (P = 0.7092) up to 4 weeks after the intensive phase. Treatment failed or disease recurred in 11 participants (6.1%).Conclusions:Our findings of more rapid sputum sterilization and similar toxicity with higher rifampin doses support investigation of increased rifampin doses to shorten tuberculosis treatment.Clinical trial registered with www.clinicaltrials.gov (NCT 01408914).