RATIONALE: Rifapentine has potent activity in mouse models of tuberculosis chemotherapy but its optimal dose and exposure in humans are unknown. OBJECTIVES: We conducted a randomized, partially blinded dose-ranging study to determine tolerability, safety, and antimicrobial activity of daily rifapentine for pulmonary tuberculosis treatment. METHODS:Adults with sputum smear-positive pulmonary tuberculosis were assigned rifapentine 10, 15, or 20 mg/kg or rifampin 10 mg/kg daily for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. The primary tolerability end point was treatment discontinuation. The primary efficacy end point was negative sputum cultures at completion of intensive phase. MEASUREMENTS AND MAIN RESULTS: A total of 334 participants were enrolled. At completion of intensive phase, cultures on solid media were negative in 81.3% of participants in the rifampin group versus 92.5% (P = 0.097), 89.4% (P = 0.29), and 94.7% (P = 0.049) in the rifapentine 10, 15, and 20 mg/kg groups. Liquid cultures were negative in 56.3% (rifampin group) versus 74.6% (P = 0.042), 69.7% (P = 0.16), and 82.5% (P = 0.004), respectively. Compared with the rifampin group, the proportion negative at the end of intensive phase was higher among rifapentine recipients who had high rifapentine areas under the concentration-time curve. Percentages of participants discontinuing assigned treatment for reasons other than microbiologic ineligibility were similar across groups (rifampin, 8.2%; rifapentine 10, 15, or 20 mg/kg, 3.4, 2.5, and 7.4%, respectively). CONCLUSIONS:Daily rifapentine was well-tolerated and safe. High rifapentine exposures were associated with high levels of sputum sterilization at completion of intensive phase. Further studies are warranted to determine if regimens that deliver high rifapentine exposures can shorten treatment duration to less than 6 months. Clinical trial registered with www.clinicaltrials.gov (NCT 00694629).
RCT Entities:
RATIONALE: Rifapentine has potent activity in mouse models of tuberculosis chemotherapy but its optimal dose and exposure in humans are unknown. OBJECTIVES: We conducted a randomized, partially blinded dose-ranging study to determine tolerability, safety, and antimicrobial activity of daily rifapentine for pulmonary tuberculosis treatment. METHODS: Adults with sputum smear-positive pulmonary tuberculosis were assigned rifapentine 10, 15, or 20 mg/kg or rifampin 10 mg/kg daily for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. The primary tolerability end point was treatment discontinuation. The primary efficacy end point was negative sputum cultures at completion of intensive phase. MEASUREMENTS AND MAIN RESULTS: A total of 334 participants were enrolled. At completion of intensive phase, cultures on solid media were negative in 81.3% of participants in the rifampin group versus 92.5% (P = 0.097), 89.4% (P = 0.29), and 94.7% (P = 0.049) in the rifapentine 10, 15, and 20 mg/kg groups. Liquid cultures were negative in 56.3% (rifampin group) versus 74.6% (P = 0.042), 69.7% (P = 0.16), and 82.5% (P = 0.004), respectively. Compared with the rifampin group, the proportion negative at the end of intensive phase was higher among rifapentine recipients who had high rifapentine areas under the concentration-time curve. Percentages of participants discontinuing assigned treatment for reasons other than microbiologic ineligibility were similar across groups (rifampin, 8.2%; rifapentine 10, 15, or 20 mg/kg, 3.4, 2.5, and 7.4%, respectively). CONCLUSIONS: Daily rifapentine was well-tolerated and safe. High rifapentine exposures were associated with high levels of sputum sterilization at completion of intensive phase. Further studies are warranted to determine if regimens that deliver high rifapentine exposures can shorten treatment duration to less than 6 months. Clinical trial registered with www.clinicaltrials.gov (NCT 00694629).
Authors: Frik A Sirgel; P Bernard Fourie; Peter R Donald; Nesri Padayatchi; Roxana Rustomjee; Jonathan Levin; Giorgio Roscigno; Jennifer Norman; Helen McIlleron; Denis A Mitchison Journal: Am J Respir Crit Care Med Date: 2005-04-01 Impact factor: 21.405
Authors: A H Diacon; R F Patientia; A Venter; P D van Helden; P J Smith; H McIlleron; J S Maritz; P R Donald Journal: Antimicrob Agents Chemother Date: 2007-05-21 Impact factor: 5.191
Authors: William J Burman; Stefan Goldberg; John L Johnson; Grace Muzanye; Melissa Engle; Ann W Mosher; Shurjeel Choudhri; Charles L Daley; Sonal S Munsiff; Zhen Zhao; Andrew Vernon; Richard E Chaisson Journal: Am J Respir Crit Care Med Date: 2006-05-04 Impact factor: 21.405
Authors: Marcus B Conde; Anne Efron; Carla Loredo; Gilvan R Muzy De Souza; Nadja P Graça; Michelle C Cezar; Malathi Ram; Mohammad A Chaudhary; William R Bishai; Afranio L Kritski; Richard E Chaisson Journal: Lancet Date: 2009-04-04 Impact factor: 79.321
Authors: Ramesh Jayaram; Sheshagiri Gaonkar; Parvinder Kaur; B L Suresh; B N Mahesh; R Jayashree; Vrinda Nandi; Sowmya Bharat; R K Shandil; E Kantharaj; V Balasubramanian Journal: Antimicrob Agents Chemother Date: 2003-07 Impact factor: 5.191
Authors: Ian M Rosenthal; Ming Zhang; Deepak Almeida; Jacques H Grosset; Eric L Nuermberger Journal: Am J Respir Crit Care Med Date: 2008-08-21 Impact factor: 21.405
Authors: Ian M Rosenthal; Ming Zhang; Kathy N Williams; Charles A Peloquin; Sandeep Tyagi; Andrew A Vernon; William R Bishai; Richard E Chaisson; Jacques H Grosset; Eric L Nuermberger Journal: PLoS Med Date: 2007-12 Impact factor: 11.069
Authors: Susan E Dorman; Payam Nahid; Ekaterina V Kurbatova; Stefan V Goldberg; Lorna Bozeman; William J Burman; Kwok-Chiu Chang; Michael Chen; Mark Cotton; Kelly E Dooley; Melissa Engle; Pei-Jean Feng; Courtney V Fletcher; Phan Ha; Charles M Heilig; John L Johnson; Erica Lessem; Beverly Metchock; Jose M Miro; Nguyen Viet Nhung; April C Pettit; Patrick P J Phillips; Anthony T Podany; Anne E Purfield; Kathleen Robergeau; Wadzanai Samaneka; Nigel A Scott; Erin Sizemore; Andrew Vernon; Marc Weiner; Susan Swindells; Richard E Chaisson Journal: Contemp Clin Trials Date: 2020-01-22 Impact factor: 2.226
Authors: E D Pieterman; S van den Berg; A van der Meijden; E M Svensson; H I Bax; J E M de Steenwinkel Journal: Antimicrob Agents Chemother Date: 2021-03-18 Impact factor: 5.191
Authors: Kelly E Dooley; Radojka M Savic; Jeong-Gun Park; Yoninah Cramer; Richard Hafner; Evelyn Hogg; Jennifer Janik; Mark A Marzinke; Kristine Patterson; Constance A Benson; Laura Hovind; Susan E Dorman; David W Haas Journal: Antimicrob Agents Chemother Date: 2015-03-30 Impact factor: 5.191
Authors: Christine Sekaggya-Wiltshire; Amrei von Braun; Mohammed Lamorde; Bruno Ledergerber; Allan Buzibye; Lars Henning; Joseph Musaazi; Ursula Gutteck; Paolo Denti; Miné de Kock; Alexander Jetter; Pauline Byakika-Kibwika; Nadia Eberhard; Joshua Matovu; Moses Joloba; Daniel Muller; Yukari C Manabe; Moses R Kamya; Natascia Corti; Andrew Kambugu; Barbara Castelnuovo; Jan S Fehr Journal: Clin Infect Dis Date: 2018-08-16 Impact factor: 9.079
Authors: Till F Omansen; Deepak Almeida; Paul J Converse; Si-Yang Li; Jin Lee; Ymkje Stienstra; Tjip van der Werf; Jacques H Grosset; Eric L Nuermberger Journal: Antimicrob Agents Chemother Date: 2019-01-29 Impact factor: 5.191