Effectiveness of Bedaquiline Use beyond Six Months in Patients with Multidrug-Resistant Tuberculosis
Letizia Trevisi, Miguel A. Hernán, Carole D. Mitnick, Uzma Khan, Kwonjune J. Seung, Michael Rich, Mathieu Bastard, Helena Huerga, Nara Melikyan, Sidney A. Atwood, Zaza Avaliani, Félix Llanos-Tejada, Mohammad Manzur-ul-Alam, Khin Zarli, A.B. Binegdie, Sana Adnan, Arusyak Melikyan, A Gelin, Afshan K. Isani, Dmitry Vetushko, Zhenisgul Daugarina, Patrick Nkundanyirazo, Fauziah Asnely Putri, Charles Vilbrun, Munira Khan, Catherine Hewison, Palwasha Khan, Molly F. Franke
Abstract
Abstract Rationale Current recommendations for the treatment of rifampicin- and multidrug-resistant tuberculosis include bedaquiline (BDQ) used for 6 months or longer. Evidence is needed to inform the optimal duration of BDQ. Objectives We emulated a target trial to estimate the effect of three BDQ duration treatment strategies (6, 7–11, and ≥12 mo) on the probability of successful treatment among patients receiving a longer individualized regimen for multidrug-resistant tuberculosis. Methods To estimate the probability of successful treatment, we implemented a three-step approach comprising cloning, censoring, and inverse probability weighting. Measurements and Main Results The 1,468 eligible individuals received a median of 4 (interquartile range, 4–5) likely effective drugs. In 87.1% and 77.7% of participants, this included linezolid and clofazimine, respectively. The adjusted probability of successful treatment was 0.85 (95% confidence interval [CI], 0.81–0.88) for 6 months of BDQ, 0.77 (95% CI, 0.73–0.81) for 7–11 months, and 0.86 (95% CI, 0.83–0.88) for ≥12 months. Compared with 6 months of BDQ, the ratio of treatment success was 0.91 (95% CI, 0.85–0.96) for 7–11 months and 1.01 (95% CI, 0.96–1.06) for ≥12 months. Naive analyses that did not account for bias revealed a higher probability of successful treatment with ≥12 months (ratio, 1.09 [95% CI, 1.05–1.14]). Conclusions BDQ use beyond 6 months did not increase the probability of successful treatment among patients receiving longer regimens that commonly included new and repurposed drugs. When not properly accounted for, immortal person–time bias can influence estimates of the effects of treatment duration. Future analyses should explore the effect of treatment duration of BDQ and other drugs in subgroups with advanced disease and/or receiving less potent regimens.