Effectiveness of Bedaquiline Use Beyond Six Months in Patients with Multidrug-Resistant Tuberculosis.

Trevisi L Hernán MA Mitnick CD Khan U Seung KJ Rich ML Bastard M Huerga H Melikyan N Atwood S Avaliani Z Llanos F Manzur-Ul-Alam M Zarli K Binedgie AB Adnan S Melikyan A Gelin A Isani AK Vetushko D Daugarina Z Nkundanyirazo P Putri FA Vilbrun C Khan M Hewison C Khan PY Franke MF
American journal of respiratory and critical care medicine 2023 Feb 21; . doi: 10.1164/rccm.202211-2125OC. Epub 2023 02 21
duration endTB observational study inverse probability weighting rifampicin-resistant tuberculosis target trial


RATIONALE: Current recommendations for the treatment of rifampin- and multidrug-resistant tuberculosis include bedaquiline used for six months or longer. Evidence is needed to inform the optimal duration of bedaquiline.

OBJECTIVES: We emulated a target trial to estimate the effect of three bedaquiline duration treatment strategies (6 months, 7-11 months, ≥ 12 months) 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.

MAIN RESULTS: The 1,468 eligible individuals received a median of four (IQR: 4-5) likely effective drugs. In 87.1% and 77.7%, this included linezolid and clofazimine, respectively. The adjusted probability of successful treatment (95% CI) was 0.85 (0.81, 0.88) for 6 months of BDQ, 0.77 (0.73, 0.81) for 7-11 months, and 0.86 (0.83, 0.88) for > 12 months. Compared with 6 months of bedaquiline, the ratio of treatment success (95% CI) was 0.91 (0.85, 0.96) for 7-11 months and 1.01 (0.96, 1.06) for > 12 months. Analyses that did not account for immortal time bias found a higher probability of successful treatment with > 12 months: ratio 1.09 (1.05, 1.14).

CONCLUSIONS: Bedaquiline use beyond six 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 can bias estimate of effects of treatment duration. Future analyses should explore the effect of duration of bedaquiline and other drugs in subgroups with advanced disease and/or receiving less potent regimens.