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

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.

Effectiveness of a bedaquiline, linezolid, clofazimine “core” for multidrug-resistant tuberculosis

“…In a cohort of individuals with MDR/RR-TB in whom a FQ was unlikely to be effective, longer regimens containing at least Bdq for five months, Lzd, and Cfz yielded high proportions of treatment success that align with those from randomized trials and observational cohorts of patients treated with longer regimens comprised of new and repurposed drugs. [1][2][3][4][5]8 The regimens reinforced with at least one Group C drug and/or a longer duration of Bdq did not substantially improve the frequency of treatment success compared with the Bdq (5 to 8 months)-Lzd-Cfz core regimen. This finding underscores that Bdq (5 to 8 months)-Lzd-Cfz was a potent regimen for treating individuals with MDR/RR-TB in whom a FQ was unlikely to be effective.…”

“…17,21 Although both biases are important considerations in observational comparative effectiveness analyses of treatment duration, methods to appropriately account for them have been applied infrequently in TB cohorts. 4,21–23…”

“…17,21 Although both biases are important considerations in observational comparative effectiveness analyses of treatment duration, methods to appropriately account for them have been applied infrequently in TB cohorts. 4,[21][22][23] The 2022 WHO guidance recommends that longer regimens for MDR/RR-TB prioritize drugs from Groups A (Bdq, Lzd, FQ) and B (Cfz and Cs). 6 Under this guidance, the recommended longer regimen for someone with FQ-resistant TB consists of at least the four-drug regimen Bdq-Lzd-Cfz-Cs.…”

Neglected Populations Not to Be Forgotten: Tackling Antimicrobial Resistance in Neonatal Infections

“…Observational studies have the advantage of including representative and diverse patient populations, allowing for treatment effects to be explored across different factors. International programmatic cohorts for cancer patients, cardiovascular disease, HIV, and TB have already proven to be a valuable source of data that can be used to answer relevant research questions in real-world scenarios [15][16][17]. Moreover, recommendations advocating for the use of observational studies in informing healthcare decisions have been made, recognising the importance replacing RCTs with observational data when the latter is very low quality, and using observational data in conjunction with RCTs when there are issues such as indirectness, imprecision, and inconsistency involved in the RCT.…”

“Weighting” the Evidence: How Much Bedaquiline Is Enough?

“…It is this last question that Trevisi and colleagues (pp. 1525–1532 ) have addressed in this issue of the Journal ( 17 ).…”