Background: Three phase II clinical trials generated the evidence for recommending bedaquiline for the treatment of rifampicin-resistant tuberculosis (RR-TB). These trials were not powered to assess the effect of bedaquiline on mortality. Observational studies reported lower mortality in patients treated with bedaquiline-containing regimens but did not fully account for differences between patients who did and did not receive bedaquiline in the real world Methods: Using data from two studies on 622 patients, of whom 195 initiated a bedaquiline-containing regimen, we applied rigorous causal inference by emulating a trial that would randomize patients diagnosed with RR-TB by the Xpert MTB/RIF assay to a bedaquiline-containing regimen or a non-bedaquiline-containing regimen. We used multiple imputation to address missing data, inverse probability of treatment weighting (IPTW) to emulate randomized assignment and estimated the odds of one-year mortality using a marginal structural logistic model Results: By using IPTW, we achieved conditional exchangeability for observed differences in age, gender, HIV status, Mycobacterium tuberculosis resistance pattern, and history of tuberculosis treatment between patients who did or did not initiate a bedaquiline-containing regimen. By emulating the design of a randomized trial, we found that had all patients been treated with a bedaquiline-containing regimen, there would have been a 67% reduction in the odds of one-year mortality compared to when none of the patients initiated a bedaquiline-containing regimen (OR: 0.33, 95%CI: 0.19-0.59) Conclusion: By emulating a randomized trial using real-world data, our results demonstrate that the initiation of a bedaquiline-containing regimen causes a 67% reduction in the odds of one-year mortality Abstract word count: 248/250 Keywords Bedaquiline, Bedaquiline-containing regimen, Target trial, Inverse probability of treatment weighting, Mortality Key message We assessed the causal effect of initiating a bedaquiline-containing regimen compared to a non-bedaquiline-containing regimen on one-year mortality. We found that a bedaquiline-containing regimen causes a 67% reduction in the odds of one-year mortality, underscoring the need for expanded access to such effective regimens

The authors have declared no competing interest.

This study did not receive any funding.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The SMARTT trial received ethical approval from the ethics committees of the University of the Free State Health Sciences Research Ethics Committee (UFS-HSD2019/0364/2004), Stellenbosch University Health Research Ethics Committee (N19/07/100), and the University of Antwerp (21/18/239). Ethical approval for EXIT-RIF study was obtained from the Human Research Ethics Committee of the University of the Witwatersrand in South Africa and the Institutional Review Board of the University of North Carolina at Chapel Hill in the United States. Approval of study activities was obtained from relevant health authorities. Participants gave verbal consent by phone (recorded). Waiver of consent was obtained for patients who had died or were LTFU from TB care prior to study enrolment and could not be contacted despite multiple attempts.

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Yes

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Yes

All data produced in the present study are available upon reasonable request to the authors.