People who smoke are at increased risk of unfavorable tuberculosis (TB) treatment outcomes compared with those who do not, but the pathways explaining this effect are unclear. We estimated the effect of smoking on a successful end-of-treatment outcome for multidrug-resistant and rifampicin-resistant (MDR/RR) TB and examined if intervening on loss to follow-up mitigates this effect.

The endTB Observational Study was a prospective cohort of people with MDR/RR-TB who were treated with longer regimens containing bedaquiline and/or delamanid. We used marginal standardization to examine the effect of smoking (≥1 cigarette daily at enrollment) on treatment success (cured/completed). To simulate intervening on lost to follow-up, we censored participants and applied inverse probability of censoring weights.

Among 1786 participants in 12 countries, 539 (30.2%) reported smoking. At the end of treatment, 73.5% of people who smoked and 80.3% of people who did not smoke had treatment success (risk difference in percentage points: -6.8, 95% CI: -11.1, -2.6). After adjusting for baseline confounders including demographics, social history, and comorbidities, the risk difference was similar (-5.2 percentage points) but 95% CIs were less precise (-14.1, 3.2). In a pseudopopulation without loss to follow-up, the risk difference was reduced (-1.9 percentage points; 95% CI: -10.2, 5.1).

People who smoked had less frequent MDR/RR-TB treatment success compared with those who did not smoke. A simulated intervention on loss to follow-up reduced this difference, suggesting that pathways related to retention in care were a driver of this effect.

Matthew L. Romo reports research funding from the National Institutes of Health with payments made to their institution. Helen R. Stagg reports research funding from the UK Medical Research Council with payments made to their institution. Carole D. Mitnick, Michael L. Rich, and Molly F. Franke report research funding from Unitaid, the National Institutes of Health, and Harvard Medical School Center for Global Health Delivery-Dubai with payment made to their institutions. Carole D. Mitnick also reports participation in scientific advisory boards for Akagera (one payment made to Partners In Health as an honorarium for service on the advisory board) and Otsuka (no payment). The remaining authors declare no potential conflicts of interest.

NCT03259269

The funder of the endTB project is Unitaid. Matthew L. Romo and Molly F. Franke were funded until May 2025 by the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health (R03AI180576, PI: Franke). Helen R. Stagg was funded by the UK Medical Research Council during this work (MR/R008345/1). Bedaquiline was donated by Janssen to the Global Drug Facility and delamanid was donated by Otsuka for initial participants enrolled in the endTB Observational Study. These companies did not have any role in study design, data analyses, data interpretation, or manuscript writing.

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 endTB Observational Study was approved by the Partners Healthcare Human Research Committee (Boston, MA, USA), the MSF Ethics Review Board (Geneva, Switzerland), IRD Institutional Review Board (Karachi, Pakistan) and in all 17 enrolling countries by local ethics committees or IRBs.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Funding: The funder of the endTB project is Unitaid. Matthew L. Romo and Molly F. Franke were funded until May 2025 by the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health (R03AI180576, PI: Franke). Helen R. Stagg was funded by the UK Medical Research Council during this work (MR/R008345/1). Bedaquiline was donated by Janssen to the Global Drug Facility and delamanid was donated by Otsuka for initial participants enrolled in the endTB Observational Study. These companies did not have any role in study design, data analyses, data interpretation, or manuscript writing.

Conflicts of interest: Matthew L. Romo reports research funding from the National Institutes of Health with payments made to their institution. Helen R. Stagg reports research funding from the UK Medical Research Council with payments made to their institution. Carole D. Mitnick, Michael L. Rich, and Molly F. Franke report research funding from Unitaid, the National Institutes of Health, and Harvard Medical School Center for Global Health Delivery-Dubai with payment made to their institutions. Carole D. Mitnick also reports participation in scientific advisory boards for Akagera (one payment made to Partners In Health as an honorarium for service on the advisory board) and Otsuka (no payment). The remaining authors declare no potential conflicts of interest.

All data produced in the present study are available upon reasonable request to the authors. endTB Observational Study data are also available upon request: https://endtb.org/access-endtb-data-through-edsi