Estimating post-treatment recurrence after multidrug-resistant tuberculosis treatment among patients with and without HIV: the impact of assumptions about death and missing follow-up

Abstract

ABSTRACT Background: Quantification of recurrence risk following successful treatment is crucial to evaluating regimens for multidrug- or rifampicin-resistant (MDR/RR) tuberculosis (TB). However, such analyses are complicated when some patients die or become lost during post-treatment-follow-up. Methods: We analyzed data on 1,991 patients who successfully completed a longer MDR/RR-TB regimen containing bedaquiline and/or delamanid between 2015 and 2018 in 16 countries. Using five approaches for handling post-treatment deaths, we estimated the six-month post-treatment TB recurrence risk overall, and by HIV status. We used inverse-probability-weighting to account for patients with missing follow-up and investigated the impact of potential bias from excluding these patients without applying inverse-probability weights. Results: The estimated TB recurrence risk was 6.6 per 1000 (95% confidence interval (CI):3.2,11.2) when deaths were handled as non-recurrences, and 6.7 per 1000 (95% CI:2.8,12.2) when deaths were censored and inverse-probability weights were applied to account for the excluded deaths. The estimated risk of composite recurrence outcomes were 24.2 (95% CI:14.1,37.0), 10.5 (95% CI:5.6,16.6), and 7.8 (95% CI:3.9,13.2) per 1000 for recurrence or 1) any death, 2) death with unknown or TB-related cause, 3) TB-related death, respectively. Corresponding relative risks for HIV status varied in direction and magnitude. Exclusion of patients with missing follow-up without inverse-probability-weighting had a small but apparent impact on estimates. Conclusion: The estimated six-month TB recurrence risk was low, and the association with HIV status was inconclusive due to few recurrence events. Estimation of post-treatment recurrence will be enhanced by explicit assumptions about deaths and appropriate adjustment for missing follow-up data.

Competing Interest Statement

CDM has served as a board member of Otsuka Scientific Advisory Board. All other authors report no potential conflicts.

Funding Statement

SMS, CDM, and MF led the conceptualization, data curation, methodology, analysis, and writing of the paper. CDM, MF, MR, KS, UK, PK MB, CH, and HH led the design of the endTB study. UK, CH, MB, DH, SL, MK, SP, SA, AKI, A Krisnanda, SCV, SB, A Kumsa, WD, KT, MM, HA, TV, TTT, KS, MR, HH, and PK contributed to data collection and curation. All authors contributed to editing and review of the paper.

Author Declarations

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:

This 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.

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Yes

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Data Availability

Some of the data included in this analysis are managed in countries governed by the European Union General Data Protection Regulation (GDPR). The data contain sensitive and potentially identifying information and cannot be sufficiently anonymized to meet GDPR standards and retain their utility. Pseudo-anonymized data will be made available upon request to an MSF Medical Director at endTB.ClinicalTrial@paris.msf.org, and execution of a data sharing agreement or alternate means that allows assurance that principles of GDPR regulations will be met.

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