Effect of prior TB preventive therapy on all-cause mortality during TB treatment among people with HIV/TB in rural eastern Uganda: a target trial emulation

Background Tuberculosis preventive therapy (TPT) is the cornerstone for preventing TB disease. However, it is uncertain whether prior TPT completion improves survival once TB disease develops in people with human immunodeficiency virus (PWH) while on anti-retroviral therapy (ART). We evaluated the effect of prior TPT completion on all-cause mortality during TB treatment among PWH who developed TB disease while on ART in rural eastern Uganda. Prior TPT completion served as a proxy for sustained engagement in HIV care. Methods We applied target trial emulation (TTE) to mimic a hypothetical randomized trial using real-world retrospective cohort data. TTE addresses design flaws in observational studies, such as immortal time bias and prevalent user bias, providing less biased causal effect estimates. Individuals who had completed a full course of TPT before the start of the index TB treatment episode formed the intervention group, while the control group comprised those with no history of TPT before the index TB treatment initiation. We defined time zero (start of follow-up) as TB treatment initiation, measured baseline covariates before this point, and applied inverse probability of treatment weighting to balance baseline covariates between the groups. We estimated all-cause mortality rates using person-time methods and Kaplan–Meier curves and performed propensity-score weighted Cox proportional hazards analysis for cause-effect estimation. We reported adjusted hazard ratios (aHR) with 95% confidence intervals (CI). Results Of 719 participants, 296 (41.2%) had completed TPT prior to the start of the index TB treatment episode, and 83 (11.5%) had died. The mortality rate was 7.13 per 10,000 person-days, higher among participants without prior TPT than those with prior TPT completion (18.0% vs. 2.4%, log-rank χ² ₍₁₎  = 35.3, p < 0.001). Median survival was 277 days (95% CI: 213–689). Prior TPT completion was associated with an 87% lower hazard of all-cause mortality (aHR 0.13, 95% CI: 0.06–0.29). Conclusion Prior TPT completion substantially reduced all-cause mortality among PWH who developed drug-susceptible TB disease while on ART. Therefore, strengthening engagement in HIV care should be prioritized across HIV programs to lower all-cause mortality among PWH, with completion of TPT serving as an important component and marker of such engagement.