Abstract / Summary
Background Loss to follow-up (LTFU) during tuberculosis treatment is a major programmatic gap, but how much excess mortality it causes has been difficult to estimate, because individuals who disengage differ from those who do not, and they must survive long enough to be recorded as having disengaged. Quantifying this excess and identifying which populations are at greatest risk are critical to informing program design and resource allocation. Methods and Findings We followed 171,048 people aged 15 years or older starting a first course of tuberculosis treatment in Sao Paulo State, Brazil, between 2013 and 2023, linking surveillance and mortality registries; 20,830 (12.2%) were LTFU. Among those LTFU, 65% had received directly observed therapy (DOT). Using a clone-censor-weight target trial emulation, we contrasted two strategies over 60 months from the first day of treatment: disengagement at any point during the first six months and remaining in care throughout. A rolling landmark analysis addressed the timing of disengagement and cause-specific mortality excess. LTFU increased standardized five-year mortality by 2.23 percentage points (95% CI 1.88-2.51), with tuberculosis accounting for 61% of the excess. Relative effects were largest in younger, stably housed individuals, whose baseline mortality was low; the largest absolute excess fell on people living with HIV (4.49 percentage points, 95% CI 2.97-5.74). The excess was similar for disengagement at any point in the first four months of treatment and attenuated thereafter. Limitations include the absence from the registry of severity markers such as radiographic extent and bacillary load, so residual confounding cannot be excluded. Conclusions Despite high DOT coverage, disengagement during the first six months of tuberculosis treatment was common and increased five-year mortality under the stated identification assumptions, with the excess concentrated in deaths attributed to tuberculosis. Interventions that provide support throughout treatment should be tested for their effectiveness in sustaining engagement and reducing mortality.