Adjusting the Effect of Integrating Antiretroviral Therapy and Tuberculosis Treatment on Mortality for Noncompliance: A Time-varying Instrumental Variables Analysis.

BACKGROUND: Using intent-to-treat comparisons, it has been shown that the integration of antiretroviral therapy (ART) and tuberculosis (TB) treatment improves survival. Because the magnitude of the effect of ART initiation during TB treatment on mortality is less well understood owing to noncompliance, we used instrumental variables (IV) analyses. METHODS: We studied 642 HIV-TB co-infected patients from the Starting Antiretroviral Therapy at Three Points in Tuberculosis trial. Patients were assigned to start ART either early or late during TB treatment or after TB treatment completion. We used 2-stage predictor substitution and 2-stage residuals inclusion methods under additive and proportional hazards regressions with a time-fixed measure of compliance defined as the fraction of time on ART during TB treatment. We moreover developed novel IV methods for additive hazards regression with a time-varying measure of compliance. RESULTS: Intent-to-treat results from additive hazards models showed that patients in the early integrated arms had a reduced hazard of -0.05 (95% confidence interval [CI]: -0.09, -0.01) when compared with the sequential arm. Adjustment for noncompliance changed this effect to -0.07 (95% CI: -0.12, -0.01). An additional time-varying IV analysis on the overall effect of ART exposure suggested an effect of -0.29 (95 % CI: -0.54, -0.03). CONCLUSION: IV analyses enable assessment of the effectiveness of TB and ART integration, corrected for noncompliance, and thereby enable a better public health evaluation of the potential impact of this intervention.