Nonhlanhla Yende-Zuma1,2,3, Henry Mwambi4, Stijn Vansteelandt5,6. 1. From the Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa. 2. MRC-CAPRISA HIV-TB Pathogenesis and Treatment Research Unit, Durban, South Africa. 3. The South African DST/NRF Centre of Excellence in Epidemiological Modelling and Analysis (SACEMA), University of Stellenbosch, Stellenbosch, South Africa. 4. School of Mathematics, Statistics and Computer Science, University of KwaZulu-Natal, Pietermaritzburg, South Africa. 5. Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Gent, Belgium. 6. Medical Statistics Unit, the London School of Hygiene and Tropical Medicine, London, United Kingdom.
Abstract
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.
RCT Entities:
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-infectedpatients 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.
Authors: Diane V Havlir; Michelle A Kendall; Prudence Ive; Johnstone Kumwenda; Susan Swindells; Sarojini S Qasba; Anne F Luetkemeyer; Evelyn Hogg; James F Rooney; Xingye Wu; Mina C Hosseinipour; Umesh Lalloo; Valdilea G Veloso; Fatuma F Some; N Kumarasamy; Nesri Padayatchi; Breno R Santos; Stewart Reid; James Hakim; Lerato Mohapi; Peter Mugyenyi; Jorge Sanchez; Javier R Lama; Jean W Pape; Alejandro Sanchez; Aida Asmelash; Evans Moko; Fred Sawe; Janet Andersen; Ian Sanne Journal: N Engl J Med Date: 2011-10-20 Impact factor: 91.245