Adjusting the effect of integrating antiretroviral therapy and tuberculosis treatment on mortality for non-compliance : an instrumental variables analysis using a time-varying exposure.

Abstract

In South Africa and elsewhere, research has shown that the integration of antiretroviral therapy (ART) and tuberculosis (TB) treatment saves lives. The randomised controlled trials (RCTs) which provided this compelling evidence used intent-to-treat (ITT) strategy as part of their primary analysis. As much as ITT is protected against selection bias caused by both measured and unmeasured confounders, but it is capable of drawing results towards the null and underestimate the e ectiveness of treatment if there is too much non-compliance. To adjust for non-compliance, \as-treated"and \per-protocol"comparisons are commonly made. These contrast study participants according to their received treatment, regardless of the treatment arm to which they were assigned, or limit the analysis to participants who followed the protocol. Such analyses are generally biased because the subgroups which they compare often lack comparability. In view of the shortcomings of the \as-treated"and \per-protocol"analyses, our objective was to account for non-compliance by using instrumental variables (IV) analysis to estimate the e ect of ART initiation during TB treatment on mortality. Furthermore, to capture the full complexity of compliance behaviour outside the TB treatment duration, we developed a novel IV-methodology for a time-varying measure of compliance to ART. This is an important contribution to the IV literature since IV-methodology for the e ect of a time-varying exposure on a time-to-event endpoint is currently lacking. In RCTs, IV analysis enable us to make use of the comparability o ered by randomisation and thereby have the capability of adjusting for unmeasured and measured confounders; they have the further advantage of yielding results that are less sensitive to random measurement error in the exposure. In order to carry out IV analysis, one needs to identify a variable called an instrument, which needs to satisfy three important assumptions. To apply the IV methodology, we used data from Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPiT) trial which was conducted by the Centre for the AIDS Programme of Research in South Africa. This trial enrolled HIV and TB co-infected patients who were assigned to start ART either early or late during TB treatment or after TB treatment completion. The results from IV analysis demonstrate that survival bene t of fully integrating TB treatment and ART is even higher than what has been reported in the ITT analysis since non-compliance has been accounted for.