%0 Journal Article
%T Generalizing the per
%A Daniel Westreich
%A Enrique F Schisterman
%A H Irene Hall
%A Haidong Lu
%A Jessie K Edwards
%A Stephen R Cole
%A Tiffany L Breger
%J Clinical Trials
%@ 1740-7753
%D 2019
%R 10.1177/1740774518806311
%X Intention-to-treat comparisons of randomized trials provide asymptotically consistent estimators of the effect of treatment assignment, without regard to compliance. However, decision makers often wish to know the effect of a per-protocol comparison. Moreover, decision makers may also wish to know the effect of treatment assignment or treatment protocol in a user-specified target population other than the sample in which the trial was fielded. Here, we aimed to generalize results from the ACTG A5095 trial to the US recently HIV-diagnosed target population. We first replicated the published conventional intention-to-treat estimate (2-year risk difference and hazard ratio) comparing a four-drug antiretroviral regimen to a three-drug regimen in the A5095 trial. We then estimated the intention-to-treat effect that accounted for informative dropout and the per-protocol effect that additionally accounted for protocol deviations by constructing inverse probability weights. Furthermore, we employed inverse odds of sampling weights to generalize both intention-to-treat and per-protocol effects to a target population comprising US individuals with HIV diagnosed during 2008¨C2014. Of 761 subjects in the analysis, 82 dropouts (36 in the three-drug arm and 46 in the four-drug arm) and 59 protocol deviations (25 in the three-drug arm and 34 in the four-drug arm) occurred during the first 2£¿years of follow-up. A total of 169 subjects incurred virologic failure or death. The 2-year risks were similar both in the trial and in the US HIV-diagnosed target population for estimates from the conventional intention-to-treat, dropout-weighted intention-to-treat, and per-protocol analyses. In the US target population, the 2-year conventional intention-to-treat risk difference (unit: %) for virologic failure or death comparing the four-drug arm to the three-drug arm was £¿0.4 (95% confidence interval: £¿6.2, 5.1), while the hazard ratio was 0.97 (95% confidence interval: 0.70, 1.34); the 2-year risk difference was £¿0.9 (95% confidence interval: £¿6.9, 5.3) for the dropout-weighted intention-to-treat comparison (hazard ratio£¿=£¿0.95, 95% confidence interval: 0.68, 1.32) and £¿0.7 (95% confidence interval: £¿6.7, 5.5) for the per-protocol comparison (hazard ratio£¿=£¿0.96, 95% confidence interval: 0.69, 1.34). No benefit of four-drug antiretroviral regimen over three-drug regimen was found from the conventional intention-to-treat, dropout-weighted intention-to-treat or per-protocol estimates in the trial sample or target population
%K HIV/AIDS
%K virologic failure
%K clinical trial
%K per-protocol effect
%K generalizability
%K antiretroviral therapy
%K intention-to-treat effect
%K external validity
%K inverse probability weighting
%K causality
%U https://journals.sagepub.com/doi/full/10.1177/1740774518806311