Generalizing the per-protocol treatment effect: The case of ACTG A5095

Haidong Lu, Stephen R. Cole, H. Irene Hall, Enrique F. Schisterman, Tiffany L. Breger, Jessie K Edwards, Daniel Westreich

Research output: Contribution to journalArticlepeer-review


Background: 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. Methods: 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 2008–2014. Results: 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). Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)52-62
Number of pages11
JournalClinical Trials
Issue number1
StatePublished - Feb 1 2019
Externally publishedYes


  • antiretroviral therapy
  • causality
  • clinical trial
  • external validity
  • generalizability
  • intention-to-treat effect
  • inverse probability weighting
  • per-protocol effect
  • virologic failure

ASJC Scopus subject areas

  • Pharmacology


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