The Use of the Restricted Mean Survival Time as a Treatment Measure in HIV/AIDS Clinical Trial: Reanalysis of the ACTG A5257 Trial

Background: The restricted mean survival time (RMST) measures have not been used as primary measure of efficacy in HIV/AIDS clinical trials. In this work, we aim to compare analysis based on the difference in RMST (Delta-RMST) measure and 2 other treatment-effect measures in a recent HIV equivalence trial, and to investigate the performance and characteristics of Delta-RMST-based analysis in a simulation study. Setting and Methods: We reanalyzed a recent HIV equivalence trial (ACTG A5257 trial) with hazard ratio and Delta-RMST, and then compared the results with the original analysis based on risk difference estimated by Kaplan-Meier curves (RDKM). In a simulation study, we investigated the performance and operating characteristics of Delta-RMST-based analysis in the setting of nonproportional hazards (PH) ratio. Results: In the ACTG A5257 trial, analyses based on Delta-RMST globally led to similar conclusions as the published finding based on RDKM. By contrast, analyses based on hazard ratio provided some discordant equivalence conclusions compared both with the initial analyses based on RDKM and the Delta-RMST. Results of simulation study indicate that the violation of the PH assumption has an impact on Delta-RMST-based analysis regarding the probability of declaring equivalence. Conclusions: Although the RMST-based analysis is an alternative measure of efficacy in HIV/AIDS, clinical trials such an analysis can be strongly impacted by departures from the PH assumption.