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 (Δ-RMST) measure and 2 other treatment-effect measures in a recent HIV equivalence trial, and to investigate the performance and characteristics of Δ-RMST–based analysis in a simulation study.
We reanalyzed a recent HIV equivalence trial (ACTG A5257 trial) with hazard ratio and Δ-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 Δ-RMST–based analysis in the setting of non-proportional hazards (PH) ratio.
In the ACTG A5257 trial, analyses based on Δ-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 Δ-RMST. Results of simulation study indicate that the violation of the PH assumption has an impact on Δ-RMST–based analysis regarding the probability of declaring equivalence.
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.
aINSERM, Sorbonne Université, Institut Pierre Louis d'Epidémiologie et de Santé Publique (IPLESP) équipe Epidémiologie clinique des maladies virales chroniques, Paris, France; and
bCenter for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, MA.
Correspondence to: Philippe Flandre, PhD, INSERM, Sorbonne Université, Institut Pierre Louis d'Epidémiologie et de Santé Publique (IPLESP), CS 81393 - 75646, Cedex 13 Paris, France (e-mail: email@example.com).
X.A. is supported by a PhD fellowship from the French Ministry of Education and Research. H.J.R. is supported by National Institute of Allergy and Infectious Diseases (NIAID) grantUM1AI68634 for the ACTG Statistics and Data Management Center. A5257 was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number UM1 AI068634, UM1 AI068636, and UM1 AI106701. Bristol‐Myers Squibb, Merck Inc., Janssen Therapeutics, and Gilead Sciences provided the study medications (atazanavir, raltegravir, darunavir, and tenofovir‐emtricitabine, respectively). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
The authors have no funding or conflicts of interest to disclose.
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Received August 31, 2018
Accepted January 03, 2019