From the aDepartment of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NCbSchool of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NCcSchool of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC.
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Background:Randomized controlled trials (RCTs) for determining efficacy of preexposure prophylaxis (PrEP) in preventing human immunodeficiency virus (HIV) infection have not been conducted among US women because their lower HIV incidence requires impractically large studies. Results from higher-incidence settings, like Sub-Saharan Africa, may not apply to US women owing to differences in age, sexual behavior, coinfections, and adherence.Methods:We propose a novel strategy for evaluating PrEP efficacy in the United States using data from both settings to obtain four parameters: (1) intention-to-treat (ITT) and (2) per-protocol effects in the higher-incidence setting, (3) per-protocol effect generalized to the lower-incidence setting, and (4) back-calculated ITT effect using adherence data from the lower-incidence setting. To illustrate, we simulated two RCTs comparing PrEP against placebo: one in 4000 African women and another in 500 US women. We estimated all parameters using g-computation and report risk ratios averaged over 2000 simulations, alongside the 2.5th and 97.5th percentiles of the simulation results.Results:Twelve months after randomization, the African ITT and per-protocol risk ratios were 0.65 (0.47, 0.88) and 0.20 (0.08, 0.34), respectively. The US ITT and per-protocol risk ratios were 0.42 (0.20, 0.62) and 0.17 (0.03, 0.38), respectively. These results matched well the simulated true effects.Conclusions:Our simple demonstration informs the design of future studies seeking to estimate the effectiveness of a treatment (like PrEP) in lower-incidence settings where a traditional RCT would not be feasible. See video abstract at, http://links.lww.com/EDE/B506.