Estimating efficacy in a randomized trial with product nonadherence: application of multiple methods to a trial of preexposure prophylaxis for HIV prevention.
Antiretroviral preexposure prophylaxis (PrEP) for persons at high risk of human immunodeficiency virus infection is a promising new prevention strategy. Six randomized trials of oral PrEP were recently conducted and demonstrated efficacy estimates ranging from 75% to no effect, with nonadherence likely resulting in attenuated estimates of the protective effect of PrEP. In 1 of these trials, the Partners PrEP Study (Kenya and Uganda, 2008-2011), participants (4,747 serodiscordant heterosexual couples) were randomized to receipt of tenofovir (TDF), coformulated TDF/emtricitabine (FTC), or placebo. Intention-to-treat analyses found efficacy estimates of 67% for TDF and 75% for TDF/FTC. We applied multiple methods to data from that trial to estimate the efficacy of PrEP with high adherence, including principal stratification and inverse-probability-of-censoring (IPC) weights. Results were further from the null when correcting for nonadherence: 1) among the strata with an estimated 100% probability of high adherence (TDF hazard ratio (HR) = 0.19, 95% confidence interval (CI): 0.07, 0.56; TDF/FTC HR = 0.12, 95% CI: 0.03, 0.52); 2) with IPC weights used to approximate a continuously adherent population (TDF HR = 0.18, 95% CI: 0.06, 0.53; TDF/FTC HR = 0.15, 95% CI: 0.04, 0.52); and 3) in per-protocol analysis (TDF HR = 0.18, 95% CI: 0.06, 0.53; TDF/FTC HR = 0.16, 95% CI: 0.05, 0.53). Our results suggest that the efficacy of PrEP with high adherence is over 80%.
Pamela M
PM
Murnane
Elizabeth R
ER
Brown
Deborah
D
Donnell
R Yates
RY
Coley
Nelly
N
Mugo
Andrew
A
Mujugira
Connie
C
Celum
Jared M
JM
Baeten
D000163:Acquired Immunodeficiency Syndrome / Q000453:epidemiology / Q000517:prevention & control; D000328:Adult; D000367:Age Factors; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D004311:Double-Blind Method; D000069480:Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination / Q000008:administration & dosage*; D005260:Female; D015658:HIV Infections / Q000453:epidemiology / Q000517:prevention & control*; D020010:Heterosexuality; D006801:Humans; D015994:Incidence; D007630:Kenya; D008297:Male; D015233:Models, Statistical; D017060:Patient Satisfaction; D065129:Pre-Exposure Prophylaxis / Q000379:methods*; D012107:Research Design; D012737:Sex Factors; D012959:Socioeconomic Factors; D016903:Drug Monitoring
D019380:Anti-HIV Agents; D000069480:Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
HIV; HIV prevention; intention-to-treat analysis; medication adherence; randomized controlled trials