Estimating efficacy in a randomized trial with product nonadherence: application of multiple methods to a trial of preexposure prophylaxis for HIV prevention
Murnane, P.M.; Brown, E.R.; Donnell, D.; Coley, R.Yates.; Mugo, N.; Mujugira, A.; Celum, C.; Baeten, J.M.; Mujugira, A.; Baeten, J.M.; Murnane, P.M.; Donnell, D.; Mugo, N.; Brown, E.R.; Yates Coley, R.; Celum, C.; Coombs, R.W.; Frenkel, L.; Hendrix, C.W.; Lingappa, J.; Juliana McElrath, M.; Fife, K.; Were, E.; Tumwesigye, E.; Ndase, P.; Katabira, E.; Ronald, A.; Bukusi, E.; Cohen, C.; Wangisi, J.; Campbell, J.; Tappero, J.; Kiarie, J.; Farquhar, C.; John-Stewart, G.; Mugo, N.Rwamba.
American Journal of Epidemiology 182(10): 848-856
2015
ISSN/ISBN: 0002-9262 PMID: 26487343 DOI: 10.1093/aje/kwv202Document Number: 641962
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%.