Counterfactual estimation of efficacy against placebo for novel PrEP agents using external trial data: example of injectable cabotegravir and oral PrEP in women

• Type of Material: Article
• Authors: Deborah Donnell, Fred Hutchinson Cancer Center; Fei Gao, Fred Hutchinson Cancer Center; James P Hughes, University of Washington; Brett Hanscom, Fred Hutchinson Cancer Center; Lawrence Corey, Fred Hutchinson Cancer Center; Myron S Cohen, University of North Carolina; Srilatha Edupuganti, Emory University; Nyaradzo Mgodi, University of Zimbabwe; Helen Rees, Wits RHI; Jared M Baeten, University of Washington, Seattle; Glenda Gray, South Africa Medical Research Council; Linda-Gail Bekker, University of Cape Town; Mina Hosseinipour, University of North Carolina; Sinead Delany-Moretlwe, Wits RHI, Johannesberg South Africa
• Language: English
• Date: 2023-06-01
• Publisher: JOHN WILEY & SONS LTD
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/jia2.26118
• Title of Journal or Parent Work: JOURNAL OF THE INTERNATIONAL AIDS SOCIETY
• Volume: 26
• Issue: 6
• Start Page: e26118
• End Page: e26118
• Grant/Funding Information: This work was made possible through funding support from the National Institute of Allergy and Infectious Diseases, Office of the Director, National Institutes of Health (NIH), National Institute on Drug Abuse and the National Institute of Mental Health, under award numbers UM1AI068619 (HIV Prevention Trials Network [HPTN] Leadership and Operations Center), UM1AI068617 (HPTN Statistical and Data Management Center [SDMC]), UM1AI068613 (HPTN Laboratory Center), UM1 AI068614 (HIV Vaccine Trials Network [HVTN] Leadership and Operations Center), UM1 AI068635 (HVTN SDMC) and UM1 AI068618, UM1 AI068619 (HVTN Laboratory Center). ECHO was funded by Bill & Melinda Gates Foundation, US Agency for International Development and the President's Emergency Plan for AIDS Relief, Swedish International Development Cooperation Agency, South African Medical Research Council and UN Population Fund. Additional funding was provided to HPTN 084 by the Bill & Melinda Gates Foundation (OPP1154174) and ViiV Healthcare. Pharmaceutical support was provided by ViiV Healthcare and Gilead Sciences.
• Keywords: tenofovir disoproxil fumarate; efficacy trial design; HIV PREEXPOSURE PROPHYLAXIS; Science & Technology; emtricitabine; PREVENTION; SERVICES; cabotegravir; ADHERENCE; Life Sciences & Biomedicine; HIV; EMTRICITABINE; INFECTION; pre-exposure prophylaxis; Infectious Diseases; Immunology; counterfactual placebo; PHASE-3
• Research Categories: Health Sciences, Oncology

Abstract

Introduction: Multiple antiretroviral agents have demonstrated efficacy for human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP). As a result, clinical trials of novel agents have transitioned from placebo- to active-controlled designs; however, active-controlled trials do not provide an estimate of efficacy versus no use of PrEP. Counterfactual placebo comparisons using other data sources could be employed to provide this information. Methods: We compared the active-controlled study (HPTN 084) of injectable cabotegravir (CAB-LA) versus daily oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) among women from seven countries in Africa to three external, contemporaneous randomized HIV prevention trials from which we constructed counterfactual placebo estimates. We used direct standardization via analysis weights to achieve the same distribution of person-years between the external study and HPTN 084, across strata predictive of HIV risk (country and selected risk covariates). We estimated prevention efficacy against a counterfactual placebo to provide information on the use of CAB-LA and FTC/TDF compared to no intervention. We compared the counterfactual placebo findings for FTC/TDF to previous placebo-controlled trials, adjusted for observed adherence to daily pills. Results: Distribution of age and baseline prevalence of gonorrhoea and chlamydia were similar among matched counterfactual placebo and observed HPTN 084 arms after standardization. Counterfactual estimates of CAB-LA versus placebo in all three settings showed a consistent risk reduction of 93%–94%, with lower bounds of the confidence intervals above 72%. Observed adherence (quantifiable tenofovir in plasma) in HPTN 084 was 54%–56%, and estimated efficacy of daily oral FTC/TDF against a counterfactual placebo was consistent with a predicted risk reduction of 39%–40% for this level of daily pill use. Conclusions: Counterfactual placebo rates of HIV acquisition derived from external trial data in similar locations and time can be used to support estimates of placebo-based efficacy of a novel HIV prevention agent. External trial data must be standardized to be representative of the clinical trial cohort testing the novel HIV prevention agent, accounting for confounders.