Longer-Term Safety and Efficacy of Emtricitabine and Tenofovir Alafenamide Versus Emtricitabine and Tenofovir Disoproxil Fumarate for HIV-1 Pre-Exposure Prophylaxis: Week 96 Results from a Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial

Background: In DISCOVER, a multinational randomized controlled trial, emtricitabine and tenofovir alafenamide compared with emtricitabine and tenofovir disoproxil fumarate demonstrated noninferior efficacy for HIV prevention and improved bone mineral density and renal safety biomarkers at week 48. Here, we report outcomes analysed after all participants had completed 96 weeks of follow up. Methods: Adult cisgender men and transgender women who have sex with men with a high risk of acquiring HIV were randomly assigned (1:1) to either of two study arms. This trial is registered with ClinicalTrials.gov, NCT02842086. Findings: 5,387 participants were randomly assigned to receive emtricitabine and tenofovir alafenamide (n=2,694) or emtricitabine and tenofovir disoproxil fumarate (n=2,693), contributing 10,081 person-years (PY) of follow-up. There were eight HIV infections in emtricitabine and tenofovir alafenamide users (0·16 infections/100 PY [95% CI 0·07–0·31]), and 15 in emtricitabine and tenofovir disoproxil fumarate users (0·30 infections/100 PY [0·17–0·49]). Emtricitabine and tenofovir alafenamide was noninferior to emtricitabine and tenofovir disoproxil fumarate for HIV prevention, as the upper limit of the 95% CI of the infection rate ratio (IRR) was less than the prespecified noninferiority margin of 1·62 (IRR 0·54 [95% CI 0·23–1·26]). Approximately 78% to 82% of participants reported taking study medication more than 95% of the time across all study visits.  Rates of sexually transmitted infections remained high and similar across arms (21 per 100 PYs for rectal gonorrhea and 28 per 100 PY for rectal chlamydia). Emtricitabine and tenofovir alafenamide continued to demonstrate superiority over emtricitabine and tenofovir disoproxil fumarate in all six prespecified bone mineral density and renal biomarkers. There was more weight gain among emtricitabine and tenofovir alafenamide users (median weight gain 1·7 kg vs. 0·5 kg, p<0·0001) Interpretation: Emtricitabine and tenofovir alafenamide is safe and effective for longer-term PrEP in cisgender men and transgender women who have sex with men. Trial Registration: This trial is registered with ClinicalTrials.gov, NCT02842086. Funding: Gilead Sciences, Inc. Declaration of Interests: DP has received research grants and/or honoraria for advisories and/or conferences from Viiv, Gilead, Janssen and MSD. CDS reports grants and personal fees from Gilead Sciences, during the conduct of the study; personal fees from AbbVie, grants and personal fees from Janssen- Cilag, grants and personal fees from MSD, grants and personal fees from ViiV Healthcare/GSK, outside the submitted work. YS, RE, SC, AK, CC, MD, and DMB are employees of Gilead and shareholders of Gilead stock. Other disclosures are forthcoming. Ethics Approval Statement: This study was approved by central or site-specific review boards or ethics committees.