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Background: Tenofovir alafenamide shows high antiviral efficacy and improved renal and bone safety compared with tenofovir disoproxil fumarate when used for HIV treatment. Here, we report primary results from a blinded phase 3 study evaluating the efficacy and safety of pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir alafenamide versus emtricitabine and tenofovir disoproxil fumarate for HIV prevention., Methods: This study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial done at 94 community, public health, and hospital-associated clinics located in regions of Europe and North America, where there is a high incidence of HIV or prevalence of people living with HIV, or both. We enrolled adult cisgender men who have sex with men and transgender women who have sex with men, both with a high risk of acquiring HIV on the basis of their self-reported sexual behaviour in the past 12 weeks or their recent history (within 24 weeks of enrolment) of bacterial sexually transmitted infections. Participants with current or previous use of PrEP with emtricitabine and tenofovir disoproxil fumarate were not excluded. We used a computer-generated random allocation sequence to randomly assign (1:1) participants to receive either emtricitabine (200 mg) and tenofovir alafenamide (25 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir alafenamide group), or emtricitabine (200 mg) and tenofovir disoproxil fumarate (300 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir disoproxil fumarate group). As such, all participants were given two tablets. The trial sponsor, investigators, participants, and the study staff who provided the study drugs, assessed the outcomes, and collected the data were masked to group assignment. The primary efficacy outcome was incident HIV infection, which was assessed when all participants had completed 48 weeks of follow-up and half of all participants had completed 96 weeks of follow-up. This full analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug and had at least one post-baseline HIV test. Non-inferiority of emtricitabine and tenofovir alafenamide to emtricitabine and tenofovir disoproxil fumarate was established if the upper bound of the 95·003% CI of the HIV incidence rate ratio (IRR) was less than the prespecified non-inferiority margin of 1·62. We prespecified six secondary bone mineral density and renal biomarker safety endpoints to evaluate using the safety analysis set. This analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02842086, and is no longer recruiting., Findings: Between Sept 13, 2016, and June 30, 2017, 5387 (92%) of 5857 participants were randomly assigned and received emtricitabine and tenofovir alafenamide (n=2694) or emtricitabine and tenofovir disoproxil fumarate (n=2693). At the time of the primary efficacy analysis (ie, when all participants had completed 48 weeks and 50% had completed 96 weeks) emtricitabine and tenofovir alafenamide was non-inferior to emtricitabine and tenofovir disoproxil fumarate for HIV prevention, as the upper limit of the 95% CI of the IRR, was less than the prespecified non-inferiority margin of 1·62 (IRR 0·47 [95% CI 0·19-1·15]). After 8756 person-years of follow-up, 22 participants were diagnosed with HIV, seven participants in the emtricitabine and tenofovir alafenamide group (0·16 infections per 100 person-years [95% CI 0·06-0·33]), and 15 participants in the emtricitabine and tenofovir disoproxil fumarate group (0·34 infections per 100 person-years [0·19-0·56]). Both regimens were well tolerated, with a low number of participants reporting adverse events that led to discontinuation of the study drug (36 [1%] of 2694 participants in the emtricitabine and tenofovir alafenamide group vs 49 [2%] of 2693 participants in the emtricitabine and tenofovir disoproxil fumarate group). Emtricitabine and tenofovir alafenamide was superior to emtricitabine and tenofovir disoproxil fumarate in all six prespecified bone mineral density and renal biomarker safety endpoints., Interpretation: Daily emtricitabine and tenofovir alafenamide shows non-inferior efficacy to daily emtricitabine and tenofovir disoproxil fumarate for HIV prevention, and the number of adverse events for both regimens was low. Emtricitabine and tenofovir alafenamide had more favourable effects on bone mineral density and biomarkers of renal safety than emtricitabine and tenofovir disoproxil fumarate., Funding: Gilead Sciences., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: HIV pre-exposure prophylaxis (PrEP) is highly efficacious, and yet most individuals indicated for it are not currently using it. To provide guidance for health policymakers, researchers, and community advocates, we developed county-level PrEP use estimates and assessed locality and policy associations., Methods: Using data from a national aggregator, we applied a validated crosswalk procedure to generate county-level estimates of PrEP users in 2018. A multilevel Poisson regression explored associations between PrEP use and (1) state policy variables of Medicaid expansion and state Drug Assistance Programs (PrEP-DAPs) and (2) county-level characteristics from the U.S. Census Bureau. Outcomes were PrEP per population (prevalence) and PrEP-to-need ratio (PnR), defined as the ratio of PrEP users per new HIV diagnosis. Higher levels of PrEP prevalence or PnR indicate more PrEP users relative to the total population or estimated need, respectively., Results: Our 2018 county-level data set included a total of 188,546 PrEP users in the United States. Nationally, PrEP prevalence was 70.3/100,000 population and PnR was 4.9. In an adjusted model, counties with a 5% higher proportion of black residents had 5% lower PnR (rate ratio (RR): 0.95, 95% confidence interval (CI): 0.93, 0.96). Similarly, counties with higher concentration of residents uninsured or living in poverty had lower PnR. Relative to states without Medicaid expansion or PrEP-DAPs, states with only one of those programs had 25% higher PrEP prevalence (RR: 1.25, 95% CI: 1.09, 1.45), and states with both programs had 99% higher PrEP prevalence (RR: 1.99, 95% CI: 1.60, 2.48). There was a significant linear trend across the three policy groups, and similar findings for the relation between PnR and the policy groups., Conclusions: In a data set comprising approximately 80% of PrEP users in the United States, we found that Medicaid expansion and PrEP-DAPs were associated with higher PrEP use in states that adopted those policies, after controlling for potential confounders. Future research should identify which components of PrEP support programs have the most success and how to best promote PrEP among groups most impacted by the epidemic. States should support the admirable health decisions of their residents to get on PrEP by implementing policies that facilitate access., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Pre-exposure prophylaxis (PrEP) is a pillar of the US Department of Health and Human Services "Ending the HIV Epidemic" (EHE) initiative in 50 EHE jurisdictions (48 U.S. counties and two U.S. cities) and seven U.S. states with high numbers of HIV diagnoses rates in rural areas. Current data systems do not provide data on PrEP uptake in counties or cities., Methods: We report on PrEP users at the county level. Data from a large, commercial pharmacy database were used; we applied the U.S. Census Bureau's method to allocate PrEP users within a ZIP3 into counties and validated the results. We report counts and rates of PrEP users in 2018 for all EHE jurisdictions. We used joinpoint regression to model the estimated annual percent change in PrEP use for each jurisdiction and state., Results: 93,156 people in the 50 EHE jurisdictions used PrEP in 2018; 94% were men and 39% were aged 25-34 years. There was more than an 80-fold difference in the range of rates of PrEP use per 100,000 population among the EHE jurisdictions (range: 8-644 per 100,000 population; median 93 per 100,000 population). PrEP use increased from 2012 to 2018 in all EHE counties and states. At current rates of growth of PrEP use, 94% of EHE counties and jurisdictions will reach their National HIV/AIDS Strategy goals of a 500% increase in PrEP use in 2020. EHE states had less variation in rates of PrEP use (range: 29-51/100,000 population; median 32/100,000 population)., Conclusions: At the outset of a major U.S. government program to reduce HIV infections, rates of PrEP use are highly variable among the 50 EHE jurisdictions. Data from commercial prescription databases will be a useful public resource to understand progress in promoting use of PrEP as part of the EHE initiative and evaluating progress in PrEP use across health jurisdictions., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Pre-exposure prophylaxis (PrEP) with oral emtricitibine/tenofovir disoproxil fumarate (TDF/FTC) reduces the risk of HIV infection by >90% when taken as prescribed. Trends in prevalence of PrEP use, which account for persons who have stopped PrEP, increased through 2016, but have not been described since., Methods: Annual prevalence estimates of unique, TDF/FTC PrEP users (individuals with ≥1 day of a filled PrEP prescription in a given year) in the United States (US) were generated for 2012-2017 from a national prescription database. A validated algorithm was used to distinguish users of TDF/FTC for HIV or chronic Hepatitis B treatment or postexposure prophylaxis from PrEP users. We calculated annual prevalence of PrEP use overall and by age, sex, and region. We used log-transformation to calculate estimated annual percent change (EAPC) in the prevalence of PrEP use., Results: Annual prevalence of PrEP use increased from 3.3/100,000 population in 2012 to 36.7 in 2017 -a 56% annual increase from 2012 to 2017 (EAPC: +56%). Annual prevalence of PrEP use increased faster among men than among women (EAPC: +68% and +5%, respectively). By age group, annual prevalence of PrEP use increased fastest among 25- to 34-year olds (EAPC: +61%) and slowest among ≥55-year olds (EAPC: +52%) and ≤24-year olds (EAPC: +51%). In 2017, PrEP use was lowest in the South (29.8/100,000) and highest in the Northeast (62.3/100,000)., Conclusions: Despite overall increases in the annual number of TDF/FTC PrEP users in the US from 2012 to 2017, the growth of PrEP coverage is inconsistent across groups. Efforts to optimize PrEP access are especially needed for women and for those living in the South., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The number of individuals who have started a regimen for HIV pre-exposure prophylaxis (PrEP) in the United States is not well characterized but has been on the rise since 2012. This analysis assesses the distribution of PrEP use nationally and among subgroups., Methods: A validated algorithm quantifying tenofovir disoproxil fumarate/emtricitabine for PrEP in the United States was applied to a national prescription database to determine the quarterly prevalence of PrEP use. HIV diagnoses from 2016 were used as an epidemiological proxy for PrEP need. The PrEP-to-need ratio (PnR) was defined as the number of PrEP users divided by new HIV diagnoses., Results: A total of 70,395 individuals used PrEP in the fourth quarter of 2017: 67,166 males and 3229 females. Nationally, prevalence of PrEP use was 26/100,000 (range across states per 100,000 [RAS/100k]: 4-73) and the PnR was 1.8 (RAS: 0.5-6.6). Prevalence of PrEP use among males and females, respectively, was 50/100,000 and 2/100,000 (RAS/100k: 7-143 and 0.3-7) and PnR was 2.1 and 0.4 (RAS: 0.6-7.1 and 0.1-4.0). Prevalence of PrEP use was lowest among individuals aged less than or equal to 24 and more than or equal to 55 years (15/100,000 and 6/100,000, RAS/100k: 1-45 and 0.4-14), with PnR 0.9 and 1.5 (RAS: 0.2-5.6 and 0.3-7.0). The Northeast had the highest PnR (3.3); the South had the lowest (1.0). States with Medicaid expansion had more than double the PnR than states without expansion., Conclusions: Available data suggest that females, individuals aged less than or equal to 24 years and residents of the South had lower levels of PrEP use relative to epidemic need. These results are ecological, and misclassification may attenuate results. PnR is useful for future assessments of HIV prevention strategy uptake., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Tenofovir disoproxil fumarate can cause renal and bone toxic effects related to high plasma tenofovir concentrations. Tenofovir alafenamide is a novel tenofovir prodrug with a 90% reduction in plasma tenofovir concentrations. Tenofovir alafenamide-containing regimens can have improved renal and bone safety compared with tenofovir disoproxil fumarate-containing regimens., Methods: In these two controlled, double-blind phase 3 studies, we recruited treatment-naive HIV-infected patients with an estimated creatinine clearance of 50 mL per min or higher from 178 outpatient centres in 16 countries. Patients were randomly assigned (1:1) to receive once-daily oral tablets containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg tenofovir alafenamide (E/C/F/tenofovir alafenamide) or 300 mg tenofovir disoproxil fumarate (E/C/F/tenofovir disoproxil fumarate) with matching placebo. Randomisation was done by a computer-generated allocation sequence (block size 4) and was stratified by HIV-1 RNA, CD4 count, and region (USA or ex-USA). Investigators, patients, study staff, and those assessing outcomes were masked to treatment group. All participants who received one dose of study drug were included in the primary intention-to-treat efficacy and safety analyses. The main outcomes were the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48 as defined by the the US Food and Drug Adminstration (FDA) snapshot algorithm (pre-specified non-inferiority margin of 12%) and pre-specified renal and bone endpoints at 48 weeks. These studies are registered with ClinicalTrials.gov, numbers NCT01780506 and NCT01797445., Findings: We recruited patients from Jan 22, 2013, to Nov 4, 2013 (2175 screened and 1744 randomly assigned), and gave treatment to 1733 patients (866 given E/C/F/tenofovir alafenamide and 867 given E/C/F/tenofovir disoproxil fumarate). E/C/F/tenofovir alafenamide was non-inferior to E/C/F/tenofovir disoproxil fumarate, with 800 (92%) of 866 patients in the tenofovir alafenamide group and 784 (90%) of 867 patients in the tenofovir disoproxil fumarate group having plasma HIV-1 RNA less than 50 copies per mL (adjusted difference 2·0%, 95% CI -0·7 to 4·7). Patients given E/C/F/tenofovir alafenamide had significantly smaller mean serum creatinine increases than those given E/C/F/tenofovir disoproxil fumarate (0·08 vs 0·12 mg/dL; p<0·0001), significantly less proteinuria (median % change -3 vs 20; p<0·0001), and a significantly smaller decrease in bone mineral density at spine (mean % change -1·30 vs -2·86; p<0·0001) and hip (-0·66 vs -2·95; p<0·0001) at 48 weeks., Interpretation: Through 48 weeks, more than 90% of patients given E/C/F/tenofovir alafenamide or E/C/F/tenofovir disoproxil fumarate had virological success. Renal and bone effects were significantly reduced in patients given E/C/F/tenofovir alafenamide. Although these studies do not have the power to assess clinical safety events such as renal failure and fractures, our data suggest that E/C/F/tenofovir alafenamide will have a favourable long-term renal and bone safety profile., Funding: Gilead Sciences., (Copyright © 2015 Elsevier Ltd. All rights reserved.)