Kenneth H Mayer1, Jean-Michel Molina2, Melanie A Thompson3, Peter L Anderson4, Karam C Mounzer5, Joss J De Wet6, Edwin DeJesus7, Heiko Jessen8, Robert M Grant9, Peter J Ruane10, Pamela Wong11, Ramin Ebrahimi11, Lijie Zhong11, Anita Mathias12, Christian Callebaut13, Sean E Collins14, Moupali Das15, Scott McCallister14, Diana M Brainard14, Cynthia Brinson16, Amanda Clarke17, Pep Coll18, Frank A Post19, C Bradley Hare20. 1. The Fenway Institute, Fenway Health, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA. 2. Infectious Diseases Department, Hopitaux Saint-Louis Lariboisière, University of Paris and INSERM U944, Paris, France. 3. AIDS Research Consortium of Atlanta, Atlanta, GA, USA. 4. Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA. 5. Philadelphia FIGHT, Philadelphia, PA, USA. 6. Spectrum Health, Vancouver, BC, Canada. 7. Orlando Immunology Center, Orlando, FL, USA. 8. Praxis Jessen(2) + Kollegen, Berlin, Germany. 9. San Francisco AIDS Foundation, and University of California, San Francisco, CA, USA. 10. Ruane Medical and Liver Health Institute, Los Angeles, CA, USA. 11. Department of Biometrics, Gilead Sciences, Foster City, CA, USA. 12. Department of Clinical Pharmacology, Gilead Sciences, Foster City, CA, USA. 13. Department of Virology, Gilead Sciences, Foster City, CA, USA. 14. Department of HIV and Emerging Viral Infections Clinical Research, Gilead Sciences, Foster City, CA, USA. 15. Department of HIV and Emerging Viral Infections Clinical Research, Gilead Sciences, Foster City, CA, USA. Electronic address: moupali.as@gilead.com. 16. Central Texas Clinical Research, Austin, TX, USA. 17. Royal Sussex County Hospital, Brighton and Sussex University Hospitals National Health Service (NHS) Trust, Brighton, UK. 18. BCN Checkpoint and IrsiCaixa-AIDS Research Institute, Barcelona, Spain. 19. King's College Hospital NHS Foundation Trust, King's College Hospital, London, UK. 20. Department of Adult and Family Medicine, Kaiser Permanente San Francisco Medical Center, San Francisco, CA, USA.
Abstract
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 withemtricitabine 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 theemtricitabine and tenofovir alafenamidegroup (0·16 infections per 100 person-years [95% CI 0·06-0·33]), and 15 participants in theemtricitabine and tenofovir disoproxil fumarategroup (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.
RCT Entities:
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.
Authors: Asante R Kamkwalala; Ankita Garg; Upal Roy; Avery Matthews; Jose Castillo-Mancilla; Jordan E Lake; Giada Sebastiani; Michael Yin; Todd T Brown; Angela R Kamer; Douglas A Jabs; Ronald J Ellis; Marta Boffito; Meredith Greene; Sarah Schmalzle; Eugenia Siegler; Kristine M Erlandson; David J Moore Journal: AIDS Res Hum Retroviruses Date: 2021-09-20 Impact factor: 2.205
Authors: Audrey Harkness; Satyanand Satyanarayana; Daniel Mayo; Rosana Smith-Alvarez; Brooke G Rogers; Guillermo Prado; Steven A Safren Journal: AIDS Patient Care STDS Date: 2021-05 Impact factor: 5.078
Authors: Melissa E Badowski; Nicholas Britt; Emily C Huesgen; Michelle M Lewis; Misty M Miller; Kathleen Nowak; Elizabeth Sherman; Renata O Smith Journal: Pharmacotherapy Date: 2021-02-27 Impact factor: 4.705
Authors: Whitney C Sewell; Patricia Solleveld; Dominika Seidman; Christine Dehlendorf; Julia L Marcus; Douglas S Krakower Journal: Curr HIV/AIDS Rep Date: 2021-01-08 Impact factor: 5.071