title: Switching from efavirenz, emtricitabine, and tenofovir disoproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-inferiority study.
abstract: Tenofovir alafenamide is a prodrug that reduces tenofovir plasma concentrations by 90% compared with tenofovir disoproxil fumarate, thereby decreasing bone and renal risks. The coformulation of rilpivirine, emtricitabine, and tenofovir alafenamide has recently been approved, and we aimed to investigate the efficacy, safety, and tolerability of switching to this regimen compared with remaining on coformulated efavirenz, emtricitabine, and tenofovir disoproxil fumarate.
  
  
  
  In this randomised, double-blind, placebo-controlled, non-inferiority trial, HIV-1-infected adults were enrolled at 120 hospitals and outpatient clinics in eight countries in North America and Europe. Participants were virally suppressed (HIV-1 RNA <50 copies per mL) on efavirenz, emtricitabine, and tenofovir disoproxil fumarate for at least 6 months before enrolment and had creatinine clearance of at least 50 mL/min. Participants were randomly assigned (1:1) to receive a single-tablet regimen of rilpivirine (25 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) or to continue a single-tablet regimen of efavirenz (600 mg), emtricitabine (200 mg), and tenofovir disoproxil fumarate (300 mg), with matching placebo. Investigators, participants, study staff, and those assessing outcomes were masked to treatment group. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of less than 50 copies per mL at week 48 (assessed by the US Food and Drug Administration snapshot algorithm), with a prespecified non-inferiority margin of 8%. This study was registered with ClinicalTrials.gov, number NCT02345226.
  
  
  
  Between Jan 26, 2015, and Aug 27, 2015, 875 participants were randomly assigned and treated (438 with rilpivirine, emtricitabine, and tenofovir alafenamide and 437 with efavirenz, emtricitabine, tenofovir disoproxil fumarate). Viral suppression at week 48 was maintained in 394 (90%) of 438 participants assigned to the tenofovir alafenamide regimen and 402 (92%) of 437 assigned to the tenofovir disoproxil fumarate regimen (difference -2·0%, 95·001% CI -5·9 to 1·8), demonstrating non-inferiority. 56 (13%) of 438 in participants in the rilpivirine, emtricitabine, and tenofovir alafenamide group experienced treatment-related adverse events compared with 45 (10%) of 437 in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group.
  
  
  
  Switching to rilpivirine, emtricitabine, and tenofovir alafenamide from efavirenz, emtricitabine, and tenofovir disoproxil fumarate was non-inferior in maintaining viral suppression and was well tolerated at 48 weeks. These findings support guidelines recommending tenofovir alafenamide-based regimens, including coformulation with rilpivirine and emtricitabine, as initial and ongoing treatment for HIV-1 infection.
  
  
  
  Gilead Sciences.
authors.affiliation: Orlando Immunology Center, Orlando, FL, USA.
authors.forename: Edwin
authors.initials: E
authors.lastname: DeJesus
authors.affiliation: Midway Immunology and Research Center, Fort Pierce, FL, USA.
authors.forename: Moti
authors.initials: M
authors.lastname: Ramgopal
authors.affiliation: The Crofoot Research Center, Houston, TX, USA.
authors.forename: Gordon
authors.initials: G
authors.lastname: Crofoot
authors.affiliation: Ruane Medical, Los Angeles, CA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Ruane
authors.affiliation: Therafirst Medical Center, Fort Lauderdale, FL, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: LaMarca
authors.affiliation: Southern California Men's Medical Group, Los Angeles, CA, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Mills
authors.affiliation: The Research Institute, Springfield, MA, USA.
authors.forename: Claudia T
authors.initials: CT
authors.lastname: Martorell
authors.affiliation: Spectrum Health Care, Vancouver, BC, Canada.
authors.forename: Joseph
authors.initials: J
authors.lastname: de Wet
authors.affiliation: ICH Study Center, Hamburg, Denmark.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Stellbrink
authors.affiliation: Hopital Saint Louis, Paris, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Molina
authors.affiliation: Kings College Hospital, London, UK.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Post
authors.affiliation: Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Ignacio Pérez
authors.initials: IP
authors.lastname: Valero
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Porter
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: YaPei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Cheng
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Quirk
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Devi
authors.initials: D
authors.lastname: SenGupta
authors.affiliation: Gilead Sciences, Foster City, CA, USA. Electronic address: huyen.cao@gilead.com.
authors.forename: Huyen
authors.initials: H
authors.lastname: Cao
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000328:Adult; D000409:Alanine; D000480:Alkynes; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D048588:Benzoxazines / Q000627:therapeutic use*; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D000068679:Emtricitabine / Q000627:therapeutic use*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008875:Middle Aged; D000068696:Rilpivirine / Q000627:therapeutic use*; D000068698:Tenofovir / Q000627:therapeutic use* / Q000031:analogs & derivatives
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D000068698:Tenofovir; C442442:tenofovir alafenamide; D000068696:Rilpivirine; D000068679:Emtricitabine; D000225:Adenine; C098320:efavirenz; D000409:Alanine