title: Switching from 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, a tenofovir prodrug, results in 90% lower tenofovir plasma concentrations than does tenofovir disproxil fumarate, thereby minimising bone and renal risks. We investigated the efficacy, safety, and tolerability of switching to a single-tablet regimen containing rilpivirine, emtricitabine, and tenofovir alafenamide compared with remaining on rilpivirine, emtricitabine, and tenofovir disoproxil fumarate.
  
  
  
  In this randomised, double-blind, multicentre, placebo-controlled, non-inferiority trial, HIV-1-infected adults were screened and enrolled at 119 hospitals in 11 countries in North America and Europe. Participants were virally suppressed (HIV-1 RNA <50 copies per mL) on rilpivirine, 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 either rilpivirine (25 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) or to remain on a single-tablet regimen of rilpivirine (25 mg), emtricitabine (200 mg), and tenofovir disoproxil fumarate (300 mg), with matching placebo, once daily for 96 weeks. Investigators, participants, study staff, and those assessing outcomes were masked to treatment group. All participants who received one dose of study drug and were on the tenofovir disoproxil fumarate regimen before screening were included in primary efficacy analyses. The primary endpoint was the proportion of participants with less than 50 copies per mL of plasma HIV-1 RNA at week 48 (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 NCT01815736.
  
  
  
  Between Jan 26, 2015, and Aug 25, 2015, 630 participants were randomised (316 to the tenofovir alafenamide group and 314 to the tenofovir disoproxil fumarate group). At week 48, 296 (94%) of 316 participants on tenofovir alafenamide and 294 (94%) of 313 on tenofovir disoproxil fumarate had maintained less than 50 copies per mL HIV-1 RNA (difference -0·3%, 95·001% CI -4·2 to 3·7), showing non-inferiority of tenofovir alafenamide to tenofovir disoproxil fumarate. Numbers of adverse events were similar between groups. 20 (6%) of 316 participants had study-drug related adverse events in the tenofovir alafenamide group compared with 37 (12%) of 314 in the tenofovir disoproxil fumarate group; none of these were serious.
  
  
  
  Switching to rilpivirine, emtricitabine, and tenofovir alafenamide was non-inferior to continuing rilpivirine, emtricitabine, tenofovir disoproxil fumarate 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: Grahame Hayton Unit, Royal London Hospital, London, UK.
authors.forename: Chloe
authors.initials: C
authors.lastname: Orkin
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: Crofoot Research Center, Houston, TX, USA.
authors.forename: Gordon
authors.initials: G
authors.lastname: Crofoot
authors.affiliation: Ruane Clinical Research Group, 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: Department of Internal Medicine, Cliniques Universitaires Saint-Luc, Bruxelles, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Vandercam
authors.affiliation: Spectrum Health Care, Vancouver, BC, Canada.
authors.forename: Joseph
authors.initials: J
authors.lastname: de Wet
authors.affiliation: Department of Internal Medicine I, University Hospital Bonn, Bonn, Denmark.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Rockstroh
authors.affiliation: Dipartimento di Malattie Infettive, Ospedale San Raffaele Srl, Milan, Italy.
authors.forename: Adriano
authors.initials: A
authors.lastname: Lazzarin
authors.affiliation: Erasmus MC, Department of Internal Medicine, Rotterdam, Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: Rijnders
authors.affiliation: Infectious Diseases Service, AIDS Unit, Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Podzamczer
authors.affiliation: Karolinska Universitetssjukhuset, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Thalme
authors.affiliation: Universitatsspital Basel, Medizinische Poliklinik, Basel, Switzerland.
authors.forename: Marcel
authors.initials: M
authors.lastname: Stoeckle
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: Hui C
authors.initials: HC
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; D019380:Anti-HIV Agents / Q000627:therapeutic use*; 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; D008297:Male; D008875:Middle Aged; D000068696:Rilpivirine / Q000627:therapeutic use*; D000068698:Tenofovir / Q000627:therapeutic use* / Q000031:analogs & derivatives
chemical_list: D019380:Anti-HIV Agents; D000068698:Tenofovir; C442442:tenofovir alafenamide; D000068696:Rilpivirine; D000068679:Emtricitabine; D000225:Adenine; D000409:Alanine