title: Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study.
abstract: BACKGROUND
  Antiretroviral regimens containing tenofovir disoproxil fumarate have been associated with renal toxicity and reduced bone mineral density. Tenofovir alafenamide is a novel tenofovir prodrug that reduces tenofovir plasma concentrations by 90%, thereby decreasing off-target side-effects. We aimed to assess whether efficacy, safety, and tolerability were non-inferior in patients switched to a regimen containing tenofovir alafenamide versus in those remaining on one containing tenofovir disoproxil fumarate.
  
  
  METHODS
  In this randomised, actively controlled, multicentre, open-label, non-inferiority trial, we recruited HIV-1-infected adults from Gilead clinical studies at 168 sites in 19 countries. Patients were virologically suppressed (HIV-1 RNA <50 copies per mL) with an estimated glomerular filtration rate of 50 mL per min or greater, and were taking one of four tenofovir disoproxil fumarate-containing regimens for at least 96 weeks before enrolment. With use of a third-party computer-generated sequence, patients were randomly assigned (2:1) to receive a once-a-day single-tablet containing elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg (tenofovir alafenamide group) or to carry on taking one of four previous tenofovir disoproxil fumarate-containing regimens (tenofovir disoproxil fumarate group) for 96 weeks. Randomisation was stratified by previous treatment regimen in blocks of six. Patients and treating physicians were not masked to the assigned study regimen; outcome assessors were masked until database lock. The primary endpoint was the proportion of patients who received at least one dose of study drug who had undetectable viral load (HIV-1 RNA <50 copies per mL) at week 48. The non-inferiority margin was 12%. This study was registered with ClinicalTrials.gov, number NCT01815736.
  
  
  RESULTS
  Between April 12, 2013 and April 3, 2014, we enrolled 1443 patients. 959 patients were randomly assigned to the tenofovir alafenamide group and 477 to the tenofovir disoproxil fumarate group. Viral suppression at week 48 was noted in 932 (97%) patients assigned to the tenofovir alafenamide group and in 444 (93%) assigned to the tenofovir disoproxil fumarate group (adjusted difference 4·1%, 95% CI 1·6-6·7), with virological failure noted in ten and six patients, respectively. The number of adverse events was similar between the two groups, but study drug-related adverse events were more common in the tenofovir alafenamide group (204 patients [21%] vs 76 [16%]). Hip and spine bone mineral density and glomerular filtration were each significantly improved in patients in the tenofovir alafenamide group compared with those in the tenofovir disoproxil fumarate group.
  
  
  CONCLUSIONS
  Switching to a tenofovir alafenamide-containing regimen from one containing tenofovir disoproxil fumarate was non-inferior for maintenance of viral suppression and led to improved bone mineral density and renal function. Longer term follow-up is needed to better understand the clinical impact of these changes.
  
  
  BACKGROUND
  Gilead Sciences.
authors.affiliation: Southern California Men's Medical Group, Los Angeles, CA, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Mills
authors.affiliation: Hospital Universitario La Paz, IdiPAZ, Madrid, Spain.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Arribas
authors.affiliation: Hospital Civil de Guadalajara CUCS, Universidad de Guadalajara, Guadalajara, Jal, Mexico.
authors.forename: Jaime
authors.initials: J
authors.lastname: Andrade-Villanueva
authors.affiliation: University Hospital Amadeo De Savoia, Turin, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: DiPerri
authors.affiliation: University Medical Center, Hamburg Eppendorf Infectious Diseases Unit, Hamburg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Van Lunzen
authors.affiliation: Instituto Dominicano de Estudios Virologicos JDEZ, Santo Domingo, Dominican Republic.
authors.forename: Ellen
authors.initials: E
authors.lastname: Koenig
authors.affiliation: George Washington University School of Medicine, Washington, DC, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Elion
authors.affiliation: Infectious Disease Service, Lausanne University Hospital and Lausanne University, Lausanne, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Cavassini
authors.affiliation: Centro de Referenda e Treinamento Em DSTIAIDS, São Paulo, Brazil.
authors.forename: Jose Valdez
authors.initials: JV
authors.lastname: Madruga
authors.affiliation: University of Toronto, Toronto, ON, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Brunetta
authors.affiliation: La Playa Medical Group, San Diego, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Shamblaw
authors.affiliation: Orlando Immunology Center, Orlando, FL, USA.
authors.forename: Edwin
authors.initials: E
authors.lastname: DeJesus
authors.affiliation: Barts and the London NHS Trust, London, UK.
authors.forename: Chloe
authors.initials: C
authors.lastname: Orkin
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Wohl
authors.affiliation: Henry Ford Health System, Detroit, MI, USA.
authors.forename: Indira
authors.initials: I
authors.lastname: Brar
authors.affiliation: Mercer University School of Medicine, Macon, GA, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Stephens
authors.affiliation: Infectious Diseases Department, Hopital Saint Antoine, Sorbonne Universites, Univ Paris and INSERM, Paris, France.
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Girard
authors.affiliation: Ruth M Rothstein Core Center, Cook County Hospital, Chicago, IL, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Huhn
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Plummer
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Ya-Pei
authors.initials: YP
authors.lastname: Liu
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Cheng
authors.affiliation: Gilead Sciences, Foster City, CA, USA. Electronic address: scott.mccallister@gilead.com.
authors.forename: Scott
authors.initials: S
authors.lastname: McCallister
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000328:Adult; D000409:Alanine; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D004338:Drug Combinations; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral; D000068698:Tenofovir / Q000627:therapeutic use* / Q000031:analogs & derivatives; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D004338:Drug Combinations; D012367:RNA, Viral; D000068698:Tenofovir; C442442:tenofovir alafenamide; D000225:Adenine; D000409:Alanine