title: Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Gilead Sciences.
authors.affiliation: Division of Infectious Diseases and Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA. Electronic address: psax@partners.org.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Sax
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: David
authors.initials: D
authors.lastname: Wohl
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Yin
authors.affiliation: Department of HIV Medicine, King's College, Hospital NHS Foundation Trust, London, UK.
authors.forename: Frank
authors.initials: F
authors.lastname: Post
authors.affiliation: Orlando Immunology Center, Orlando, FL, USA.
authors.forename: Edwin
authors.initials: E
authors.lastname: DeJesus
authors.affiliation: Department of Medicine, University of Alabama Birmingham, Birmingham, AL, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Saag
authors.affiliation: Department of Medicine, Chelsea and Westminster Hospital, NHS Foundation Trust, London, UK.
authors.forename: Anton
authors.initials: A
authors.lastname: Pozniak
authors.affiliation: AIDS Research Consortium of Atlanta, Atlanta, GA, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Thompson
authors.affiliation: HIV Unit, Infectious Disease Service. Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Podzamczer
authors.affiliation: Hôpital Saint Louis, Paris, France.
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Molina
authors.affiliation: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Oka
authors.affiliation: Instituto Dominicano de Estudios Virologicos (IDEV), Santo Domingo, Dominican Republic.
authors.forename: Ellen
authors.initials: E
authors.lastname: Koenig
authors.affiliation: Clinique Medicale L'Actuale in Montreal, Montreal, Canada.
authors.forename: Benoit
authors.initials: B
authors.lastname: Trottier
authors.affiliation: Unidad de VIH del Hospital Civil de Guadalajara, CUCS, U de G Guadalajara, Mexico.
authors.forename: Jaime
authors.initials: J
authors.lastname: Andrade-Villanueva
authors.affiliation: Gordon Crofoot Research, Houston, TX, USA.
authors.forename: Gordon
authors.initials: G
authors.lastname: Crofoot
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Custodio
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: Lijie
authors.initials: L
authors.lastname: Zhong
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Huyen
authors.initials: H
authors.lastname: Cao
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Hal
authors.initials: H
authors.lastname: Martin
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Callebaut
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.
authors.forename: Marshall W
authors.initials: MW
authors.lastname: Fordyce
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: McCallister
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000328:Adult; D000409:Alanine; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000627:therapeutic use*; D018771:Arthralgia / Q000139:chemically induced; D015519:Bone Density / Q000187:drug effects; D018791:CD4 Lymphocyte Count; D002219:Carbamates / Q000008:administration & dosage* / Q000009:adverse effects; D000069547:Cobicistat; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004311:Double-Blind Method; D004338:Drug Combinations; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D006261:Headache / Q000139:chemically induced; D006801:Humans; D007668:Kidney / Q000187:drug effects; D008297:Male; D009325:Nausea; D063065:Organophosphonates / Q000008:administration & dosage* / Q000009:adverse effects; D015363:Quinolones / Q000008:administration & dosage* / Q000009:adverse effects; D012120:Respiration Disorders / Q000139:chemically induced; D007319:Sleep Initiation and Maintenance Disorders / Q000139:chemically induced; D000068698:Tenofovir / Q000031:analogs & derivatives; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D019562:Viral Load / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D002219:Carbamates; D004338:Drug Combinations; D063065:Organophosphonates; D015363:Quinolones; D013844:Thiazoles; D003841:Deoxycytidine; C509700:elvitegravir; D000068698:Tenofovir; C442442:tenofovir alafenamide; D000068679:Emtricitabine; D000225:Adenine; D000069547:Cobicistat; D000409:Alanine