title: Single-agent tenofovir versus combination emtricitabine plus tenofovir for pre-exposure prophylaxis for HIV-1 acquisition: an update of data from a randomised, double-blind, phase 3 trial.
abstract: BACKGROUND
  Antiretroviral pre-exposure prophylaxis (PrEP), with daily oral tenofovir disoproxil fumarate or tenofovir disoproxil fumarate in combination with emtricitabine, has been shown to be efficacious for HIV-1 prevention. Although the use of more than one antiretroviral agent is essential for effective HIV-1 treatment, more than one agent might not be required for effective prophylaxis. We assessed the efficacy of single-agent tenofovir disoproxil fumarate relative to combination emtricitabine plus tenofovir disoproxil fumarate as PrEP.
  
  
  METHODS
  We did a randomised, double-blind, placebo-controlled three-group phase 3 trial of daily oral tenofovir disoproxil fumarate and emtricitabine plus tenofovir disoproxil fumarate PrEP in HIV-1 uninfected individuals in heterosexual HIV-1 serodiscordant couples from Kenya and Uganda. After an interim review, the trial's placebo group was discontinued and thereafter the active groups were continued, and participants initially randomly assigned to placebo were offered rerandomisation in a 1:1 ratio to tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate as PrEP. The primary endpoints were HIV-1 seroconversion and safety. This trial is registered with ClinicalTrials.gov, number NCT00557245.
  
  
  RESULTS
  4410 (99·6%) of 4427 couples received tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate and were followed up for HIV-1 acquisition. Of 52 incident HIV-1 infections, 31 occurred in individuals assigned tenofovir disoproxil fumarate (incidence 0·71 cases per 100 person-years) and 21 were in those assigned emtricitabine plus tenofovir disoproxil fumarate (0·48 cases per 100 person-years); HIV-1 incidence in the placebo group until discontinuation was two cases per 100 person-years. HIV-1 prevention efficacy with emtricitabine plus tenofovir disoproxil fumarate was not significantly different from that of tenofovir disoproxil fumarate alone (hazard ratio [HR] 0·67, 95% CI 0·39-1·17; p=0·16). Detection of tenofovir in plasma samples, compared with no detection and as measured in seroconverters and a subset of non-seroconverters, was associated with an 85% relative risk reduction in HIV-1 acquisition for the tenofovir disoproxil fumarate group (HR 0·15, 95% CI 0·06-0·37; p<0·0001) and 93% for the emtricitabine plus tenofovir disoproxil fumarate group (0·07, 0·02-0·23; p<0·0001). No significant differences were noted in the frequency of deaths, serious adverse events, or serum creatinine and phosphorus abnormalities between the two groups.
  
  
  CONCLUSIONS
  These results do not rule out the potential for a slight difference in HIV-1 protection with tenofovir disoproxil fumarate compared with emtricitabine plus tenofovir disoproxil fumarate, but show that once-daily oral tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate regimens both provide high protection against HIV-1 acquisition in heterosexual men and women.
  
  
  BACKGROUND
  Bill & Melinda Gates Foundation and US National Institutes of Health.
authors.affiliation: Department of Global Health, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA. Electronic address: jbaeten@uw.edu.
authors.forename: Jared M
authors.initials: JM
authors.lastname: Baeten
authors.affiliation: Department of Global Health, University of Washington, Seattle, WA, USA; Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Donnell
authors.affiliation: Department of Global Health, University of Washington, Seattle, WA, USA; Centres for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya.
authors.forename: Nelly R
authors.initials: NR
authors.lastname: Mugo
authors.affiliation: Department of Global Health, University of Washington, Seattle, WA, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Ndase
authors.affiliation: Department of Global Health, University of Washington, Seattle, WA, USA.
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Thomas
authors.affiliation: Centers for Disease Control and Prevention, Entebbe, Uganda.
authors.forename: James D
authors.initials: JD
authors.lastname: Campbell
authors.affiliation: AIDS Support Organization, Kampala, Uganda.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Wangisi
authors.affiliation: Centers for Disease Control and Prevention, Atlanta, GA, USA.
authors.forename: Jordan W
authors.initials: JW
authors.lastname: Tappero
authors.affiliation: Department of Global Health, University of Washington, Seattle, WA, USA; Microbiology Research, Kenya Medical Research Institute, Nairobi, Kenya; Department of Obstetrics and Gynecology, University of Nairobi and Kenyatta National Hospital, Nairobi, Kenya; Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, CA, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Bukusi
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, CA, USA.
authors.forename: Craig R
authors.initials: CR
authors.lastname: Cohen
authors.affiliation: Infectious Disease Institute, Makerere University, Kampala, Uganda.
authors.forename: Elly
authors.initials: E
authors.lastname: Katabira
authors.affiliation: Infectious Disease Institute, Makerere University, Kampala, Uganda; Department of Medicine, University of Manitoba, Winnipeg, Canada.
authors.forename: Allan
authors.initials: A
authors.lastname: Ronald
authors.affiliation: Kabwohe Clinical Research Center, Kabwohe, Uganda.
authors.forename: Elioda
authors.initials: E
authors.lastname: Tumwesigye
authors.affiliation: Department of Reproductive Health, Moi University, Eldoret, Kenya.
authors.forename: Edwin
authors.initials: E
authors.lastname: Were
authors.affiliation: Department of Medicine, Indiana University, Indianapolis, IN, USA.
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Fife
authors.affiliation: Department of Global Health, University of Washington, Seattle, WA, USA; Department of Obstetrics and Gynecology, University of Nairobi and Kenyatta National Hospital, Nairobi, Kenya.
authors.forename: James
authors.initials: J
authors.lastname: Kiarie
authors.affiliation: Department of Global Health, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA.
authors.forename: Carey
authors.initials: C
authors.lastname: Farquhar
authors.affiliation: Department of Global Health, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: John-Stewart
authors.affiliation: Department of Global Health, University of Washington, Seattle, WA, USA.
authors.forename: Lara
authors.initials: L
authors.lastname: Kidoguchi
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA, USA; Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Coombs
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Hendrix
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Marzinke
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA; Seattle Children's Hospital Research Institute, Seattle, WA, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Frenkel
authors.affiliation: Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Haberer
authors.affiliation: Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Bangsberg
authors.affiliation: Department of Global Health, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA.
authors.forename: Connie
authors.initials: C
authors.lastname: Celum
mesh_terms: D000225:Adenine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000009:adverse effects / Q000379:methods; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007630:Kenya; D008297:Male; D063065:Organophosphonates / Q000009:adverse effects / Q000627:therapeutic use*; D010919:Placebos / Q000008:administration & dosage; D065129:Pre-Exposure Prophylaxis / Q000379:methods*; D000068698:Tenofovir; D016896:Treatment Outcome; D014454:Uganda
chemical_list: D019380:Anti-HIV Agents; D063065:Organophosphonates; D010919:Placebos; D003841:Deoxycytidine; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine