title: Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial.
abstract: BACKGROUND
  Randomised placebo-controlled trials have shown that daily oral pre-exposure prophylaxis (PrEP) with tenofovir-emtricitabine reduces the risk of HIV infection. However, this benefit could be counteracted by risk compensation in users of PrEP. We did the PROUD study to assess this effect.
  
  
  METHODS
  PROUD is an open-label randomised trial done at 13 sexual health clinics in England. We enrolled HIV-negative gay and other men who have sex with men who had had anal intercourse without a condom in the previous 90 days. Participants were randomly assigned (1:1) to receive daily combined tenofovir disoproxil fumarate (245 mg) and emtricitabine (200 mg) either immediately or after a deferral period of 1 year. Randomisation was done via web-based access to a central computer-generated list with variable block sizes (stratified by clinical site). Follow-up was quarterly. The primary outcomes for the pilot phase were time to accrue 500 participants and retention; secondary outcomes included incident HIV infection during the deferral period, safety, adherence, and risk compensation. The trial is registered with ISRCTN (number ISRCTN94465371) and ClinicalTrials.gov (NCT02065986).
  
  
  RESULTS
  We enrolled 544 participants (275 in the immediate group, 269 in the deferred group) between Nov 29, 2012, and April 30, 2014. Based on early evidence of effectiveness, the trial steering committee recommended on Oct 13, 2014, that all deferred participants be offered PrEP. Follow-up for HIV incidence was complete for 243 (94%) of 259 patient-years in the immediate group versus 222 (90%) of 245 patient-years in the deferred group. Three HIV infections occurred in the immediate group (1·2/100 person-years) versus 20 in the deferred group (9·0/100 person-years) despite 174 prescriptions of post-exposure prophylaxis in the deferred group (relative reduction 86%, 90% CI 64-96, p=0·0001; absolute difference 7·8/100 person-years, 90% CI 4·3-11·3). 13 men (90% CI 9-23) in a similar population would need access to 1 year of PrEP to avert one HIV infection. We recorded no serious adverse drug reactions; 28 adverse events, most commonly nausea, headache, and arthralgia, resulted in interruption of PrEp. We detected no difference in the occurrence of sexually transmitted infections, including rectal gonorrhoea and chlamydia, between groups, despite a suggestion of risk compensation among some PrEP recipients.
  
  
  CONCLUSIONS
  In this high incidence population, daily tenofovir-emtricitabine conferred even higher protection against HIV than in placebo-controlled trials, refuting concerns that effectiveness would be less in a real-world setting. There was no evidence of an increase in other sexually transmitted infections. Our findings strongly support the addition of PrEP to the standard of prevention for men who have sex with men at risk of HIV infection.
  
  
  BACKGROUND
  MRC Clinical Trials Unit at UCL, Public Health England, and Gilead Sciences.
authors.affiliation: MRC Clinical Trials Unit at UCL, London, UK; 56 Dean Street, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK. Electronic address: s.mccormack@ucl.ac.uk.
authors.forename: Sheena
authors.initials: S
authors.lastname: McCormack
authors.affiliation: MRC Clinical Trials Unit at UCL, London, UK.
authors.forename: David T
authors.initials: DT
authors.lastname: Dunn
authors.affiliation: MRC Clinical Trials Unit at UCL, London, UK; HIV & STI Department, Public Health England Centre for Infectious Disease Surveillance and Control, London, UK.
authors.forename: Monica
authors.initials: M
authors.lastname: Desai
authors.affiliation: MRC Clinical Trials Unit at UCL, London, UK.
authors.forename: David I
authors.initials: DI
authors.lastname: Dolling
authors.affiliation: MRC Clinical Trials Unit at UCL, London, UK.
authors.forename: Mitzy
authors.initials: M
authors.lastname: Gafos
authors.affiliation: The Mortimer Market Centre, Central and North West London NHS Foundation Trust, London, UK; Research Department of Infection and Population Health, University College London, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Gilson
authors.affiliation: St Stephen's Centre, Chelsea and Westminster Healthcare NHS Foundation Trust, London, UK.
authors.forename: Ann K
authors.initials: AK
authors.lastname: Sullivan
authors.affiliation: Claude Nicol Centre, Royal Sussex County Hospital, Brighton & Sussex University Hospitals NHS Trust, Brighton, UK.
authors.forename: Amanda
authors.initials: A
authors.lastname: Clarke
authors.affiliation: Homerton University Hospital NHS Foundation Trust, London, UK.
authors.forename: Iain
authors.initials: I
authors.lastname: Reeves
authors.affiliation: Manchester Centre for Sexual Health, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Schembri
authors.affiliation: St Mary's Hospital, Imperial College Healthcare NHS Foundation Trust, London, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Mackie
authors.affiliation: Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
authors.forename: Christine
authors.initials: C
authors.lastname: Bowman
authors.affiliation: York Teaching Hospital and Hull York Medical School, University of York, York, UK.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Lacey
authors.affiliation: Ambrose King Centre and Barts Sexual Health Centre, Barts Health NHS Trust, London, UK.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Apea
authors.affiliation: King's College Hospital NHS Foundation Trust, London, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Brady
authors.affiliation: Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Fox
authors.affiliation: Birmingham Heartlands Hospital, Heart of England NHS Foundation Trust, Birmingham, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Taylor
authors.affiliation: 56 Dean Street, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.
authors.forename: Simone
authors.initials: S
authors.lastname: Antonucci
authors.affiliation: University of Liverpool, Liverpool, UK.
authors.forename: Saye H
authors.initials: SH
authors.lastname: Khoo
authors.affiliation: Gilead Sciences Foster City, CA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Rooney
authors.affiliation: HIV & STI Department, Public Health England Centre for Infectious Disease Surveillance and Control, London, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Nardone
authors.affiliation: Claude Nicol Centre, Royal Sussex County Hospital, Brighton & Sussex University Hospitals NHS Trust, Brighton, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Fisher
authors.affiliation: 56 Dean Street, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: McOwan
authors.affiliation: Research Department of Infection and Population Health, University College London, London, UK.
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Phillips
authors.affiliation: Research Department of Infection and Population Health, University College London, London, UK.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Johnson
authors.affiliation: St Stephen's Centre, Chelsea and Westminster Healthcare NHS Foundation Trust, London, UK.
authors.forename: Brian
authors.initials: B
authors.lastname: Gazzard
authors.affiliation: HIV & STI Department, Public Health England Centre for Infectious Disease Surveillance and Control, London, UK.
authors.forename: Owen N
authors.initials: ON
authors.lastname: Gill
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D001727:Bisexuality; D017280:Condoms / Q000706:statistics & numerical data; D000069480:Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination / Q000627:therapeutic use*; D004739:England; D015658:HIV Infections / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1; D018451:Homosexuality, Male; D006801:Humans; D008297:Male; D010865:Pilot Projects; D065129:Pre-Exposure Prophylaxis / Q000379:methods*; D016896:Treatment Outcome; D047568:Unsafe Sex
chemical_list: D019380:Anti-HIV Agents; D000069480:Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination