HIV Insight: 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

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).

FINDINGS:

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.

INTERPRETATION:

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.

Below: Trial profile

*First to deferred and subsequently to immediate; considered in the deferred group for analyses but continued on pre-exposure prophylaxis. †19 pairs of partners were allocated to the same group (14 to immediate, five to deferred) including six pairs (all assigned to the immediate group) not enrolled concurrently. ‡One participant who was allocated to the deferred group was prescribed immediate pre-exposure prophylaxis in error; he was included in the deferred group for analyses but continued on pre-exposure prophylaxis. §Includes unable to contact, moved away, and non-attendance as no longer at risk. ¶HIV status ascertained if confirmed HIV-positive or HIV-negative test after 48 weeks or after Oct 13, 2014.

Full article at: http://goo.gl/JzMn11

By: McCormack S1, Dunn DT2, Desai M3, Dolling DI2, Gafos M2, Gilson R4, Sullivan AK5, Clarke A6, Reeves I7, Schembri G8, Mackie N9, Bowman C10, Lacey CJ11, Apea V12, Brady M13, Fox J14, Taylor S15, Antonucci S16, Khoo SH17, Rooney J18, Nardone A19, Fisher M6, McOwan A16, Phillips AN20, Johnson AM20,Gazzard B5, Gill ON19.

1MRC 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.
2MRC Clinical Trials Unit at UCL, London, UK.
3MRC Clinical Trials Unit at UCL, London, UK; HIV & STI Department, Public Health England Centre for Infectious Disease Surveillance and Control, London, UK.
4The 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.
5St Stephen's Centre, Chelsea and Westminster Healthcare NHS Foundation Trust, London, UK.
6Claude Nicol Centre, Royal Sussex County Hospital, Brighton & Sussex University Hospitals NHS Trust, Brighton, UK.
7Homerton University Hospital NHS Foundation Trust, London, UK.
8Manchester Centre for Sexual Health, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
9St Mary's Hospital, Imperial College Healthcare NHS Foundation Trust, London, UK.
10Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
11York Teaching Hospital and Hull York Medical School, University of York, York, UK.
12Ambrose King Centre and Barts Sexual Health Centre, Barts Health NHS Trust, London, UK.
13King's College Hospital NHS Foundation Trust, London, UK.
14Guy's and St Thomas' NHS Foundation Trust, London, UK.
15Birmingham Heartlands Hospital, Heart of England NHS Foundation Trust, Birmingham, UK.
1656 Dean Street, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.
17University of Liverpool, Liverpool, UK.
18Gilead Sciences Foster City, CA, USA.
19HIV & STI Department, Public Health England Centre for Infectious Disease Surveillance and Control, London, UK.
20Research Department of Infection and Population Health, University College London, London, UK.
Lancet. 2016 Jan 2;387(10013):53-60. doi: 10.1016/S0140-6736(15)00056-2. Epub 2015 Sep 9.