SummaryBackgroundRandomised 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.MethodsPROUD 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).FindingsWe 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.InterpretationIn 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.FundingMRC Clinical Trials Unit at UCL, Public Health England, and Gilead Sciences.

Table of Contents 1. Levels of evidence1.1 Reference2. Introduction3. Auditable targets4. Table summaries4.1 Initial diagnosis4.2 Assessment of ART‐naïve individuals4.3 ART initiation4.4 Initial assessment following commencement of ART4.5 Routine monitoring on ART4.6 References5. Newly diagnosed and transferring HIV‐positive individuals5.1 Initial HIV‐1 diagnosis5.2 Tests to determine whether acquisition of HIV infection is recent5.3 Individuals transferring care from a different HIV healthcare setting5.4 Communication with general practitioners and shared care5.5 Recommendations5.6 References6. Patient history6.1 Initial HIV‐1 diagnosis6.2 Monitoring of ART‐naïve patients6.3 Pre‐ART initiation assessment6.4 Monitoring individuals established on ART6.5 Assessment of adherence6.6 Recommendations6.7 References7. Examination7.1 Recommendations8. Identifying the need for psychological support8.1 References9. Assessment of immune status9.1 CD4 T cell counts9.2 CD4 T cell percentage9.3 References10. HIV viral load10.1 Initial diagnosis/ART naïve10.2 Post ART initiation10.3 Individuals established on ART10.4 Recommendations10.5 References11. Technical aspects of viral load testing11.1 References12. Viral load kinetics during ART and viral load ‘blips’12.1 References13. Proviral DNA load13.1 References14. Resistance testing14.1 Initial HIV‐1 diagnosis14.2 ART‐naïve14.3 Post treatment initiation14.4 ART‐experienced14.5 References15. Subtype determination15.1 Disease progression15.2 Transmission15.3 Performance of molecular diagnostic assays15.4 Response to therapy15.5 Development of drug resistance15.6 References16. Other tests to guide use of specific antiretroviral agents16.1 Tropism testing16.2 HLA B*5701 testing16.3 References17. Therapeutic drug monitoring17.1 Recommendations17.2 References18. Biochemistry testing18.1 Introduction18.2 Liver function18.3 Renal function18.4 Dyslipidaemia in HIV‐infected individuals18.5 Other biomarkers18.6 Bone disease in HIV‐infected patients18.7 References19. Haematology19.1 Haematological assessment and monitoring19.2 Recommendations19.3 References20. Serology20.1 Overview20.2 Hepatitis viruses20.3 Herpes viruses20.4 Measles and rubella20.5 Cytomegalovirus (CMV)20.6 References21. Other microbiological screening21.1 Tuberculosis screening21.2 Toxoplasma serology21.3 Tropical screening21.4 References22. Sexual health screening including anal and cervical cytology22.1 Sexual history taking, counselling and sexually transmitted infection (STI) screening22.2 Cervical and anal cytology22.3 Recommendations22.4 References23. Routine monitoring recommended for specific patient groups23.1 Women23.2 Older age23.3 Injecting drug users23.4 Individuals coinfected with HBV and HCV23.5 Late presenters23.6 References Appendix

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