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Background of the HIV epidemic among MSM in the Netherlands The HIV epidemic in the Netherlands is concentrated in men who have sex with men (MSM). MSM accounted for 71% of new HIV diagnoses in the Netherlands in 2013. Amsterdam is the epicentre of the Dutch HIV epidemic among MSM, illustrated by the fact that 45% (4,885/10,753) of HIV-positive MSM are registered at HIV treatment centres in the city of Amsterdam. In spite of intensive prevention efforts, including condom provision, free testing for HIV and sexually transmitted infections (STIs), behavioural interventions and information and awareness campaigns, the HIV incidence rate among MSM is not declining. Clearly current prevention methods are not effective in curbing the epidemic. UNAIDS set an ambitious goal for 2030: a reduction in HIV incidence by 90%. In order to reach that goal, new intervention approaches are needed. Pre-exposure prophylaxis Pre-exposure prophylaxis (PrEP) is a new prevention intervention, which was shown to significantly reduce the HIV incidence in several large, international, randomised controlled trials. The efficacy of PrEP in successful trials varied between 44% and 86%. PrEP entails taking daily (or intermittent) antiretroviral medication. The largest challenge in HIV prevention through PrEP is ensuring high adherence. Two trials, conducted in heterosexual populations in Africa, failed to show an effect of PrEP; the adherence in the study populations of these trials was very low. The drug combination most often used for PrEP is tenofovir/emtricitabine (TDF/FTC). This drug combination has been licensed by the Food and Drug Administration for use as PrEP in the USA. Both the World Health Organization and the Centers for Disease Control and Prevention recommend the use of PrEP for risk groups. In Europe, TDF/FTC has not yet been registered for a prevention indication. PrEP has only been provided in randomised controlled trials or small demonstration projects. Guidance on PrEP in European countries (who should use it; when; who should prescribe it; when; how should high adherence be ensured) is currently lacking, and there are no data on the feasibility of PrEP and its challenges in a routine public health setting in the Netherlands or other European countries. It is unknown which proportion of men would prefer intermittent, event-driven PrEP above daily PrEP. AMPrEP In Amsterdam the Public Health Service of Amsterdam (GGD) will start a PrEP demonstration project among MSM in April 2015, the Amsterdam Pre-exposure Prophylaxis project (AMPrEP). Over the course of 26 months we aim to include 370 HIV-negative MSM, who are at high risk for HIV infection. Men will be screened for eligibility; if eligible, and after providing informed consent, they will be enrolled and be able to choose between daily PrEP and intermittent, event-driven PrEP. They will be followed up 3-monthly and assessed for HIV, STIs, serum creatinine, and proteinuria. Adherence will be measured by pill count, self-report, and an online diary (through an app for mobile phone). Participants may switch PrEP modality at every visit. Follow-up will continue until 1 December 2018. The conduct of AMPrEP is funded through grants from Soa Aids Nederland, the GGD, and an in-kind contribution of the manufacturer of TDF/FTC. Aim of this study proposal The aim of this application to ZONMW is to obtain financing for the evaluation of AMPrEP and for conducting a randomized controlled trial on adherence support interventions. Research questions This study has the two main research questions: (1) What is the uptake, acceptability, usability and cost-effectiveness of a comprehensive HIV infection prevention program for MSM at risk for HIV, through two intervention modalities: (a) daily PrEP and (b) intermittent, event-driven PrEP; and does risk compensation (i.e. increases in condomless anal sex and in incidence rates of other STIs) occur among PrEP users? (2) What is the effect of individualised feedback of PrEP medication adherence on subsequent PrEP medication use? Secondary research questions concern determinants (behavioral and demographic) of modality choice; rate of and reasons for switching between PrEP modalities; occurrence and determinants of risk compensation; adherence to PrEP and determinants of good adherence; occurrence of serious adverse events; occurrence of HIV resistance mutations among those who, in spite of the intervention, acquire an HIV infection. Expected outcomes This project will provide much-needed data necessary for clinical guidance and decision making regarding PrEP implementation at national and international level. Important questions regarding demand for PrEP among MSM, acceptability, continuation rates among those who start PrEP, risk compensation, adherence, adverse events, and cost-effectiveness will be answered for the Dutch situation and inform decision-making regarding wide-spread implementation in the Netherlands.