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Pre-exposure prophylaxis (PrEP) for men who have sex with men in Europe: review of evidence for a much needed prevention tool
  1. Thijs Reyniers1,
  2. Elske Hoornenborg2,
  3. Bea Vuylsteke1,
  4. Kristien Wouters3,
  5. Marie Laga1
  1. 1 Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium
  2. 2 Department of Infectious Diseases, Public Health Service Amsterdam, Amsterdam, Netherlands
  3. 3 Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
  1. Correspondence to Dr Thijs Reyniers, Department of Public Health, Institute of Tropical Medicine, Antwerp, Nationalestraat 155, Antwerp 2000, Belgium; treyniers{at}


In many Western countries with good coverage of antiretroviral treatment (ART) programmes the annual number of HIV infections is still high and not (yet) declining among men who have sex with men (MSM). This might indicate that antiretroviral treatment roll-out alone will not turn around the course of the epidemic and that new, additional tools are needed. Antiretrovirals used as prevention tools for people not yet infected with HIV, such as pre-exposure prophylaxis (PrEP) could be such important additional tools. PrEP is a new type of biomedical prevention, which involves the use of antiretrovirals before, during and after (periods of) sexual exposure to HIV. In this review, we will focus on PrEP as a new prevention tool for MSM at high risk in Europe, including its evidence for effectiveness, challenges for implementation, ongoing European demonstration studies; as well as how PrEP relates to other existing prevention tools. In light of European Medicines Agency's recent recommendation for approval of PrEP we briefly review the potential implications.

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In many Western countries with good coverage of ART programmes, such as the UK or the Netherlands, the annual number of HIV infections is still high and not (yet) declining among MSM.1 ,2 This might indicate that antiretroviral treatment roll-out alone will not turn around the course of the epidemic and that new, additional tools are needed. Antiretrovirals used as prevention tools for people not yet infected with HIV, such as pre-exposure prophylaxis (PrEP) could be such important additional tools. PrEP is a new type of biomedical prevention, which involves the use of antiretrovirals before, during and after (periods of) sexual exposure to HIV. In this review, we will focus on PrEP as a new prevention tool for MSM at high risk in Europe, including its evidence for effectiveness, challenges for implementation, ongoing European demonstration studies; as well as how PrEP relates to other existing prevention tools. In light of European Medicines Agency's recent recommendation for approval of PrEP we briefly review the potential implications.

Pre-exposure prophylaxis for MSM

Evidence of effectiveness

Pre-exposure prophylaxis entails the use of antiretroviral medication before, during and after exposure to HIV and can be used orally or topically (eg, vaginal gel), whereas currently other modes of administration are also being evaluated (eg, long-acting vaginal rings or injectable agents).3 The effectiveness of oral PrEP containing tenofovir Tenofovir Disoproxil Fumarate (TDF) has been demonstrated in 11 clinical trials among different populations and different geographical areas.4 It has been shown that oral PrEP provides high levels of protection—provided that adherence is high, that it is safe—apart from small decreases of renal function reported in two trials, and that the risk of TDF or emtricitabine resistance among PrEP users is low.4

In 2015, two European trials among MSM and transgender women—the PROUD study in the UK,5 and the IPERGAY study in France,6—confirmed the high protective effect of PrEP (86% in both trials) and created a momentum for PrEP related work in Europe. PROUD, in which men were randomised to immediate use of PrEP versus delayed use (12 months after intake), answered some critical questions. It confirmed that MSM interested to participate in the study (and taking PrEP) were at high risk for HIV, illustrated by the high HIV incidence in the deferred arm of the trial (9.0 per 100 person years). Moreover, the study showed high adherence to daily use of PrEP and no significant occurrence of risk compensation (eg, an increase in sexual risk behaviour) among the participants. Levels of STI were high and condom use was low, but this did not differ significantly between PrEP users and non-users.5 The IPERGAY study was the first to study the use of PrEP around sex, which is referred to as ‘event-driven PrEP’ or ‘PrEP on demand’. This regimen includes the start of Truvada between 2 hours and 24 hours prior to sex and continues for 2 days after last sexual contact, every 24 hours since the last pill (see table 1). Compared with placebo, this regimen also showed a similar protective effect of 86%.6

Table 1

Overview of different PrEP dosing regimens used in PrEP trials

In conclusion, the efficacy of both event-driven and daily PrEP for the prevention of HIV among MSM is now confirmed. In order to have an impact on the HIV epidemics in Europe, PrEP will have to be taken by those who would benefit the most (ie, those at highest risk for HIV), and to be used appropriately.

Ensuring PrEP uptake among those at highest risk

Studies show that PrEP awareness among MSM has risen in the past few years in the USA and Australia, which is attributed to increased media coverage and targeted campaigns.8–10 However, such high awareness does not necessarily translate into a high PrEP uptake among MSM.8 ,11 ,12 Until 2 years after the US Food and Drug Administration (FDA) approval, PrEP uptake has been slow in the USA,13 ,14 and while it has risen significantly between 2013 and 2016, this increase is still relatively small, except for cities such as San Francisco and New York.15–17 PrEP roll-out started in France in January 2016, and for the first 6 months 1077 persons came forward, with more than 95% being MSM.18 This relatively limited number of PrEP users is expected to rise with the increased capacity of sites to deliver PrEP and increased awareness. Investing in raising awareness of PrEP among the target population is essential,19 and preferably done in close collaboration with the gay community. Moreover, special attention should be paid to those groups most disadvantaged for prevention.9 ,20

Importantly, research shows that those who are at higher risk of HIV (eg, report condomless anal sex in the last months) or who perceive themselves at risk, are more likely to want to use PrEP.21–24 Raising HIV risk awareness therefore is an important step in increasing PrEP uptake.24 ,25 Other potential barriers for PrEP uptake include concerns about the short-term and long-term effects, the high costs of PrEP, or potential stigmata surrounding PrEP use (eg, being linked to HIV, or to promiscuity).8 ,21 ,23 ,26–29 To achieve its full potential in reducing HIV, future PrEP implementation in Europe should take into account such important barriers. The role of PrEP users speaking out in public will be an important component.

Ensuring appropriate PrEP use

Adherence to PrEP is essential, and new ways to support MSM in appropriate use of PrEP are much needed (eg, mobile phone applications).30 Appropriate use of PrEP entails adherence to the daily medication, and correct use of the medication in situations or periods of increased risk for HIV for those following a non-daily regimen. More recently, the ADAPT study has been evaluating a time-driven regimen including two tablets per week with a postsex boost, and an event-driven regimen (one before and one after sex) which is different from IPERGAY (see table 1).31 Preliminary results of the ADAPT trial, presented in July 2016 at the International Aids Society (IAS) Conference in Durban, show that both the daily and non-daily dosing regimens were associated with high coverage of sex acts and high adherence.32

It becomes increasingly clear that PrEP will be most useful if its dosing regimen is adaptable to the lifestyles of MSM, and matches periods of risk. In the IPERGAY trial, monthly pill use varied in most participants, possibly reflecting such changes in perceived risk.6 ,33 Periods associated with increased sexual risk include travelling,34 leaving home or moving to another city, coming out as an MSM and ending a relationship.35 Such non-daily regimens could eventually lead to a decrease in the overall number of pills used, and as a result reduce cost, possibly leading to less side effects and would be more suitable for persons with infrequent risky sex.31 ,33 Disadvantages may be that it is more complicated, requires advanced sex planning and that it is less forgiving for missed doses.33 ,36 Enabling users to cover periods and situations of high risk for HIV, regardless of which PrEP dosing regimen is a challenge that needs to be addressed by future implementation programmes.

Demonstration projects in Europe

Building on the PROUD and IPERGAY studies, two European PrEP studies started in 2015: the Amsterdam PrEP Project (AMPrEP), conducted by the Public Health Service of Amsterdam; and the Be-PrEP-ared project, by the Institute of Tropical Medicine in Antwerp. The objectives of these feasibility studies are to collect real-life data on uptake of PrEP among MSM at high risk of HIV infection, as well as their preferences towards different PrEP dosing regimens, their adherence to the medication and whether risk compensation could occur, when PrEP is provided as part of a combination prevention package. Both studies aim to gain further insights into the implementation challenges as described above. The ultimate goal of these studies is to provide the necessary knowledge and insights to shape national and European guidelines with regard to PrEP implementation and allow for an optimal integration within the current prevention strategies.

Based on the efficacy data from PROUD and IPERGAY, AMPrEP and Be-PrEP-ared decided to include both PrEP dosing regimens (ie, daily and event-driven), at choice of the participant. Additionally, during follow-up, participants may choose to discontinue PrEP or switch dosing regimen. Both studies will provide the necessary insights of how many and why people choose or switch regimen, how this relates to their sexual activities and other factors that may be related. At the International AIDS Conference in Durban in 2016, an interim analysis of 198 participants' preferences of AMPrEP was presented.37 Of the first 198 participants, 144 (72%) chose to start daily PrEP. Daily PrEP users were younger (mean age 38 years vs 44 years, p value 0.015) and had more anal sex partners in the preceding 3 months (15 vs 10, p value 0.017).

The AMPrEP project currently is fully enrolled with 370 MSM at high risk of HIV infection, to whom Truvada will be provided until June 2018. The Be-PrEP-ared study, will include 200 MSM at high risk of HIV infection by the end of 2016 and each participant will be followed for 18 months.

Postexposure prophylaxis and its relation to PrEP

Post-exposure prophylaxis (PEP) was recommended as a biomedical intervention to prevent HIV infection among healthcare providers after the publication of a retrospective case control study in 1997.38 ,39 The rationale for the use of ART after exposure (PEP) to prevent HIV acquisition is based on the observation that HIV can take up to 72 hours to be detected in lymph nodes and up to 5 days to be detected in blood, following exposure.40 ,41 If ART is given within this window, virus replication can be blocked and thus prevent establishment of an infection.42 ,43 Because of the similarities between occupational and non-occupational exposures, and data on genital tract exposure in animal models,44 use of PEP was proposed for use after a sexual risk incident, mainly among MSM and victims of sexual assault. In this case PEP is provided as a prevention option, integrated into a package of services such as counselling on risk-reduction, condom provision, partner notification, testing and treating of HIV and STIs, and more recently also PrEP. Direct evidence for the preventive effectiveness of PEP following sexual exposure is absent, and this is likely to remain so.45 It is recommended to take three antiretroviral drugs (as for treatment of HIV-infected persons), starting within 72 hours of exposure, and for a duration of 28 days.46 ,47

Evaluation of PEP implementation programmes among MSM show that the approach is feasible, acceptable and safe.48 In ‘Dean street clinic’ in London, out of 530 MSM who had taken PEP after unprotected anal intercourse, 183 were repeat users, suggesting an ongoing risk. During follow-up, 57 men seroconverted, and while most cases could not be confirmed as PEP failures, the authors concluded that PEP on its own is not a successful preventive strategy for MSM at high risk for HIV.49 Due to a low demand and uptake among MSM in Europe, its public health impact may be limited.45

Several studies have reported high HIV incidence rates from 1.27 to 6.4 per 100 person years among MSM who used PEP.50–52 A potential explanation for this persistent high risk could be that MSM who use PEP continue to have more condomless (receptive) anal sex than those who do not take PEP.53 Therefore, the use of PEP could be used for targeting those who are at substantial risk of HIV infection, thus providing a rationale to use PEP as a bridge for PrEP.54 We can anticipate that PrEP, when more widely available, will reduce the demand of PEP among MSM at high risk.

However, it is recommended that PEP will remain an option on its own, as part of a larger package of HIV prevention options, for MSM who are using condoms consistently but experience condom breakage, an episode of condomless sex without consent or for those one-off high-risk events.

STI and condom use among PrEP users

Trends in STI have been rising among MSM in Europe for a decade and long before.55 This can be attributed to a large extent to an increase in condomless sex, as observed in several surveys.2 ,55–57 The question of how the introduction of PrEP in Europe will affect this trend, remains, however, unanswered. In all PrEP trials among MSM, high rates of STIs were seen but no significant differences in rates between PrEP users, non-users or placebo users have been observed.4–6 This indicates that participants in those studies were indeed at high risk for HIV, and that adoption of PrEP did not lead to risk compensation.5 The data from the open-label phase of the IPERGAY study, and real-world implementation of PrEP in San Francisco, showed a slightly different picture, with reported decreases in condom use, and further increases in STI rates among MSM using PrEP.58–60 Important to note is that in those settings, low condom use and high STI rates did not undermine effectiveness of PrEP for HIV.

How to promote condom use among potential PrEP users is a matter of debate today and will need to be clarified further. In most trials, PrEP was presented as a tool that should be used together with condoms.3 ,5 ,6 Data from demonstration projects among MSM have shown that men presenting for PrEP are in fact those who report frequent condomless sex, or no condom use at all.61 The objective is to provide the best evidence-based advice, taking into account the individual choices about condom use, and options according to context. A way of messaging about PrEP and condoms could include the following: (1) PrEP does not intend to replace condoms but if taken as prescribed, PrEP on its own has the same high level of protection against HIV as consistent condom use; (2) PrEP combined with condoms provides the safest protection against both HIV and other STIs; and (3) consistent condom use, if feasible and acceptable, provides high levels of protection for HIV and STI, and PrEP may not be necessary in this case.62

At programmatic level it is important to keep a pivotal role for condoms, particularly with the introduction of new powerful approaches such as PrEP or Treatment as Prevention (TasP). Consistent condom use (in the absence of TasP and PrEP) has prevented millions of infections worldwide among different populations, also among MSM.63 Even if consistent condom use is challenging, condom promotion for MSM should continue. Condoms are easily available, cost less, and protect against both HIV and other STI. So far, PrEP is costly in Europe, requires regular medical follow-up and is currently only available for a limited number of MSM participating in research projects, except for France.61 PrEP and condoms should therefore be combined in the best possible way to obtain the highest coverage of sexual acts that have to be protected, taking into account health as well as well-being.

PrEP as a catalyst for combination prevention and sexual health among MSM

PrEP is a new, additional tool for HIV prevention, to be provided as part of a combination prevention strategy.64 PrEP is best viewed not as a stand-alone product, but as a prevention option that needs to be provided alongside and together with other prevention methods such as behavioural interventions, increased HIV testing or the promotion of condom use. In that sense, PrEP may also serve as a new entry point to provide multiple HIV prevention options. Moreover, PrEP provides opportunities to reach people who would otherwise be missed: for example, increased HIV testing among HIV-negative individuals. In some European countries those services already exist, such as the public health services in the Netherlands or genitourinary medicine Genitourinary Medicine (GUM) clinics in the UK, where HIV-uninfected MSM are followed up regularly, and in which PrEP could easily be integrated.61 In most other countries, the provision of PrEP can become a catalyst to rethink the sexual health services for MSM at risk, including novel ways of HIV testing and STI screening (using self-sampling), adherence counselling using mobile applications and peer support, within a holistic gay-friendly care setting.61

PrEP reduces one’s risk of HIV infection, and may have a positive impact on sexual health and well-being. Men already using PrEP report reduced anxiety, more sexual satisfaction and a feeling of empowerment.65 This is important, as it could lead to an increase in PrEP uptake and may serve as a mediating factor in ensuring appropriate use.

PrEP services, including the 3-monthly follow-up, offer a unique opportunity to regularly screen for STIs. In the PROUD study in the UK, 57% (152/265) of participants in the immediate group versus 50% (124/247) in the deferred group were diagnosed with one or more bacterial STI during follow-up, most commonly gonorrhoea (GC) or chlamydia (CT). After adjustment for more frequent screenings in the immediate group, there was no significant difference between both groups. Six incident hepatitis C infections occurred, three in each group.5 In the US PrEP Demo Project overall STI incidence was 90 per 100 person-years (95% CI 81.2 to 98.9), providing a clear rationale for regular screening among PrEP users.66 An evaluation of the STI programme showed that if screening was conducted only semiannually or based on symptoms, instead of every 3 months, 62 (34.3%) participants with GC, 86 (41.0%) with CT and 11 (20.4%) with syphilis would have been missed.67 Those data reinforce the need of routine STI screening in PrEP users, preferably every 3 months, and to perform extragenital screening, even when asymptomatic, in particular for those with a past history of STIs. Most STIs in the studies were rectal infections, which are likely to be asymptomatic. STI services are therefore an ideal setting to provide PrEP, in combination with STI screening, risk reduction counselling and condom promotion.68

Time for implementation of PREP in Europe

At the time of writing this paper, the European Medicines Agency has recommended the approval of Truvada for preventive use.69 ,70 This will be a decisive step for national regulatory agencies to accelerate access of PrEP for MSM in Europe.

France had not waited for this European approval, and had started rolling out PrEP, fully reimbursable throughout the country since January 2015, as part of a temporary approval. After the successful PROUD trial, and despite evidence of cost-effectiveness of PREP, it is only temporarily made available by NHS England.71 PrEP provision is limited to early implementer sites and PROUD participants, at a £2 million cost for the next 2 years. It remains to be seen how PrEP access programmes will evolve in other European member states in the next years.

In conclusion, the rates of HIV infection among MSM in western Europe are still unacceptably high, and the current prevention approaches do not seem sufficient to contain the epidemic. PrEP has the potential to be the game changer for the HIV epidemic among MSM. While demonstration projects will provide precious information, and further PrEP research is needed, we cannot justify waiting any longer to take the necessary steps to make this safe and highly effective preventive tool available to those at highest risk of HIV throughout Europe.

Key messages

  • PEP and pre-exposure prophylaxis (PrEP) are important additional prevention tools for MSM at high risk of HIV infection in Europe.

  • Although PEP might not be a successful prevention strategy on its own, it will remain an important additional tool within HIV prevention.

  • PrEP has the potential to be the game changer for the HIV epidemic among MSM in Europe, requiring further research and implementation to make this tool available to those at highest risk.


AMPrEP is part of the HIV Transmission Elimination AMsterdam (H-TEAM) consortium.


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  • Handling editor Jackie A Cassell

  • Contributors All authors contributed to drafting the first version of the manuscript. The final version was drafted by TR and ML.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; externally peer reviewed.