Considerations regarding antiretroviral chemoprophylaxis in MSM

Poynten, I. Mary; Zablotska, Iryna; Grulich, Andrew E.

doi: 10.1097/COH.0b013e3283582c71

Purpose of review: HIV infection among MSM remains a significant issue. Data relevant to MSM populations from animal models, pharmacokinetic studies and clinical trials are summarized and challenges and potential consequences of use of preexposure prophylaxis (PrEP) by MSM are discussed.

Recent findings: Rectal simian–human immunodeficiency virus transmission in macaque models can be prevented by intermittent PrEP dosing. The Preexposure Prophylaxis Initiative (iPrEx) study found that daily oral emtricitabine-tenofovir disoproxyl fumarate (TDF/FTC) decreased HIV infection by 44% among 2499 high-risk MSM. Men with detectable levels of TDF or FTC in plasma and peripheral blood mononuclear cells experienced more than 90% protective effect, emphasizing the importance of adherence. In iPrEX and other studies, PrEP was generally safe and well tolerated. However, it appears that TDF use is associated with a small but significant decrease in mean bone mineral density. No risk compensation has been demonstrated, but this remains an area of potential concern when PrEP is used outside the setting of a placebo-controlled trial. Numerous PrEP trials in MSM are currently underway.

Summary: Oral FTC/TDF is effective in preventing HIV infection among MSM. Optimal PrEP agents and dosing regimens now need to be identified. Understanding the patterns of and impediments to PrEP use among MSM is vital and these should be monitored in ongoing demonstration projects and open-label studies.

HIV Epidemiology and Prevention Program, The Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia

Correspondence to Professor Andrew E. Grulich, HIV Epidemiology and Prevention Program, The Kirby Institute, University of New South Wales, Sydney, NSW 2052, Australia. Tel: +61 2 9385 0956; fax: +61 2 9385 0920; e-mail:

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HIV diagnoses have increased significantly internationally since the late 1990s among MSM [1,2], who are primarily at risk of acquiring HIV through unprotected anal intercourse (UAI) [3–5]. In the USA, over half of the 56 000 new HIV infections diagnosed annually are among MSM [6]. Despite successes in some situations, HIV transmission has not been adequately reduced by the prevention methods currently available to gay men, such as various behavioural interventions, condoms and treatment of sexually transmitted infections, as demonstrated by the continuing spread of the HIV epidemic [7–9]. There has been considerable discussion and investment by researchers, governments, public health organisations and affected communities, to identify and develop HIV prevention strategies for MSM that are more effective and sustainable.

In the past 2 years, there have been major advances in the field of biomedical prevention of sexually transmitted HIV, including a landmark efficacy trial of preexposure prophylaxis (PrEP) with antiretroviral drugs (ARVs) to prevent HIV infection among MSM and transgender women, the iPrEX (Preexposure Prophylaxis Initiative) study [10▪▪]. This review explores the current status of research into HIV chemoprophylaxis among MSM, the issues and challenges specific to this population and the potential consequences of widespread implementation and uptake of PrEP as a biomedical prevention strategy by MSM.

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Tenofovir disoproxil fumarate (TDF) alone, or in combination with emitricitabine (FTC) has until recently been the primary oral ARV trialled in HIV prevention studies. This is a result of its long half-life, good safety profile and efficient penetration into genital tract tissues [11–13]. The great majority of HIV infections in MSM occur via the anorectum. Much of the understanding of the effect of TDC (±FDC) on rectal transmission of HIV has come from animal studies, particularly from a macaque model in which animals were repeatedly exposed to rectal simian–human immunodeficiency virus (SHIV). In one study [14], four groups of six animals received different schedules of PrEP: either daily subcutaneous FTC, daily oral TDF and oral FTC, daily subcutaneous FTC and higher dose TDF or intermittent subcutaneous FTC and higher dose TDF 2 h before and 24 h after a series of weekly virus challenges. Compared with macaques receiving no drug, daily PrEP at dosing equivalent to that used in humans provided only partial protection, although increased protection was seen when TDF was added to FTC. Complete protection was afforded by increasing TDF dosages, and all six animals who received intermittent PrEP were also protected. These results strengthen the evidence for use of combination ARVs as PrEP and indicate that intermittent higher dose PrEP may be as effective as daily PrEP [14]. To investigate different schedules of intermittent oral dosing as compared with daily dosing, at dosages that result in similar drug exposures and distribution as in humans, Garcia-Lerma et al.[15] administered oral FTC/TDF to macaques over a 14-week period. PrEP was administered one, 3 or 7 days before rectal SHIV exposure followed by a second dose 2 h after exposure. Although not completely protective, intermittent dosing was found to be as protective as daily drug administration and to result in a reduction of infection of up to 16.7 fold, compared with untreated control animals. A group of six macaques were given only the preexposure subcutaneous FTC/ tenofovir (TFV) dose, and two of six of the animals became infected during the 14 challenges. Another six animals were administered this regimen as postexposure prophylaxis (PEP), without the preexposure dose. In this group, PEP had no preventive effect greater than that seen with the untreated controls. Their findings showed that postexposure dosing was necessary to provide optimum protection and importantly that postexposure dosing provided no protection if the first dose was delayed at least 24 h after exposure. These results expand knowledge of optimal timing and dose to ensure effective exposure and sufficient coverage of target tissues by PrEP regimens and suggest that an optimal intermittent PrEP regimen would involve dosing around a day before and soon after exposure.

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Findings from a number of recent pharmacokinetic studies suggest that some ARVs achieve very high levels in the rectum compared with other sites of HIV exposure. A 14-day, open-label study conducted in the USA in 2008–2010 included eight healthy HIV-negative male volunteers, who were administered a single oral dose of TDF/FTC. From rectal tissue biopsies, TDF and its active intracellular phosphorylated metabolite, tenofovir-diphosphate (TFV-DP) were consistently detected for 14 days after dosing. The TDF concentration in rectal tissue was 34-fold higher than in blood plasma and the cumulative exposure of rectal tissue to TDF was 100-fold higher than that in female volunteers’ cervicovaginal tissues. Interestingly, although FTC could also be detected in rectal tissue throughout the study, emtricitabine-triphosphate concentrations were 10-fold to 15-fold higher in vaginal and cervical tissue than in rectal tissue. The implications of these differences in drug concentrations between tissues are as yet unknown [16▪]. A pharmacokinetic study of long-acting rilpivirine, administered once intramuscularly to six HIV-negative men found that rectal concentrations of rilpivirine at days 7 and 14 were equivalent to those in plasma [17].

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Evidence supporting efficacy of ARVs for HIV prevention in the postexposure setting has come from a variety of settings including animal studies [18–20], randomized trials of prevention of maternal–child transmission [21–24], case–control studies of occupational PEP [25] and PEP after sexual exposure to HIV. There have been no randomized trials of the effectiveness of PEP as a prevention modality for sexual exposure to HIV, but numerous observational studies of cohorts of PEP users, many of them MSM, have shown that PEP use has averted HIV infection [26–30]. Even in countries with national PEP guidelines and reasonable levels of availability to those at high risk, PEP has had limited public health impact [30]. This strongly indicates that PEP will never be a stand-alone prevention strategy [23,31]. The concern that use of ARVs following HIV sexual exposures may potentially affect HIV risk behaviour and lead to a possible reduction in the use of other risk reduction strategies has been discussed in the context of PEP [23]. However, the observational studies that have specifically investigated this issue among MSM found that PEP use was not associated with subsequent increased risk behaviour [28,32,33].

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The iPrEx study investigated safety and efficacy of daily oral TDF/FTC in 2499 high-risk MSM in Brazil, Ecuador, Peru, South Africa, Thailand and the USA [10▪▪]. The iPrEx study demonstrated that TDF/FTC decreased the likelihood of HIV infection by 44% among high-risk MSM, randomly assigned to receive active study drug rather than placebo. Adherence to study medications was crucially linked to efficacy: those participants who took at least 90% of study drug had a greater than 70% level of protection and men with detectable levels of TDF or FTC in plasma and peripheral blood mononuclear cells experienced a greater than 90% protective effect. This was further investigated in a substudy examining intracellular drug concentrations in HIV-negative active-arm controls compared with all 48 active-arm HIV seroconverters. Cases had significantly lower rates of drug detection than controls both at HIV diagnosis and in the 90 days prior. Relative to placebo, a TFV-DP concentration of greater than 15.6 fmol/M viable cells was associated with a more than 90% decrease in risk of HIV infection. It was estimated that four or more doses per week were required to reach such concentrations [34].

In iPREX, the study drug regimen was generally well tolerated. However, participants taking TDF/FTC were more significantly likely to report moderate nausea (22 versus 10 events, P = 0.04) and experience unintentional weight loss of 5% or more in the first few weeks (34 versus 19 events, P = 0.04) than participants on placebo. There was a trend towards a higher incidence of reversible elevations in serum creatinine levels (2 versus 1%, P = 0.08) in participants on TDF/FTC compared with those on placebo. There was no difference in the number of bone fractures in either study arm during the study (15 versus 11 events, P = 0.41) [10▪▪]. Adverse clinical effects thus occurred uncommonly in the iPrEX study and were either self-limited or resolved when study medications were temporarily stopped. However, ongoing clinical and laboratory monitoring is important for individuals who are using TDF/FTC for PrEP [35].

Another completed trial of PrEP in MSM was a phase II extended safety study of TDF among 400 HIV-negative men in the USA. TDF was found to be safe and well tolerated, with no increase in nephrotoxicity, nor any evidence of increased behavioural risk taking. Back pain was more common in the TDF arm (13 versus 6%) [36]. A subset of 184 participants at the San Francisco study site underwent measurements of bone mineral density (BMD). TDF use was associated with a small but significant decrease in BMD at the total hip and femoral neck [37▪].

Ongoing and planned PrEP trials involving MSM include the iPrEX Open-Label Extension study: HIV-negative iPrEx participants from the 11 original study sites have been offered the opportunity to enrol in an 18-month open-label extension study of daily FTC/TDF use. Adherence, long-term safety and efficacy and effects of PrEP use on sexual risk behaviour will be examined; The HIV Prevention Trials Network (HPTN) 069 (Novel Exploration of Therapeutics for PrEP) study: this is a planned randomized, four-arm, placebo-controlled phase II study of the safety and tolerability of the HIV entry inhibitor, maraviroc (MVC), TDF and FTC in different combinations. In total, 400 at-risk MSM at 12 US sites will be randomized to 48 weeks of MVC, MVC and FTC, MVC and TDF or TDF/ FTC. Measurements of adherence, safety, behaviour change and in a subset of participants, pharmacokinetic and drug interactions will be performed; The HPTN 067 Alternative Dosing to Augment PrEP pill-Taking study: this is an ongoing phase II, randomized, open-label, pharmacokinetic and behavioural study of 30 weeks of intermittent oral TDF/FTC as PrEP enrolling 180 heterosexual women in South Africa and 180 MSM in Thailand. The three arms are daily dosing, time-driven dosing, with twice weekly dosing and a postexposure boost and event-driven dosing in which PrEP is taken before and after a potential exposure to HIV infection; A phase III randomized, placebo-controlled study conducted by the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) of on-demand intermittent TDF/FTC taken at coitus and shortly afterwards. Recruitment has commenced for an initial pilot study of 300 at-risk MSM, which will be followed by recruitment of a total of 1900 MSM in Paris and Lyon, France and Montreal and Canada (the ANRS Preventive Intervention Risk Exposure with and for Gays study) [38], the Adolescent MedicineTrials Network 082 study, a 24-week phase II, randomized, placebo-controlled safety, acceptability and feasibility study of daily oral TDF/FTC in 99 young high-risk MSM in the USA. There are three study arms, including daily TDF/FTC, daily placebo and a no pill control arm. Each arm will also have a group-level behavioural intervention, the 3MV (Many Men, Many Voices) and a US National Institute of Allergy and Infectious Diseases-funded PrEP demonstration study. Approximately 500 at-risk MSM at Sexually Transmitted Diseases clinics in Miami and San Francisco are currently being enrolled for up to 12 months of TDF/FTC. Safety, adherence and behavior will be monitored [39,40] (Table 1).

The results from the iPrEx study, as well as those from randomized trials among serodiscordant heterosexual couples and heterosexual women have reinvigorated the biomedical HIV prevention field. They strongly suggest that chemoprophylaxis is an effective and feasible strategy that can and should be utilised [41]. From a policy perspective, the Centers for Disease Control and Prevention (CDC) responded to the release of the iPrEx results by publishing provisional guidelines on the use of oral PrEP for MSM at high risk for sexual acquisition of HIV [42▪], and there is ongoing work on developing PrEP guidelines by CDC and the World Health Organisation [43]. The British HIV Association/British Association for Sexual Health were more circumspect, publishing a position statement that recommended against ad hoc prescription of PrEP and advised that PrEP be prescribed in the United Kingdom only in a research study setting [44▪]. On May 10th, the US Food and Drug administration (FDA) Antiviral Drugs Advisory Panel voted that daily oral TDF/FTC was safe and effective when used to prevent HIV infection and recommended approval of PrEP for healthy people who are at high risk of contracting HIV, including gay and bisexual men and heterosexual couples with one HIV-positive partner. A final decision by the FDA is expected by September 2012.

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The strong connection between effectiveness of a biomedical HIV prevention technology and adherence has been a major theme recently. This has been discussed in detail in a recent publication in which the need to identify and quantify minimal levels of adherence that will provide sufficient drug concentrations at target genital and rectal sites was highlighted [45▪▪]. Others have looked for analogies in the experiences with other prophylactic regimens, such as malaria prophylaxis and the oral contraceptive pill, to identify the main issues surrounding adherence and to provide a framework for maximizing adherence. They found that structural issues, education at prophylaxis initiation and comprehensive support mechanisms during use of PrEP were critical [46]. The 18-month Enhancing PrEP in Community settings study conducted by the San Francisco Department of Public Health will investigate the potential of a multimodal intervention of context-driven counselling and short message system support to promote adherence and reduce risk among 300 MSM PrEP users (Albert Liu, personal communication).

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Knowledge of the existence of PrEP and reported prior use by MSM around the world has been low thus far. Only six (0.5%) of 1161 gay men reported prior use of PrEP in a national, online cross-sectional survey conducted in Australia in 2011. Interest in PrEP was much higher, however, with over a quarter of the men who responded in the survey (n = 327; 28.2%) willing to use PrEP [47]. In cross-sectional, US internet-based surveys of MSM conducted 2 months before and 1 month after publication of the iPrEx results, PrEP use was uncommon (0.7% before, 0.9% after) and awareness of PrEP was limited both before and after publication of the iPrEx findings (13 and 19%, respectively). However, men were positive about taking PrEP, with over three quarters of men reporting interest in PrEP after they were educated about it [48]. Similarly in a serial community-based survey among MSM in London in 2011, only 2.1% (17) MSM reported having ever used PrEP, and 50.3% reported that they would be likely to use PrEP if it were to become available as a daily pill [49]. Among 180 HIV-negative MSM in New York City enrolling in a trial of a behavioural intervention between September 2007 and July 2009, 1.7% had used PrEP, 23.2% had heard of PrEP and almost 70% reported that they would be likely to use PREP if it were at least 80% effective in preventing HIV [50]. Twenty of 25 (80%) of HIV-negative MSM in serodiscordant relationships in a mixed method study conducted in Los Angeles expressed willingness to adopt PrEP for HIV prevention [51]. Thus, although knowledge and reported use of PrEP are low among MSM populations, there appears to be a significant amount of interest in PrEP as an HIV prevention strategy. Awareness and knowledge are likely to be rapidly changing in response to the recent results and emerging community discussion about PrEP.

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The important issue of how to implement PrEP with maximum benefits while avoiding potential adverse consequences now needs to be addressed [52]. Along with poor adherence, the potential for ‘risk compensation’ has been repeatedly raised by many researchers, policy makers and affected communities [35,53,54]. Risk compensation is defined as an increase in HIV risk behaviours, following the implementation of an HIV prevention strategy such as the use of PrEP, which may undermine its benefits [46]. PrEP use may potentially change an individual's perception of risk, resulting in a feeling of being “biologically protected” and a reduction or cessation of his or her use of condoms [35]. There is obviously also a pleasure-related aspect to this in which PrEP use may remove the impetus for condom use [50]. No evidence for increases in high-risk behaviour, or risk compensation, was found in the iPrEX trial. Indeed, reported numbers of receptive UAI partners decreased from baseline and condom use by partners increased in both the placebo and active drug arms [10▪▪]. Although these finding from the iPrEX trial, along with data from a number of PEP studies [28,32][33] provide evidence that risk compensation is not inevitable, the ‘real life’ situation may be very different. In the small Los Angeles study of HIV serodiscordant MSM couples discussed above, almost two thirds of participants indicated that there may be an increase in their sexual risk behaviours, and a 60% reported they may decrease or cease condom use [28,32,51]. Concerns about an increase in HIV risk behaviour should not impede the introduction of effective HIV prevention strategies; however maintaining or improving risk reduction behaviors must be central to supporting individuals using PrEP in implementation programs. Studies measuring potential risk compensation need to be conducted in the setting of demonstration projects in which men are educated about PrEP's efficacy and are aware they are on active drug and not potentially on placebo.

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The last few years have seen PrEP emerge as the first biomedical strategy with proven potential to prevent HIV in MSM. The iPrEX study found a 44% reduction in HIV infection among MSM in the TDF/FTC study arm; a level of protection that improved with increasing adherence. This is compelling evidence that proof of concept of PrEP has been achieved. Focus now needs to be directed towards identifying optimal PrEP agents and dosing regimens. As adherence is crucial to the success of PrEP as HIV prevention, understanding the patterns of and impediments to PrEP use among MSM is vital. Future studies should anticipate the potential impact of PrEP on men's perception of risk and subsequent risk behaviour. There is a strong imperative to monitor these in ongoing demonstration projects and open-label studies involving MSM.

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Conflicts of interest

I.M.P. is supported by a Postdoctoral Training Fellowship (#1016307) from the National Health and Medical Research Council, Australia. AEG was supported by a NHMRC Principal Research Fellowship (#568819). The Kirby Institute (formerly NCHECR) is affiliated with the Faculty of Medicine, University of New South Wales and is funded by the Australian Government Department of Health and Ageing. The views expressed in this publication do not necessarily represent the position of the Australian Government.

No conflicts of interest for I.M.P., I.Z. or A.E.G. is declared.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 610).

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The landmark iPrEx study found that daily oral FTC/TDC reduced the risk of HIV infection by 44% among 2499 MSM, compared with placebo. Efficacy increased with increasing adherence. No significant difference in renal or bone safety measurements was reported, and no evidence of increased risk behaviour was found.

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Here, the TDF concentration in rectal tissue was markedly higher than in blood plasma and cervicovaginal tissues. Conversely FTC-TP concentrations were higher in vaginal and cervical tissue than in rectal tissue. Although the significance of this difference is unknown, these findings suggest that different PrEP agents may be more effective for different HIV routes of exposure.

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This study on a subset of 184 participants in a phase II extended safety study of TDF among HIV-negative men in the USA found that TDF use was associated with a small but significant decrease in bone mineral density at the total hip and femoral neck. These findings reinforce the need for effects on bone to be monitored in long-term safety studies of PrEP.

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antiretroviral; HIV; MSM; preexposure prophylaxis; prevention

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