Pre-exposure Prophylaxis for HIV Prevention: Why, What, Who and How

This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

Ten randomised controlled trials have investigated the use of PrEP utilising tenofovir, five providing evidence for the effectiveness of daily oral tenofovir disoproxil fumarate [1, 2] or Truvada (tenofovir disoproxil fumarate/emtricitabine fixed dose combination tablet) [3‐5], one for event-driven Truvada taken before and after sex [6], two for event-driven topical tenofovir gel [7, 8] and two for daily tenofovir vaginal gel [9, 10].

Effectiveness for oral tenofovir-based regimens has been demonstrated in men who have sex with men (MSM) [3, 4, 6], heterosexual serodiscordant couples [1], young heterosexual adults (male and female) [5]) and injecting drug users [2]. Tenofovir 1% vaginal gel applied before and after sex resulted in a modest reduction in HIV incidence in women in Kwazulu-Natal [7] but no reduction in a further trial conducted in South Africa [8]. Two randomised placebo-controlled trials conducted in women in Sub-Saharan Africa observed no benefit for daily oral tenofovir or Truvada or daily tenofovir 1% vaginal gel [9, 10]; these studies however experienced low levels of retention and adherence, and biological efficacy is supported by subset analyses in women using gel who had detectable drug in plasma (and demonstrated protection) [8, 10].

The iPrEx study was a double-blind, placebo-controlled study of daily Truvada-based PrEP in men and male-to-female transgender adults who reported sex with men in the 6 months prior to enrolment in 6 countries. An overall 44% risk reduction was seen, which increased to 73% where self-reported adherence was >90% and to 92% in those with detectable plasma drug levels [4]. In the open-label extension of the iPrEx study (iPrEx OLE), 100% efficacy was reached in those taking four or more doses a week [11].

More recently two randomised trials using Truvada in European MSM populations were reported. PROUD was an open-label design (daily Truvada versus no drug) [3] and IPERGAY a placebo-controlled design evaluating event-based Truvada (two tablets before sex and one a day for 2 days after the last condomless anal sex act) [6]. In both trials the HIV incidence in the control group was much higher than anticipated, 9.0/100 person years in PROUD and 6.6/100 person years in IPERGAY. Indeed the incidence in PROUD was seven fold higher than in MSM attending sexual health clinics. The reductions in HIV acquisition in both trials (by ITT analysis) were 86%, which is the highest efficacy observed in PrEP trials to date. Interestingly, IPERGAY achieved this using half the number of doses compared to daily dosing of the drug. Concern that PrEP would reduce condom use when knowingly taking PrEP was assessed in the open-label PROUD study whereby patients knew whether they were taking effective PrEP or not and no difference was found in sexually transmitted infections between the groups [3].

One study (from Thailand) has explored tenofovir-based PrEP in preventing HIV transmission via intravenous drug use and found an almost 50% risk reduction in HIV acquisition [2].

Tenofovir-based PrEP is not without potential toxicities with reduction in bone mineral density [12, 13] and renal function [14] observed albeit in low numbers. As a result other PrEP agents are being investigated: tenofovir alafenamide (TAF) is a pro-drug of tenofovir with theoretical advantages in terms of decreased renal and bone adverse events and decreased monitoring requirements. However, although macaque data appear promising [15], there are presently no efficacy data in humans and vaginal drug levels appear to be lower than those achieved with tenofovir disoproxil [16]. Whether 3TC could be used instead of FTC in PrEP has not been evaluated in a clinical trial; however, a systematic review and meta-analysis of randomised trials concluded that there would be comparative efficacy of lamivudine and emtricitabine for PrEP efficacy (p = 0.88) [17] (Table 1).

Maraviroc has not shown protection from HIV in ex−vivo challenge models, whether via stat dosing across rectal and vaginal mucosa or daily dosing across rectal mucosa [18, 19]. Taken orally in combination with other antiretroviral agents, Maraviroc is well tolerated but PrEP efficacy is not known [20, 21]. Cabotegravir (as 2−monthly injections) also shows promise [22] and a phase 3 efficacy study is underway. Two randomised control trials of the dapivirine intravaginal ring reported consistent results. Although the ITT benefit was small, post hoc analyses excluding younger women (less than 25 years of age) who were less likely to have detectable drug revealed modest protection benefits [61% (32–77) risk reduction] [23].

Daily tenofovir-based PrEP has shown good efficacy in a variety of populations, but requires good adherence and frequent repeat HIV testing to minimise the associated antiretroviral resistance that can occur as a consequence of PrEP failure [24]. It can also lead to drug wastage if taken during periods of low sexual risk and potentially cause toxicity (principally bone and renal) if taken long term [25]. Renal and bone monitoring may be unavailable or operationally difficult and costly (especially in resource-poor/remote settings), and toxicities may differentially affect specific populations. For example, bone loss (which is pronounced in adolescents) is of particular concern in countries such as Botswana where up to 7% of healthy young adults have low bone mineral density [12].

Event-driven PrEP has only been investigated in MSM populations (and therefore efficacy is unproven with heterosexual or needle-based transmission). If efficacy is substantiated in future studies, this strategy has the potential to improve cost effectiveness, whilst reducing drug wastage, reduce toxicity and monitoring requirements—as there will be natural interruptions during periods of no risk. Furthermore, in contrast to daily PrEP, event-driven PrEP has not (to date) led to any cases of drug-resistant HIV. However this may change as implementation is rolled out. Transmitted tenofovir resistance is already a concern in Sub-Saharan Africa, South/Southeast Asia and the Latin America/Caribbean region [24, 26‐29]; it is essential that PrEP does not drive drug resistance, further reducing treatment options for HIV-positive individuals.

The main practical limitation of event-driven PrEP is the complexity of the IPERGAY regime, which has led to concerns that adherence may be difficult. As such further evaluation in a variety of settings and risk groups is required. Furthermore, this regimen is not indicated in those with active hepatitis B infection because of the risk of hepatic flares when the drug is interrupted.

Overall, the critical factors when deciding upon a PrEP regimen are adherence and the evidence base for the individual in question. Data support daily PrEP in MSM, heterosexual men and heterosexual women. However, data for event-based PrEP are limited to MSM only (one study only) and further data on tenofovir in women are desirable. It is likely that, as for HIV acquisition risk, PrEP requirements may differ for vaginal, penile and anal HIV acquisition prevention [30].