Pre-exposure prophylaxis can successfully prevent HIV transmission if taken correctly and consistently and as part of a multi-pronged interventional approach
Pre-exposure prophylaxis can successfully prevent HIV transmission if taken correctly and consistently and as part of a multi-pronged interventional approach
Nadia Naous MPharm
Lead Pharmacist – HIV and Sexual Health, Imperial College Healthcare NHS Trust, London, UK
Email: [email protected]
At the end of 2014, there were approximately 36.9 (34.3–41.4) million people living with Human Immunodeficiency Virus (HIV), with 2.0 (1.9–2.2) million people becoming newly infected in 2014 globally.1 Despite the success of antiretroviral therapy (ART), HIV infection rates remain high and implementation of measures to prevent transmission remains a challenge.
The HIV virus is present in the blood, pre-seminal fluid, semen, rectal fluids, vaginal fluids and breast milk of infected individuals. These fluids must come into contact with a mucous membrane or damaged tissue, or be directly injected into the bloodstream, for transmission to occur. The main routes of HIV transmission are through sexual contact, sharing injecting equipment with an HIV-infected person, or from an HIV-infected mother to her child (vertical transmission) before or during birth, or through breastfeeding.
Prevention of transmission
HIV transmission is preventable. There is currently no effective vaccine for the prevention of HIV infection; however, studies are ongoing.
The main strategies for prevention of HIV transmission are:
- Correct and consistent use of condoms: the use of male and female condoms during vaginal or anal penetration can protect against the spread of sexually transmitted infections
- Voluntary medical male circumcision: when safely provided by appropriately trained health professionals, male circumcision has been shown to reduce the risk of heterosexually-acquired HIV infection in men by approximately 58%.2 Data on transmission risk in men who have sex with men (MSM) are conflicting and a meta-analysis of 17 studies of male circumcision and HIV acquisition by MSM has found the protective association to be statistically non-significant3
- Safe injecting practice for injecting drug users can minimise risk of infection by taking appropriate precautions. These include interventions such as using sterile injecting equipment for each injection
- Mother-to-child transmission: all pregnant women should be tested for HIV routinely. Most maternity services in the UK have an ‘opt-out’ system for HIV testing of pregnant women. This increases the number of expectant mothers who are tested and helps to make routine testing more acceptable to service users
- Treatment as prevention: data from several studies of serodiscordant couples (that is, one partner is HIV-positive and the other is HIV-negative) have demonstrated that when an HIV-positive partner adheres to anti-retroviral therapy (ART), the risk of transmitting the virus to his/her uninfected sexual partner is substantially reduced.4,5 This is known as treatment as prevention (commonly referred to as TasP)
- Post-exposure prophylaxis (PEP): PEP involves the administration of antiretroviral medicines within 72 hours of exposure to HIV to prevent infection. PEP is often given to health professionals following occupational exposure to needles and potentially infectious fluids at work. It can also be used after sexual exposure to the virus. The standard course of PEP is a 28-day course of antiretrovirals
- Pre-exposure prophylaxis: clinical trials in serodiscordant couples have demonstrated that antiretroviral medicines taken by HIV-negative partners can prevent HIV transmission; this is known as pre-exposure prophylaxis (PrEP).
Efficacy of PrEP
The efficacy data on use of antiretroviral therapy in HIV negative partners have shown outcomes which vary according to study design, antiretroviral(s) used and population and risk group of subjects. The majority of studies have used the combination of oral tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC), which is widely used as part of antiretroviral treatment and PEP regimens, although there are a variety of other approaches and delivery methods. Subjects in PrEP studies are conventionally stratified into the following risk groups:
- Men who have sex with men (MSM)
- Transwomen (people who are born as a male but identify themselves as a woman)
- Heterosexual men and women
- Serodiscordant couples
- People who inject drugs (PWID).
Early studies examining of efficacy of PrEP demonstrated a 39% risk reduction for TDF vaginal gel in in women age 18–40 years in South Africa in 2010,6 and 44% efficacy for daily oral PrEP among men and transgender women who have sex with men.7 Here, a significantly high correlation was seen between efficacy of oral PrEP and adherence to PrEP use. Further studies demonstrated overall efficacy of oral PrEP ranging from 62% to 75% in young heterosexuals and serodiscordant couples, respectively (81% and 79% among those more adherent).8,9 In contrast, the FEMPrEP trial10 and the VOICE trial11 (which evaluated efficacy of topical as well as oral PrEP) demonstrated no benefit, which can be explained by low levels adherence levels to the prescribed regimen.
In 2015, results from two pivotal PrEP randomised controlled trials (RCTs) were reported. These studies were the PROUD study12 and the IPERGAY study,13 which were both conducted in MSM populations.
PrEP to prevent the acquisition of HIV-1 infection (PROUD)
This documented effectiveness from the pilot phase of a pragmatic open-label randomised trial in 13 sexual health clinics in England. Subjects were HIV-negative gay and other MSM who had had anal intercourse without a condom in the 90 days prior to enrolment. These participants were randomly assigned to receive the combination of TDF (245mg) and FTC (200mg) in an oral daily dose, either immediately or after a deferral period of one year in a 1:1 ratio. Non-pharmacological interventions to reduce risk were offered to all participants according to routine practice at the study site. 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 pilot phase was designed to test the feasibility of a large-scale trial, with a sample size of 5000 participants, powered to detect a 50% reduction in HIV incidence from 2.5 to 1.25 infections per 100 person-years. However, the unexpectedly large number of HIV infections enabled the investigators to present findings on the effectiveness of PrEP, as well as safety, adherence, and risk compensation.
A total of 544 participants were enrolled, of which 275 were randomised to the immediate group and 269 to the deferred group. Due to early evidence of efficacy of the PrEP, the trial steering committee recommended, almost two years after the start of the pilot, 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. During follow up, three HIV infections occurred in the immediate group versus 20 in the deferred group (relative reduction 86%; 90% CI 64–96, p=0·0001).
In the deferred group, 174 prescriptions of post-exposure prophylaxis were recorded. The investigators concluded that 13 men (90% CI 9–23) in a similar population would need access to one year of PrEP to avert one HIV infection. No serious adverse drug reactions occurred in the study and the most common adverse events were nausea, headache, and arthralgia. No significant difference in the occurrence of other sexually transmitted infections was observed, suggesting that risk compensation among some PrEP recipients was not evident.
IPERGAY
In contrast to the daily regimen in PROUD, IPERGAY was a double-blinded RCT, which set out to assess an on-demand regimen taken by MSM before and after sex. The trial design was based on the rationale that lower drug exposure could reduce the risk of toxicity as well potentially being more cost effective than a once-daily regimen. The on-demand dosing of TDF/FTC was compared with placebo, as the investigators were uncertain of the biological efficacy of an ‘on-demand’ regimen in comparison. Participants were randomly assigned, in a 1:1 ratio, to take a combination of active drug or placebo before and after sexual activity.
Participants were instructed to take a loading dose of two TDF/FTC tablets or placebo with food 2–24 hours before sex; this was followed by a third tablet 24 hours after the first dose and a fourth tablet 24 hours later. In case of multiple consecutive episodes of sexual intercourse, participants were instructed to take one tablet daily until the last episode of sexual intercourse and then to take two post-exposure pills. When resuming PrEP, participants were instructed to take a loading dose of two tablets unless the last drug intake was less than one week earlier, in which case they were instructed to take only one tablet. All participants received risk-reduction counselling and condoms in addition to regular testing for HIV and other sexually transmitted infections.
A total of 414 participants were randomised, and 400 of these, who did not have HIV infection, were enrolled. A total of 199 subjects were randomised to the in the TDF/FTC arm of the study and 201 to the placebo group. All participants were followed for a median of 9.3 months. During follow-up, two HIV-1 infections occurred in the group receiving active drug (incidence, 0.91 per 100 person-years) and 14 infections in the placebo group (incidence, 6.60 per 100 person-years). These results demonstrated a relative reduction in the TDF/FTC group of 86% (95% CI 40–98; p=0.002). The rates of serious adverse events were similar in the two study groups. Compared with the placebo group, there were higher rates of gastrointestinal adverse events (14% vs 5%, p=0.002) and renal adverse events (18% vs 10%, p=0.03) in the TDF/FTC group.
The emerging evidence to support the use of PrEP clearly demonstrates that it works if taken correctly and consistently. The World Health Organization (WHO) and Joint United Nations Programme on HIV/AIDS (UNAIDS) recommend that when deciding to offer PrEP, the needs and benefits should be balanced with harm (possible adverse events), costs and feasibility. People who are at substantial risk of acquiring HIV would achieve the greatest benefit from being able to access PrEP as an additional prevention choice.14 Experience of use of TDF and FTC in antiretroviral regimens demonstrates that these drugs are generally well tolerated. Decline in renal function is a side effect of TDF seen in HIV-positive populations, which requires monitoring and rarely a switch to an alternative agent. TDF can also cause a measurable loss in bone mineral density; however, the long-term clinical relevance of this is unknown.
Available regimens
Tenofovir alefenamide (TAF), a prodrug of tenofovir, has recently become commercially available. Clinical studies have shown TAF has reduced impact on markers of renal function and bone mineral density, which may be advantageous for long term use in both HIV-positive and -negative individuals, although the long-term clinical significance of this is unknown. A preclinical proof-of-concept study has demonstrated that TAF plus FTC protected macaques from infection with an HIV-like virus; therefore further investigation in its use for PrEP is warented.15 Studies are also underway to evaluate the safety and efficacy of alternative agents and delivery methods such as vaginal rings to deliver a novel ARV (dapivirine), long-acting injectable drugs, such as cabotegravir and rilpivirine, and subcutaneous implants with TDF derivatives.
Guidance from the European Aids Clinical Society (EACs)16 recommends that PrEP can be used in adults at high-risk of acquiring HIV infection. The guidelines state that it can be used in HIV-negative MSM and transgender individuals who are inconsistent in their use of condoms with casual partners, or with HIV-positive partners who are not on treatment. Recent sexually transmitted infections or use of PEP may be indicators of this risk. PrEP use can also be considered in HIV-negative heterosexual women and men who are inconsistent in their use of condoms and likely to have HIV-positive partners who are not on treatment. The guidelines discuss both continuous regimens in these risk groups and ‘on-demand’ regimen for MSM as possible strategies.
Conclusions
Healthcare professionals can support patients with taking PrEP and should remember that it is to be used as an intervention that forms a multi-pronged prevention strategy. Counselling should be tailored to the individual’s need. Important points to cover include emphasising that PrEP does not prevent/protect from other sexually transmitted infections, and regular screening is advised. Patients should also be made aware of potential toxicities of the drugs they are receiving.
Key points
- HIV transmission is preventable.
- Pre-exposure prophylaxis (PrEP) use has been demonstrated in a number of risk groups.
- Tenofovir with emtricitabine, either daily or on-demand, is currently the recommended regimen.
- PrEP should form part of a broader prevention strategy.
- Further studies are required to investigate the use of other drugs and populations where data are scarce.
References
- World Health Organization. HIV/AIDS factsheet 360;November 2015.
- Byakika-Tusiime J. Circumcision and HIV infection: assessment of causality. AIDS Behav 2008;12:835–41
- Vermund SH, Qian HZ. Circumcision and HIV prevention among men who have sex with men: no final word. JAMA 2008;300(14):1698–700.
- Cohen MS et al. Antiretroviral treatment of HIV-1 prevents transmission of HIV-1: where do we go from here? Lancet 2013;382(9903):1515–24.
- Rodger A et al. HIV transmission risk through condomless sex if HIV+ partner on suppressive ART: PARTNER study. 21st Conference on Retroviruses and Opportunistic Infections 2014; Abstract 153LB.
- Abdool Karim Q et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 2010;329:1168–74.
- Grant RM et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010;363:2587–99.
- Thigpen MC et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med 2012;367:423–34.
- Baeten JM et al; and the Partners PrEP Study Team. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012;367:399–410.
- Marrazzo J et al. Tenofovir-based pre-exposure prophylaxis for HIV infection among African women. N Engl Med 2015;372:509.18
- Marrazzo J et al. Pre-exposure prophylaxis for HIV in women: daily oral tenofovir, oral tenofovir/emtricitabine or vaginal tenofovir gel in the VOICE study (MTN 003). Conference on Retroviruses and Opportunistic Infections 2013; Oral Abstract 26LB.
- McCormack S et al. Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial. Lancet 2016;387:53–60.
- Molina J et al. On demand PrEP with oral TDF-FTC in MSM: results of the ANRS Ipergay trial. Conference on Retroviruses and Opportunistic Infections 2015; Abstract 23LB.
- Oral pre-exposure prophylaxis: putting a new choice in context, Geneva: UNAIDS, 2015. www.unaids.org/sites/default/files/media_asset/UNAIDS_JC2764_en.pdf (accessed July 2016).
- Massud I et al. Chemoprophylaxis with oral FTC/TAF protects macaques from rectal SHIV infection. Conference on Retroviruses and Opportunistic Infections 2016; Abstract 107.
- EACS guidelines v.8.0. www.eacsociety.org/guidelines/eacs-guidelines/eacs-guidelines.html (accessed July 2016).
