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Pre-exposure Prophylaxis (PrEP) is intended for people at-risk of exposure
Pre-exposure prophylaxis (PrEP) is a special course of HIV treatment that aims to prevent people from becoming infected with HIV. PrEP is intended for people at-risk of exposure, for example in the case of couples where one partner is HIV-positive and the other is HIV-negative.
What is pre-exposure prophylaxis (PrEP)?
PrEP refers to a form of treatment that can be taken before exposure to a disease in an attempt to prevent infection. In respect to HIV, PrEP consists of antiretroviral drugs to be taken before potential HIV exposure in order to reduce the risk of HIV infection.
Does PrEP work?
Pre-exposure prophylaxis has been studied in animal and human trials (see below). Results from a human trial published in late 2010 were the first to provide proof that PrEP has an effect. 1 One of the main ways that a person taking PrEP can help to ensure that it works is through ensuring that they adhere to the medication properly. 2 3 By adhering to PrEP well, their risk of HIV infection is reduced by 90 percent. 4
Where is PrEP used?
A 2006 study suggested that some men who have sex with men (MSM) were already experimenting with the use of tenofovir to prevent HIV transmission. 5 However, health authorities are divided on the subject of whether pre-exposure prophylaxis is developed enough for general use: the British HIV Association have deemed that PrEP should not yet be prescribed outside of a clinical trial context, 6 whilst the US Centers for Disease Control (CDC) released guidelines in 2011 on prescribing PrEP for gay and bisexual men. 7
In July 2012, for the first time, an antiretroviral drug was approved for use as a pre-exposure prophylaxis. In the United States of America, the drug with the brand name ‘Truvada’, can be prescribed for high-risk groups, such as the partners of HIV-positive people and gay men. 8 People have to take an HIV test before using it, and ensure that they have no flu-like symptoms, which can be an indicator of early, acute HIV-infection. Truvada, which is produced by Gilead Sciences Inc., is a combination of tenofovir disoproxil fumarate and emtricitabine.
Risks and side-effects
Taken once a day, these drugs have limited side effects, though appear to commonly cause nausea and vomiting. 9 There are concerns around the possibility of PrEP increasing the likelihood of a person developing drug-resistant HIV, though there haven’t been documented cases of this occurring in humans. 10 However, a study testing the use of tenofovir as PrEP on monkeys found that some of the animals developed a mutation of the virus that was associated with drug-resistance. 11
Who can use PrEP?
WHO guidelines 2012
The World Health Organisation in 2012, published guidance on the use of PrEP for serodiscordant couples, and men and transgender women who have sex with men. Specifically the HIV-negative partner of a serodiscordant couple should take daily tenofovir, or tenofovir + emtricitabine. Men and transgender women who have sex with men should take tenofovir + emtricitabine. 12 13
- Serodiscordant couples: There are cases of couples wishing to conceive a child where one partner is HIV positive and the other HIV negative. PrEP could help couples to conceive without transmitting HIV. The method has been used as an alternative to sperm washing, a procedure currently being used in many parts of the developed world by HIV different couples. Sperm washing is costly and is believed to have a low conception rate, which is why PrEP could be a more effective option. 14 PrEP could also be used as an added protection in conjunction with timed intercourse, where couples only have intercourse without using a condom when the woman is especially fertile. 15 When used with ‘ treatment as prevention’ this prevention method has been found to be very effective.
- People who are unable to insist on condom use: It has been suggested that PrEP would be an effective way for people who are victims of sexual violence or coercion, or who are unable to insist that their partners use condoms, to protect themselves. 16 Worldwide the most common form of HIV transmission is through unprotected vaginal sex with an infected partner. Therefore millions of people could conceivably benefit from taking a pill a day as a way of reducing their risk of contracting HIV. Microbicides are a similar concept currently being developed.
- Other populations at higher risk: A review of PrEP published by the Center for HIV Identification, Prevention, and Treatment Services, explains that in California PrEP would benefit men who have sex with men (MSM), female partners of MSM and injection drug users and their partners. 17 Other UK-based studies involving interviews with gay men have found that PrEP would be an acceptable prevention method for half of those questioned. 18
CDC guidelines 2014
The US Centers for Disease Control and Prevention (CDC) released specific guidelines for the use of PrEP in the United States, in May 2014. 19 The guidelines suggest that PrEP is offered to HIV-negative people who fall under one or more of the following criteria:
- Serodiscordant relationship: Anyone who is in an ongoing sexual relationship with an HIV-infected partner.
- Gay or bisexual: A gay or bisexual man who has had sex without a condom or has been diagnosed with a sexually transmitted infection within the past six months, and is not in a mutually monogamous relationship with a partner who recently tested HIV-negative.
- Heterosexual: A heterosexual man or woman who does not always use condoms when having sex with partners known to be at risk for HIV (for example, injecting drug users or bisexual male partners of unknown HIV status), and is not in a mutually-monogamous relationship with a partner who recently tested HIV-negative.
- Injects drugs: Anyone who has, within the past six months, injected illicit drugs and shared equipment or been in a treatment program for injection drug use. 20
These guidelines are a welcome development since the FDA approved the use of Truvada for PrEP in 2012. 21
Trials and development of PrEP
Pre-exposure prophylaxis is relatively new within HIV prevention, and its development continues to generate ground-breaking results, controversies and debate. It was announced in June 2012 that up to 33,000 people could take part in trials that assess the feasibility of PrEP within the next three years. 22 These trials will build upon the body of research that has already shown PrEP to be potentially useful as an HIV prevention method:
Animal studies of pre-exposure prophylaxis
The drug used in most of the animal studies is an antiretroviral known by the brand name, Truvada. This fixed-dose antiretroviral is a combination of tenofovir and emtricitabine. One study involved injecting 6 macaque monkeys with a course of PrEP both before and after infecting them with a combination of HIV and simian immunodeficiency virus (SIV), known as SHIV. 23 The results showed that all of the monkeys were protected from infection. 20 of the 21 monkeys that did not receive PrEP became infected with SHIV.
The combination of tenofovir and emtricitabine has also been tested on humanised BLT (Bone Marrow Liver Thymic) mice. These mice have fully developed human immune systems and can produce the infection-fighting cells that in humans are specifically targeted by HIV. In the study the mice were vaginally infected with HIV. Some were then given antiretrovirals once a day for seven days and some were not given any antiretroviral treatment. Seven of the eight mice that didn’t receive the drug became infected, while none of the mice that did receive the antiretrovirals became infected with HIV. The researchers concluded that PrEP could be a very effective method for preventing vaginal HIV-1 transmission. 24
Human trials of pre-exposure prophylaxis
In November 2010 results from a Phase III large-scale study, iPrEx, showed PrEP provided an additional 44 percent protection from HIV acquisition. 25 The study enrolled 2,499 men who have sex with men and transgender women who have sex with men (who were all at high risk of HIV infection), from Peru, Ecuador, South Africa, Brazil, Thailand and the United States. Half the study subjects were given once-daily oral FTC-TDF (emtricitabine and tenofovir disoproxil fumarate), brand name Truvada, and the other half were given a placebo. All subjects received monthly HIV testing and risk-reduction counselling. Among those taking FTC-TDF, 36 became infected with HIV during the trial, compared to 64 in the placebo group. The protective effect was even higher among those with good pill adherence.
Although the results from iPrEX were seen as a dramatic breakthrough in the field, they were still treated with widespread caution.
“No single HIV prevention strategy is going to be effective for everyone... and it is important to note that the new findings pertain only to the effectiveness of PrEP among men who have sex with men and cannot at this point be extrapolated to other populations. Therefore, we must continue to conduct PrEP research among other study populations, such as women and heterosexual men, to provide a comprehensive picture of its potential utility as an HIV prevention tool.” Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases 26
Following the release of the trial results the CDC issued guidance for using PrEP for the prevention of HIV infection among MSM in the USA. 27 The guidance states:
"For MSM at high risk for HIV infection, PrEP may represent a much-needed additional prevention tool. However, PrEP should be used only in combination with other HIV prevention strategies, requires strict adherence, and is an intensive approach that won't be right for everyone." 28
Concerns around iPrEx
The AIDS Healthcare Foundation (AHF) in the United States highlighted concerns about the use of PrEP in a letter addressed to Gilead - the manufacturer of the FTC-TDF combination. 29 AHF argued that the iPrEx trial results cannot support the use of FTC-TDF as an HIV prevention tool for gay men due to lack of effectiveness, the potential decrease of condom-use, the increased risk of drug resistance and the uncertainty of the effects of PrEP if users have no trial support.
Not long after the letter, AHF released results of a commissioned online survey of more than 882 men who have sex with men. 30 According to AHF, the findings illustrate the potential difficulties of rolling out a prevention strategy based on PrEP. The survey found that although 79 percent of respondents said they would take a pill every day if it would prevent HIV, only 63 percent said it would be 'very likely' that they would remember to take it every day and less than half said they would take it if it meant having to pay for doctor visits or laboratory costs. Moreover, a majority of the respondents said they would be reluctant to take the pill if it increased the risk of medical conditions such as bone loss and/or resistance to other HIV medication.
FEM-PrEP and Partners PrEP study
In April 2011, Family Health International announced it was stopping FEM-PrEP - a trial in South Africa, Kenya and Tanzania investigating the effect of PrEP among 2,000 women at high risk for HIV. An interim review of data revealed no signs of efficacy of PrEP among study participants and the decision was made to stop the trial. 31
Conversely, in July 2011, the University of Washington led the Partners PrEP study which involved 4,758 serodiscordant heterosexual couples in Kenya and Uganda. The study that found PrEP was effective. The group of HIV negative partners who received a daily tablet of tenofovir (TDF) were found to have 62 percent less HIV infections than those on the placebo pill, while those who took a combination of tenofovir and emtricitabine (FTC) had 73 percent less infections than those on the placebo pill. A similar study, led by the Centers for Disease Control and Prevention (CDC) in Botswana, found a 63 percent reduced risk of HIV transmission among the 1,219 HIV negative participants who took a combination of TDF and FTC. 32
As a result of the discrepancy between the FEM-PrEP trial and the University of Washington and CDC led trials, researchers from the FEM-PrEP trial re-examined the study. 33 It was found that the main difference between the two trials was adherence; in the Partners PrEP trial, adherence to the medicine was very high, but in the FEM-PrEP trial, less than half of the women took their pills regularly. 34
Monthly, injectable rilpivirine
A UK-based organisation has trialled an injectable, once-a-month formulation of the HIV-drug rilpivirine as a pre-exposure prophylaxis. 35 This trial recruited only 27 volunteers, but was enough to find that in theory the levels of the drug that remained in the participants’ bodies should be enough to protect them against HIV. 36
Human trials of PrEP and ethical issues
With human trials of PrEP there are ethical issues both with using a placebo and withholding a potentially effective treatment. Research trials in Cambodia, Cameroon and Nigeria were cancelled due to ethical concerns. Most notably the study of 960 female commercial sex workers in Cambodia was cancelled after a highly publicised demonstration at the XV International AIDS Conference in Bangkok, Thailand in 2004. 37 The main reasons for the protesting included concerns about the level of health care for the volunteers before and after the trial; the apparently low level of counselling the volunteers were receiving before their trial; and the possibility that the volunteers might not get treatment if they became infected with HIV during the study. Family Health International (FHI) who led the trials, reassured that this would not be the case.
Similarly a study of 400 sexually active women in Cameroon was halted by Cameroon’s Minister of Public Health in 2005. FHI agreed to comply with the Ministry’s recommendations, stating that “the safety and welfare of study participants is Family Health International’s highest priority". 38 They further declared, “FHI is committed to addressing all concerns identified in the Ministry’s careful review of the tenofovir study and has already made significant progress in doing so”.
There are concerns around the contradiction of offering PrEP to study subjects in countries where treatment is not available:
“People who need PrEP the most and in whom most of the trials were done will be the last to get it.” - Manuel Gonçalves of ViiV Healthcare 39
Manuel Gonçalves further commented that this was the same situation as was seen when HIV treatment was first trialled and rolled out, and it should not be allowed to happen again.
Is there a future for PrEP?
It has been argued that pre-exposure prophylaxis could have an enormous impact on the worldwide HIV epidemic. Mathematical models estimate that if tenofovir PrEP was used by 90 percent of high-risk people and was effective 90 percent of the time, potentially the spread of HIV infection could be reduced by more than 80 percent in a few years. 40 For sub-Saharan Africa, it is estimated that approximately 2.7 million to 3.2 million new HIV-1 infections could be prevented over the next ten years by using PrEP and preventing high-risk behaviours among the most sexually active population groups. 41
Despite these estimates, it is highly unlikely that everybody who could benefit from PrEP would receive the antiretroviral drugs. Most of the countries that are facing the full impact of an HIV/AIDS epidemic do not have the infrastructure or economic resources to implement such a strategy.
- 1. Grand, RM et al (2010) 'Preexposure chemoprophylaxis for HIV prevention in men who have sex with men', The New England Journal of Medicine, published online 23rd November 2010
- 2. Cairns G. (2012, 6th March) ‘ A tale of two trials: how adherence is everything in PrEP’ National AIDS Manual (NAM)
- 3. The New York Times (2012, 8th March) ‘ Setback on AIDS drug is re-evaluated’
- 4. CDC (2014) ' Press release: New guidelines recommend daily HIV prevention pill for those at substantial risk'
- 5. Cohen, J (2006, 22nd January) ‘Protect or Disinhibit?’ The New York Times.
- 6. Cairns, G (2012, 1st March) ‘ PrEP needs more study before being provided, UK physicians conclude’ National AIDS Manual (NAM)
- 7. CDC (2011) ‘ CDC Interim Guidance on HIV Pre-exposure Prophylaxis for Men Who Have Sex with Men’
- 8. FDA (2012, July 16th) ‘ FDA Approves First Medication to Reduce HIV Risk’
- 9. Cairns G. (2012, 6th March) ‘ A tale of two trials: how adherence is everything in PrEP’ National AIDS Manual (NAM)
- 10. Cairns G. (2012, 6th March) ‘ A tale of two trials: how adherence is everything in PrEP’ National AIDS Manual (NAM)
- 11. Metzner K. et al (2011, 23rd October) ‘ Tenofovir treatment augments anti-viral immunity against drug-resistant SIV challenge in chronically infected rhesus macaques’ Retrovirology (3)
- 12. WHO (2012, July) ‘ Guidance on oral pre-exposure prophylaxis (PrEP) for serodiscordant couples, men and transgender women who have sex with men at high risk of HIV’
- 13. WHO (2013, June) ' Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: Recommendations for a public health approach'
- 14. Collins, S. (2007, August-September) ‘ Use of pre-exposure prophylaxis (PrEP) by sero-different couples wanting to conceive a child’.
- 15. Vernazza P. L. et al (2011, 23rd October) ‘ Preexposure prophylaxis and timed intercourse for HIV-discordant couples willing to conceive a child’ AIDS 25 (16)
- 16. AVAC (2005, March) ‘Will a pill a day prevent HIV?’.
- 17. Szekeres, G. et al (2004, November) ‘ Anticipating the efficacy of HIV pre-exposure prophylaxis (PrEP) and the needs of at-risk Californians’.
- 18. Pebody, R (2012, 21st April) ‘ PrEP acceptable to UK gay men, studies find’ National AIDS Manual (NAM)
- 19. CDC (2014) ' Press release: New guidelines recommend daily HIV prevention pill for those at substantial risk'
- 20. US Public Health Service and CDC (2014) ' Preexposure Prophylaxis for the Prevention of HIV Infection in the United States – 2014 Clinical Practice Guideline'
- 21. aidsmap (2014, May) ' New US guidelines recommend PrEP'
- 22. aidsmap / nam (2012, 25th June) ' The Road to PrEP: Trials, regulation and roll-out'
- 23. Cohen M. S. and Kashuba A. D. (2008, February) ‘ Antiretroviral Therapy for Prevention of HIV Infection: New Clues From an Animal Model.’ PLoS Medicine 5 (2)
- 24. EurekAlert! (2008, January 14th) ‘Existing antiretroviral drugs may thwart vaginal HIV transmission, researchers report’.
- 25. Grand, RM et al (2010) 'Preexposure chemoprophylaxis for HIV prevention in men who have sex with men', The New England Journal of Medicine, published online 23rd November 2010
- 26. U.S. Department of Health and Human Services (2010, 23rd November) 'Daily dose of HIV drug reduces risk of HIV infection'
- 27. CDC (2011, February) 'Pre-exposure prophylaxis (PrEP) for HIV prevention: Promoting safe and effective use in the United States'
- 28. CDC (2011, February) 'Pre-exposure prophylaxis (PrEP) for HIV prevention: Promoting safe and effective use in the United States'
- 29. AIDS Healthcare Foundation (2011) 'There is no magic pill: An open letter to Gilead on PrEP'
- 30. Medical News Today (2011, May) ' AHF Survey Of Gays Raises Questions About Gilead's Truvada For HIV Prevention'
- 31. CDC (2011, 18th April) 'Results of FEM-PrEP clinical trial examining pre-exposure prophylaxis (PrEP) for HIV prevention among heterosexual women'
- 32. CDC (2011, July 13th) ' CDC Trial and Another Major Study Find PrEP Can Reduce Risk'
- 33. CDC (2011, July 13th) ' CDC Trial and Another Major Study Find PrEP Can Reduce Risk'
- 34. Cairns G. (2012, 6th March) ‘ A tale of two trials: how adherence is everything in PrEP’ National AIDS Manual (NAM)
- 35. Cairns, G (2012, March) ‘ Once-a-month HIV drug maintains good levels for prevention; few side-effects so far’ National AIDS Manual (NAM)
- 36. Jackson, A. et al (2012, March) ‘ Rilpavirine-LA Formulation: Pharmacokinetics in Plasma, Genital Tract in HIV– Females and Rectum in Males’ 19th Conference on Retroviruses and Opportunistic Infections
- 37. Singh, J.A. & Mills, E.J. (2005, 19th July) ‘The abandoned trials of pre-exposure prophylaxis for HIV: What went wrong?’ PLOS Medicine.
- 38. FHI (2005, 22nd February) ‘Participant follow-up resumed in FHI’s oral tenofovir study in Cameroon’.
- 39. aidsmap / nam (2012, 25th June) ' The Road to PrEP: Trials, regulation and roll-out'
- 40. Cohen, J (2006, 22nd January) ‘Protect or Disinhibit?’ The New York Times.
- 41. Abbas, U.L, Anderson, R.M, Mellors,, J.W (2007, September) ‘Potential impact of antiretroviral chemoprphlaxis on HIV-1 transmission in resource-limited settings’ PLos One.