Post Exposure Prophylaxis and Pre-exposure Prophylaxis

Post-exposure prophylaxis (PEP) and pre-exposure prophylaxis (PrEP) are special courses of antiretroviral treatment that aim to prevent people from becoming infected with HIV. Post-exposure prophylaxis and pre-exposure prophylaxis are part of what is becoming widely known as 'HIV treatment as prevention'.

back to top What is post-exposure prophylaxis (PEP)?

The antiretroviral drug stavudine, marketed as Zerit The antiretroviral drug stavudine, marketed as Zerit

Post-exposure prophylaxis is antiretroviral drug treatment that is started immediately after someone is exposed to HIV. The aim is to allow a person’s immune system a chance to provide protection against the virus and to prevent HIV from becoming established in someone’s body. In order for post-exposure prophylaxis to have a chance of working the medication needs to be taken as soon as possible, and definitely within 72 hours of exposure to HIV. Left any longer and it is thought that the effectiveness of the treatment is severely diminished.

Post-exposure prophylaxis (PEP) usually consists of a month long course of two or three different types of the antiretroviral drugs that are also prescribed as treatment for people with HIV. As with most antiretrovirals these can cause side effects such as diarrhoea, headaches, nausea/vomiting and fatigue. Some of these side effects can be quite severe and it is estimated that 1 in 5 people give up the treatment before completion. The most common drugs prescribed for post-exposure prophylaxis are zidovudine, lamivudine and nelfinavir.

Does post-exposure prophylaxis work?

Post-exposure prophylaxis has been studied in animal trials and human trials. The evidence from each individual study is not enough to confirm whether post-exposure prophylaxis works or not. However, the cumulative evidence is enough to suggest that PEP might be effective in reducing the risk of HIV infection. This conclusion is widely recognised and as a result, a number of countries have produced guidelines suggesting the possible use of post-exposure prophylaxis in both occupational and non-occupational circumstances. They tend to suggest that, as it is not guaranteed to work, post-exposure prophylaxis should only be used as a very last resort.

Animal studies of post-exposure prophylaxis

Various animal studies have been carried out to test the effectiveness of post-exposure prophylaxis. Macaques, a type of old world monkey, tend to be used in animal HIV drug trials. As macaques cannot be infected with HIV, the drugs are tested against either HIV type-2, simian immunodeficiency virus (SIV) or a combination of HIV and SIV known as simian/human immunodeficiency virus (SHIV).

One monkey study investigated whether 16 pig-tailed macaques would be protected from infection when given the antiretroviral drug tenofovir after intravaginal exposure to HIV type 2.1 None of the 4 macaques that started the treatment 12 hours after exposure became infected. The outcome was the same with the 4 macaques that received post-exposure prophylaxis 36 hours after exposure. In the 72-hour group, one of the macaques became infected after 16 weeks. The study concluded that early intervention with an antiretroviral form of PEP such as tenofovir might be successful in preventing infection after vaginal exposure.

The timing of administering post-exposure prophylaxis and the duration of the course of treatment has been a highly significant factor in all of the animal studies. HIV takes around 3 days to reach the lymph nodes (components of the immune system), and it takes a further 2 days to reach the blood cells. There is therefore a small temporary “window” during which the infection can be blocked. This can be seen in another study of tenofovir post-exposure prophylaxis tested on 24 macaques.2 The results showed that a 4-week regimen of tenofovir started within 24 hours of exposure completely protected the macaques from SIV. Starting the treatment between 48 and 72 hours of infection was largely ineffective. Treatment started within 24 hours of exposure but only administered for 3 days proved to be just as ineffective.

Human trials of post-exposure prophylaxis

A number of small scale studies have investigated the efficacy of post-exposure prophylaxis in humans by looking at occupational exposures to HIV. Health care workers tend to be at a slightly higher risk of being infected with HIV due to the nature of their work (although this risk is still very low). The most frequent exposures to HIV-infected blood in the occupational setting are caused by needle stick injuries or cuts with sharp objects. Zidovudine is the drug that is primarily prescribed after an occupational exposure to HIV and it is the only drug that has been tested in trials on health care workers. Nowadays most treatment starter packs contain a combination of zidovudine, lamivudine and nelfinavir, as it is generally thought that combination drug therapy is more effective than zidovudine alone.

A generic version of zidovudine (AZT) combined with lamivudine (3TC) A generic version of zidovudine (AZT) combined with lamivudine (3TC)

The results of one occupational exposure study showed that taking a course of zidovudine after exposure reduced the risk of HIV infection by approximately 81 percent.3 These results cannot be taken as absolute, especially when there have been at least 13 reported cases where PEP has failed in health care workers worldwide.4 For some of these cases there was no plausible explanation for why PEP might have failed and therefore PEP cannot be considered as 100 percent effective.

One study enrolled 891 people who had requested post-exposure prophylaxis after possible non-occupational HIV exposure (e.g. sexual exposure or injecting drug use).5 The participants were all provided with a 28-day course of various combinations of zidovudine, lamivudine, stavudine and didanosine. 6 out of the 700 that returned for testing after 12 weeks were HIV positive. However all 6 had had possible HIV exposures up to 6 months before commencing PEP. Therefore it was very difficult to determine the exact moment of exposure and whether PEP had been successful or not. There is a distinct lack of definitive evidence to show that PEP can be effective in non-occupational settings. Studies have generally concluded that PEP ‘might’ reduce the risk of HIV infection, but none have been able to say that it is a definite preventative.

Other observational evidence has been gathered from studies of survivors of sexual assault. In a South African study of 480 rape survivors taking a 6-week course of zidovudine and lamivudine, only one woman became HIV positive.6 Another study looked at 2,000 non-occupational exposures to HIV from four countries (Australia, France, Switzerland, and the United States). Out of 350 people treated with PEP who reported being exposed to HIV-infected sources, none became infected as a result of PEP failure.

Who can benefit from post-exposure prophylaxis?

Since the beginning of the 1990s in most areas of North America and Europe, post-exposure prophylaxis has been available to health workers as an important aspect of safety in the workplace. In 2005, clinical guidelines from the United States Department of Health and Human Services (HHS) were drafted to extend the recommendations on using PEP to non-occupational circumstances. Nowadays, anybody who believes they have been exposed to HIV is able to ask for post-exposure prophylaxis treatment at accident and emergency areas in hospital, through GUM or HIV clinics, and via some medical doctors experienced in treating HIV in several countries.

The question of who should receive PEP has proved to be quite controversial. Several cost-benefit analyses have revealed that providing PEP to all non-occupational exposures is not an economically efficient use of limited HIV treatment resources.7 PEP appears to be cost-effective only when the patient has engaged in unprotected receptive anal intercourse or when the patient knows the HIV status of the partner. However, the demand for PEP does not always reflect cost-effectiveness. A ten year review of non-occupational PEP requests recorded at a Swiss clinic found an 850 percent increase in the number of people requesting PEP in the ten-year period and 58 percent of requests were for heterosexual exposure.8

Some believe that the increasing availability of PEP will lead to behavioural changes. The theory is that if PEP is readily available people will be less likely to use condoms or will be less cautious, knowing that there is a potential back up.9

“Rape survivors are not receiving vital anti-HIV treatment due to ignorance and a lack of basic treatment procedure at government health facilities and justice departments.”

It has also been suggested that if PEP is available more widely, people may use PEP repeatedly. However, various studies have shown that increasing awareness and availability of PEP does not lead to increasing risky behaviour. There is also little evidence showing that people would frequently rely on PEP, probably due to the adverse side effects that the treatment can involve. In particular a study in the US showed that “people reduced their risk behaviour after using PEP, rather than increasing it”.10

Unfortunately there are still some places around the world where PEP is being denied to people who need it. For example research in South Africa revealed that many victims of rape were not receiving PEP treatment.

“Rape survivors are not receiving vital anti-HIV treatment due to ignorance and a lack of basic treatment procedure at government health facilities and justice departments”(IRIN, 2007)11 .

Homophobia and lack of understanding regarding male-on-male rape also explain why some men in South Africa do not access PEP treatment.12

back to top 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. The antiretroviral drugs that are currently being tested for PrEP treatment are tenofovir and emtricitabine or tenofovir alone. Taken once a day, these drugs have limited side effects and slow development of associated drug resistance.13

Does PrEP work?

Pre-exposure prophylaxis has been studied in animal and human trials. Results from a human trial published in late 2010 were the first to provide proof of concept for PrEP.14

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.15 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.16

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.17 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 Diseases18

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.19 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."20

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.21 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.22 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.

The following table summarises other Phase III and IIb ongoing PrEP trials.23

Location Population Expected completion date
Thailand 2,400 injecting drug users 2012
South Africa, Uganda, Zimbabwe 5,000 heterosexual women 2013

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.24

Conversely, in July 2011, a University of Washington led study which involved 4,758 serodiscordant heterosexual couples in Kenya and Uganda was stopped early due to high levels of efficacy shown by PrEP.25 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.26

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 are reexamining that study.27  

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 2004.28 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 the FHI protocols would provide antiretroviral therapy if anyone did become infected.

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 FHI’s highest priority".29 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”.

Who would be likely to benefit from PrEP?

Different groups of people could potentially benefit from PrEP in the antiretroviral drug form. There are cases of couples wishing to conceive a child where one partner is HIV positive and the other HIV negative. It has been thought that couples with different HIV status may be able to conceive without transmitting infection by using the antiretroviral drug form of PrEP. PrEP could be 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.30

It has been suggested the PrEP would be an effective way to “protect women (and men) who are victims of sexual violence or coercion, or who are afraid to insist that their partners use condoms”.31 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.

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.32 One study suggests some MSM have already tried taking tenofovir to prevent HIV transmission.33

back to top Is there a future for PEP and PrEP?

Post-exposure prophylaxis is not going to be enough to significantly reduce the worldwide spread of HIV. It is a short-term preventative measure that is used as an ‘emergency’ precaution. PEP is considered as the very last resort in HIV prevention and should only be used when all other methods of HIV prevention have failed. However, with increasing widespread availability and further awareness, PEP can offer more people control over their own health.

On the other hand, it has been argued that pre-exposure prophylaxis could have an enormous impact on the worldwide HIV-1 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.34 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.35

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.

References back to top

  1. Otten. R. A et al (2000, 14th July) ‘Efficacy of postexposure prophylaxis after intravaginal exposure of pig-tailed macaques to a human-derived retrovirus (Human immunodeficiency virus type 2)’ Journal of Virology, 74, 20 (9771-9775)
  2. Tsai, C.C. et al (1998, May) ‘Effectiveness of postinoculation (R)-9-(2-phosphonylmethoxypropyl) adenine treatment for prevention of persistent simian immunodeficiency virus SIV infection depends critically on timing of initiation and duration of treatment’, Journal of Virology, 72, 5 (4265-4273)
  3. Cardo, D.M. et al (1997, 20th November) ‘A case-control study of HIV seroconversion in health care workers after percutaneous exposure’, New England Journal of Medicine 337 (1485-1490)
  4. Cardo, D.M. et al (1997, 20th November) ‘A case-control study of HIV seroconversion in health care workers after percutaneous exposure’, New England Journal of Medicine 337 (1485-1490)
  5. Roland, M. et al (2004, February) ‘HIV seroconversion following non-occupational post-exosure propylaxis’, Presented at the 11th Conference on Retroviruses and Opportunistic Infections; San Francisco. Abstract 888.
  6. CDC (2005, 21st January) ‘Antiretroviral post-exposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposure to HIV in the United States’ MMWR 54 (1-20)
  7. Pinkerton, S.D, Holtgrave, D.R, Bloom, F.R. (1998, 18th June) ‘Cost-effectiveness of post-exposure prophylaxis following sexual exposure to HIV’, AIDS, 12 (1067-1078)
  8. Tissot, F et al. (2010) 'Nonoccupational HIV post-exposure prophylaxis: a 10-year retrospective analysis' HIV Medicine 11
  9. BASHH (2006, February) ‘UK guideline for the use of post-exposure prophylaxis for HIV following sexual exposure’, International Journal of STD and AIDS, 17 (81-92)
  10. Harding, A. (2007, 23rd November) ‘Post-exposure HIV drugs won’t boost risky behaviour’ Reuters.
  11. IRIN (2007, 1st May), ‘HIV prevention services miss rape survivors’.
  12. IRIN (2007, 1st May), ‘HIV prevention services miss rape survivors’.
  13. CDC (2009, January) ‘CDC trials of pre-exposure prophylaxis for HIV prevention’.
  14. 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
  15. Highleyman, L (2007, 7th October) ‘Double-dose pre/post-exposure prophylaxis with tenofovir plus emtricitabine may provide protection against sexually transmitted HIV’.
  16. EurekAlert! (2008, January 14th) ‘Existing antiretroviral drugs may thwart vaginal HIV transmission, researchers report’.
  17. 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
  18. U.S. Department of Health and Human Services (2010, 23rd November) 'Daily dose of HIV drug reduces risk of HIV infection'
  19. CDC (2011, February) 'Pre-exposure prophylaxis (PrEP) for HIV prevention: Promoting safe and effective use in the United States'
  20. CDC (2011, February) 'Pre-exposure prophylaxis (PrEP) for HIV prevention: Promoting safe and effective use in the United States'
  21. AIDS Healthcare Foundation (2011) 'There is no magic pill: An open letter to Gilead on PrEP'
  22. Medical News Today (2011, May) 'AHF Survey Of Gays Raises Questions About Gilead's Truvada For HIV Prevention'
  23. AVAC (2010, November) 'Ongoing PrEP Trials'
  24. CDC (2011, 18th April) 'Results of FEM-PrEP clinical trial examining pre-exposure prophylaxis (PrEP) for HIV prevention among heterosexual women'
  25. University of Washington (2011, July 13th) 'Pivotal Study Finds that HIV Medications are Highly Effective as Prophylaxis Against HIV Infection in Men and Women in Africa'
  26. CDC (2011, July 13th) 'CDC Trial and Another Major Study Find PrEP Can Reduce Risk'
  27. CDC (2011, July 13th) 'CDC Trial and Another Major Study Find PrEP Can Reduce Risk'
  28. Singh, J.A. & Mills, E.J. (2005, 19th July) ‘The abandoned trials of pre-exposure prophylaxis for HIV: What went wrong?’ PLOS Medicine.
  29. FHI (2005, 22nd February) ‘Participant follow-up resumed in FHI’s oral tenofovir study in Cameroon’.
  30. Collins, S. (2007, August-September) ‘Use of pre-exposure prophylaxis (PrEP) by sero-different couples wanting to conceive a child’.
  31. AVAC (2005, March) ‘Will a pill a day prevent HIV?’.
  32. Szekeres, G. et al (2004, November) ‘Anticipating the efficacy of HIV pre-exposure prophylaxis (PrEP) and the needs of at-risk Californians’.
  33. Cohen, J (2006, 22nd January) ‘Protect or Disinhibit?’ The New York Times.
  34. Cohen, J (2006, 22nd January) ‘Protect or Disinhibit?’ The New York Times.
  35. 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.