Pre-exposure prophylaxis (PrEP)

  • PrEP involves taking antiretroviral drugs in order to prevent infection.
  • Several studies are currently investigating the effectiveness of daily PrEP for people at high risk of HIV infection.

Pre-exposure prophylaxis (PrEP) is the use of antiretrovirals prior to exposure to HIV to prevent infection. PrEP is intended for use by people who may be at frequent risk for HIV. This includes people in high-risk behaviour groups such as commercial sex workers, injecting drug users, and people who have unsafe sex with multiple partners (or whose partners have multiple partners). Currently, no antiretroviral is yet approved for use as PrEP.

Much of the data on PrEP result from research conducted in monkeys. These have included studies examining the effects of single drugs, notably tenofovir (Viread) in preventing infection with HIV and similar viruses in monkeys, as well as a recent trial examining the effects of combining tenofovir with FTC (emtricitabine, Emtriva).

In general, these studies have demonstrated that PrEP can decrease the risk of infection.1 2 3 4 However, they used different models for testing, such as different doses of virus and routes of viral inoculation and drug delivery, making comparisons across studies difficult.

The only human data to date, from a Family Health International study of tenofovir PrEP in which recruitment was abandoned at two sites due to a controversy over post-trial care, show no serious safety concerns during an average of nine months’ follow-up, but the study was inadequately powered to provide any evidence of efficacy.5

Seven PrEP studies are underway:

  • An efficacy study of tenofovir among injecting drug users in Thailand  – expected to report efficacy results in 2009.
  •  A safety study of tenofovir among men who have sex with men in the United States – expected to report safety results in 2009.
  •  An efficacy study of Truvada among heterosexuals in Botswana – expected to report efficacy data in 2010.
  • An efficacy study of Truvada among men who have sex with men in Peru and Ecuador – expected results in 2010.
  • An efficacy study of Truvada among women in southern Africa – expected results in 2011.
  • An efficacy study comparing tenofovir, Truvada, a tenofovir microbicide or placebo for women in southern Africa – expected results in 2011.
  • An efficacy study comparing tenofovir, Truvada or placebo for serodiscordant heterosexual couples in Kenya and Uganda – expected results in 2012.

Premature halting of early studies

Despite the promise of this approach, clinical trials into PrEP have faced difficulties over the past few years. Trials of tenofovir PrEP were prematurely halted at two sites, Cambodia and Cameroon, because activists were concerned that trial participants may not be offered antiretroviral therapy should they become infected during the study. Concerns were also raised about the provision of independent counselling on safer sex and injection practices and the availability of condoms and sterile needles.

Tenofovir trials at two further sites were stopped on different grounds. In Nigeria, the sites were not able to comply with the appropriate laboratory and clinical conditions needed for the safe conduct of the trial. In Malawi, there were broader concerns regarding the ability of the government to implement PrEP, if it were proven effective.

In response to the controversies associated with these trials, the International AIDS Society convened a stakeholder consultation to address some of the ethical concerns and ensure that future studies proceed with the support of local and international communities.

Questions for the future

What if PrEP studies demonstrate that either tenofovir or Truvada have some protective effect? The implementation of PrEP may well raise some thorny issues.

Although the results from one trial will probably not change international public health policy, gay men in particular might begin to adopt PrEP informally if they hear of positive results from the first trials. At the moment there’s little evidence that tenofovir or Truvada are being used systematically as PrEP by gay men in the UK. But gay newspapers in the US have reported the informal use of tenofovir in several large cities, and one HIV physician (Marcus Conant of San Francisco) has gone on record to say he has prescribed it to some gay male patients.

In fact PrEP is already being provided by some clinicians to partners of HIV-positive people, to assist in risk reduction when the couple is trying to conceive. Moreover, Swiss researchers in 2007 successfully used two doses of PrEP to protect HIV-negative women trying to conceive with HIV-positive men. These women’s partners had undetectable viral loads and they only had unprotected sex on the days when the woman was most likely to conceive.

Initially PrEP is likely to be prescribed through sexual health clinics, accompanied by regular HIV testing. But some advocates want the drugs with the best safety records eventually to be available over the counter. This approach would shift the cost of providing PrEP to the user, making it more affordable to the NHS in the long term.

The short-term cost of PrEP could be enormous at current drug prices, but its cost needs to be considered in the context of the long-term cost of 7000-plus new people with HIV per year in the UK, each of them requiring antiretroviral therapy for 20 to 40 years or so at an annual cost of £10,000 a year for drugs and care.

The greatest impact on new infections would probably come from targeting PrEP to men with histories of serial risk-taking and repeat testing, to HIV-negative gay men with a high number of sexual partners, and to HIV-negative men and women in HIV-discordant relationships, especially women seeking to conceive.

However, the first generation of trials may still leave a range of questions partially unanswered:

  • Is daily dosing necessary or can episodic dosing provide equivalent protection? Will other drugs with longer half-lives make episodic dosing a possibility?
  • How long does PrEP remain effective in a population? Is there a decline in adherence?
  • What effect does taking PrEP have in individuals who acquire HIV infection? Do they develop resistance and do they transmit drug-resistant virus?
  • Are there any long-term side effects associated with use of PrEP? People will generally tolerate some side-effects when treating a life-threatening condition, but will be less tolerant of side-effects when guarding against an infection.
  • What effect does PrEP have on risk-taking – both among those who take it and in the wider community?
  • How does PrEP compare with a topical microbicide containing tenofovir? The VOICE study will test this question in a study that may report in 2011.
  • A further strategy may be to combine different types of drugs to prevent infection, such as the use of topical microbicides with oral drug treatment to prevent infection.

References

  1. Tsai CC et al. Prevention of SIV infection in macaques by (R)-9-(2-phosphonylmethoxypropyl)adenine. Science 270: 1197-1199, 1995
  2. Van Rompay KK et al. Two low doses of tenofovir protect newborn macaques against oral simian immunodeficiency virus infection. J Infect Dis 184: 429-438, 2001
  3. Garcia-Lerma JG Intermittent antiretroviral prophylaxis with tenofovir and emtricitabine (FTC) protects macaques against repeated rectal SHIV exposures. Sixteenth International HIV Drug Resistance Workshop, St Michael, Barbados, Abstract 85, 2007
  4. Garcia-Lerma J et al. Prevention of rectal SHIV transmission in macaques by tenofovir/FTC combination. 13th Conference on Retroviruses and Opportunistic Infections, Denver, abstract 609, 2006
  5. Peterson L et al. Findings from a double-blind, randomized, placebo-controlled trial of tenofovir disoproxil fumarate (TDF) for prevention of HIV infection in women. 16th International AIDS Conference, Toronto, abstract ThLb0103, 2006
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