In 2012 over a million new cases of HIV were recorded, according to the World Health Organization. Numerous strategies have been implemented to reduce the transmission of the virus, from the use of condoms and voluntary medical male circumcision to harm reduction strategies for intravenous (IV) drug users. Although this has reduced infection rates in some countries, the HIV epidemic continues to spread. In an effort to stem this, in 2012 the US Food and Drug Administration (FDA) approved two oral antiretroviral drugs for the prevention of HIV infection in high-risk individuals. However the use of pre-exposure prophylaxis (PrEP) is a controversial topic, receiving mixed responses, particularly in Europe where this measure has not yet been approved. Jean-Michel Molina from the University of Paris Diderot, France, and colleagues analyse the issues that need to be tackled in order for PrEP to be accepted as a global strategy for HIV prevention, focusing specifically on the European situation, as published in their review article in BMC Medicine – part of the special series’ ‘HIV thirty years on’ and ‘Medicine for global health’. Here Molina discusses the reasons behind the PrEP controversy as well as addressing some of the challenges that lie ahead.
What is PrEP in HIV medicine?
PrEP or pre-exposure prophylaxis is a risk reduction strategy to limit the risk of HIV acquisition among people at high risk of HIV-infection. PrEP relies on the use of antiretroviral drugs that are given to HIV-uninfected people to reduce their risk of HIV-infection. This new preventative strategy will likely complement other risk reduction strategies to curb the rising incidence of new HIV infection in high-risk individuals around the world. PrEP should not be seen as an alternative to existing preventive tools such as condoms, but as an additional tool that people might seek to use in certain situations.
What is the best way to use PrEP and how should it be delivered?
PrEP can be used as a daily pill regimen containing the fixed dose formulation of emtricitabine and tenofovir disoproxil fumarate (FTC/TDF or Truvada®, a combination of two nucleoside reverse transcripase inhibitors) or as a vaginal gel containing TDF that women would use within 12 hours before and after sexual intercourse.
Future PrEP regimens might include newer antiretrovirals from different classes (such as entry inhibitors (maraviroc), integrase inhibitors and non-nucleoside reverse transcriptase inhibitors), newer schedules (coitally dependant oral regimens) and newer modes of delivery (vaginal ring, vaginal film, rectal gel and long acting injectable agents).
How do you identify people who might benefit from PrEP
People who might benefit the most from PrEP are those with the highest risk of HIV acquisition. These people are those with multiple partners, little or no condoms use, who live in high endemic areas, and have a history of sexually transmitted infections. Sex workers and IV drug users in certain countries where free and sterile syringes are not available are also to be included in these high risk groups. The seronegative (uninfected) partner of a serodiscordant couple where the HIV-infected partner is not under antiretroviral therapy might also benefit from PrEP. Although the benefit of treating the HIV-infected partner is still greater than the use of PrEP when it comes to reducing the risk of HIV transmission to the HIV-uninfected partner. A number of people do not acknowledge being at high risk of HIV-acquisition, and for these people being aware of their risk of HIV infection is the first step towards a risk reduction strategy.
What are the reasons behind the controversy around the use of PrEP to prevent HIV infection?
There remains controversy about the real effectiveness of this strategy, which has only been approved so far in the US with the daily use of a pill (TDF/FTC). This controversy is due to the lower than expected effectiveness (42 percent reduction in HIV incidence) seen with the pill in the iPrEX study in men who have sex with men (MSM), and the lack of efficacy of this same regimen in two other trials in women in Africa. The highest effectiveness has been demonstrated in serodiscordant couples when the HIV-infected partner was not receiving antiretroviral therapy, a situation that will become less and less frequent due the incentive to treat HIV infection early in most guidelines.
Also, although the use of a vaginal TDF gel used before and after sexual intercourse was able to reduce the incidence of HIV infection in high risk women in one trial by just under 40 percent, the daily gel was not able to provide any protection against HIV in another trial. New placebo-controlled studies using TDF gel are now underway in South Africa.
What are the main issues that need to be addressed in order for PrEP to be effectively implemented on a large scale?
In all the trials discussed earlier, adherence to the PrEP regimen seems to play a major role in treatment effectiveness, although this was a post-hoc finding in the placebo-controlled trials, not protected by randomization. Improving adherence to PrEP regimens remains critical to increase their effectiveness and ways to improve adherence are to be explored.
The safety of PrEP regimens in healthy individuals is also critical and monitoring PrEP safety especially with daily use is key. Included in overall safety is the risk of developing resistance among patients failing PrEP. Although rarely seen in trials (probably because adherence was low), regulatory agencies have asked the pharmaceutical companies to closely monitor this risk of HIV-resistance in PrEP users, in particular because drugs used in PrEP regimens today are those also recommended for the treatment of HIV-infection.
Other issues raised by PrEP are its cost-effectiveness (especially in populations at low risk of HIV-acquisition), its sustainability with a daily regimen, and the risk of sexual disinhibition and reduced condom use that could theoretically offset its benefit.
Ongoing randomized placebo-controlled studies as well as demonstration projects will hopefully confirm the efficacy of PrEP and show that a high adherence rate to PrEP regimens can be sustainable without significant changes in risk behavior. Also, cost-effectiveness analyses are needed to identify the best PrEP strategy for each country and for each high risk group.
How can PrEP be made available to those who need it?
There is a clear lack of knowledge about PrEP in the general population and in high risk groups as well. Information about the prevention of HIV, including PrEP, should be promoted. PrEP could be seen as a way to attract more interest in HIV prevention. It should be made available to those who might benefit from this strategy and access should be easy and affordable. Once the different issues raised by PrEP are addressed, in particular its effectiveness, it should be part of a comprehensive prevention package.
PrEP should be delivered ideally in sexual health clinics where people at high risk of HIV-infection will benefit not only from PrEP but also from a range of other preventive tools, including: risk reduction counseling, free condoms and lubricant, regular testing for HIV and other sexually transmitted infections, post-exposure prophylaxis for HIV (four weeks of combination antiretroviral therapy to high-risk individuals following a clear exposure to HIV with a seropositive partner not receiving treatment), treatment for sexually transmitted infections, vaccination against HBV or HAV, HPV screening, and detection of rectal and cervical dysplasia and cancer. These clinics should also offer drug addiction counseling, psychiatric support when needed, and have the ability to monitor the safety and efficacy of PrEP.
What is your vision for the future of PrEP for HIV prevention?
The results of the first PrEP trials and the approval by the US FDA of TDF/FTC for PrEP have fostered interest in this strategy to reduce the incidence of new HIV infections. PrEP should be seen as one of the multiple tools available to reduce the risk of HIV acquisition among high-risk groups. PrEP is an opportunity to put HIV prevention at the forefront of HIV research, and might help to contain the spread of HIV infection in high risk groups.
Questions from Claire Barnard, Senior Editor for BMC Medicine.