JOHANNESBURG, SOUTH AFRICA—Nearly four years after political pressure shut down two trials that would have tested whether a once-a-day pill could prevent high-risk HIV-negative people from catching the AIDS-causing virus, there’s a surge of renewed interest in the concept, known as Pre-Exposure Prophylaxis, or PrEP.
Western doctors and organizations that funded the halted trials of the anti-HIV drug tenofovir in Cameroon and Cambodia say they've learned their lesson from the debacle in 2004 and 2005, when activist groups questioned the quality of medical care impoverished study participants would receive if they suffered side effects or the became infected by HIV. Today, with at least seven U.S.-funded PrEP trials underway at a cost of $39.5 million, researchers are working with local advocates, who have traditionally been distrustful of Big Pharma, to push the studies forward.
"The whole prevention community really had a wake-up call," says Linda-Gail Bekker, an infectious disease researcher at the University of Cape Town’s Desmond Tutu HIV Center, who is running the South African study site for a new PrEP trial that will eventually involve at least 3,000 gay men in South Africa, Asia, South America and the U.S. The study, which is enrolling trial participants now, is being funded by the U.S. National Institutes of Health (NIH) and the Bill & Melinda Gates Foundation. Its first results are expected in 2010.
In August 2004, Cambodian Prime Minister Hun Sen stopped a trial of PrEP on prostitutes in his country under pressure from activists who said the study was exploiting vulnerable trial participants. Cameroon, which was to be part of a larger, three-country western Africa PrEP trial, shut the trial there down in early 2005 after questions were raised about the trial’s health care provisions for participants.
PrEP researchers now acknowledge they made a mistake by not involving local advocates from the start. After years of being told that antiretroviral drugs were toxic, the idea of using them in uninfected people seemed reckless to many. Local activists, along with their international supporters, believed the trials were being run by profit-hungry pharmaceutical companies who were coming to poor countries to do dangerous research that would later pad their own pockets and only end up benefiting people in the developed world.
In fact, the trials were being conducted by university and nonprofit researchers, and funded by the U.S. government and the Bill & Melinda Gates Foundation. Gilead Sciences, Inc., tenofovir's maker, provided the drugs for free but was otherwise not involved in the trial. And the drug's safety had already been proved in previous HIV treatment trials—many of them conducted in the U.S.
“I don’t think there was some wild, unethical conduct,” said Mitchell Warren, executive director of the AIDS Vaccine Advocacy Coalition, which has helped facilitate dialogue on PrEP issues. “But there was a little defensiveness and a lot that got lost in translation.”
ACT UP/Paris, which is part of the international AIDS awareness activist coalition and was involved in the Cameroon controversy, and the Treatment Action Campaign (TAC), South Africa's largest organization of people with AIDS, have been involved in new trials from their earliest stages. New guidelines have also been written setting standards for community involvement in prevention trials, which recommend, for example, that researchers hold meetings with communities prior to the beginning of new trials to address what health care will be provided to participants.
The renewed interest in PrEP comes after two high-profile trials of a vaccine candidate produced by Merck were stopped early in 2007. At least 2.7 million people around the world are HIV-positive, according to the United Nations. Public health experts believe an arsenal of effective prevention tools against HIV is needed to curb its spread, because not everyone will practice existing methods known to work, such as condom use, monogamy between uninfected partners, and abstinence. Trials of potential microbicides, a woman-controlled prevention method that would work similarly to spermicides and other topical birth control methods by blocking or killing HIV during sex, have also been disappointing so far and may not be practical for all women to use. PrEP would offer an alternative.
The trials are investigating whether a daily dose of one of two antiretroviral drugs—either tenofovir disoproxil fumarate (TDF), commercially known as Viread, or Truvada (TDF combined with emtricitabine) can protect people at high risk of HIV from becoming infected.
Antiretroviral drugs, which stop retroviruses like HIV from replicating, are used to treat HIV-positive people. In certain cases they are also employed as a prophylactic to prevent the transmission of the virus from a mother to her newborn or to reduce the chance that someone who has been exposed to the virus, such as through rape or a needle prick, becomes infected.
TDF and emtricitabine are being tested for use as PrEP because they are known to cause low levels of resistance and fewer side effects, and because they remain in the bloodstream for a long time.
Results from studies in gay American men and injecting drug users in Thailand may be available next year. But the first full study testing whether PrEP stops the transmission of HIV through heterosexual sex (the main driver of the epidemic in Africa), which is being carried out in Botswana with plans to expand into South Africa, is not expected to yield results until 2011. And the three biggest trials, involving a total of 12,000 people across Africa, will not be complete until at least 2012.
Researchers are already looking forward to the potential issues that will arise if PrEP is found to be effective, such as whether the use of antiretroviral drugs as preventives will lead to increased resistance or how it could affect the future treatment options of people who later become infected.
If it does work, the public health community will also have to grapple with the tough question of when and how to use PrEP as well as how to balance the need to keep drug-resistant strains of HIV from thriving in the population while saving lives in the short term.
"PrEP has to be implemented as part of a formal program with guidelines and a funding stream. We have to start planning for that," says Lynn Paxton, a PrEP researcher at the U.S. Centers for Disease Control and Prevention.