For the first time, a study has demonstrated that an anti-HIV pill can protect uninfected people from contracting the AIDS virus through sex. The much-anticipated results show that an already approved drug can cut transmission rates nearly in half, which could provide a powerful new tool to curb the AIDS epidemic. "It's a game changer," says one of the dozens of clinicians who participated in the study, Kenneth Mayer of Fenway Health in Boston. But experts say the success also raises a dizzying array of complicated issues about human behavior, resources, risk, and public health.
The strategy, called pre-exposure prophylaxis, or PrEP, was tested in 2499 HIV uninfected men and transgender women who have sex with men. Half of the group received a placebo. In the treatment group, transmission dropped by 44%, despite the fact that many study participants in the trial frequently skipped doses. When the researchers analyzed a small subset of people who received the treatment and not the placebo, they found an astonishing 92% protection rate in people who had detectable levels of the drug in their blood—in other words, in those who took the drug regularly.
Nearly 30 large-scale HIV prevention studies have failed, making these results that much more heartening. The new study, called the Pre-Exposure Prophylaxis Initiative, or iPrEx, cost $43.6 million and was conducted in six countries between July 2007 and December 2009. "The iPrEx study results are extremely important and providing strong evidence that PrEP can reduce HIV acquisition among a segment of society that is disproportionately affected by HIV/AIDS," said Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases (NIAID) at a teleconference for the press held yesterday. NIAID provided two-thirds of the funding for the study, and the Bill & Melinda Gates Foundation covered the other third.
As reported online today in The New England Journal of Medicine, the study recruited people at extremely high risk of becoming infected with HIV: Participants reported an average of 18 sexual partners in the past 12 weeks, and about 60% said they had unprotected receptive anal intercourse in that time frame. Everyone received regular counseling about how to reduce their risks of becoming infected as well as condoms and treatment for other sexually transmitted infections. At the end of the trial, 36 out of 1251 people who received a pill that contained a combination of two anti-HIV drugs, tenofovir and emtricatbine (co-formulated as Truvada and made by Gilead Sciences of Foster City, California), became infected. Of the 1248 people who received a placebo pill, 64 became infected.
Robert Grant, a virologist at the University of California, San Francisco (UCSF), headed the study, which took place in Peru, Ecuador, Brazil, the United States, Thailand, and South Africa. "I was overjoyed that we showed clear evidence that oral Truvada added protection to [men who have sex with men] receiving comprehensive prevention services," says Grant. "It's a robust result." Although some researchers feared drug resistance might surface or that people might increase their rates of risky behavior because they believed the drug provided protection, neither problem was seen in the study, he says.
But Grant emphasizes that the findings only apply to men and transgender women who have sex with men; other studies are underway to evaluate PrEP in heterosexual men and women and injecting drug users.
Several AIDS researchers not involved in the study told Science that they are impressed with its thoroughness and statistically significant results. But they worry how well the strategy will work in the real world. Although participants reported taking the drugs about 90% of the time, the researchers doubt this was accurate because of studies of drug levels in blood. "The questions that remain are more behavioral than biological," says Robert Schooley, a virologist at the University of California at San Diego (UCSD). Grant of UCSF suggests that adherence to the regimen may have been low because people did not know whether the drug worked or whether they were receiving placebo. Truvada did not cause any serious side effects, but many people complained of nausea and headaches, which also may have affected adherence. Grant is planning a follow-up study to explore these and other questions.
The results come on the heels of a widely celebrated positive finding from the so-called CAPRISA 004 trial in South African women, which this summer reported that a vaginal gel laced with tenofovir reduced infection by 39%. "This plus CAPRISA means we've crossed the Rubicon," says Mayer, who ran one of the two iPrEx sites in the United States. "Antiviral chemoprevention works, no question."
One major difference between the iPrEx and CAPRISA trials is that the gel is an experimental product and is not on the market. Truvada, in contrast, is a popular anti-HIV treatment, and can be prescribed for "off-label use" by any physician. But it remains unclear whether insurance companies will pay for this off-label use; costs run from $11 per month for a generic version to nearly $1000 per month for product made by Gilead.
Gilead says it wants to have "frank" talks with the U.S. Food and Drug Administration and other stakeholders before it decides to seek licensure for Truvada as a preventive. "We'll have, I imagine, a very interesting discussion about the potential risks and benefits associated with this kind of a modality, and I think that will govern what we choose to do," says Howard Jaffe, president of the Gilead Foundation, a nonprofit started by the company to help poor communities combat HIV and hepatitis B and C.
This new prevention success also raises fundamental questions about how to best spend money to thwart the AIDS epidemic. "For a country that has not yet reached the level of care in terms of providing antiretovirals to save people's lives, I think it's going to be quite a while before we'd start using oral antiretrovirals for prevention," says Salim Abdool Karim, an epidemiologist a the University of KwaZulu-Natal in Durban, South Africa, who co-ran the CAPRISA study.
Another thorny ethical issue is whether vaccine and other prevention studies with men who have sex with men now should use Truvada as the placebo, which clearly offers more benefit than the standard dummy preparation. Fauci says NIAID will now examine this question in every prevention study they have planned or underway.
UCSD's Schooley, echoing many of his colleagues, cautions that no single preventive by itself can stop HIV, which infects people by different routes under a wide variety of conditions. "People looking for a single intervention to impact the epidemic are the same ones who want a single battle to end the war in Afghanistan," says Schooley. "But it's quite clear the most potent tools we have right now are drugs."