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A Powerful and Perplexing New HIV Prevention Tool - PrEP Iprex Study Commentary by Jon Cohen Science Mag
  Jon Cohen
Science 3 December 2010:
Vol. 330 no. 6009 pp. 1298-1299
DOI: 10.1126/science.330.6009.1298
On 2 October, two dozen AIDS researchers gathered at the Eden Roc hotel on Millionaire's Row in Miami Beach, Florida, to learn whether an HIV prevention study they had just completed would become a millstone or a milestone for the field. In the six-country study, 1251 men and transgender women who have sex with men and were not infected with HIV at the study's start took an antiretroviral pill each day to see whether it could ward off infection with the virus. Another 1248 carefully matched participants took a placebo. Failure would cast a pall over the whole concept of oral pre-exposure prophylaxis (PrEP), which is now being tested in four other efficacy trials that involve 16,000 heterosexuals and injecting drug users (see table). Success would offer a powerful new option to dodge the virus-and might even slow HIV's spread in entire communities.
Unlike the many HIV prevention trials that have failed or had positive but barely significant results, the study-called the Pre-Exposure Prophylaxis Initiative (iPrEx)-showed unequivocally that the treated group had 44% fewer infections after an average of 1.2 years. More encouraging still, most of the failure seemed to occur among those who did not take the pill as directed: A small substudy found that risk of infection plummeted by 92% in people who had measurable drug levels in their blood. The researchers applauded and some even cried when they heard the bottom line. "It was very, very dramatic," says Robert Grant, a virologist with the J. David Gladstone Institutes at the University of California, San Francisco (UCSF), who headed the trial. "People were overjoyed to be among one of the few prevention trials to have shown a protective effect."
The New England Journal of Medicine published a full report of the iPrEx results on 23 November. The global response was ecstatic, prompting no less than U.S. President Barack Obama to issue a statement. "I am encouraged by this announcement of groundbreaking research on HIV prevention," said Obama. "While more work is needed, these kinds of studies could mark the beginning of a new era in HIV prevention." But the good news was tempered by a dizzying array of complicated issues about human behavior, ethics, resources, risk, and public health.
The iPrEx study, which cost $43.6 million and was conducted between July 2007 and December 2009, has one clear-cut message: A pill can dramatically lower the chances of transmission of HIV through receptive anal intercourse in men who have many partners-on average, 18 in the 12 weeks preceding the start of the trial-and frequently do not use condoms. The pill, Truvada, made by Gilead Sciences in Foster City, California, combines two anti-HIV drugs, tenofovir and emtricitabine. Truvada is already on the market and widely used as a treatment in AIDS drug cocktails, which means doctors can immediately start prescribing it "off-label" as a preventive.
Yet PrEP's role in public health remains anything but clear. "We don't think, 'Let's just sprinkle Truvada in the water supply and it solves the problem,'" says Kenneth Mayer, who headed an iPrEx study at Fenway Health in Boston, one of two U.S. sites. (Nine other trial sites were in Peru, Ecuador, South Africa, Brazil, and Thailand.) "It's an imperfect tool."
First, iPrEx shows only that the drug works in the specific high-risk population studied. Mayer and others stress that, as was done in the study, the drug should be offered as part of a prevention package that includes condom promotion and counseling. Experts worry that PrEP might lead people to take more risks than they would otherwise, offsetting the benefit of the pill, although this wasn't seen in the study.
PrEP could do harm, too, if it drove the evolution of Truvada-resistant HIV strains. When used as treatment, Truvada alone, versus in combination, is not strong enough to keep the virus in check. Theoretically, if people did not know they were already HIV-infected and took Truvada, the virus could mutate around the drug. An increase in Truvada-resistant strains, which are already circulating at low levels, could undermine both treatment and PrEP. Again, such drug resistance did not surface in iPrEx, but the researchers were rigorous in their efforts to exclude HIV-infected people and tested participants for new infections every 4 weeks.
For policymakers, the PrEP results raise difficult ethical and practical questions. Funding for HIV/AIDS is already insufficient: Ten million infected people who need treatment currently have no access to drugs. "I think it's going to be quite a while before we'd start using oral antiretrovirals for prevention," says epidemiologist Salim Abdool Karim of the University of KwaZulu-Natal in Durban, South Africa, which has more infected people than any country.
In wealthy countries, no one knows whether insurance companies will cover the use of Truvada as a preventive, and there are no guidelines for prescribing PrEP, although in the next few weeks, the U.S. Centers for Disease Control and Prevention says it will publish interim guidance.
Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Diseases (NIAID), which paid for two-thirds of iPrEx (the Bill and Melinda Gates Foundation picked up the balance), says Truvada's success as PrEP could have far-reaching impact on other HIV prevention studies. Ethical principles demand that researchers minimize risk for people who participate in studies, which means offering known effective interventions in the control arms of trials of vaccines or other PrEP compounds. Fauci says NIAID will now review "virtually every study that we have ongoing or planned" to assess whether trials that have placebo controls should instead offer Truvada. "It's going to create welcome work for everyone in HIV prevention science," says Jeremy Sugarman, a bioethicist at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. Sugarman, who chairs the ethics working group of the NIAID-funded HIV Prevention Trials Network, stresses that he's thrilled about the positive results. "If they make our ethical questions harder to answer, so be it."
UCSF's Grant contends that the iPrEx results create new opportunities that might mitigate some of the potential downsides. First, he wonders whether real-world adherence might be better than in a clinical trial setting, as people know that they are taking an active drug and that it works. Adherence also could differ in different populations. Epidemiologist Connie Celum of the University of Washington, Seattle, is currently heading a PrEP study in 4700 Kenyan and Ugandan heterosexual couples in which only one partner is known to be infected. The Partners PrEP Study carefully monitors drug adherence, and preliminary evidence suggests it is much higher than in iPrEx, which Celum suspects is because the uninfected long-term partners are highly motivated.
As for resource limitations sidelining PrEP, prophylactic use of Truvada could create more competition and lead to a reduction in the price of the drug, which ranges from $11 per month for a generic version sold in poor countries versus up to nearly $1000 per month for the retail Gilead product. And PrEP costs would fall if people do not need to take it every day: Truvada has a long half-life, and ongoing and future studies will assess whether it will work with less frequent dosing. CAPRISA 004, a PrEP trial with a vaginal microbicide that contained tenofovir, revealed in July that inserting the gel before and after sex alone cut transmission by 39%.
In keeping with a push to link prevention and treatment-treated people are likely less infectious-PrEP might encourage more people to undergo HIV tests. "No one is getting tested hoping to be positive and start treatment," says Grant. "People are hoping to be negative. This becomes a potent motivator to get a test."
Ultimately, PrEP's popularity may be tied to whether Gilead asks the U.S. Food and Drug Administration (FDA) for a label change to include its use as a preventive. Although not required, insurers will often reimburse only for indications approved by regulatory bodies, and many countries follow the lead of FDA. Gilead says it wants to have "frank" talks with FDA 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.
Confusing as PrEP's fate might seem, Fenway Health's Mayer stresses that the iPrEx results are an important milestone for the failure-weary HIV prevention field. "This plus CAPRISA means we've crossed the Rubicon," says Mayer. "Antiviral chemoprevention works, no question."
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