Preexposure Chemoprophylaxis Reduces HIV Infections in Gay and Bisexual Men

November 23, 2010

November 23, 2010 — A combination of oral antiretroviral therapy for preexposure chemoprophylaxis (PrEP) against HIV demonstrates moderate effectiveness in a major, multicontinent clinical trial that heralds a new — and expensive — means of curbing the spread of AIDS.

The study, called iPrEx (for the Spanish name for the study, which translates to Prexposure Prophylaxis Initiative), involved 2499 men and transgender women (1% of the group) who have sex with men. All tested HIV seronegative at baseline but reported engaging in sexual practices that put them at high risk for infection. Half of the subjects received a placebo and the other half received a combination pill of 2 antiretroviral drugs — emtricitabine, 200 mg, and tenofovir disoproxil fumarate, 300 mg (Truvada; Gilead Sciences), which is currently approved by the US Food and Drug Administration for treatment of HIV infection. Both cohorts in the study, who were followed up for a median of 1.2 years, also received HIV education, testing, and condoms.

As a result of the iPrEx study findings, experts are expecting an increase in off-label prescription of emtricitabine-tenofovir for HIV-negative men who want extra protection. In addition, experts are advising such individuals that they should still use condoms and take other precautions in addition to antiretrovirals.

"PrEP is best conceived as a back-up," said Robert Grant, MD, lead study author of an article published online today in the New England Journal of Medicine thatreports the study findings.

The HIV infection rate of 2.88% in the treatment group was 44% lower than the infection rate of 5.13% in the placebo group. Although the additional level of protection offered by emtricitabine-tenofovir was less than the study authors hoped for, they said the risk for infection decreased by more than 70% for individuals who took their pills on 90% or more of the days in the study. Temporary adverse effects, such as nausea, and the knowledge that they were given either a placebo or an unproven medication may have explained why some participants did not take their medicine faithfully, or at all.

Mitchell Warren, executive director of AVAC, an international organization that promotes HIV prevention, called the 44% reduction in HIV risk "modest" and needing improvement but nevertheless "thrilling."

"This is a game-changing trial result," Mr. Warren told Medscape Medical News. "What comes next is how we motivate people for pill-taking behavior."

Paul Sax, MD, an associate professor at Harvard Medical School and clinical director of the HIV Program in the Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, called iPrEx "a landmark study."

"We've been waiting some time to find out whether PrEP using oral medications would work," said Dr. Sax. "It seems to, although the efficacy turned out to be a bit lower than some had predicted."

The $43.6 million study was conducted in 11 sites in 6 countries — the United States, South Africa, Thailand, Peru, Ecuador, and Brazil. The National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health paid for roughly two-thirds of the cost, with the rest funded by The Bill & Melinda Gates Foundation. Gilead Sciences donated the emtricitabine-tenofovir and placebo agents.

Adherence Could Improve in Open-Label Study

The iPrEx is the second major study this year demonstrating the efficacy of PrEP. In July, South African researchers in the so-called CAPRISA 004 trial published an article in Science Express reporting how a vaginal gel containing tenofovir lowered the risk of HIV infection in sexually active women by 39%.

The iPrEx study has quickly garnered superlatives, but more research lies ahead before the "chemical condom" becomes accepted clinical practice.

"This is just one study," NIAID Director Anthony Fauci, MD, said at a press conference yesterday. The study results apply only to men who have sex with other men, Dr. Fauci explained, and the results cannot be extrapolated to other groups. Upcoming PrEP studies will look at the value of the treatment for women and heterosexual men.

In addition, Dr. Grant's research team will conduct a follow-up study in which all iPrEx subjects, including those in the placebo group, can receive emtricitabine-tenofovir for 18 months on an open-label basis. This study, scheduled to start in early 2011, will provide more information about the 'therapy's long-term effectiveness as well as the pill-taking behavior of participants and how to improve adherence. The hope is that adherence will increase because patients will know that they are taking a proven medication, which was not the case in the original iPrEx study published today.

Dr. Grant, a senior investigator at the J. David Gladstone Institutes at the University of California–San Francisco, told Medscape Medical News that getting gay men to take a daily pill to ward off HIV is a feasible goal.

"People use cholesterol-lowering medicine every day," said Dr. Grant. "Women use oral contraceptives every day."

One bonus of PrEP, Dr. Grant and coauthors write in their New England Journal of Medicine article, is that daily pill taking can remind patients to be more diligent about other safe-sex practices. During the iPrEx trial, for example, the percentage of participants in both the placebo and treatment groups who had sex without using a condom decreased from 60% at baseline to roughly 30%. Likewise, the number of their sexual partners decreased. These findings run counter to the fear that patients may drop other safe-sex practices because of a belief that all they need is PrEP.

CDC Issues Precautions for Off-Label PrEP

Experts expect the iPrEx study results will increase off-label use of emtricitabine-tenofovir as a preexposure prophylactic.

"There will be more people walking into the doctor's office and saying, 'Will you write me a prescription?' " Dr. Fauci said at yesterday's press conference.

By all accounts, a smattering of clinicians already prescribe emtricitabine-tenofovir as a form of PrEP.

"There are providers caring for high-risk patients who will do it on an intermittent basis when a patient is going on a trip or heading off for a series of parties," said Dr. Sax at Harvard Medical School. The iPrEx study, Dr. Sax told Medscape Medical News, will be "a license for a small number of providers to do this on a broader scale."

Anticipating heightened interest in off-label prescribing, the Centers for Disease Control and Prevention (CDC) today published "immediate cautions" for gay and bisexual men about using emtricitabine-tenofovir for PrEP. The agency stressed that PrEP is not a first-line defense against HIV and that gay and bisexual men should still use condoms consistently and correctly, reduce their number of sexual partners, get tested to know their HIV status, take their medication every day in collaboration with a healthcare professional , and start using it only if they are HIV negative. HIV-positive individuals starting a PrEP regimen run the risk of developing drug-resistant HIV, noted AVAC's Mitchell Warren.

Despite the precautions, Kevin Fenton, MD, director of the CDC's National Center for HIV/AIDS, Viral Hepatitis, STD & TB Prevention, described the findings about PrEP in a press release as "a major advance in HIV prevention research."

"Given the heavy burden among gay and bisexual men, a new tool with potential additive benefit is exciting and welcome news," Dr. Fenton said. The CDC, he noted, will publish interim guidance on PrEP in the coming weeks followed by formal US Public Health Service guidelines.

Kenneth Mayer, MD, an iPrEx site investigator in Boston, told Medscape Medical News that off-label prescribing makes sense if clinicians "have all their ducks lined up to monitor patients and make sure they're ready for this intervention." Mayer said he does not want to see gay and bisexual men buying emtricitabine-tenofovir on their own, perhaps online.

"The study is clear that this [PrEP] is a biomedical intervention," said Dr. Mayer. "It requires seeing a physician."

PrEP Can Cost Between $6000 and $14,000 Annually

In the United States at least, PrEP comes with a huge price tag. At the low end, emtricitabine-tenofovir can cost $17 per day, or $6154 per year, according to Mitchell Warren at AVAC. Dr. Fauci at the NIAID quotes $14,000 a year at the high end. "You'll see a wide range of prices," he said.

In developing countries, where generic versions of emtricitabine-tenofovir are available, the price can be as low as 40 cents a day, said Warren.

The high cost in the United States raises the question of whether private insurers and public programs such as Medicare and Medicaid eventually will foot the bill for PrEP.

"There will be a big public debate on this," Dr. Mayer said.

A detailed statement about authors' potential conflicts of interest can be found on the New England Journal of Medicine Web site. Commentator Paul Sax, MD, serves on a scientific advisory board for Gilead Sciences and has received grants from the company to conduct HIV clinical trials. Mitchell Warren, executive director of AVAC, said his organization has received support from the Bill & Melinda Gates Foundation.

N Engl J Med. Published online November 23, 2010.

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