Questions on Tactics to Prevent HIV [PrEP]

PrEP is short for PreExposure Prophylaxis and may be part of comprehensive HIV prevention services in which HIV negative people who are at high risk, take antiretroviral medication daily to try to lower their chances of becoming infected with HIV if they are exposed to it.

To date, PrEP has been shown to be effective in men who have sex with men (MSM) and heterosexual men and women.

The effectiveness of biomedical approaches to prevent HIV infection was a key theme of the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2011), held July 17-20, 2011, in Rome.

Among the major studies presented, Robert Grant from the Gladstone Institute of the University of California at San Francisco described final data from the iPrEx trial, which showed that pre-exposure prophylaxis (PrEP) using tenofovir/emtricitabine (Truvada) reduced new HIV infections by 42% overall, and by more than 90% among people who demonstrated good adherence.

The US Centers for Disease Control and Prevention (CDC) has recommended testing patients for HIV before they begin taking the drugs and again at two- to three-month intervals. The FDA could also require drug companies to set up a registry of patients taking the drugs and ask that patients provide proof of a negative HIV test before getting their medications refilled.

Deciding who to treat with PrEP could also be a challenge. The CDC reported on 3 August that rates of new HIV infection in the United States are stable overall, but are rising in young men who have sex with men. Yet if these men aren’t using the prevention measures already available, there’s little reason to think doctors will have an easier time convincing them to take a daily pill.

The question of who should get PrEP is more difficult in many developing nations, which cannot even afford to treat everyone currently infected with HIV. PrEP would cost hundreds of dollars per patient per year in developing countries, and many thousands of dollars in rich nations.

Even with regimens costing less than £1 per day, developing nations will be forced to choose between providing more treatment for those who already need it and potentially preventing new infections. Myron Cohen, a doctor and researcher at the University of North Carolina at Chapel Hill, points out that half of young girls in some parts of sub-Saharan Africa become infected with HIV by their mid-twenties. “That’s unacceptable, so I see that as one potential population for PrEP,” says Cohen.

Although the cost-effectiveness of PrEP increases in higher-risk populations, it will be politically dicey for financially strapped countries to justify distributing drugs to those in these groups. “Even if you thought the best use of the pills would be for sex workers, it would be very difficult to take a limited supply of pills and give them to high-risk populations at the expense of people who are dying of infection,” says Cohen.

In the past year, three landmark clinical trials have shown that a daily dose of the antiretroviral medication Truvada can protect individuals from infection with H.I.V.— a significant discovery, given the failure so far of all efforts to develop a vaccine against the virus.

Now researchers in San Francisco and Miami are planning to test this prevention strategy, called pre-exposure prophylaxis, or PrEP, in a pilot study supported by the National Institutes of Health. The researchers will soon recruit up to 500 uninfected men who have sex with men, especially those considered to be at greatest risk of infection, such as younger gay men and, in particular, African-Americans.

The men will be asked to take Truvada daily, and the researchers will monitor their compliance with the regimen, their sexual behavior and their health status. Already, though, the prospect of antiretroviral drugs’ being used for prevention as well as treatment is raising complex questions for researchers and advocates.

Will healthy uninfected people consistently take an expensive and powerful drug that can cause a range of side effects? Is it fair to provide medications to H.I.V.-negative individuals when so many of those already infected do not have access? Will those receiving the drug be more likely to engage in risky sex because they believe they are protected — even if they do not always take it as prescribed?

The issues are more than academic: According to anecdotal reports, some doctors are already prescribing the medications to some H.I.V.-negative patients, said Dr. Kenneth Mayer, a chairman of the Fenway Institute, a research and advocacy center for  gay, lesbian, bisexual and transgender health in Boston, who has been involved in research into PrEP.

“I think that’s going to increase, but it’s very incremental,” said Dr. Mayer, who believes PrEP is an important new weapon in the H.I.V. prevention arsenal. “People have a lot of questions.”

AIDS advocates have generally expressed optimism that the strategy, if applied carefully, could help reduce the approximately 50,000 new H.I.V. infections that occur annually in the United States. But one major provider of services to people with H.I.V., the AIDS Healthcare Foundation in Los Angeles, has initiated a media and ad campaign raising serious concerns.

The foundation’s president, Michael Weinstein, noted that participants in the first round of PrEP research were counseled extensively that not following the protocol could reduce any protective effect, and yet many still failed to take their pills as prescribed. Adherence to the regimen is likely to be even worse under real-world conditions, he said.

“We deal with tens of thousands of patients here who are positive, and a high percentage of them have adherence issues,” said Mr. Weinstein. “So the idea that young gay men who don’t have this disease are going to take this routinely is highly questionable.”

Mr. Weinstein is particularly concerned that the Food and Drug Administration could soon approve Truvada for use in H.I.V. prevention as well as treatment, which would undoubtedly lead to greater use of the drug. Gilead Sciences, the company that makes the drug, has said it is likely to file such an application with the F.D.A. early next year.

Once the F.D.A. approves a drug for any use, doctors can legally prescribe it “off-label” for other purposes. Drug companies, however, are allowed to promote their products only for indications specifically approved by the agency.

In one of the three earlier clinical trials, among men who have sex with men, PrEP reduced new infections by 44 percent over all. Among men who adhered closely to the prescribed daily regimen, however, protection against infection was greater than 90 percent.

Some researchers worry that sexually active individuals who only sporadically adhere to the PrEP regimen may not realize that they are still at risk for infection; at the same time, feeling “protected,” they may be less vigilant about practicing safe sex and getting regular H.I.V. testing.

And inconsistent use of medications among those who do not realize they are infected could encourage new drug-resistant forms of H.I.V., some experts fear.

Dr. Grant Colfax, director of H.I.V. prevention and research at the San Francisco Department of Public Health, said he hopes that the new research will yield important information about how best to use the emerging strategy.

“The question is, will people be able to maintain the regimen?” said Dr. Colfax, whose agency is a major partner in the study. “What are the risks and benefits outside of a randomized clinical trial? Will they want to take the pill, will there be changes in their risky behavior, will they come back to get H.I.V. testing on a quarterly basis?”

Dr. Howard Jaffe, chairman and president of the Gilead Foundation, acknowledged that adherence was a problem in earlier studies. But he said that participants in the upcoming research, unlike those in the trials, will all know that they are receiving the actual drug, not a placebo, and that the drug can prevent H.I.V. infection if taken as directed. That critical new information, he said, could help motivate them to stick to the prescribed regimen.

The three recent PrEP trials focused on different populations: heterosexual couples in East Africa in which one person was H.I.V.-positive and the other was not; sexually active young adults in Botswana; and men who have sex with men in the United States and five other countries. (A fourth trial, among African women, was stopped early because PrEP was not found to be working.)

The trial involving the East African couples reported that the infection rate was 73 percent lower in the group taking Truvada; among the group in Botswana, there was a 63-percent drop.

“Now that it’s been proven to be effective, the discussion is a much different discussion than when you’re enrolling people for a placebo-controlled trial,” Dr. Jaffe of the Gilead Foundation said.

Truvada combines two antiretroviral drugs, Viread and Emtriva, both also made by Gilead. Besides the upcoming study in the United States, results from additional research into the use of Truvada as H.I.V. prevention are expected over the next few years.

The drug currently costs thousands of dollars a year. A recent editorial in the medical journal Lancet Infectious Diseases raised ethical concerns about the new approach, noting that many people with H.I.V. do not have access to the lifesaving medications.

“How can these drugs be provided as prevention to those high-risk populations, while people with the disease in need of treatment continue to go without?” said the editorial.

In response, proponents of PrEP say that it would be unethical not to explore the new approach, given its potential to reduce infection rates, especially among vulnerable populations whose members have often found it difficult to consistently practice safe sex.

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