Great results from iPrEx study add to trifecta of good news on prevention

Truvada PrEP provided protection in MSM+transgender

Close on the heels of the first positive findings reported in microbicides and vaccine research ventures, the iPrEx study has shown that a pre-exposure prophylaxis (PrEP) combination drug demonstrates 44% additional protection from HIV infection.

"We were really heartened to see these findings," says Albert Liu, MD, MPH, director of HIV prevention intervention studies at the HIV research section of the San Francisco Department of Public Health in California. Liu is one of the investigators involved in the study of the antiretroviral combination of tenofovir and emtricitabine (Truvada®) as a PrEP treatment. Liu also is an assistant clinical professor at the University of California at San Francisco (UCSF).

The iPrEx study enrolled 2,499 HIV-sero-negative men or transgender women who have sex with men. They received a combination of emtricitabine and tenofovir or placebo once daily, and they were followed for a median of 1.2 years.1

"IPrEx is the first study to show that an oral pill can be used to prevent HIV infection when given as part of a comprehensive prevention package," Liu says. "It's also the first biomedical intervention to show efficacy in men who have sex with men (MSM), so we think this is a really great advance for HIV prevention."

HIV clinicians should view PrEP as part of a comprehensive prevention strategy that might include microbicides and, perhaps, an HIV vaccine, suggests Kenneth H. Mayer, MD, infectious disease physician at Miriam Hospital and professor of medicine and community health at Brown University in Providence, RI. Mayer, who also was an investigator on the iPrEx study, is the medical research director at Fenway Health in Boston, MA.

"Ultimately, we still want a vaccine," Mayer says.

Developing an effective HIV vaccine is critically important in HIV prevention, Liu says.

"In the long term, a vaccine likely will be the best strategy at eliminating HIV infections worldwide," he adds. "We need as many prevention strategies as possible to drive down infection rates, so we remain committed to exploring multiple strategies, including vaccines, PrEP, microbicides, and behavioral interventions."

Achilles heel is adherence

Vaccine researchers reported in September, 2009, that a combination of two vaccines that previously had failed in clinical trials was successful over three years with 31.2% of people receiving the vaccination in a phase III Thailand clinical trial. The combination vaccine included Sanofi Pasteur's Alvac and Global Solutions for Infectious Diseases' AIDSVAX. The Thailand trial enrolled 16,000 people. The vaccine provided protection against HIV in about half of the study volunteers during the first year, but lessened over time.

Then, in July, 2010, researchers announced that the CAPRISA 004 microbicide trial using tenofovir gel vaginally resulted in 39% fewer HIV infections among women who used tenofovir gel before and after sex than those who used placebo. The microbicide's effectiveness was higher for women who had 80% or greater adherence.

"What is exciting is that both the microbicides and PrEP approaches were successful," Mayer says.

However, they are not simple interventions, Mayer notes.

"In both studies the Achilles heel is adherence," Mayer says. "Those who were adherent had much higher levels of protection."

The key for clinicians will be to identify people who will most benefit from the strategy and to help them with adherence.

The tenofovir/emtricitabine PrEP intervention has the advantage of being immediately available.

"I think it has more immediate public health implications because these are medications prescribable right now," Mayer says. "Whereas, the gel is not yet available, and to make the gel accessible to women will take a scaling-up effort that will take time."

And, vaccine research will continue as investigators seek an approach with greater protection than the initial success story reported.

The iPrEx study's efficacy findings held up in a variety of ways as investigators looked at study volunteers' ages, level of education, and other demographic data, Liu notes.

The study started in Peru and Ecuador in South America and was expanded to San Francisco, CA, and Boston, MA, Brazil, Thailand, and South Africa, Liu says.

"We looked at the results in a variety of different ways, and it seems that PrEP appears to be effective for a variety of different groups."

Whether any PrEP or microbicides prevention strategy will prove to be a successful way to reduce new infection rates in a population will depend on how successfully public health officials convince people to adhere to the treatment.

"HIV prevention will succeed or fail based upon the ability of people to adhere to these strategies for the duration of time they're at risk of being infected," says David Bangsberg, MD, MPH, director of the Massachusetts General Hospital Center for Global Health and associate professor at Harvard Medical School in Cambridge, MA.

"We have some really promising findings with CAPRISA and the iPrEx study, which show antiretroviral prevention is possible, and that's exciting," he adds. "But we still have more questions than answers, and sustained adherence to these approaches is one of the top questions that we have yet to answer."

Investigators measured adherence in various ways and found that people who had higher rates of pill taking had higher rates of protection, Liu says.

"We did find that by self-report pill-taking was quite high," he says.

But when researchers tested a small amount of blood samples they found that only 9% of people who became HIV infected had detectable drug versus 51% having detectable drug among those who remained HIV negative, he explains.

"So that shows that people who had detectable drug were more likely to be protected from HIV," Liu adds.

Important variables

Side effects, cost, and length of time are two important variables in PrEP adherence.

"Overall, the study found Truvada appeared to be safe and well tolerated," Liu says. "The rates of serious adverse events or side effects were similar between the two arms of the study of Truvada and the placebo group, but we did see that nausea was slightly more common in the group that received Truvada."

The nausea was resolved within one to three months in most participants, he adds.

"We actually have this initial start-up syndrome, often seen in HIV-positive people who are starting to take medications," Liu says. "So providing support to participants and managing these transient side effects will be important in helping people take the pill more consistently."

There are a number of possible scenarios regarding how long people would need to take PrEP in order to achieve personal protection from HIV infection, as well as for the prevention approach to make an impact on HIV prevalence in any particular population.

"I think it's not clear that men will need to take this life-long," Liu says. "People move in and out of periods of risk, and if PrEP is combined with other prevention strategies then it might help people as they are adopting other behavioral change strategies."

It could be that PrEP helps keep a generation of at-risk people healthy as they wait for an HIV vaccine. Also, PrEP is only necessary for people who are engaging in risky behaviors. For some people, their risky behaviors might be limited to a certain period of years. After this period ends, they might be safe in discontinuing PrEP.

"We'll need to do additional studies to see how long people will need to take the drug and how long the protective benefits will last and whether other dosing regimens are safe and effective," Liu says.

Investigators studied daily dosing in the iPrEx study, but it's possible less frequent dosing would prove effective in preventing HIV infection as well.

"The important point is that people who decide to use PrEP should do it under medical supervision, frequent HIV testing, and monitoring for side effects," Liu says. "Intermittent use is not recommended because we don't have data on that."

Cost also is a factor since ARTs are very expensive and it's unclear who would pay for a PrEP approach.

In the United States, daily Truvada treatment can cost $10,000 a year. In low-resource countries where generic drugs have been approved, the treatment can cost $500 to $600 per year, Mayer says.

While it's plausible that some people at risk for HIV infection will try to take Truvada on their own, this would be a mistake since this is a biomedical intervention that requires physician supervision, Mayer notes.

For instance, Truvada use could result in an elevation of creatinine, indicating kidney issues. This was found in 1% of iPrEx study participants on placebo and 2% on Truvada, he says.

"It went away when the medication was stopped, and it didn't come back, so it was a transient and reversible kidney problem," Mayer adds. "But the important point is that taking a pill is different from using a condom or getting a vaccine, and so people should be monitored by professionals."

From an HIV clinician's perspective, media coverage of the study's findings likely will mean some partners of HIV patients will inquire about using PrEP as a way to prevent HIV infection.

For example, some HIV-discordant couples are intent on conceiving a child, and it would be unfortunate to not make PrEP available to sero-negative women who want to have a child with their HIV-positive partner, Mayer says.

"I would handle these on a case-by-case basis," Mayer suggests. "I certainly would consider making PrEP available to someone where I understood their pattern of risk and had a sense they'd be adherent to medication and knew what they were getting themselves into."

However, there's a need for the Centers for Disease Control and Prevention (CDC) to come up with guidance for providers and education on PrEP and HIV treatment for non-HIV physicians.

"Most providers who are going to take care of these clients are not HIV specialists, so a lot of education needs to go on to scale this up for wider public health intervention," Mayer says.

The initial study found that risk behavior declined as part of the trial, which had included a comprehensive prevention package of HIV testing, counseling, free condoms and lubricants, and regular treatment for sexually-transmitted diseases, Liu notes.

IPrEx investigators are continuing study of the PrEP with plans to offer participants a rollover protocol. If enrollment is successful, researchers will monitor participants' behavior to see if they continue to maintain a lower level of risk or if their risky behaviors increase, Mayer says.

"The first step was to demonstrate oral PrEP would prevent HIV, which we've done in this study," Liu says. "Now we'll be talking with community members, health care providers, and regulatory agencies to figure out how this might best be used, and this also will inform how PrEP might be paid for."

Reference

  1. Grant RM, Larna JR, Anderson PI, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. NEJM. 2010;Nov. 23:1-11 [epub ahead of print].