Truvada trials hold promise for new HIV prevention strategy

Once-a-day might keep HIV away

Researchers and public health officials say they hope ongoing research will eventually show efficacy with a new prevention strategy that involves giving uninfected people at risk for HIV a simple combination reverse transcriptase inhibitor (RTI) therapy. But it’s too early in the research to draw conclusions or for individuals to attempt the strategy, says Lynn Paxton, MD, MPH, team leader for the antiretroviral prophylaxis and microbicides team at the Centers for Disease Control and Prevention (CDC).

The good news is that there are ongoing trials in Botswana to study the use of tenofovir (Viread) and emtricitabine (Emtriva) in a combination drug called Truvada for the prevention of HIV infection among a population of people, ages 18 to 29 years, she adds.

"Animal data suggest tenofovir may be a potentially promising strategy for pre-exposure prophylaxis," 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 San Francisco.

Called pre-exposure prophylaxis (PrEP), the combination of antiretroviral drugs could one day serve as a daily prophylactic for people at high risk for HIV infection. The idea is for people to take antiretroviral medicine before they have a potential exposure.

CDC literature notes that a daily oral preventive of tenofovir or Truvada could help meet the need for a female-controlled prevention method for women worldwide who are unable to negotiate condom use.

This approach also might appeal to at-risk men and women who would like an additional safety net. But the idea is that it would be taken daily by uninfected adults and not in response to any particular HIV exposure.

"So PrEP is not a morning-after pill," says Liu. The CDC already has issued guidelines for post-exposure prophylaxis (PEP), he points out. "After a high risk exposure, under PEP, people take a combination of antiretroviral drugs — two or three drugs — for 28 days," Liu explains.

Any hope for public health success with PrEP shouldn’t turn into action on the part of clinicians or their patients until the data are in, Paxton says.

Widespread national media reports in March 2006 touted the drug combination’s potential in combating HIV, but the important research has a long way to go before the strategy can be employed.

"What we’ve been worried about is we’re afraid the news of this strategy is coming out a little too positive with this bent that it works," Paxton says.

"Obviously, we think there’s merit to this or we wouldn’t be studying it, and there’s a strong background in the literature," Paxton says. "We’re just very worried because a lot of people jump on the newspaper article headline and go ahead with using drugs."

CDC officials are worried that people at high risk for HIV infection will self medicate with Truvada and stop using condoms and other proven prevention strategies, Paxton says.

Although animal data showed promise, it was limited in that only six monkeys were given the tenofovir/emtricitabine combination, Liu notes. "And there are significant limitations in extrapolating data from monkeys into what will happen in humans. So while we feel that the data are encouraging for the field, it’s still very important that we gather both safety and efficacy data in people."

It’s the CDC’s role to explore all promising interventions, and the Truvada PrEP is one possibility, but that’s all it is at this time, Paxton says. "We find it worrisome that people might be using this drug, so we want to get the word out that people should not be using [ART] under the assumption that it will protect them because we simply do not know that yet," Paxton says.

Anecdotal evidence suggests that some people are using PrEP either through finding antiretroviral drugs on their own or by convincing physicians to prescribe them the medication, Liu says. "We don’t know the extent to how this is happening, so we’ve launched a survey of 400 men who have sex with men in the San Francisco bay area," Liu says. "We’re asking whether they’ve heard about PrEP, whether they’ve heard of people using it, or whether they’ve used it themselves in an unmonitored fashion."

Liu is involved in a CDC-sponsored trial involving giving tenofovir to HIV-negative men. It’s called Project T, and trial locations are in San Francisco and Atlanta. The study was designed with tenofovir because many animal studies have looked at PrEP, using tenofovir, and because it is a once-a-day pill that has a relatively favorable safety profile and resistance profile, Liu explains.

"I believe that looking at daily tenofovir or other HIV medications is one of several promising new HIV prevention strategies, and it’s worth exploring," Liu says.

In San Francisco, there are 15 to 20 new HIV infections per week, and there are 14,000 new infections per day worldwide, Liu notes. "While we know behavior change remains the cornerstone of all prevention, we need a range of prevention strategies to further drive down infections, because no one size fits all," Liu says.

"Our hope is that PrEP when combined with condoms and other proven prevention strategies can further reduce infections around the world, but we need to first look at the safety of this approach," Liu adds.

"We’re studying 400 healthy, HIV-negative gay and bisexual men, first looking at the biological safety of tenofovir in this population, including looking at side effects and tolerability of this medication," Liu says. "Secondly, we’re looking at the behavioral safety of taking an HIV pill on a daily basis, and specifically, we’re looking at whether men, as a result of taking a daily pill, might change or increase or decrease risk behavior."

The double-blinded, placebo-controlled trial has a unique design in that there’s an immediate tenofovir group and a delayed tenofovir group, along with two placebo arms. Two arms to the study begin taking a pill at the enrollment visit, and then two arms wait nine months before they start taking the pills, Liu says.

"So they’re still in the study and come in for a visit, but they don’t take the pill until nine months later," Liu says. "What this design enables us to study is the direct result of taking the pill on risk behavior."

Investigators will see if there are any changes in risk behavior, and they’ll look at the issue of antiretroviral adherence among a healthy population, Liu adds. "We’ll see whether people experience any types of social harms while being in the clinical trials," Liu says.

The study’s extensive informed consent process involves describing the nature of the study and reinforcing the fact that they might receive a placebo and even if they receive the drug, there’s no evidence that tenofovir can work to prevent HIV. The participants are given risk reduction counseling, free condoms and lubricants, and they receive a test for HIV at each of the three-month visits, Liu says.

More than 100 volunteers, ages 18 to 60, have been enrolled in the two-year trial in San Francisco, and altruism is listed as their main reason for participating, Liu says.

"They want to contribute to HIV prevention in some way," Liu says. "This is one way they can give back to their community, and that’s the most common reason we hear for why they enroll."

The study results will probably be available in late 2008 or 2009, Liu says.

Meantime, the CDC has changed one tenofovir study to include the combination therapy of Truvada. The Botswana study had begun as a tenofovir study, but was retooled as a phase III study to look at Truvada, Paxton says.

"It may be five more months to get all the required protocol approvals from IRBs and to get the drug imported into Botswana," Paxton says.

When that work is complete, the study will begin to enroll 1,200 young adults, who are within the age group of the highest incidence of HIV infection, Paxton says.

It probably will take about 15 months to fully enroll participants, and then all participants will be followed until the last person enrolled has been followed for 12 months, Paxton explains.

Since the phase III study was built upon extensive work involving the study of tenofovir alone, phase II preliminary data are available, and this information contains both safety and efficacy results, Paxton says.

"What we originally planned was a combined phase II/III study, but after the first 200 persons were enrolled, we put the study on hold, looked at safety data to make sure there was nothing untoward going on, and we rolled it over into a phase III trial, Paxton says.

Safety data will continue to be collected, and ongoing data will be reviewed by a data safety monitoring board, Paxton notes.

Some literature reports have discussed possibly lowering the viral set point among people who get early antiretroviral therapy, so it’s possible that these people who had ART during the early days of their infection might end up with an attenuated course of infection, Paxton says.

It’s a theoretical idea, but investigators will watch for it, she adds. "If a person becomes HIV infected during the trial they will go into the seroconverter protocol where — at specified intervals — they will have intensive follow-up, getting CD4 cell counts checked, viral resistance profile followed," Paxton explains. "And we’ll see whether there are any differences in their HIV course that may possibly be due to having been exposed to an antiretroviral early on."

Researchers don’t expect very many seroconverters during the trial, and even for those who do seroconvert, they won’t be on the drugs very long, Paxton says.

"They’re tested for HIV every month, and as soon as they turn positive they are taken off the drugs, so the longest amount of time they would be Truvada would be a month," Paxton says.

The seroconverters will be provided with intensive counseling and follow-up care, but they won’t meet the criteria for ART until their CD4 cell count lowers to below the 200 to 250 range, Paxton says.

Trial participants who do not seroconvert will remain on the study drug until the last person enrolled has been on the drug for 12 months, Paxton says.

The costs of Truvada, which was developed by Gilead Sciences, are provided at cost for the trial, Paxton says. "It costs about 57 cents per pill for tenofovir and 87 cents per pill for Truvada," she says.

Even if Truvada as PrEP proves effective in clinical trials, it will always be promoted in conjunction with condoms, abstinence, knowing your partner’s status, and all the other things that public health officials know works, Paxton says.

"And studying PrEP doesn’t prevent us from exploring microbicides, vaccines, and other things, as well," she adds. "We do think this could show promise, but we won’t know if it works until the trials are completed."