Prepping for the Future

The iPrEx study provides another dose of good news for the HIV prevention field, but implementation is likely to be challenging

By Regina McEnery and Kristen Jill Kresge

Should the HIV Prevention toolbox be viewed as half-full or half-empty?

Last November, on the cusp of World AIDS Day, researchers announced the results of a long-awaited efficacy trial known as iPrEx, which showed that daily administration of the antiretrovirals (ARVs) emtricitabine (FTC) and tenofovir (TDF) was 44% effective in preventing HIV infection among nearly 2,500 men and transgendered women who have sex with men at 11 clinical sites in the US, South Africa, Brazil, Thailand, Peru, and Ecuador. These were the first efficacy results for pre-exposure prophylaxis (PrEP)—the administration of ARVs prior to HIV exposure—and followed a string of good news in HIV prevention research.

Last July, microbicide researchers reported that vaginal application of a 1% gel formulation of TDF was 39% effective in blocking HIV infection, and in September 2009 researchers reported results from the RV144 trial in Thailand that showed a prime-boost vaccine regimen provided about 31% protection against HIV infection.

The iPrEx results, which were published in the New England Journal of Medicine (NEJM) in December, have accelerated discussions about the possible implementation of PrEP, pending results from other efficacy trials that are expected to be released in the coming months. A host of factors from clinical to financial that could stand in the way of making PrEP a viable weapon in the battle against HIV are now being considered.

One of the biggest obstacles to implementing PrEP as an HIV prevention strategy will be adherence—for the drug to work, individuals at risk of HIV infection must take it consistently. In the iPrEx trial, the odds of HIV infection were 12.9 times lower among individuals in the FTC-TDF group who had detectable drug levels in their blood, corresponding to a 92% reduction in risk of HIV infection, as compared to volunteers in the FTC-TDF group who did not have detectable levels of the drugs in their blood.

And as the iPrEx results suggest, self-reported adherence isn't always accurate. In the iPrEx study, volunteers were counseled on a monthly basis to adhere to the daily dosing regimen and at the monthly visits, investigators collected self-reported information on adherence as well as pill counts. Drug levels were also measured using a blood test designed to detect TDF 14 days or more after the last dose was taken. The drug levels indicated that self-reported adherence was not an accurate measure of how often volunteers had actually taken the pill.

Investigators in the iPrEx trial speculate that side effects, including nausea and unintended weight loss, associated with initiation of the study drugs may have contributed to the low adherence.

Monitoring side effects associated with PrEP will be another important consideration before this strategy is implemented. In the iPrEx study, investigators observed a trend toward more elevated serum levels of creatinine—a chemical waste product that can impair kidney function—in the FTC-TDF group compared to placebo recipients. Although this side effect only occurred in a small subset of volunteers and appeared to reverse upon discontinuation of the study drugs, Nelson Michael, director of the US Military HIV Research Program, who wrote an editorial in theNEJM on the iPrEx study, concluded that “this finding raises both safety and monitoring concerns regarding possible cumulative toxic effects associated with large-scale exposure to daily FTC-TDF therapy for an extended period.”

Another concern with PrEP is the potential for development of drug resistance if a person unknowingly becomes HIV infected and continues taking the drugs. In the iPrEx study, none of the volunteers in the FTC-TDF group or the placebo group who became HIV infected during the course of the trial developed drug resistance except for two volunteers who received FTC-TDF because their HIV infections were not detected at enrollment. Researchers speculate that the lack of any drug resistance may have been due in part to the overall low adherence to the study drugs.

Other substantial challenges will be how to pay for PrEP and who receives it. According to the most recent report from the Joint United Nations Programme on HIV/AIDS, an additional 1.2 million HIV-infected people in low- and middle-income countries received ARVs in 2009, bringing the total to 5.2 million, a 30% increase over 2008. Despite this progress only a third of HIV-infected individuals in need of ARVs are currently receiving them. One of the biggest conundrums should PrEP become part of the standard prevention package is whether ARVs should be given to uninfected individuals when so many HIV-infected individuals aren’t receiving treatment.

Before any implementation issues are addressed, Robert Grant, an associate professor of medicine at the Gladstone Institute of Virology and Immunology and the principal investigator of the iPrEx study, says researchers must still answer several clinical questions, including whether FTC-TDF is as effective in preventing HIV infection in other high-risk populations, such as injection drug users or women in areas of high HIV prevalence.

Grant says it will also be important to determine if daily dosing is needed, or whether intermittent dosing before and after sex, which is being studied in clinical trials, will be sufficient to protect against HIV infection. “I think the durability of how long people can use this is also an open question,” adds Grant. “The median duration of follow-up in the iPrEx trial was 1.2 years, the maximum was 2.8 years. It is conceivable though that people might want to use [FTC-TDF] for a longer period of time.”

The iPrEx trial results have prompted discussions among AIDS vaccine investigators and advocates about how or if PrEP might impact clinical trials of AIDS vaccine candidates (see sidebar, below). There are also discussions about how the iPrEx results may affect ongoing vaccine trials, such as the HVTN 505 trial involving 1,350 men who have sex with men in the US. There are now questions about whether volunteers should be offered PrEP or if the trial should be adapted to include a PrEP study arm. On January 28, the US Centers for Disease Control and Prevention (CDC) provided interim guidance for healthcare providers on the use of PrEP. At this time, the CDC recommends PrEP only be considered for adult MSM who are at high risk of HIV infection through sex, noting, however, that these drugs are not licensed to be used for HIV prevention and long-term safety of PrEP is not yet known. Formal US guidelines for PrEP use in MSM are in development.

Implications for Vaccine Research  
 The results of the iPrEx trial prompted discussions about how implementation of pre-exposure prophylaxis (PrEP) might affect the research and development of HIV vaccine candidates. To address this question, VAX turned to Mitchell Warren, the executive director of AVAC, a leading HIV prevention research advocacy organization based in New York City.

What impact could PrEP have on vaccine trials?

If PrEP is found to be effective and introduced, it makes things more complex. There are already conversations about what to do among the men who have sex with men who are participating in the HVTN 505 vaccine trial (see Spotlight, this issue). With that, there is the really immediate issue about whether to integrate PrEP into an ongoing trial. This has implications in terms of a trial’s scope and size.

With future trials, even if PrEP works, we don’t know where it will be introduced. If PrEP becomes part of the standard prevention regimen among serodiscordant couples [in which one partner is HIV infected and the other isn’t], it may no longer be possible to conduct vaccine trials within this cohort. But that is a big if, and a reason why the ongoing PrEP study in serodiscordant couples is so important. Even if PrEP works well in this cohort, many people could opt out of it.

There are also opportunities to study the efficacy of these methods [PrEP and vaccines] in combination. If you look at the results of RV144, the vaccine was modestly effective in a low-risk population. It raises the question, could PrEP lower the risk of transmission in high-risk populations enough so a vaccine like RV144 would not have to work as hard? I get very excited about that possibility.

Are there studies planned to look at this?

There are a lot of conversations occurring but I would like to see a specific scientific agenda developed.

Does PrEP lessen the need for an AIDS vaccine?

Not at all. How PrEP is delivered and to whom, and who pays for that delivery, is anything but certain. It will take a great deal of time, effort, and resources to help us understand that. User-controlled methods are a critical backbone of HIV prevention, but they are never enough. We have seen that with condoms. They are more efficacious than PrEP or the vaccine combination in RV144, but adherence matters. In the PrEP trial, adherence was poor, so when I look back at the past year of results from prevention trials like CAPRISA and iPrEx, it tells me how important a vaccine is.