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Q&A: HIV prevention pill still holds promise, despite trial failure

The news out this week that women taking the HIV prevention pill Truvada were no more likely to evade infection than those on placebo was a huge disappointment for infectious disease researchers and the AIDS community alike. Trial investigators had hoped to enroll 3,000 HIV-negative women in Kenya, Tanzania and South Africa. But a preliminary analysis of the nearly 2,000 study participants registered to date showed that 56 new HIV infections had occurred, with an equal number coming from those taking the drug and those assigned to the dummy pill. As a result, organizers announced on Monday that they had halted the trial prematurely.

Scientists are at a loss to explain the data. Yet despite the negative results, they are not giving up on the preventative strategy, known as pre-exposure prophylaxis, or PrEP. Buoyed by last year’s findings that Truvada dramatically reduced the rate of HIV infection in gay and bisexual men, researchers are forging ahead with large-scale PrEP trials in intravenous drug users in India, heterosexual couples in which one partner is HIV-positive in East Africa and high-risk women across Africa.

Grant.jpgTo put the most recent findings in perspective, Nature Medicine spoke with Robert Grant, an HIV researcher at the University of California–San Francisco’s Gladstone Institute of Virology and Immunology who led the successful PrEP study in men who have sex with men.

What has the scientific community learned from these latest results?

One thing we learned in the last week is how important it is to study interventions in different populations and not to make assumptions that what works in one setting will automatically work in another setting. A study like this gives us the opportunity to think through under what circumstances PrEP might not be as effective as it was in men who have sex with men. It’s critically important that we learn everything that we can, and apply what we learn to guide implementation of PrEP as we move forward.

Does this trial failure take the wind out of PrEP’s sails?

This new information doesn’t really diminish our enthusiasm for the use [of PrEP] in gay and bisexual men. However, we are disappointed that this approach did not show protection for heterosexual women in this particular study, and we look forward to more analysis of the most recent study to really learn what happened there. Was it a problem with adherence? Did people just stop taking the pill? Were there issues with women also taking contraception? Was there something about this particular group of people that led to them not being protected in this particular study? But this is just one of several studies in heterosexual populations in Africa, and something like oral PrEP or an effective topical gel could be very important for other groups.


Why might heterosexual women have responded differently to PrEP than gay men?

The way that men [who have sex with men] mainly become infected with HIV is after rectal exposure, whereas women typically become infected with HIV through vaginal exposure. There are very important differences between the rectal mucosa and the vaginal mucosa — one is columnar epithelium, the other is stratified squamous epithelium. There is a huge difference in thickness — the rectal mucosa only has one cell layer, whereas the vaginal mucosa is layered 20- to 30-cells thick. There could be very important differences between the amount of drug that is available at the surface where HIV is trying to get into the body, and it could be that drug levels are higher after oral dosing in the rectum than they are in the vagina.

What about differences in sexual behavior?

That’s also a possibility, but I think we have to wait and see what the studies of drug levels and adherence show in the different groups.

In light of these latest findings, where does the field of HIV prevention sit today?

If you think about it, there is good evidence that we can block HIV transmission regardless of the type of exposure that occurs. We have combination antiretroviral treatment that effectively blocks maternal-to-child transmission, and that combination therapy also helps prevent transmission by sexual contact. We have clean needles, and vaginal gels containing tenofovir that are highly protective in women who are exposed by vaginal intercourse. Male circumcision has been demonstrated in three out of three clinical trials to help protect heterosexual men, and we also have oral Truvada, which was effective for gay men. If you think about it, regardless of the way people become exposed, we have something new that we can offer to different populations that is highly effective at preventing transmission. Now is a good time to be enthusiastic about learning how to best use these strategies and offer them in combination.

Image: Gladstone Institute of Virology and Immunology

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