As many of the local HIV epidemics around the world demonstrate, receptive anal intercourse is an incredibly efficient route of HIV transmission. Unfortunately, the science around it has largely been held hostage by the usual thugs of stigma, denial and silence. That backdrop makes the early-phase clinical trial results that were presented by Peter Anton from the University of California-Los Angeles pretty exciting to a lot of people who've been waiting for some news on this front for a long time.
Fourteen men and four women who volunteered for the study -- the second rectal microbicide trial ever -- gave us some important information about how the 1% tenofovir (TDF, Viread) vaginal gel used in previous trials for HIV prevention (most notably the landmark CAPRISA 004 study) might work when applied rectally. The two compartments are strikingly different -- duh, right? -- so understanding how a promising prevention tool such as this works in each one is a big deal.
Anton et al were looking primarily at whether the vaginal gel could be safely used rectally. But they also explored whether volunteers found it acceptable, whether it caused any damage to the rectal mucosa and how the drug was metabolized in the blood, tissue and genital fluids. In addition, they took measurements assessing orally administered tenofovir versus the 1% tenofovir gel.
The study had three stages, each of which involved two weeks of sampling and was followed by a two-week washout period. In the first stage, all volunteers received one dose of oral tenofovir. In the second, volunteers were randomized 2:1 to receive one rectal application of 1% tenofovir gel or placebo. In the third, volunteers were randomized 2:1 to receive a daily 1% tenofovir gel application (or placebo) for seven days. All told, the investigators collected 10,000 samples (blood, genital secretions, vaginal tissue and rectal tissue) and performed 2,000 biopsies.
The study showed that the gel is mostly safe, but it is "not fully optimal" when used rectally, as Anton put it. No one showed any mucosal damage, but two of the 12 volunteers who used the gel had some repeated serious side effects (five grade-three adverse events) during the part of the trial in which they were applying the gel daily for seven days. These consisted mainly of lower gastrointestinal (GI) tract distress.
Interestingly, 75% of the people who used the gel said they would use it again if it were effective, even though they reported more discomfort and less overall satisfaction with the gel than the placebo group. One might wonder if that's how people respond when presented with a prevention tool they can control, even if it isn't perfect.
Regarding drug metabolism, the level of tenofovir in the rectal tissue 30 minutes after gel dose was 100 times greater than with the oral dose in 80% of the volunteers. The investigators did not find any tenofovir in the blood plasma after seven days of daily rectal gel doses, but the rectal concentration of tenofovir at that point was still five times greater than after a single gel dose.
While this study did not look primarily at prevention of HIV transmission, the investigators explored this by taking samples of volunteers' rectal tissue that had been exposed to tenofovir gel and seeing how well it inhibited HIV in the lab. They found a significant reduction in infectivity in the tissue that had been exposed to daily doses of tenofovir gel for a week compared to the placebo group.
On a side note, hurray for study volunteers. Each of the 18 people who entered the trial in Pittsburgh, Pa., and Los Angeles, Calif., endured 12 study visits over three and a half months, including eight flexible sigmoidoscopies (scopes of the rectum and descending colon). Everyone who started this intensive trial finished it -- and helped move some important science forward along the way.
So, the 1% tenofovir gel demonstrated it's capable of preventing HIV when applied to rectal tissue. But it is going to have to be safe and something people like to use before it ever gets anywhere near the clinic. Anton said he suspects the lower GI discomfort seen in this study is due to the hyperosmolar nature of the carrier gel, which draws fluids out of the gut cells. A potentially more rectal-friendly version is in development, so stay tuned.
Anton and other researchers who presented studies at CROI 2011 on antiretroviral-based oral and gel pre-exposure prophylaxis discussed their findings at a press conference. The transcript of that press conference is available here.
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