Research suggests new path to HIV prevention

Drug concentrations high in rectal tissue

Investigators are studying the way antiretroviral (ART) drugs penetrate the body, particularly focusing on the genital tracts to examine the potential for these drugs to impact the areas where HIV transmission most often occurs.

In a pilot study, researchers made a startling discovery that rectal tissue exposure after multiple dosing with the CCR5 antagonist maraviroc was 10-fold higher than what had been measured for vaginal tissue and much higher than blood plasma exposure.1

"We were surprised at the high exposures in rectal tissue," says Kevin Brown, PharmD, an academic HIV pharmacology fellow at the University of North Carolina School of Pharmacy in Chapel Hill.

After a week of dosing, the concentrations were 26 times higher than concentrations in blood plasma, he adds.

"We went through calculations to make sure these numbers were correct," Brown says. "We were pretty conservative with the data we got."

Their findings also showed that semen concentrations were lower than concentrations found in blood plasma, but cervical/vaginal concentrations were several times higher than concentrations found in blood plasma, Brown adds.

"We chose to study maraviroc because it's an entry inhibitor and prevents the virus from getting into the cell," says Angela Kashuba, PharmD, an associate professor at the University of North Carolina School of Pharmacy.

"If we can block the receptor, we block most of the viruses transmitted," she adds.

Researchers are unsure of why the drug's concentration levels are so high in rectal tissue.

"It could be part of the vasculature as rectal tissues are very vascularized," Brown says. "For multiple doses we can explain the concentrations with the idea that they're building up and not necessarily clearing as quickly."

With maraviroc, about 25% of the dose that is swallowed passes through the gastrointestinal tract unmetabolized, he adds.

So when the drug is seen on the inside of the rectum, it's an extra source of the drug as opposed to the drug being completely absorbed in the small intestine and distributed throughout the body, he explains.

These study findings could point to a promising way to provide primary protection of HIV infection, Brown says.

"The problem is we don't know what concentrations are required to prevent HIV infection, and so we can't say right now whether it will work," Kashuba says. "Anything active therapeutically should be active for preventing HIV infection, but we don't know for sure."

With the study's data, researchers could explore the relationship between concentration and effect, she adds.

"So we can do that either in tissues in the culture system or in an animal model, and we could understand whether these concentrations we are seeing in people could be protected in a lab setting or in an animal model," Kashuba says. "And if that looks promising then it could move forward to a clinical trial; but we need those data to link exposure to efficacy."

This research is focusing on oral drugs as an HIV prevention strategy, she notes.

"Just recently, the power of the pharmacokinetic-pharmacodynamics relationship in prevention strategies has been apparent, but it's hard to move drugs from animal exposure to humans," Kasuba says. "No one has been measuring drug exposures, and very little drug exposure material has come out of the prevention field, so we're leading that effort."


  1. Brown K, Patterson K, Malone S, et al. Antiretrovirals for prevention: Maraviroc exposure in the semen and rectal tissue of healthy male volunteers after single and multiple dosing. Poster presented at the 17th Conference on Retroviruses and Opportunistic Infections, held Feb. 16-19, 2010, in San Francisco, CA.