AIDS Alert International

Study recommends monthly HIV tests for women in ART microbicide trials

Tests could reduce resistance cases to a few

The latest microbicide clinical trials will use antiretroviral therapy (ART), which holds both promise and more challenges for investigators.

One of the challenges will be to reduce the risk of drug resistance among women using the products.

Experiences with mother-to-child transmission (MCT) prevention measures have shown that the development of drug resistance is possible even under low dose or short-term drug exposure experiences.

"People are concerned that ART microbicides could be fairly effective, but also result in drug resistance," says Sally Blower, PhD, a professor at the David Geffen School of Medicine, University of California - Los Angeles.

Blower and co-investigators have developed a mathematical model that predicts HIV drug resistance among a phase III trial involving 10,000 female sex workers who have an HIV incidence of 5 percent.1

The study concluded that participants in microbicide trials should be tested monthly to eliminate drug-resistant cases almost entirely, and that the benefits of the microbicide research would outweigh the potential risks.1

"We addressed two questions: How many drug resistant cases would be expected to develop during the trial? And, how frequently should participants be tested to minimize the number of resistant cases?" Blower explains.

"What we modeled is exact trial structure, tracking women in four mutually-exclusive states: uninfected, infected with undetected HIV infection, detectable HIV infection, and having acquired drug resistance," Blower says.

One of the factors is whether the drug is absorbed into the blood stream, so the model includes two analyses, with one predicting a high absorption rate of 50 percent to 90 percent, and the other predicting a low absorption rate of 1 percent to 3 percent, Blower explains.

"One very uncertain factor is what amount of time it would take an infected woman to develop resistance, given that the drug is absorbed," Blower notes. "And we looked at that issue and saw that it was from six months to never."

Investigators also dealt with uncertain parameters with widely varying ranges.

"We varied microbicide efficacy over a wide range," Blower says. "We looked at a range from zero to 90 percent because that also affects the development of microbicide resistance."

For instance, if a drug is 100 percent effective, then no one in the trial will acquire HIV infection and there is no possibility of resistance, she says.

The questions investigators studied are as follows:

  • How effective is the microbicide?
  • How much of it is absorbed?
  • How quickly will someone develop drug resistance?
  • How many infections would the population have?
  • How many infections would become drug resistant?

"So we made the model based on the fact that drug resistance may never happen to it's highly likely to happen," Blower says.

"We found that the best thing to do is test the women monthly in a 12-month trial," Blower says. "If you tested more frequently, you could pick up more [HIV infections], but that becomes ridiculous."

The study found that if the absorption rate of the ART is low, then there would be almost no cases of resistance developed," she says.

But even at a high absorption rate, the number of drug-resistant cases would be very small if the women are tested monthly for HIV infection, Blower adds.

"We found that the number of resistant cases developed in a 12-month trial would be 34 cases, but if you tested monthly, you'd only get three cases," Blower says. "So even if the drug absorption is high, you can prevent resistance by having frequent testing, and if drug resistance is low you have nothing to worry about."

If a microbicide eventually is found effective and makes it to the market, then it'll be important for the final product to have a low absorption rate since drug resistance will become an issue among the populations using the product.

"The efficacy of the microbicide is independent of absorption," Blower notes. "It's meant to act in the vagina, and the absorption gets into the bloodstream, so they need a microbicide that doesn't readily get into the bloodstream."

Finding a microbicide that can prevent HIV infection among even 30 to 40 percent of a population that uses it would be great, Blower says.

"That would be acceptable to quite a few people, and it would be relatively easy to roll it out in Africa and make sure that most people who want a microbicide can have one," she says.

"You're going to protect both men and women with microbicides," Blower adds. "Women get the direct protection and then the incidence rate goes down, so the chance that men get infected is decreased over time."

Reference:

  1. Wilson D; Wilson D; Coplan P, et al. Modeling microbicide phase III clinical trials: assessing the risk of the development of resistance. Abstract presented at the 14th Conference on Retroviruses and Opportunistic Infections, held Feb. 25-28, 2007, in Los Angeles, CA. Abstract: 999.