Microbicide advances are ahead of vaccines but still years away

Prevention approaches are varied

Recent research has shown that the microbicide field is alive with an array of prevention approaches to stopping HIV transmission during sexual intercourse.

However, most researchers admit that while the pipeline of microbicide research is further along than the vaccine pipeline, it still could be five to 10 years before the ideal candidate is marketed.

Also, about $775 million needs to be invested in testing products already in development before it’s likely there will be a successful product by 2010, according to UNAIDS of Geneva and an estimate by the Rockefeller Foundation of New York City.

The first microbicide phase III clinical trial to study HIV infection involved Nonoxynol-9, which was a disappointment to the microbicide field when the product apparently increased risk of HIV infection among study subjects. However, most researchers agree that it wasn’t a major surprise, and it hasn’t hindered the progress of new approaches to finding an HIV microbicide.

"Essentially, the trial was carried out because the product was already out there as a spermicide," says Robin Shattock, PhD, a reader in cell biology of infection in the department of cellular and molecular medicine, infectious diseases at St. George’s Hospital Medical School in London. Shattock was scheduled to speak about microbicides at the recent Microbicides 2004 conference, held March 28-31 in London.

"Nonoxynol-9 would never have been chosen based on laboratory research as it has a therapeutic index of one — the difference between its cytotoxicity and activity against HIV," he says. "Probably, the major confounding factor in the N9 trials was that the product was tested in a sex worker community that may have been applying the gel up to seven times a day."

This was significantly different than using the product occasionally as a spermicide, and it’s likely that the repeated use led to breakdown of protective epithelial barriers, Shattock says.

"As N9 did not come out of any pre-clinical research, enthusiasm for products that have been specifically designed as microbicides has not been dampened," he adds. "If anything, the trial has galvanized research efforts to get scientifically tested safe and effective products into trials."

Now, with dozens of products and approaches in the microbicide pipeline, there are a number of hurdles that need to be overcome.

One snag involves studying microbicides and evaluating their efficacy, says Tom M. Folks, PhD, chief of the HIV and Retrovirology Branch of the Centers for Disease Control and Prevention (CDC) in Atlanta.

Phase III trials are very expensive, costing about $40 million per trial, and they require large numbers of volunteers, Shattock explains. "Currently, there is insufficient funding and infrastructure to support all planned phase III trials. A second potential hurdle is the issue of burdens imposed by regulatory authorities."

For example, evidence suggests that populations will have to be followed for up to two years from the completion of a study, he adds. "This will be very difficult in study populations that contain large numbers of migrants. Furthermore, the documentation that is usually required for a phase III trial in the developed world may be impractical or highly expensive in the developing world setting."

Another obstacle is that the products will need to be registered as over-the-counter products in order to be successful, and this normally requires 10 years of use under prescription, Shattock says.

Also, studying microbicides in clinical trials is more challenging than the study of antiretroviral drugs or vaccines, says Melissa Pope, PhD, a scientist with the Population Council in New York City. "Vaccine trials are so much easier — you just give that person the vaccine at the time of visit, and you know they’ve taken it," she says. "With a microbicide, you give it to people and trust they use it as directed when having intercourse."

Also, the study of antiretrovirals used as a prophylactic, as a sort of oral microbicide, is advancing more quickly than the vaginal microbicide field, Folks says.

The main issue is that most microbicide research is being done with the goal of preventing HIV transmission among women in the developing world, where heterosexual transmission is the chief problem. As such, an effective microbicide will need to be cheap, easy to use, and culturally sensitive.

It’s the latter stipulation that poses the most challenges, some researchers say.

Often, women in sub-Saharan Africa and other regions lack power in their relationships and may not be able to insert a microbicide an hour before a sexual encounter. So some researchers say that the most effective microbicide might have to be in the form of a vaginal ring or some other such device that could be inserted once a month and slowly release chemicals that would prevent HIV infection.

Then there’s the problem of having trial subjects use a product within the context of their own cultural beliefs, and the clinical trial suddenly becomes quite challenging, Pope adds. "If the culture says they can’t use any lubrication, then this could be a restriction," she explains. "Some suggest a vaginal ring that’s inserted in women and lasts a month with a slow release might be more acceptable because there’s no sign of lubrication."

A further issue is whether a particular microbicide also works as a contraceptive. This dual purpose may be unacceptable in some cultures where many of the women who are at risk for HIV infection are married and intend to have children.

"We need to tailor prevention messages to meet the lives of women, many of whom are caregivers, taking care of families; and these have to be integrated into their lifestyle," says Nancy Padian, PhD, professor of obstetrics, gynecology and reproductive sciences at the University of California, San Francisco (UCSF).

Padian also is the director of international research for the AIDS Research Institute at UCSF. Microbicides are particularly appealing as a prevention strategy in the developing world because women would have power over their use, she says. "It’s a lot easier for a woman to use a microbicide than to convince a man to use a condom, and it’s more clandestine than a female condom."

A few microbicide approaches in the pipeline also might work for anal intercourse and still more are being designed to prevent transmission of other sexually transmitted diseases (STDs), but the greatest effort has been directed to preventing vaginal HIV transmission, which is the biggest factor in the AIDS epidemic worldwide, the experts say.

"The majority of studies at this point are focusing on vaginal use, mainly because it’s a more controllable environment," Pope says.

"Potentially, it’s going to be that much more difficult to work with rectal tissue because it’s an open-ended tract, and the female reproductive tract is a closed environment." Another factor is that vaginal tissue is thicker than rectal tissue, she adds.

However, Pope and other researchers agree that eventually there will need to be a microbicide on the market for anal intercourse.

"It’s of paramount importance to stop the spread of HIV vaginally on the global basis, but we also realize the rectal environment is going to be important as well," says Ron A. Otten, PhD, a research microbiologist with the CDC.

Practically speaking, it’s likely that any vaginal microbicide that makes it to the market also will be used in the rectal environment, and so it’s important for researchers to study rectal environment efficacy, as well, he says.

Otten and other CDC researchers have been involved in studying a microbicide called cellulose acetate phthalate (CAP) that has shown efficacy in the vaginal route and soon will be studied in a rectal environment.

The Alliance for Microbicide Development of Silver Spring, MD, web site at www.microbicide.org reveals that there are more than 30 microbicide studies in the pipeline.

Research presented at the recent conferences also shows that there are some approaches that are just in the beginning stages of research.

Until recently, there hasn’t been a great deal of microbicide research done at the basic research level, Pope notes.

"What was lacking before was much more funding from the National Institutes of Health (NIH), and now NIH is funding a lot of basic research," she says. "There are other announcements that NIH has put out to encourage microbicide research that also is related to blocking STD infection."

Pope has been involved in the study of the microbicide Carraguard, which is a gel that is inserted through an applicator into the vaginal vault about an hour before intercourse.

The first phase III clinical trials are beginning this year in Africa, and these include the study of Carraguard; a dextrin sulphate gel (Emmelle), which is a sulphated polysaccharide, and Pro 2000/5, a sulphonated naphthalene polymer.

The latter two products are designed to block the entry of the HIV virus to susceptible cells. Emmelle is developed by the Medical Research Council, and Pro 2000/5 is developed by Indevus Pharmaceutical Inc.