Va. school's research on HIV continues after drug setback

NORFOLK -- Researchers at Eastern Virginia Medical School had zeroed in on what they had hoped would be a way to prevent HIV infections.

The idea was that the substance, a virus-fighting gel, could be inserted into the vagina, where it would block HIV from entering. If it worked, the implications were global.

Women make up about half the estimated 33 million people worldwide infected with HIV. In some sub-Saharan African countries, women make up an estimated 60 percent or more of HIV cases.

"There are places in the United States where HIV is fairly high," said Henry Gabelnick, executive director of Contraceptive Research and Development, or CONRAD, a research program created in 1986 at EVMS.

The initial focus was developing contraceptives, and that was expanded to HIV prevention. One hope is to develop microbicides that can do both -- prevent pregnancy and HIV infection.

"We are talking about needing to find a product that is safe enough for women to use every day . . . but at the same time you are talking about something that has the capacity to incapacitate a virus like HIV," said Anna Forbes, deputy director of the Washington-based group Global Campaign for Microbicides.

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Phase III clinical trials led by EVMS researchers got under way in 2005 on the gel, a compound called cellulose sulfate. More than 1,300 women in HIV hot spots around the world -- cities and towns in Benin, South Africa, Uganda and India -- were enrolled in studies.

But the gel did not work.

Women who used the compound actually showed higher rates of HIV infection than women using a placebo, or dummy, gel. In January 2007, the EVMS researcher-led study, and later, another research group's work on cellulose sulfate, were stopped early, something done only when letting research continue presents a clear risk to participants.

The results were a disappointment for the Norfolk medical school, which had nurtured the first U.S. physician-researchers to help a woman become pregnant using in vitro fertilization. If cellulose sulfate had worked, there was another chance for shared international acclaim for the school. Cellulose sulfate was the lead product in the research portfolio of the medical school's well-regarded contraception and microbicide research-and-development program.

"Depending on who you talk to, it was either the worst thing that ever happened in the world, or for those of us in the microbicide field, it was something we expect," said Jim A. Turpin, a scientist at the National Institute of Allergy and Infectious Diseases, a federal agency that funds some microbicide research.

"There is an old saying: If you move five compounds to Phase III studies, two will not work, two will cause harm, and maybe one, if you are lucky, will give you what you want," he said.

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The failure of cellulose sulfate was a setback but not a defeat, if funding for the institute since then is any indication.

Just months after the studies were stopped, CONRAD received a $28.5 million grant from the Bill & Melinda Gates Foundation for microbicide research. And this past September, the research group received a five-year, $100 million grant for microbicide research from the U.S. Agency for International Development, an independent agency that funds health programs around the world.

"We are trying to develop strategies that are female-controlled, that the female can use and can do it overtly, talking the situation out with her partner, but can also do it discreetly if need be," said Dr. Gustavo F. Doncel, one of CONRAD's lead researchers.

Cellulose sulfate was studied extensively in the lab and in animals before going to human safety trials, Doncel said. What might have happened? Doncel said there are several theories, and researchers are doing more studies to explore them.

"Women were using the compound and were protected while using the compound. At the same time, they were attracting cells that were infectable cells. Stop using these compounds and they [still] have these cells . . . that are more receptive of HIV," Doncel said.

The ideal microbicide destroys the virus before it gets into tissue, Doncel said. But those products tend to be too strong to insert into the vagina. Another class of microbicides blocks HIV from entering cells. The study gel is that type. Other microbicides stop the virus from replicating once inside a cell. Another type stops HIV from integrating into the cell.

"The microbicide field and the vaccine field, both I think, underestimated this virus," Doncel said. "The virus is very tricky, and its subverts the immune defenses."

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Disappointments such as the cellulose-sulfate study results have to be put in perspective, said Forbes of the Global Campaign for Microbicides.

"This is a very common scenario in new-drug development," she said. "As many as 100 products may go into the pipeline at the beginning of the research process for every one that emerges."

While much of the research on microbicides is focused on stemming the HIV pandemic in Africa and Asia, the benefits of a successful product would extend beyond those places. Forbes said any woman who has found it difficult to persuade a partner to use a condom should care about microbicides.

"It's really crucial for women to have a way to protect themselves from something as serious as HIV that is in our own hands, that we can control ourselves," Forbes said.

Susan Tellier, HIV testing services coordinator at the Fan Free Clinic in Richmond, wonders whether microbicides would be made affordable and whether they would undo years of educating people to practice safe sex.

"What is going to be the role of condoms if this product is available? Are people going to stop using condoms? . . . There are still the other [sexually transmitted diseases] and unwanted pregnancy," Tellier said.

Contact Tammie Smith at (804) 649-6572 or TLsmith@timesdispatch.com.