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IAC: Blocking HIV Entry Shows Promise With Peril


TORONTO -- The target of most HIV therapy is the virus itself, but researchers said here that another approach -- blocking cells' entry points and locking the virus out -- is also starting to show promise.

TORONTO, Aug. 18 -- The target of most HIV therapy is the virus itself, but researchers said here that another approach -- blocking cells' entry points and locking the virus out -- is also starting to show promise.

Compounds that block two key viral-entry points -- the cell-surface receptors CCR5 and CD4 -- can drive down viral loads in HIV patients with a long history of antiretroviral therapy, researchers said in several late-breaking presentations at the 16th International AIDS Conference.

TNX-355, a monoclonal antibody that blocks the CD4 receptor, resulted in a statistically significant reduction in viral load, compared with placebo, reported Robin Hardwicke, Ph.D., of the University of Texas Health Science Center in Houston.

In a 48-week, randomized, double-blind, placebo controlled study, 82 patients were treated with an optimized background regimen, combined with placebo or one of two doses of TNX-355.

The medication, delivered by intravenous infusion every two weeks, was given at 10 mg/kg 15 mg/kg of body weight, Dr. Hardwicke said.

Both doses resulted in significant reductions in viral load compared with placebo, at P

It's not yet clear why the malignancies developed, Dr. Gulick said. The study was supported by Schering Plough, Monogram Biosciences, and the National Institute of Allergy and Infectious Diseases.

Researchers at Pfizer reported that their CCR5 antagonist, maraviroc, is safe and well-tolerated in patients whose virus will use either CCR5 or another entry point, CXCR4, or both.

In such patients, investigators worried that blocking CCR5 would lead to more CXCR4-tropic HIV, which is known to be more aggressive, said Howard Mayer, M.D., of Pfizer.

But in 186 "dual-tropic" and highly treatment experienced patients with advanced HIV disease, the fear was not realized, Dr. Mayer said.

The researchers randomized the patients to one of two doses of maraviroc or placebo, combined with the best available combination therapy. Viral load reduction from baseline was substantial -- about a factor of 10 in all three arms, Dr. Mayer said -- and there were no significant differences.

Both maraviroc arms had mean CD4-positive T-cell increases that were about twice that for the placebo arm, he said, and Grade 3 and 4 adverse events occurred with equal frequency in all three arms. There were no cases of lymphoma or adenocarcinoma.

Patients who failed the maraviroc therapy (combined with optimized background) were more likely to do so with a CCXCR4-tropic virus than those on placebo and optimized background, he said, but even they had CD4 increases similar to those seen in successful maraviroc patients.

Because these drugs act on the target cell, rather than the virus, they may be less likely to cause drug resistance, said Mark Wainberg, Ph.D., director of the McGill University AIDS Center in Montreal, and co-chair of the conference.

"The pressure for mutagenesis is not on the virus, but on the cell, which is much more difficult," Dr. Wainberg said

However, he said, "all of us in the field are concerned about the long-term toxicity with anything that targets a cell receptor that is ostensibly there for some normal physiological purpose."

The exception may be CCR5, because in a small fraction of people the receptor is naturally disabled -- without apparent harm. "Not having a CCR5 receptor doesn't seem to greatly worsen your chances of having a long and happy life," Dr. Wainberg said.

But there's no such evidence that blocking the CD4 receptor or others that are used by HIV can be done safely, he said. That knowledge will have to come from clinical trials, which experts will watch carefully.

On the other hand, he commented, the malignancies seen in the trial of vicriviroc are a clear cause for concern and need further study, although the data are not clear on the link between the drug and the cancers.

"That's why we do clinical trials," Dr. Wainberg said.

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