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Regardless of how they work, what all entry inhibitors share is an ability to thwart the virus outside the cell, before it has an opportunity to infect healthy immune cells. And that, some experts believe, may give them a better chance of dispatching HIV than the currently available antivirals, all of which work inside cells that have already been infected. "Working outside the cell gives them in theory a major advantage, says Dr. David Ho, director of the Aaron Diamond AIDS Research Center in New York City, "because cell membranes can present barriers to some drugs, and some have molecules that pump out drugs that manage to get inside." This suggests that the new drugs might be effective at lower doses, making fusion inhibitors safer for the patient in the long run. Trimeris' studies support this; so far, neither of its compounds seems to cause any of the serious toxic side effects associated with today's AIDS drugs, such as nausea, vomiting and abnormalities in fat metabolism.
If the early promise of the fusion inhibitors bears out, they will be a welcome and badly needed addition to the HIV drug arsenal. For while the available antivirals have had a dramatic impact in reducing the death rate from AIDS, they are not enough. As more patients take these cocktails of powerful drugs for more and more years, the dual problems of resistance and toxicity are beginning to tarnish the promise they once held.
About 30% of patients who begin therapy with a combination of antiviral drugs have to stop, either because their bodies cannot tolerate the toxic side effects or because they cannot keep up with the grueling regimen of strictly scheduled pill popping. An additional 30% to 50% are currently in salvage therapy, which is what AIDS specialists call the last-ditch potions of drug cocktails given to patients who have become resistant, one by one, to every class of antiviral on the market. "We have, by treating lots of individuals relatively successfully for varying periods of time, accumulated a new target of patients now in desperate need of new options and new drugs," says Bolognesi.
So far, Trimeris has concentrated its testing of T-20 on these very patients. The company's latest data, on 70 patients with advanced AIDS who are no longer responding to most of the currently available drugs, are promising. After almost a year of taking T-20 in combination with other antivirals, 56% of the patients showed sharp declines in the amount of HIV in their blood--at least tenfold below their starting levels and in some cases to levels undetectable by current tests. The only disadvantage to T-20 therapy at the moment is that it's an injection that needs to be given twice a day. But Trimeris is working on making the molecule easier to take, possibly as a skin patch.
Buoyed by the success of these trials, researchers are busy investigating other compounds that would interrupt HIV's reproductive cycle at critical points. One particularly attractive target: a molecule that could prevent HIV from inserting its genes into its host's genome. That would give doctors two new ways to block HIV, complementing existing drugs such as AZT (which keeps HIV from converting its viral genome into one that is compatible with human DNA) and protease inhibitors (which hinder HIV's final assembly before leaving the cell).