New class of AIDS drugs found highly potent in tests


Small preliminary studies that will be reported this week at a national medical meeting show that a new class of drugs is highly effective in knocking out the virus that causes AIDS and allowing the immune system to recover, at least in the short term.

But investigators advise caution in interpreting the results, noting that many promising early findings have failed to lead to effective treatments for AIDS patients.

The new results are from studies with protease inhibitors, drugs that block a key viral enzyme. The drugs currently on the market block a different enzyme, reverse transcriptase, and these drugs are generally acknowledged to be weak, at best, in stanching the progress of infection with HIV, the human immunodeficiency virus that causes acquired immune deficiency syndrome.

But the protease inhibitors appear different. Dr. George Shaw of the University of Alabama at Birmingham said the new results were "groundbreaking."

Dr. John Leonard, who directs protease inhibitor studies at Abbott Laboratories, said the company was "very optimistic." He added, "I think we may be at a point where we are really turning the corner in dealing with HIV infections."

But others were wary. John Doorley, a spokesman for Merck & Co., which will report on its protease inhibitor, L524, at the Second National Congress on Human Retroviruses and Related Infections in Washington this week, counseled caution. "We're encouraged," he said, "but it is still early."

Dr. Leonard said Abbott would report that its drug, ABT-538, can shut off 99 percent of the virus' replication and can reduce the number of virus particles in the blood by 70 percent to 99 percent.

Dr. David Ho, the director of the Aaron Diamond AIDS Research Center in New York, said that the protease inhibitors were about 10 times more effective than AZT and other reverse transcriptase inhibitors in halting the virus' replication.

The Abbott investigators also found that when the virus is held in check, the T4 cells of the immune system, which are infected by the AIDS virus, spring back. After three months of taking the drug, many patients had 100 or more T cells per milliliter of blood.

Dr. Leonard said that with drugs like AZT, the peak increase in T cells occurred in four to six weeks and was just 30 to 35 cells per milliliter of blood.

The most dramatic response to the Abbott drug was in a man whose T cell count went from 68 to 680. Dr. Ho, who performed one of the Abbott studies, said that the man's immune system went "from grossly abnormal to something that could pass for normal." Dr. Ho said that the Merck protease inhibitor produced similar effects.

Recent studies by Dr. Ho and Dr. Shaw have found that HIV infection is a raging battle between the immune system and the virus, with as many as a billion new viruses bursting forth from infected T cells each day and more than a billion new white blood cells released each day to fight the virus.

The problem is that with so many viruses being made each day and with the infection lasting 10 years or longer, the virus finds it easy to produce mutants that, by chance, will be resistant to drugs.

So far, the virus seems to take a fairly long time to develop resistance to protease inhibitors. Dr. Leonard said that Abbott had been following some patients for six months and their viruses still were sensitive to the drug. With the right dose of the drug, Dr. Leonard said, "We can't speculate on whether resistance will occur."

Dr. Ho said he often saw resistance to the Abbott drug within months, although he confirmed that some patients had not developed resistance for six months. Mr. Doorley said Merck found that the virus became resistant to its protease inhibitor within weeks to months.

Dr. Ho said the best bet would be to combine drugs in the hope of finding a drug cocktail that the virus could not escape. It will be reported at the meeting, for example, that AZT and another reverse transcriptase inhibitor, 3TC, taken together, are a much more potent force than anyone predicted.

"The mutants that are resistant to AZT are very sensitive to 3TC and the mutants that are resistant to 3TC are very sensitive to AZT," Dr. Ho said. "That sort of combination is what we need for protease inhibitors."

Other specialists say they are waiting to see large studies that show that patients taking the drugs or drug combinations live longer or have fewer symptoms of HIV infections before they get too excited.

Mr. Doorley said that Merck had learned the pitfalls of AIDS drug development. Since 1986, he said, the company has spent more than $400 million on AIDS research and had four drugs in clinical trials, but none made it to market. "You get a lot of disappointments in clinical trials," he said.

In fact, Mr. Doorley said, Merck has not even made up its mind yet about whether to do large-scale clinical trials with its protease inhibitor. "We are looking at the data and deciding whether to move ahead," he said.

Abbott, in contrast, is committed. "We will aggressively pursue the development of this compound," Dr. Leonard said.

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