AIDS EXPERTS HOPEFUL, CAUTIOUS ABOUT NEW DRUG\Doctors 'optimistic' about new AIDS therapy.

Byline: Lawrence K. Altman The New York Times

An experimental drug has nearly halved both the death rate resulting from advanced AIDS and the number of serious complications of the disease in a large international study that lasted seven months, the drug's developer reported at a scientific meeting here Thursday.

Many of the 2,100 participants enthusiastically greeted the report that the drug, ritonavir, prolonged the lives of some patients in the study.

"Patients need to know this is promising, all signs are optimistic, and it is wrong not to be optimistic," said Dr. William Paul, who heads the federal office of AIDS research.

Nevertheless, Paul and many others cautioned that there is no way to determine how long the drug's beneficial effect would last. Participants pointed to some disquieting data in the report that raised questions whether resistant strains of the AIDS virus might have taken over early in the treatment period, jeopardizing longer-term results.

Among the reasons scientists are cautious about the findings is that many remember how enthusiastic they were when AZT was first shown to prolong life compared to a placebo in relative short-term studies. But longer term studies showed that AZT's benefits, though real, wore off.

Ritonavir is a member of a new class of drugs known as protease inhibitors that have excited participants at the Third Conference on Retroviruses and Opportunistic Infections, which ended Thursday. Studies reported earlier this week showed that another protease inhibitor, indinavir, when combined with standard AIDS drugs, appeared to be the most powerful AIDS therapy ever tested in infected patients.

One study focused on the amount of HIV in the body, showing that the indinavir combination reduced the amount of HIV to levels that could not be detected by standard laboratory tests in 26 patients over 24 weeks.

Earlier studies have shown that protease inhibitors lead to a sustained rise in the number of CD-4 cells, which are the specialized white cells in blood that are crucial for immune system function and that are destroyed by HIV.

In the ritonavir study, involving nearly 1,100 patients, 13 percent died or suffered further progression of severe AIDS compared with 27 percent of patients receiving a placebo, Dr. John M. Leonard, an Abbott Laboratories official reported. Disease progression was defined as the onset of a new AIDS-related illness like thrush in the gullet, a cancer known as Kaposi's sarcoma, infection of the retina with cytomegalovirus or pneumocystis carinii pneumonia.

In terms of death alone, the death rate was 4.8 percent among 543 patients who received ritonavir compared to 8.4 percent among 547 patients who received a dummy pill, or placebo, Leonard said.

The study was designed to allow all patients in both groups to continue receiving all anti-AIDS virus drugs that they were taking before the ritonavir study began. Thus the participants were taking many combinations of anti-HIV drugs. But the participants from 67 medical centers in the United States, Canada, Australia and seven European countries agreed to let the selection of ritonavir or placebo be made by lot.

Participants had to meet several criteria before entering the study. One was to have been taking one or two marketed anti-HIV drugs for at least nine months at some time in the past. Another was to be free of any active infection with one of the many microbes that can complicate AIDS.

A third was to have a CD-4 count less than 100 cells per microliter. The normal count is from 800 to 1,200 but ranges widely.

The participants first learned they were HIV-infected about six years before entering the study.

About one-quarter of the participants took either of two other anti-HIV drugs known as AZT or d4T. None was allowed to take 3TC, a drug that was combined with indinavir and AZT in the study reported earlier this week. Protease inhibitors act on a different part of the HIV life cycle than AZT and other marketed anti-HIV drugs.

Some data reported in the ritonavir study was troubling because it showed that the amount of HIV rose steadily after dropping precipitously within the first two weeks of therapy. But Leonard said that other studies suggest the anti-viral effect will be more sustained.

Dr. Anthony S. Fauci, the head of the National Institute of Allergy and Infectious Diseases, asked Leonard whether the unfavorable trend was due to the appearance of strains of HIV resistant to ritonavir. Leonard said resistance studies had not been completed.

In the new study, the CD-4 count rose and stayed elevated for 16 weeks. The numbers of CD-8 cells, a different type of immune white cell in the blood, also rose.

About 15 percent of patients taking ritonavir dropped out of the study because of side effects, chiefly nausea and other gastrointestinal problems. This was about double the 7 percent rate in the placebo group. Kidney stones were not reported as an adverse effect from ritonavir, as had been the case in 2 to 3 percent of patients taking indinavir.

Late last year, the FDA approved the marketing of the first protease inhibitor, saquinivir, which is made by Roche. In December, Abbott asked the Food and Drug Administration for permission to market ritonavir. Merck & Co. is asking for approval to market indinavir. An advisory committee to the Food and Drug Administration is expected to review such requests at meetings in several weeks.