WASHINGTON — In the first good news to come out of the battle against AIDS in this decade, researchers reported Tuesday that a new family of drugs called protease inhibitors can sharply reduce replication of the human immunodeficiency virus and restore immune system functioning in patients in the early stages of the disease.
Results from preliminary clinical trials of two of the drugs indicate that they are 10 to 20 times as powerful as AZT--the currently used drug--in clearing the virus from patients' bodies and that immune system regeneration can persist for at least six months.
At least seven protease inhibitors--which attack an enzyme unique to HIV--are now in trials in humans, with several more expected to begin soon. Although no single one of them appears to be a "magic bullet," many researchers now believe that a "drug cocktail" of protease inhibitors and antiviral drugs could provide a potent antiviral punch against HIV, Dr. Martin Markowitz of the Aaron Diamond AIDS Research Center told the Second National Conference (on) Human Retroviruses and Related Infections.
Researchers cautioned, however, that this is not a cure but rather a way to slow the progression of the disease. Moreover, they said that highly successful preliminary results of antiviral activity often prove ephemeral as the AIDS virus finds new ways to subvert efforts to control it. In all the trials, the new drugs began to lose some effectiveness after several weeks or months, but researchers said they thought they could overcome that problem with the cocktail approach.
"We are encouraged by these data," said Dr. John Leonard of Abbott Laboratories, "but because of the small number of patients involved and the short duration of the trial, many questions remain to be answered."
Other highlights of the meeting included a report from the Centers for Disease Control and Prevention indicating that AIDS has now surpassed accidents as the leading cause of death among Americans ages 25 to 44, new insight into why HIV cannot be spread by kissing and stronger evidence that Kaposi's sarcoma is caused by a previously unrecognized herpes virus.
But most of the excitement Tuesday centered on the clinical trials of protease inhibitors, results that Dr. George Shaw of the University of Alabama at Birmingham called "groundbreaking."
AIDS scientists have been searching almost frantically for new types of drugs. Members of the only existing class--the so-called nucleoside analogs, including AZT, ddI and ddT--have proved only modestly effective and are plagued by severe side effects because they interfere with cellular enzymes similar to the viral enzyme they target.
In contrast, the viral enzyme protease, which is important in HIV replication, is unlike enzymes in human cells. Researchers have high hopes that drugs designed to inhibit this enzyme will not interfere with normal cellular activity. So far, that has proved to be the case. The main side effects from the seven drugs tested so far have been nausea, diarrhea and occasional lightheadedness.
The protease inhibitors, Markowitz said, "are a major advance in therapy."
Markowitz and Dr. David Ho of the Aaron Diamond Center in New York City studied Abbott's protease inhibitor, called ABT-538, and found that it shut down more than 99% of HIV replication in AIDS patients and reduced the number of virus particles in the blood by 70% to 90% over a three-month period.
And when the virus was held in check, they said, the number of virus-fighting CD4 cells more than doubled, on average, rebounding much more sharply than with AZT. In one dramatic case, a man's CD4 count rose from 68 cells per milliliter of blood to 680 cells, and his immune system went "from grossly abnormal to something that could pass for normal," according to Ho.
Researchers from Merck reported that high doses of their protease inhibitor, called L-735,524, reduced virus levels by more than 99% and tripled blood CD4 levels. The virus eventually developed some resistance to the higher doses but not as rapidly as with lower levels, which lost effectiveness after six months.
Hoffman-La Roche Inc. reported that it had completed enrollment of 1,000 patients in a trial of its protease inhibitor, saquinavir, and planned to seek marketing approval from the Food and Drug Administration later this year.
Perhaps the most discouraging note of the day involved the drug SC-52151, produced by G. D. Searle. Although that compound appeared very promising in test tube trials, the first results in humans were very disappointing. Company researchers said they have identified a protein in human blood that binds to the drug, blocking its action. They believe that the same protein binds to many other protease inhibitors as well, reducing their efficiency.