New Drugs Offer Hope in Battle Against AIDS : Health: Preliminary trials of protease inhibitors show that they are 10 to 20 times as powerful as AZT.
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.
Because HIV ultimately develops resistance to each of the protease inhibitors, Markowitz emphasized that no one of them should be viewed as a cure. “Nobody sitting at home should say, ‘Oh my God, I have to get this drug,’ ” he said.
One way around this resistance, they said, might be to overwhelm the virus with an attack from several directions, including one or two antiviral agents in combination with two, three or more protease inhibitors to wipe out the virus before it can mutate into a resistant form.
That was the approach, he added, that was ultimately successful in curing childhood leukemia. “One drug won’t work. Two drugs won’t work. Three drugs might work. Four drugs can cure,” he said.
The increasing importance of AIDS as a public health problem was noted by Dr. Harold W. Jaffe of CDC, who said that more than 440,000 cases of AIDS have been reported in the United States through 1993--about 75% of them in the 25-to-44 age group. AIDS had become the leading cause of death among men in that age group in 1992 and surged into the overall lead in 1993, he said, but is still fourth among women, behind cancer, accidents and heart disease.
Researchers have long argued that AIDS cannot be spread by kissing, and now they think they know why. Dr. Tessie McNeely and Dr. Sharon Wahl of the National Institute of Dental Research reported here that they identified a protein in saliva, called SLPI, that specifically blocks infection of blood cells by HIV.
McNeely and Wahl also found that SLPI is present in the bloodstream, but only in very small amounts. They speculated that it might be possible to boost quantities of the protein in blood, or to use a drug that mimics its action, as a kind of vaccine to block the spread of the virus.
Also on Tuesday, Dr. Steven Miles of UCLA and Dr. Patrick Moore of the Columbia College of Physicians and Surgeons provided new evidence to bolster their contention that Kaposi’s sarcoma, the disfiguring skin tumor that has become a hallmark of AIDS, is caused by a previously unrecognized herpes virus.
Miles and his colleagues reported in December that they had found DNA sequences similar to those from known herpes viruses in tumors from AIDS patients.
The team reported Tuesday that they had now identified the DNA sequences in Kaposi’s patients who do not have AIDS. Miles said: “I am convinced it is both a herpes virus and a cause of Kaposi’s sarcoma.”
