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Protease inhibitors make splash in AIDS care (7/30/97)

Seventeen years into the war on AIDS, drug therapy has advanced to the point that it is holding the AIDS virus in check - at least in some prisoners of the war.

Physicians are mounting a major offensive on the disease thanks to new drugs called protease (pro-tee-ace) inhibitors. These therapeutics are being used in combination with the older generation of anti-AIDS drugs, such as AZT, to produce promising results in many patients.

"Clearly protease inhibitors are the most potent anti-HIV drugs we've had," said Jean Smith, MD, associate professor of medicine at The University of Texas Health Science Center at San Antonio and staff physician at University Hospital and Audie L. Murphy Memorial Veterans Hospital. "They've had a tremendous impact. Some people who could expect a limited life span just a few years ago are now readjusting and even thinking about saving for retirement."

Infection with the human immunodeficiency virus (HIV) leads to the condition AIDS, short for acquired immune deficiency syndrome. At least 750,000 people were infected with HIV in North America at the end of 1996, according to United Nations estimates.

Today's combination therapy strategies were prompted by experiences with patient outcomes and development of new drugs to fight HIV.

"Many investigators have found that the best results are attained with at least a three-drug combination," Dr. Smith said. For most patients, she said, one protease inhibitor is recommended along with two ''reverse transcriptase inhibitors" (such as AZT). The different groups of drugs short-circuit the HIV infection at different steps in its replication.

A virus grows by infecting a cell and using that cell's machinery to re-copy itself (or replicate). When the copies are mature in their formation, they break out to infect other cells. "Protease inhibitors block maturation of HIV so that once it leaves a cell it is unable to infect new cells and repeat the cycle," said Jane Appleby, MD, assistant professor of medicine at the Health Science Center, staff physician at University and Audie L. Murphy hospitals, and medical director of the San Antonio AIDS Foundation.

Protease is an enzyme that constructs a coating needed for the virus to survive outside the cell, Dr. Appleby explained. Without this coating, HIV cannot assume its adult, virulent form.

Unfortunately, the virus is a resilient adversary. In some patients, the protection offered by drugs is short-lived as the virus adapts and becomes resistant to intervention. "Ideally, you'd like to have all three of the drugs you're giving the patient be ones he has not taken before," Dr. Smith said.

Side effects depend on the medication taken. The drug Saquinivir, for example, is the least potent protease inhibitor and the easiest for patients to tolerate, Dr. Appleby said. Taken three times every eight hours, this oral medicine may cause loose stools and abdominal cramping.

Ritonivir is a very strong protease inhibitor that may interact unfavorably with other medications, giving people a tingling feeling around the mouth, a metallic taste in the mouth, nausea, vomiting and other effects. Patients take six Ritonivirs every 12 hours.

"Another major side effect is cost," Dr. Appleby said. "These drugs are very expensive. For example, estimates are $14 to $22 day for Ritonivir and $13 to $19 a day for Saquinivir."

What percentage of AIDS patients will respond to this therapy? ''Studies show it's about 90 percent, if the patients haven't been treated at all previously or have been treated for a short time with only AZT," Dr. Smith said. "Other patients who have been extensively treated with AZT and similar drugs may not have as high a chance of response to protease inhibitors."

Other powerful HIV medicines are expected in the near future. That, combined with the ability to more sensitively measure viral particles in blood plasma, should result in greater management of patients' immune systems.

Contact: Will Sansom (210) 567-2570