Los Angeles Times - Saturday, September 19, 1998
Marlene Cimons, Times Staff Writer

The newest addition is regarded as one of the most important new AIDS drugs ever. It brings with it a paradoxical--although clearly not unwelcome--dilemma: The strongest and most effective AIDS drugs are becoming available faster than experts know how to use them.

"The good news is that there are a lot of options now," said Dr. Oren Cohen, assistant director for science policy at the National Institute of Allergy and Infectious Diseases. "The bad news is that we really don't know yet the best way to prescribe them."

In recent years, AIDS specialists have realized that the most effective AIDS therapy is to give combinations, or "cocktails," of three different classes of drugs that attack the human immunodeficiency virus at different stages of its replication cycle. In approving efavirenz, made by DuPont Pharmaceuticals of Wilmington, Del., the FDA is telling physicians to use it as part of their cocktail prescriptions but is not specifying which other drugs to use with it.

The multiple punch therapy is believed to keep the virus at virtually undetectable levels, resulting in prolonged survival and a high quality of life.

But the drugs used in the cocktails have side effects, require complicated and cumbersome dosing schedules and still can lose their effect as the virus ultimately develops resistant strains.

The crucial question now facing AIDS researchers is finding which combinations of which drugs work best--and when to give them.

"Although efavirenz is an important new drug, it will not replace any of the other drugs," said Dr. Robert T. Schooley, who chairs the executive committee of the federal government's AIDS Clinical Trial Group.

"We need to use them together . . . to have the most effective control of viral replication," Schooley said. "This gives us more opportunity to treat the virus, but it also emphasizes the need to do the research to find out how best to use" the various drugs.

To this end, the federal government is about to launch a major study using all of the drugs in the three classes in various combinations, Schooley said.

The latest drug is in the class of drugs known as non-nucleoside reverse transcriptase inhibitors. It will be marketed under the name Sustiva and is the third in this class of antiviral drugs to receive approval. Experts regard it as exceptionally important, however, because it is many times more powerful than the two currently available non-nucleoside drugs--delavirdine and nevirapine--and because it is easy to take.

In fact, they believe it is just as potent as another class of drugs, the protease inhibitors, which has generated the most excitement among doctors and patients in recent years.

The introduction of protease drugs in the mid-'90s has been credited with dramatically improving the health and extending the lives of many AIDS patients and of prompting the first declines in AIDS deaths since the epidemic began in 1981.

But the protease drugs are not effective when used by themselves, and their positive effect--even in combination--does not appear to last indefinitely.

The cocktails are typically composed of drugs from each of the three classes of drugs--a protease drug, a non-nucleoside drug and a nucleoside drug, such as AZT.

Until now, the most potent drugs by far have been the protease inhibitors, and they have been used aggressively--early on after infection--with the other weaker therapies.

But with the introduction of a such a potent non-nucleoside as efavirenz and the expected FDA approval soon of a powerful new nucleoside drug--Glaxo Wellcome's abacavir, which is reported to be several times more potent than AZT--the debate has escalated about which specific drugs to use and when.

Should patients take the most potent combinations immediately, or save them for later? Should they delay a protease-containing combination--or start with one?

"Do you take a chance and blow your ace at the beginning? Or save your big guns for later?" asked Dr. Henry Masur, chief of the critical care medicine department at the National Institutes of Health clinical center and former chairman of an FDA advisory committee that evaluates experimental antiviral drugs. "Scientifically, we just don't know yet. It is a dilemma--but one that is fueled by opportunity."

Efavirenz is more convenient for patients than many of the drugs with which it must be used. Unlike the protease drugs, which require multiple doses taken on an empty stomach, efavirenz is taken once a day, usually at bedtime, and can be taken with or without food.

Its side effects include dizziness, insomnia, abnormal dreams, impaired concentration and drowsiness. The symptoms often resolve after several days, the FDA said.

However, the agency warned that there have been some rare reports of delusions and severe acute depression, predominantly in patients with a history of mental illness or substance abuse.

The FDA has recommended that efavirenz be used in combination with other drugs, a protease inhibitor and/or a nucleoside drug, although it does not specify which ones. Also, it is known that, if the drug is taken alone, viral resistance to it--and the other two drugs in the class--develops more quickly and easily than with other antiviral drugs.

"If you use this drug incorrectly, that is, alone, you can ruin the effect of all of the non-nucleosides," Schooley said. "With some drugs, the virus has to make multiple mutations to escape the drug. With efavirenz, one mutation and it's gone and the other two drugs in the class are gone--you can't use them again. You lose all three. It's a very potent drug. But there is little margin for error, and it should never be used alone or prescribed by physicians with no experience in treating people with AIDS."

Schooley said that the planned study eventually would provide more detailed answers for physicians seeking to prescribe these drugs most effectively.

The research is designed to determine which combinations are the most effective and the optimal time to give them.

The research will compare different patient groups to others on different drug combinations "to see what provides the most durable response," Schooley said, meaning the longest period of viral suppression.

For example, one group of patients will receive two nucleoside drugs plus a protease drug. A second group will get two nucleosides plus one of the three non-nucleoside drugs, either efavirenz, delavirdine or nevirapine. And a third group will be given efavirenz, a protease inhibitor and a nucleoside drug.

"We will be looking for how long . . . before the virus develops resistance," Schooley said. "What we do will depend on how fast people's regimens fail. . . . Once a regimen fails, you switch to another one."

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