The San Francisco Examiner - Monday, Sept. 29, 1997
Lisa M. Krieger Examiner Medical Writer

Slightly more than half of the patients in a San Francisco General Hospital-based study developed evidence of drug failure after six months of treatment, and saw their AIDS virus levels rise, according to a study released Monday.

More optimistic are the results from the rest of the patients in the study: One year after the initiation of treatment, their virus remains persistently undetectable, suggesting long-term good health.

"In our clinics, we appear to be seeing the epidemic split in two," said Dr. Steven Deeks, assistant professor of medicine at UC-San Francisco, who is presenting his findings at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy in Toronto.

"About half of our patients will see a long-term, possibly permanent, response to these drugs while the other half may begin to exhibit disease progression again," said Deeks.

The 53 percent of patients who had evidence of failure after at least six months of therapy tended to be people who already had very advanced HIV disease, defined by researchers as a low immune system CD4 cell count and high levels of virus. Most had tried multiple anti-viral drugs in the past.

The 47 percent of patients who obtained lasting benefit from the drugs, called protease inhibitors and often used in combination with one or more other anti-viral agents, were those who were more recently infected and who had not been treated with earlier generations of anti-viral medicines.

Until this S.F. General-based study, no one knew what proportion of "average" patients taking the drug combination was benefiting from it. Doctors generally do not track a therapy's success the way researchers do in the clinical studies that first document its results.

Clinical trials showed unqualified success with the drugs, which offered bright hope in a dark time. The often-disappointed AIDS community was told that things were different now - that the triple-drug combinations might turn AIDS into a chronic, manageable disease, a lifelong affliction rather than a fatal illness.

The news was so compelling that people at all stages of disease rushed to seek treatment.

But these latest findings show that for some people, lasting benefit is as elusive as ever. While drug combinations can delay disease and death, they have serious limitations. Keeping HIV at bay, even with the most potent three-drug cocktails now available, is not always possible.

For many patients, combination therapy is another in a long list of bitter disappointments.

The irony is that those less likely to be helped by the new drugs tend to be highly educated and engaged patients - often AIDS activists - who were infected long ago and conscientiously tried each of the AIDS drugs individually as they were introduced over the years. Now, this early conscientiousness may have worked against them, because they are resistant to the entire combination.

The failure of current therapies demands new and better drugs, said Deeks. "The pharmaceutical industry, the government and all researchers need to remain vigilant and continue to develop new therapeutic options for HIV-positive patients."

Unlike the patients selected for well-controlled, industry-sponsored clinical trials, "real world" San Francisco AIDS patients, particularly those treated in a public clinic like that at S.F. General Hospital, arrive with the odds stacked against them.

They tend to have been infected a long time, have tried a litany of other agents, and may have trouble complying with the complicated treatment regimen. So while clinical trials show a success rate of 80 to 90 percent, the more typical patient population may have only a 50-50 chance of enduring benefit.

"Clinical trials tend to enroll patients who are healthy, who haven't been on much therapy in the past and who are highly motivated; they are not the typical patient," explained Deeks.

The 136 patients in the study had, on average, a low CD4 count of 169. A normal CD4 count ranges from 500 to 1,000 and AIDS is defined by a CD4 count of under 200. They had a high viral load of 70,000 copies of HIV per milliliter of blood. They were treated with a protease inhibitor, such as indinavir or ritonavir, in combination with at least one and often two other anti-viral drugs, such as AZT and 3TC.

There is a biological basis for the problems encountered by this population: A virus that is exposed to sub-optimal doses of inferior drugs learns to sidestep treatment. Because early treatments offered only partial suppression of the virus, HIV survived and rebounded, with a genetic diversity that then made it resistant to all available agents.

A companion paper, also presented by Deeks, offers the disappointing news that people who fail one treatment with a protease inhibitor have only limited success with a second. In this second study, 16 patients who failed one protease inhibitor were treated with an aggressive combination of two powerful protease inhibitors and two other anti-viral drugs. Most of the 16 had a limited and short-lived response to the drugs, Deeks said.

"This finding suggests that there is cross-resistance among protease inhibitors and that patients may have only one shot at achieving long-term viral suppression," he said.

But those patients who succeed in combination treatment may have a bright future.

"For those who made it past six months and have stayed undetectable for as long as they continue to take drugs, I predict they will stay undetectable," said Deeks. "If people fail (treatment), failure comes early," usually within six months.

Researchers at the conference await results from a trial by Dr. Roy Gulick of New York University, which is expected to show that the same 27 out of 30 people whose viral levels were undetectable after six months of three-drug therapy remained undetectable two years later.

Also anticipated is a study from France suggesting a dramatic new approach to treatment: "Maintenance therapy" for patients in whom the virus is consistently undetectable. Rather than keeping patients on three drugs for many years, perhaps decades, researchers there say they have had success in ithdrawing the potent protease inhibitor, while maintaining anti-viral benefit.

Most researchers have abandoned the idea, at least for now, of attempting to stop treatment entirely, said Deeks. The terms undetectable and eradication may be chimera. Just because HIV can't be found doesn't mean the virus isn't there - or that it isn't replicating. HIV insinuates itself into the DNA of the body's cells and when treatment stops, the virus surges back without so much as a pause, experts now believe.
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