The San Francisco Examiner - Sunday, Jan. 26, 1997
Lisa M. Krieger, Examiner Medical Writer

Here at the Fourth Annual Conference on Retroviruses and Opportunistic Infections, there are plenty of troubling reminders that, despite a string of major therapeutic successes, a cure for AIDS is still well out of reach.

"I would not expect the majority of patients to eradicate the virus . . . with our current regimens," said conference organizer Dr. Robert Schooley of the University of Colorado Health Science Center in Denver. "We need to be realistic about what can be expected with our current generation of drugs.

"But even if we can't eradicate the virus," he added, "we may be able to keep it from replicating for years."

There is new evidence that the protease inhibitors work in even very sick patients. Scientists reported that the drug indinivir (Crixivan), made by Merck Labs, was able to suppress HIV to "undetectable" levels in 65 percent of patients with very advanced AIDS.

But other studies presented at the five-day conference suggest that despite such successes, the new therapies might not completely reverse the damage the immune system incurs from long-standing HIV infection.

In other cases, the new therapies are limited because HIV is already resistant and can sidestep any anti-viral effect.

"The right direction'

"There are a number of difficulties with our current regimens," admitted Schooley. "It is an incremental process, but we're headed well in the right direction."

Scientists here are scratching their heads over a case study reported by Dr. Mark Jacobson of UC-Med Center, examining five cases of AIDS-related blindness in people who, at least on paper, seemed well out of danger.

The blindness, called CMV retinitis, is almost always seen only in people with immune cell counts below 50. But these five men - sick but recovering, thanks to triple-drug therapy, with immune cell counts over 200 and climbing - still succumbed to blindness.

It suggests that the immune systems of patients with "undetectable" levels of virus might look normal but not act right, said experts at the conference.

Dr. H. Clifford Lane at the National Institutes of Allergy and Infectious Disease took a closer look at "recovering" patients - and found that when HIV is suppressed, certain types of immune cells, called "memory cells," return in great abundance. But others - notably, the "naive" cells needed to recognize future invaders - have disappeared.

A second study was more optimistic. Scientists at Case Western Reserve University Hospitals of Cleveland found that the immune systems of patients given the combination showed signs of a gradual return to normal. It is unknown what accounts for the conflicting observations, but may relate to the specific drug treatment or severity of patients' illness.

It is dangerous - even in cases of patients with Lazarus-like turnarounds - to prematurely withdraw the drugs that protect them from CMV, pneumocystis pneumonia and other AIDS-related illnesses, scientists concluded.

While viral eradication is a worthy goal, what kills people with AIDS is not the virus itself but infectious microbes, they said.

"We need to know how extensive and how profound the reversal of immune deficiency is likely to be in those with controlled viral replication," Schooley said. "This issue will be critical in the next 18 to 24 months."

For many, the new drug regimens don't work. For others, they are complicated, costly and difficult for some patients to maintain.

Reasons for optimism

Scientists at the conference reported on better versions of anti-viral drugs that have emerged in recent months. It is hoped that these agents are not only more effective but also simpler to take.

A next-generation protease inhibitor is Abbott's ABT-378, for which clinical trials on humans are just starting. It is more powerful than the three already licensed protease inhibitors.

Nelfinavir, under study by Agouron Pharmaceuticals, is another new protease inhibitor. HIV already has resisted this drug, but does so in a different way than with other drugs. So, nelfinavir may hold promise for patients who have not benefited from other protease inhibitors. Agouron also has a new drug called GW141, which, unlike earlier protease inhibitors, attacks HIV in the brain.

There is also optimism about a combination of a new protease inhibitor, called GW-141, and a nucleoside analog, GW-1592, both made by the drug company Glaxo Wellcome. Although GW-1592 is in the same category of drugs as older treatments, such as AZT, it attacks the virus at a different base of its genetic code than the others.

"The disease is not over," said Schooley. "But we can't put patients in liquid nitrogen and say "Come back when I know what to do.""

"It is important for patients to feel not that they have failed but that we, as doctors, have failed to completely control the disease," he said.
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