Wall Street Journal - September 29, 1997
Michael Waldholz

AIDS researchers at a conference in Toronto will present evidence today suggesting they are closer to the answer.

The researchers, from New York University and Merck & Co., will tell several thousand doctors, scientists and AIDS activists this morning that a "cocktail" of three drugs continues to fight off HIV, the AIDS virus, in 79% of patients treated for two years in the longest of any clinical trial of the new combination drug therapy.

Perhaps even more impressive, the researchers will show that the patients' disease-fighting immune system strengthens the longer the drugs work. This is the first time an HIV therapy has been shown to accomplish this for such a prolonged period.

The new data, though it involves only about two dozen test subjects, is strong enough to suggest a new emerging model for fighting AIDS: Patients who can remain on the therapy have a chance to keep the virus at bay and also to bolster their body's ability to fend off infections that are the cause for most illness and death related to AIDS.

"We are really encouraged, and a bit surprised, by the increasing return" in strength of the patients' immune systems, says Roy Gulick, a physician at NYU who heads the research team and will present the study's results to those gathered for the beginning of the four-day Interscience Conference on Antimicrobial Agents and Chemotherapy, an annual meeting where scientists highlight advances in treating infectious diseases.

"Everyone hoped that suppressing the virus would allow [immune-system] cells to repopulate," Dr. Gulick says. "Now, we finally have some evidence that it can happen." He adds: "The key is finding the right combinations of drugs to keep the virus [levels in the bloodstream] below detectable levels as long as possible."

The study, sponsored by Merck and employing its Crixivan version of the new protease inhibitor drugs, is an admittedly small test but it is being closely watched as a landmark for how long patients can be treated before the virus develops resistance and the drugs no longer work.

It was this study, dubbed 035, that first indicated to researchers at the international AIDS conference last year that a milestone had been reached in the 16-year AIDS pandemic.

But the AIDS treatment field has been holding its collective breath about the cocktails' durability, especially since anecdotal evidence from doctors and patients suggests that many people who receive the new therapy relapse after developing resistance to the drugs, often after doing well for several months. Earlier this month, data following 035 test subjects for 48 weeks was finally formally published in the New England Journal of Medicine. The new results detailed today follow the same group of 28 patients for 100 weeks.

Dr. Gulick will report that in 22 of the 28 patients receiving a combination of Merck's Crixivan and two other older anti-HIV drugs -- Glaxo Wellcome PLC's AZT and 3TC -- the virus appeared to be eliminated from circulating blood. In those patients, even the most sensitive test, which can detect as little as 50 virus particles in a drop of blood, was unable to find evidence of HIV. Untreated patients infected with HIV can carry 100,000 to one million particles of virus in the same amount of blood. Dr. Gulick says he believes that data from this test and others suggest that about 20% to 30% of treated patients will develop resistance. That is because the virus often seeds itself in cells in the body unreachable by the drugs, or because the virus is able to reproduce itself into a version invulnerable to the drugs.

"We've known that by combining a powerful protease drug with [older medicines] we can drive down the virus to undetectable levels for a good portion of treated patients," says Emilio Emini, the director of Merck's antiviral research who led the team that discovered Crixivan. "The question on everyone's mind is how long can you keep the virus down and what is the beneficial effect on the patient. The 035 test, simply because it is the longest, is giving us some answers."

Healthy people with intact immune systems have about 1,000 infection-fighting white blood cells, called CD4 T-cells, in a milliliter of blood. Someone with AIDS has a T-cell count of 200 or less. After 48 weeks on the triple-drug therapy, subjects in 035 had a median rise of 150 T-cells per milliliter of blood. In the latest two-year results, the T-cells jumped a median of 230 in the 23 patients whose HIV remained undetectable. Scientists familiar with the data being released today say the rise in T-cells suggests that, at least in some patients who are able to adhere consistently to the difficult drug regimen, the new therapy can restore health by reviving a previously crippled immune system.

"The whole key right now is finding a combination that works," says Scott Hammer, a research physician at Beth Israel Deaconess Medical Center in Boston. "Our frustration continues for those patients who simply don't respond, largely because they are already very sick or they have previously developed resistance to some of the drugs."

Dr. Hammer and others say that while the 035 trial is an important bellwether test, because it is so small they continue to await results from several dozen other combination drug tests now under way. Indeed, those gathered in Toronto this week will hear numerous presentations about a wide variety of combinations of drugs developed by Merck, Glaxo, Abbott Laboratories, Roche Holding PLC, Agouron Pharmaceuticals Inc., DuPont Co. joint venture DuPont Merck Pharmaceutical Co. and others. Researchers say that because many patients will relapse and because many others, especially the poor, can't afford the expensive drug therapy, new and more powerful drugs must still be discovered and developed by the drug makers.

"The advance we've seen over the past year or so proves drugs can drive down the virus and keep it down in many patients, something we only hoped for a few years back," says Merck's Dr. Emini. "But we have to be careful not to get too excited. We have a lot more work to do to discover less-expensive, easier-to-use and more-powerful drugs to use in combination therapies."

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