The Wall Street Journal - February 1, 2000
Michael Waldholz, Staff Reporter

This is one of the more intriguing and controversial issues being addressed at a major AIDS science meeting this week in San Francisco. Several new but very preliminary studies presented at the conference Monday show that, in some instances, test subjects whose drug therapy is intermittently interrupted for several weeks or months are still able to keep HIV, the AIDS virus, from exploding out of control.

In addition, new evidence suggests that the underlying virus doesn't necessarily develop resistance to the drug therapy. In one study, three patients who stayed off drug therapy for four months were later able to resume their drug regimen without any drug resistance or long-term health problems.

New Way to Fight AIDS?

New reports suggest that temporary interruptions of AIDS-drug therapy may help, rather than hurt, long-term efforts to fight HIV, the AIDS virus.

When the therapy is halted, virus levels in the bloodstream rise, triggering a new immune-system response.

The new immune response often includes so-called "killer" cells that may augment the effectiveness of drug therapy when it is resumed. Scientists warn that patients shouldn't attempt such "drug holidays" on their own.

AIDS researchers said the new findings are important because they suggest that brief periods of "drug holidays" for certain people may stimulate an especially powerful immune-system response against HIV that doesn't generally occur when patients closely adhere to the drug regimen. Such an intensified immune response, some scientists said, may help prolong the effectiveness of drug therapy and may allow some patients to reduce the amount of drugs they need to take to keep the virus in check. In some instances the boosted immune response may allow some patients to stay off drug therapy altogether.

Possibly Giving the Wrong Message

Scientists conducting the new studies, however, said they are worried the new reports may inadvertently encourage some AIDS patients, especially those who have grown tired of the arduous multidrug therapy, to halt treatment on their own. The researchers point out that the new data, while tantalizingly suggestive of a new way to fight the virus, is coming from a handful of very small controlled studies and anecdotal reports -- a far cry from the kind of convincing evidence required for widespread therapy changes.

Still, "the whole area of research is very exciting," said Bruce Walker, a researcher at Massachusetts General Hospital in Charlestown, Mass., who led one of the studies presented Monday. "For the first time we are seeing evidence that we may be able to call on the immune system to help the drugs fight off the virus."

The treatment of AIDS has been revolutionized since 1996 when doctors began treating patients with a "cocktail" of three or four drugs, including a so-called protease inhibitor. In many patients, especially those treated soon after initial HIV infection, the combination of drugs can drive the amount of HIV in the bloodstream below the point where it can be detected by the most sensitive tests.

Decline in Death Rates

By keeping the virus levels down, many patients are living longer. The annual death rate from AIDS in the U.S. is about one-third of what it was more than four years ago, primarily because of use of the drug regimens.

But the drugs can cause problems; the treatment is expensive, typically more than $10,000 a year, and adhering to the daily routine of numerous pills can be difficult, especially since the drugs can cause serious side effects for some. Also, the virus can generate resistance to the drugs over time, meaning the therapy's effectiveness can wane.

"We all know we need to find a way to augment the drug therapy, to make it better, longer-lasting," said Franco Lori, co-director of the Research Institute of Genetic and Human Therapy based in Washington, D.C., and Pavia, Italy. "Many of us now strongly believe we need to generate a stronger immune response against the virus, and the new research indicates that briefly interrupting drugs therapy may be one way to do that."

One study led by Dr. Lori and his colleague, Julianna Lisziewicz, compared two small groups of patients, all of whom were able to keep their virus levels under control with drug therapy. In the test, patients halted therapy several times for at least eight weeks each time, and the therapy was resumed only if virus levels rose sharply.

'Killer' White Blood Cells

In one group of 10 patients who received a combination of two drugs, Videx and hydroxyurea, virus levels rose only slightly after the drug therapy was halted. The virus levels of a similar group of 10 patients taking a cocktail of three or four drugs rose much faster and higher during the interruption period.

Dr. Lori said he believed the Videx and hydroxyurea combination may help boost the immune response but that the test was too small to make such a claim. Both drugs are made by Bristol-Myers Squibb Co. Much more important, he said, was evidence in both groups that when the therapy was halted and the virus re-emerged, the patients generated a different kind of immune response than occurred before therapy was stopped.

In the study by Dr. Lori and in several of the other studies presented Monday, the re-emerging virus triggered the immune system to produce high levels of so-called cytotoxic, or "killer" white blood cells. There is increasing experimental evidence that these killer cells are more able to keep HIV in check than are other types of immune-system white cells. The killer cells aren't generated when the virus levels are very low, but the new research indicates that when drug therapy is halted and the virus levels rise, the immune system goes on heightened alert and sends out armies of the anti-HIV killer cells.

More Work Is Needed

Dr. Lori has pioneered the notion of interrupting therapy. He has studied two patients who have been able to keep HIV in check without drugs, after they were treated for a long time and then ended therapy on their own. The new research is an attempt to replicate or understand why temporary interruptions of therapy may be helpful.

In a study from Mass General, researchers halted therapy twice in a test involving seven patients. During a second interruption of therapy, the virus levels of three patients remained low, while the amount of killer cells in their bloodstream rose sharply. Three patients were able to stay off drugs for four months before their virus levels rose to the point that doctors decided to resume drugs.

"The theory is that when the virus is kept below detection, the immune system isn't seeing enough virus to launch a powerful attack on its own," Dr. Walker of Mass General said. "The new studies provide us some powerful hints that we may be able to figure out how to harness the immune system against HIV. But a great deal more work will need to be done before we know for sure."

Write to Michael Waldholz at mike.waldholz@wsj.com1
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