AZT MAY LIMIT AIDS PATIENTS' OPTIONS : DRUG'S USE COULD INHIBIT NEW THERAPIES.

Byline: Associated Press

AIDS patients who used early treatments such as AZT inadvertently may have doomed their chances of using new breakthrough therapies, researchers said.

Between 5 percent and 30 percent of AIDS patients will receive little or no benefit from promising drug ``cocktails'' that use protease inhibitors, researchers said.

The patients, who took older antiviral drugs, may have fortified the surviving AIDS virus, which subsequently spawned mutations that the earlier drugs missed.

Those mutations may be out of the reach of current therapies, experts said.

``The irony is that what we as physicians did a few years ago in trying to fight the disease has left a number of patients with fewer options,'' said Daniel Kuritzkes, an AIDS researcher at the University of Colorado.

``We haven't seen the end of the dying,'' said Michael Gottlieb, the pioneering AIDS researcher who gave the disease its name in 1983.

AIDS has killed an estimated 343,000 Americans.

New treatments involve a class of drugs that inhibit HIV protease, an enzyme that the AIDS virus needs to reproduce. The protease inhibitor is taken in combination with two older antiviral drugs.

Because the drugs must work together, the cocktail therapy is weakened if an AIDS strain is resistant to one of its constituents.

No formal studies have been conducted to determine how widespread the resistance problem is, and currently there is no way to predict which patients will be resistant.

Good intentions led to the current problem in 1987. AZT, developed for cancer therapy, became the first drug that seemed to halt the progression of the AIDS virus.

Early results looked good.

``People talked in those years about the virus becoming latent,'' Gottlieb said. ``But what we know now is that the virus is never latent. From the time a person acquires HIV, this virus is an active infection.''

So active, in fact, that the virus makes copies of itself 10 billion times a day, said Douglas Richman, a leading researcher at the University of California, San Diego.

AZT taken alone only slowed that replication rate.

Worse, every millionth replication resulted in an imperfect copy of the virus that sometimes proved resistant to an antiviral drug, Gottlieb said. The mutations rapidly multiplied.

Doctors switched patients to new drugs as AZT lost its effectiveness, but resistant AIDS strains often were immune.

``The drugs came along one at a time when we did not appreciate the rapid rate of reproduction, the high frequency of mutation,'' Gottlieb said. ``It was a resistance accident waiting to happen.''

Researchers are working on the problem. Several trials are being conducted with combinations that include two protease inhibitors and only one older drug.

David Ho, Time magazine's Man of the Year and head of a New York AIDS research clinic, is conducting a study that uses four drugs: two protease inhibitors and two older ones.