AZT May Mute Benefits of New AIDS Therapy

Even as excitement grows that new treatments have vastly improved the outlook for AIDS patients, a cruel irony has emerged--those who were most conscientious about treating their disease in the past may have put themselves beyond help from the promising new discoveries.

Widely heralded new treatments have raised hopes that AIDS, which has killed an estimated 343,000 Americans, may finally become a manageable disease, that new drug cocktails built around protease inhibitors could suppress the virus to the point of being undetectable. Researcher David Ho was named Time magazine’s “Man of the Year” for his part in its development.

But in the months since protease inhibitors raised worldwide hopes, some researchers and clinical practitioners report that many patients--their estimates range from 5% to 30%--will get little or no benefit from the new treatments.

These patients, who took long courses of AZT and other earlier antiviral drugs, in effect strengthened the surviving AIDS virus in their systems, some experts say. In these cases, the virus spawned mutations that the earlier drugs missed--mutations that now flourish beyond the reach of current protease inhibitor therapy.

“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 who is working on the resistance problem.

“We haven’t seen the end of the dying,” said Michael Gottlieb, pioneer AIDS physician who gave the disease its name as a UCLA researcher in 1983, and now heads a clinic in North Hollywood.

“A lot of patients have burned bridges, but of course we didn’t know we were doing that at the time,” Gottlieb said. “Some survive longer than they would have, but they may eventually become resistant and may very well die of AIDS in the next couple of years.”

“Among the patients I see, I would say that as high as 20% are in this situation.”

Other estimates range from 30% by Andre Pernet--vice president of research and development for Abbott Laboratories, which developed a protease inhibitor--to less than 10% by Kuritzkes and Douglas Richman, a leading researcher at UC San Diego.

The protease inhibitor therapies are still a major advance for most patients. “Nothing is 100% in this world, except death and taxes,” Richman said. “But this is pretty damn good.”

The new treatments rely on a new drug--a protease inhibitor designed specifically to attack the AIDS virus--taken in combination with two of the older antivirals. The combination is commonly known as a protease cocktail.

The drugs must work together. The ultimate effect is greatly weakened if an older drug is ineffective against the mutated virus.

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

“At first there is a 100% response to the cocktail,” said Pernet. “It’s over time that the virus escapes the cocktail. About six to 12 months after treatment begins, probably as many as 30% escape it.”

This resistance problem began, inadvertently, in 1987 when clinical trials produced promising evidence that a drug developed for cancer therapy seemed to stop the progression of HIV.

The drug, AZT, became the first AIDS medicine known to work directly on the virus. Until then, doctors could treat only the devastating illnesses caused by the virus’s crippling of the immune system--not the virus itself.

Ideally, drugs that target viruses are taken in combination with other anti-virals. But as AZT was the only drug of its type available at the time, it was given by itself, called monotherapy.

Initial results were hopeful.

“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.”

When fully active, HIV replicates at the astonishing rate of 10 billion times a day, Richman said. AZT at least slowed the rate. But the HIV never stopped reproducing. Worse yet, it sometimes makes deadly mistakes.

Approximately every millionth replication, according to Gottlieb, the virus turns out an imperfect copy, a mutation.

“There is no evil purpose for the virus,” said Pernet, “it’s just sloppy in its replication. And most of the time, the mistakes do not matter.”

But occasionally, a mutation proves resistant to whatever antiviral drug the patient is taking, freeing that mutation to multiply rapidly. The attack on the immune system resumes full force.

Until the patient’s health began to seriously falter--usually about two years after starting AZT therapy--doctors did not know the drug had been somehow compromised. Many of these patients were switched to another drug, ddI, that had in the meantime been shown to be effective against HIV.

Again, good results were obtained at first, but eventually, resistance often won out with each new drug.

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

There were patients who, for a variety of reasons, did not take any of the monotherapies--which may have unwittingly put them in a stronger position today.

Matthew Rosen discovered in December 1989, just before his 27th birthday, that he was HIV-positive. His physician suggested he begin taking AZT.

“But I didn’t want to take it right then,” said Rosen, now 34. “I had the luxury of not being very sick. I sort of considered AZT to be a kind of trump card if I did get sick.”

Eventually, his doctor insisted. “He said, ‘We’re in the arm-twisting stage, nearing the full headlock stage,’ ” Rosen said.

Still, Rosen held out and his health remained good. “It was just dumb luck” he refused, Rosen says now.

By 1990, doctors began experimenting with combination therapies, first with AZT and ddI, and then AZT with a drug called ddC. Results were mixed, but somewhat better than monotherapy.

But the next big step in fighting the virus directly did not come until 1995, when the first clinical trials for a protease inhibitor were announced.

These new drugs attacked an enzyme called HIV protease, which is crucial to the virus’ ability to replicate. The older drugs also curbed replication, but at another point in the virus’ life cycle. In a multi-drug treatment, the virus is attacked at several stages of its reproduction cycle.

In July, scientists announced at an international AIDS conference that protease inhibitor therapy could drastically slow the replication of the virus.

The new drug was the breakthrough, but other drugs had to be included in the therapy to prevent emerging mutations from multiplying. Therein lay the problem for patients already resistant to the older drugs.

“For those people, just to add the protease is almost monotherapy,” said Jules Levin, a former Wall Street trader who founded the National AIDS Treatment Advocacy Project. The project is well known among medical professionals and patients for its detailed Internet Web site that includes up-to-date information on clinical trials and test results.

Levin, HIV-positive for eight years, knows this from personal experience.

“Five years ago I started taking AZT,” he said. “About two years ago, we added 3dc.”

AZT and 3dc are two key drugs used in the protease inhibitor cocktail.

Researchers are working on the resistance problem. Several trials are now being conducted with combinations that include two protease inhibitors and only one older drug. Ho, the head of a New York AIDS research clinic who got the Time award, is conducting a study that uses four drugs: two protease inhibitors and two older ones.

Abbott labs has begun testing a protease inhibitor designed to be five times more powerful than those now available. The hope is that with all that potency, the new drug will be able to keep the virus in check by itself.

Glaxo Wellcome is testing a drug that researchers hope will leave virtually no resistant viruses, even though it works in a manner similar to AZT.

Levin is on one of the newer regimens--he declined to specify which--and is cautiously optimistic. “Because of what I know has happened in the past, I’m trying not to get overconfident,” he said.

“But in the last few months, my test results have been very good.”

The new regimens might come too late for George Prindle, 38, who exemplifies those who may be trapped by the aftereffects of first-generation drugs.

“I’ve seen the whole spectrum of drugs come and go, that’s for sure,” said Prindle, at his home in La Habra Heights.

He has been HIV-positive for 11 years, and until he had to stop working eight years ago, ran the business operations of an animation company that did work for such firms as Disney and ABC. His partner in the business, as well as in life, died five years ago of complications due to AIDS.

Prindle has been on AZT steadily for almost nine years. At various times, he also has taken courses of ddI and ddC, as well as other antivirals. These drugs may have helped keep him alive, but resistant viruses flourished.

He was enrolled in early clinical trials for protease inhibitors and has already been on several different protease cocktail regimens.

None worked. Recent tests showed that he had 1.25 million particles of HIV per cubic centimeter of blood. By comparison, some patients in whom the new therapies are successful have an undetectably low virus blood level.

Prindle said he has been told by his doctor that unless a new therapy is made available soon, he probably has only about six months to live.

“Well, for the last 11 years they’ve been telling me I’d be dying in two years, and I’m still here,” he said with a smile. “Maybe they’re wrong this time, too.”

For Rosen, who refused the earlier drugs, the outlook is far more favorable. He finally decided to begin drug therapy.

“This time, I think there is real data to indicate that this particular drug regimen holds the virus in check,” he said.

Just before Christmas, he took his first protease inhibitor cocktail.

“I’m a little nervous,” he said, “but I think the time is right.”