Companies Race to Market
With 'Protease Inhibitors'
After Good Test Results
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'I Feel Wonderful, Incredible'

Fifteen years into the global AIDS epidemic, researchers are seeing the first glimmerings of a cure.

A new combination of drugs shows startling evidence of success in driving the AIDS virus into remission, making it unable to wreak its lethal havoc on the immune system. For dozens of test subjects -- and perhaps thousands of patients now in treatment -- the prospect of imminent death is giving way to a remarkable rebound in health. It is the first time any medical therapy has shown the potential for rescuing people on the verge of succumbing to the disease.

"I'm excited. I feel strong. I feel hopeful. I feel normal again," says Eduardo Torreau, a 39-year-old former dancer in New York who has been on the new multidrug treatment for 20 months. Like many of the two dozen other patients interviewed for this story, he feels as if a death sentence has been commuted.

Two years ago, with his immune system crippled by the virus, Mr. Torreau spent four months in the hospital fighting tuberculosis and pneumonia and bracing himself for certain death. Now, he says, he has gained 35 pounds of muscle and is starting a new career; this week he began taking classes in computer graphics.

Even many usually cautious physicians are astonished and inspired by the recent turn of events. While it is too early to claim an outright cure, "it now appears, at the very least, we may finally have the tools to turn [AIDS] into a long-term manageable and treatable disease, much like hypertension and diabetes," says Roy Gullick, a research physician at New York University's medical school. "Almost every one of my patients is doing significantly better."

Progress hasn't come easily. The path to the new therapy has wound through a decade of disappointment and frustration, unexpected product failures, intense corporate rivalries and secrecy -- and, in one instance, a blinding stroke of luck involving a test subject known as "Patient 142." Along the way, several drug giants shuttered their research efforts entirely. All told, researchers synthesized, analyzed and rejected tens of thousands of chemical compounds before finding a few that seem to be effective. In the process, scientists have begun to alter some long-held assumptions about how the virus does its devastating work.

Central to the current wellspring of hope is a new class of medicines known as protease inhibitors. In development for 10 years, these drugs block the workings of protease, an enzyme crucial to an early step in the reproductive cycle of the human immunodeficiency virus, HIV, which causes AIDS.

Although the new class is many times more powerful than anything tried before, even it can't defeat HIV by itself. But the new drugs are proving to be incredibly effective when used in a "cocktail" with two additional drugs based on AZT, which blocks another enzyme central to HIV replication.

Results just surfacing from clinical trials and lab studies suggest that scientists may finally have cornered the long-elusive virus, attacking it with unparalleled force from so many sides that it doesn't readily escape and spread as it has before.

Researchers emboldened by the findings are about to pursue a particularly historic undertaking: They are aiming for a full-fledged cure by working with patients who have only recently contracted HIV, instead of those in advanced stages of the disease. The new approach could fundamentally rewrite the battle plan for attacking AIDS. The effort "will answer the question of whether HIV infection can be eradicated in man," says researcher Martin Markowitz of the Aaron Diamond AIDS Research Center in New York. He adds: "We didn't have any way to even think about trying this before."

Already, almost 60,000 Americans, and 10,000 more people overseas, have received the new drugs, most of them since mid-March. Industry executives say an additional 50,000 to 250,000 people may be on the therapy in another year. Between 650,000 and 900,000 Americans are currently infected with HIV, according to the federal Centers for Disease Control.

The rollout of the new drugs is moving unusually fast: The first protease inhibitor to market, Hoffmann-La Roche Inc.'s Invirase, won approval from the Food and Drug Administration only in mid-December. Two more, Abbott Laboratories' Norvir and Merck & Co.'s Crixivan, were cleared just three months later. Two other entrants are in advanced stages of human testing, and corporate labs are racing to get several other experimental versions ready for human studies.

Despite all the enthusiasm, no one is yet ready to declare a cure. "I can't use that word, not yet," says Emilio Emini, who directs the protease project at Merck. And, certainly, there is good reason for caution. HIV has always managed to out-smart highly touted treatments in the past. Scientists suspect that a dormant reservoir of the virus still lurks inside recovering patients, ready to leap into action if they quit taking the drugs or if the virus mutates and stumbles upon a way to circumvent the cocktail's powers.

"I have enough respect for this virus to know that even if there is a very low rate of replication going on, that may be enough to reverse the gains we're seeing," says Robert Schooley, a veteran AIDS researcher at University of Colorado in Denver. "We need to watch these people and wait. Only time will tell us what we've got."

Some protease inhibitors also have painfully annoying side effects, albeit not nearly as toxic as those of AZT and its cousins, until recently the only promising class of AIDS drugs. Some of the new medicines have to be taken on a strict daily schedule: A raft of pills must be swallowed on an empty stomach three times a day, eight hours apart, and the patient must follow a rigid diet. Skipping the drugs even just a few days allows HIV to re-emerge dangerously in some patients.

Hefty Expense

Cost is another problem: Treatment will run $12,000 to $16,000 a year, and patients will probably have to stay on the drugs for many years, perhaps for the rest of their lives. The hefty expense and complicated dosing may push the new therapy out of reach for many members of the fastest-growing HIV population: the inner-city poor. Insurance coverage varies.

Still, even skeptical veterans of the AIDS struggle are finding it difficult to restrain their optimism. Says Mark Harrington, a longtime AIDS activist and critic of corporate and government efforts: "The recent abundance of good news is almost unbelievable. Fifteen years of public and private AIDS research efforts are paying off spectacularly."

Such optimism will likely gain momentum next month at the 11th International Conference on AIDS in Vancouver, where various scientists are expected to describe, albeit cautiously, the striking results of their latest clinical experiments.

In one notable trial, in which patients with advanced AIDS are taking daily doses of the multidrug regimen involving Merck's Crixivan, 25 of 26 subjects have gone eight months without any detectable signs of HIV infection in their blood. Even more impressive, eight of nine patients on the new treatment for almost a year appear to be entirely free of the virus.

Another report will come from David Ho, who directs the Aaron Diamond center in New York. He and Dr. Markowitz started giving various versions of the new therapy to two dozen healthy men a few weeks after the men became infected with HIV. In one 12-man group, 10 patients who have stayed on the therapy have no signs of virus in their blood. "We believe the way to beat HIV is to hit the virus hard and hit it early, with three drugs or more, at the first sign of infection," Dr. Ho says.

Jubilant Experiences

After a year of treatment, Dr. Ho plans to remove the therapy from several healthy patients to see whether the virus reappears; if it doesn't, that would be evidence that these patients might actually have been cured.

Encouraging clinical reports, exciting as they are, don't begin to capture the jubilant experiences of HIV patients for whom the new approach is providing, quite literally, new life. Last October, Andrew Howard of Huntington Beach, Calif., took his "last vacation," traveling to Hawaii with his companion, Charles Bouley. There, they spread the ashes of a friend who had just died of AIDS. Weakened from fever and dizziness and steadily wasting away, Mr. Howard barely had the strength to leave his bed each day. He turned over his power of attorney and installed oxygen equipment at his home.

In November, after months of badgering by Mr. Bouley, researchers at Stanford University admitted Mr. Howard into a clinical trial of Merck's new drug, Crixivan, with AZT and a related drug, 3TC. "I was desperate," says Mr. Bouley, a singer. "Andy's spirit had broken."

Just four weeks later, Mr. Howard's symptoms subsided. By March, "Andy seemed healthier than he had in years," Mr. Bouley says. The 29-year-old Mr. Howard has since gained 50 pounds, works out at a gym every day and has hired an agent to "shop around" the screenplays he writes. "I feel wonderful, incredible," he says. "I hope it lasts."

Merck Cocktail

Scott Higginson, 36, of San Jose, Calif., first tested positive for HIV in 1984. Three years ago, it turned into full-blown AIDS, forcing him to quit as manager of a child-care program. By last year, he was losing weight and suffering, daily, from diarrhea, nausea, fevers and cramps. "Everything was failing," he says.

Last summer, he started taking a cocktail containing Merck's protease inhibitor in a special trial. One month into treatment, his "T-cell count" (a measure of the infection-fighting white blood cells in his immune system) had soared to 100 from 38; by the third month, the count was up to 168, where it has remained. This is still low compared with the 1,100 mark of a non-HIV patient, but it is remarkable all the same. He has put on 12 pounds and is thinking about returning to work. "It's changed my life a lot," Mr. Higginson says. His doctor, Jonathan Shapiro, adds, "I'm seeing a lot of patients do about as well. It's pretty amazing."

Stephen Mendenhall of Kansas City, Mo., suffering from a constant fever and flu-like illnesses, started a regimen based on Roche's protease drug last January. In just three months, the amount of virus in his blood had been battered down to about 1/400th of what it was before he began treatment. His appetite has returned, enabling him to gain 24 pounds. Before he took the drugs, he says, "I was knockin' on death's door."

Such turnarounds, whether they prove to be temporary or long-lasting, are extraordinary given the litany of failures that has characterized most AIDS research. Half a dozen major campaigns to create a vaccine have all faltered. AZT and four similar drugs that followed it onto the market have never lived up to initial hopes for extending patients' lives significantly.

Isolating Protease

In 1986, scientists found a chink in HIV's armor when they isolated the protease enzyme. They soon began unlocking secrets to its crucial role in the HIV life cycle and realized that the enzyme was a new target they could hit with medical compounds. The protease breakthrough provided reassuringly familiar terrain, because most new drugs these days work by blocking some enzyme involved in the disease-causing process.

"The protease enzyme is very similar in structure to an enzyme involved in hypertension that we had been researching for years," says Andre Pernet, the head of research at Abbott Labs. "It's why we got involved in the search for an AIDS drug in the first place."

HIV destroys the immune system by invading and killing T-cells, the white blood cells that marshal an attack against an intruder. Once inside a healthy T-cell, HIV takes over the cell's genetic machinery, co-opting its components to churn out vast numbers of copies, which are dispatched to other T-cells, where the HIV copies do the same thing.

Biological Scissors

The protease inside HIV plays a key role after the virus has penetrated the T-cell's exterior. The enzyme acts as a kind of biochemical scissors, snipping apart a large protein inside the virus to form smaller fragments that the virus uses to assemble new copies of itself.

Drug-company scientists quickly realized that if they could wedge the right chemical compound between the protease and large protein, they might be able to shut down the virus's manufacturing operations. Research labs soon initiated projects to exploit the protease discovery.

But "we all soon ran into serious problems," says Suvit Thaisrivongs, the protease-project leader at Pharmacia & Upjohn Inc.'s U.S. labs in Kalamazoo, Mich. It quickly became apparent that the protease enzyme's active site, the area on its outer surface that locks onto the HIV protein to snip it into pieces, was like a yawning molecular cavern. Blocking protease would require plugging that wide gap with a new chemical -- but such a compound would, most likely, be too big to travel intact through the human digestive system.

Chemists at the drug companies synthesized bulky compounds that obstructed the protease's cutting site in test-tube experiments, but none were small enough to get into the bloodstream. "By 1990 we decided we'd have to pursue a completely different route," Dr. Thaisrivongs says. Instead of taking a big compound and trying to redesign it to slim it down, his team needed to find new, sleeker substances that might work just as well.

Trial and Error

Over the next few years, Upjohn's lab screened more than 100,000 candidates from its library of natural and man-made chemicals in its search. One chemical, a rat poison known as warfarin, worked pretty well, but it was too toxic. The chemical Upjohn ultimately would pick turned out to be a distant cousin of warfarin; the company hopes to push it into human trials by next year.

Other teams struggled. SmithKline gave up on its effort in 1991. Merck found a likely suspect, but it was too toxic when injected into lab animals. A separate project by a Merck-DuPont Co. joint venture fashioned a small and potent molecule using computer-aided design but discarded it after dangerous side effects cropped up in human trials. And at Abbott Laboratories, which in 1988 had quietly begun a large-scale protease push without telling rivals, chemists cranked out about 1,000 prototypes. By 1991, they had latched on to three that the company decided to try out in humans.

That is when a critical coincidence occurred. A top Abbott chemist, Dale Kempf, discussed the three protease prototypes at an AIDS science conference in Florida. In the audience was Dr. Ho. Then a virologist at the University of California's Los Angeles campus, Dr. Ho was pushing the unpopular notion that scientists had been wrong about key assumptions in how the AIDS virus worked and had vastly underestimated its ferociousness in the early stages of infection.

Dr. Ho realized the Abbott prototypes might provide him with an ideal tool to test his theory. He pitched the idea when he ran into Abbott's Dr. Kempf in an airport check-in line. "Dale agreed that maybe we could help each other," Dr. Ho says.

So began a collaboration that transformed Dr. Ho's career and the fortunes of Abbott's protease project.

Mutated Strains

The old view was that HIV lies dormant for years after an initial infection and kicks into high gear only later on. Then it reproduces so rapidly that, among its progeny, it churns out mutated strains that sidestep any new drug's defenses. This ability to mutate into a drug-resistant strain was seen as the central problem that limited the usefulness of every previous AIDS drug, including AZT.

So doctors usually waited as long as possible to introduce a drug that the virus is bound to find a way to beat. But Dr. Ho suggested that this may be too late. His new theory held that HIV starts reproducing rapidly immediately after invading the body but that patients and doctors don't notice it because the immune system wages a valiant defense. Only later is it outflanked and overwhelmed.

"That the surface [of the patient] is for many years relatively calm is a tribute to the heroic efforts of the immune system," Dr. Ho says. "The meanest streets are nothing by comparison." Attack early with a battery of drugs to curb the millions of new HIV copies, he argues, and the virus's chances of spinning off mutant versions that outmaneuver the medications can be sharply reduced. "Do you wait for any other kind of infection to get really bad before you treat it? Of course not!" Dr. Ho says.

By July 1993, Abbott researchers had narrowed their focus to just one possibility, which later became Norvir. As he worked with the compound, Dr. Ho says, "I was very impressed. Its power [in the test tube] was beyond anything we'd ever seen from the company or anyone else."

In a series of experiments with a handful of patients, Dr. Ho, who by then had joined the Diamond Center in New York, and colleague Dr. Markowitz were able to clear all detectable virus from test subjects in a matter of days. But within two weeks, the virus had generated drug-resistant mutants. By following how quickly these mutations arose, they calculated how many virus particles were churned out each day by infected cells, something no one had been able to measure before.

The answer took them aback, largely bearing out Dr. Ho's theory and making him realize that Abbott and other drug makers had to change their strategies if they were ever to vanquish HIV. No single drug was going to outsmart HIV; it would take a combination of drugs aiming at different vulnerabilities in the virus.

Drs. Ho and Markowitz discovered that an infected person can produce 100 million to one billion new virus particles every day, many times more than anyone had guessed was possible. The findings "told us that HIV infection is a raging blaze that is burning all the time," Dr. Ho says. Dr. Markowitz adds: "What David has argued, and we believe now has been shown, is that unless you shut off viral replication completely, you will develop resistance to the treatment -- and resistance means failure."

In working with the Abbott drug, Dr. Ho and some collaborators were the first to identify exactly how HIV gets around the protease inhibitor over time by spinning out one of three or four different mutations. He also showed that, to sidestep a two-drug remedy consisting of AZT and a related medication, 3TC or Epivir, the virus had to produce an offspring that contains about four mutations -- a more difficult but still manageable task.

High Barrier

But to thrive against the three-drug mix of AZT, 3TC and a new protease blocker, the virus would have to spin out a new version containing eight mutations all together, a near impossibility. "We have found that for one virus to produce progeny with that many mutations in the presence of such a high [drug] barrier is mathematically impossible," Dr. Ho maintains. "And that's the key, the reason multiple-drug therapy is working so well."

Many AIDS doctors, however, question whether the drugs have a long enough track record to justify such optimism. "Maybe I'm conservative, but I don't think we're there yet," says Donald Abrams, a longtime AIDS doctor at San Francisco General Hospital. Of such doubters, Dr. Ho counters: "I'm sure they are great doctors, but they haven't seen what we've learned about the virus."

Dr. Ho passed along his lab's findings to Abbott, which soon afterward began testing Norvir, known chemically as ritonavir, in a combination with other existing drugs. "By mid-1994 we knew ritonavir was a go," says Abbott's research head, Dr. Pernet. The results of the study were so encouraging that Abbott pushed up its timing by a full year, filing for FDA approval of Norvir last December.

Abbott's FDA filing stunned researchers at Merck. "It kicked us in the behind," says one person involved in Merck's protease research. The Merck scientists thought they were running comfortably in second place after Roche, which had won outright approval of its protease drug the same month. Finally, they were getting encouraging results in patient trials after two years of frustrating setbacks.

Patient 142

In fact, if not for one remarkable test subject, a 41-year-old HIV-infected man called "Patient 142," Merck might well have dropped its protease project by early 1994. "Every research project has a turning point," says Edward Scolnick, who oversees Merck's $1.6 billion-a-year worldwide research operation. "That patient kept ours going."

When Merck started testing its protease drug, Crixivan, on a dozen HIV patients in 1993, initial progress in each patient always gave way to a recurrence of the virus -- except for Patient 142.

Week after week, long after the other subjects displayed resistance, 142 "kept hanging in there and hanging in there," says Merck's Dr. Emini. In February 1994, Merck research officials gathered to discuss whether to scale back plans to expand the Crixivan test to several hundred patients.

"Because of 142, some of us argued that [Crixivan] was doing something right," Dr. Emini says. "We sat around and argued about it and finally decided to go forward, to try some new things, to up the dosage and combine [Crixivan] with other drugs. If not for 142, it's possible we might have ditched the whole thing."

Patient 142, an engaging, wise-cracking law student, is euphoric these days about his role in the research. After 130 weeks of therapy, he still has no trace of virus in his bloodstream, the longest anyone tested has gone without developing resistance. "This is the most intensely satisfying experience of my life," says the patient, who doesn't want to be identified. Three years ago, "I was spiraling down very quickly. Now, I feel I'm in remission."

He adds: "Maybe someday I can stand up in public and say I was the first person to conquer AIDS."