TOXIC HOPE : WIDELY EMBRACED, THE AIDS DRUG IS NOW UNDER HEAVY FIRE. : THE AZT STORY
It was such a shocking incident that it seemed to unfold in slow motion. Researcher Peter Mansell, normally cerebral and brooding, was almost jovial as he reeled off figures from a nationwide test of ribavirin, a drug to combat AIDS. A ripple of excitement swept through the capacity crowd gathered in an unremarkable meeting room in the Washington Hilton hotel for the third International Conference on AIDS in June, 1987.
Mansell’s presentation of dull scientific data didn’t obscure his underlying message: ribavirin worked. HIV patients who took the drug were less likely to develop AIDS than those who didn’t. “Dr. Mansell, a man shouted from the back of the room. “Do you or any of the other researchers have a financial interest in the approval of this drug of the company that makes it?
The audience erupted. Mansell, a veteran cancer researcher at M.D. Anderson Hospital in Houston, had a spotless reputation. The implication that he, or any of the scientists conducting the study, had acted unethically was outrageous.
Suddenly, another man jumped up on the podium and grabbed the microphone, a larger-than-life blur in the blinding dress whites of the U.S. Public Health Service. “Frank Young, FDA, he said, identifying himself as the commissioner of the Food and Drug Administration. Young told the stunned crowd that the FDA thought the ribavirin study was biased, perhaps even fraudulent, and that the Securities and Exchange Commission suspected ICN Pharmaceuticals, the Costa Mesa, Calif., company that made the drug, had used bogus test results to artificially inflate the price of its stock.
“It was like God coming down, recalls Peter Heseltine, who tested ribavirin at USC. He could not remember ever witnessing a government official publicly humiliating a respected researcher.
Subsequently, the FDA and the SEC launched separate investigations, raiding researchers’ offices and confiscating file cabinets full of documents. Months later, they issued similar verdicts. Everyone was exonerated: The test data was deemed accurate, and no stock manipulation had occurred.
The affair still pains Heseltine, now director of the HIV clinic at Los Angeles County-USC Medical Center, where one-third of the county’s AIDS patients are treated. “The humiliation fades, he says. “But the guys who literally gave their lives to do these studies and test ribavirin, the fact that their sacrifice was wasted, that’s sticks with me. This was a potentially useful drug, but it was never given a chance.
A scant six months before the conference, scientists at the National Institutes of Health and officials at the FDA had lined up behind another drug, zidovudine, nicknamed AZT for its chemical components. AZT was a chemotherapy that had been sitting in an NIH shelf for 20 years because it was expensive and toxic to produce and didn’t do much against cancer. But it had a rich producer with influential friends--Burroughs Wellcome, one of the pharmaceutical giants--and the enthusiastic backing of Dr. Samuel Broder, then associate director of the National Cancer Institute, one the behemoth research facilities that compose the NIH.
As with any war on disease, there is only so much money, only so many scientists. But in the mid-80’s, AIDS activists were bringing intense pressure against the political and medical establishment, including candlelight vigils on the White House lawn and sit-down strikes at NIH headquarters. The medical community, desperate for something that would alleviate patients’ suffering, began to focus almost all its resources on AZT. Nothing else, aside from two similarly designed chemotherapies, ddI and ddC, has been approved for use in combatting HIV since AZT was sanctioned by the FDA in 1987. Only today, six years later, is ribavirin--along with a few other AIDS drugs--finally being tested on humans.
Until 1991, of the more than $420 million that has poured into the NIH’s AIDS Clinical Trials Group, which conducts tests of experimental AIDS drugs in humans, 80% went toward studies on AZT. “We’ve lost many valuable years because of the sole preoccupation with AZT and its close relatives, ddC and ddI, says Michael Lange, an FDA adviser and assistant chief of infectious diseases at St. Luke’s-Roosevelt Hospital in New York.
Now a new European study, the Concorde, casts doubts about whether AZT, which is used by 180,000 people worldwide and whose sales topped $385 million in 1992, should be taken by HIV-positive people who aren’t yet ill. Some critics contend the drug may actually hasten the deterioration of the immune system associated with AIDS. In the post-mortems on AZT, some AIDS activists now admit that in their haste to get the drug approved, caution was swept aside.
The stark reality is that 12 years and 10 billion taxpayer dollars into this epidemic, there’s no cure in sight. The story of how AZT was transformed from an unused chemotherapy into the most widely prescribed AIDS drug, despite accusations of sloppy research and political manipulation, is a cautionary tale of hasty decisions and inexact science.
Big science costs big money. In 1990 dollars, the price of developing a drug, any drug, from scratch and shepherding it through the federal approval process is estimated at $194 million. Consequently, the quest for a cure for an illness, whether heart disease, cancer or AIDS, requires a massive infusion of money and a firm commitment on the par of the federal government scientists at major universities, and the pharmaceutical industry. In a perfect world, academic scientists would only do basic research, deciphering the root causes of a disease in unfettered isolation--information that drug makers would use to formulate new treatments. Unfortunately, “federal funding has dried up, so academics are doing more and more applied research, says Joseph DiMasi, senior research fellow at the Center for the Study of Drug Development at Tufts University in Boston. “Simultaneously, pharmaceutical firms these days are taking a hard look at their R & D programs and trying to wring out whatever inefficiencies they can. Consequently, only the most promising avenues are explored, often sending researchers stampeding down one path.
With AIDS, an epidemic that blindsided the biomedical establishment, all these endemic problems were magnified. Scientists, desperate to conquer the disease that was sucking the life out of so many, jumped on the hypothesis that HIV was the lone AIDS assassin; they embraced AZT because it seemed to work by destroying some HIV when nothing else even came close. And because this disease hit a vocal and extraordinarily well-organized population, the scrutiny and political pressures have been intense.
But science is not always predictable. Scientific knowledge moves forward incrementally, with each new discovery built upon the bricks of the last. Many of the greatest breakthroughs--such as Alexander Fleming discovering the bacteria-fighting ability of penicillin after he saw mold forming in a petri dish in 1928--have been serendipitous. The likelihood of these fortuitous accidents increases if research is proceeding down many paths rather than intractably sticking to one road--which could be a dead end.
“I think we made a terrible mistake when we narrowed our focus, says Joseph Sonnabend, head of the Community Research Initiative on AIDS in New York, which conducts community-based tests of AIDS drugs. “Because if the role (of other factors besides HIV) had been worked out, then we might have come up with (other treatment) that could have helped people.
Many dedicated AIDS researchers, however, have wearied of all this criticism from the sidelines. “There’s a fascinating phenomenon here--there’s a couple hundred people who are doing the studies and generating data, and a few thousand commentators, says Douglas Richman, a top AIDS researcher and a professor of pathology and medicine at UC San Diego. “These ‘experts’ all say the same thing--AZT was done too quickly, and drug development is going too slowly. We can’t win. Still, progress has been incredibly fast. This virus was discovered less than 10 years ago, and we have three drugs approved and a whole bunch more that look promising.
“We’re very proud of the speed with which we developed AZT, says Burroughs Wellcome spokesperson Kathy S. Bartlett. “Since 1985, we’ve supported more than 30 million clinical trials with AZT involving more than 20,000 patients. It’s the most thoroughly studied antiretroviral medication there is. People need to remember a little bit what it was like back in 1985 and ‘86--how hard people worked to find a treatment for this disease. AZT certainly has its limitations, but it has made a big difference in people’s lives.
Nonetheless, there is a consensus that politics shackled AIDS drug development. In the competitive world of AIDS research, dissent has often been stifled, and scientists who have challenged the twin pillars of AIDS research--that HIV is the sole cause of AIDS and that AZT is its only effective combatant--find it difficult to get grants. “It’s a bit like the war on cancer in Nixon’s time, observes Gunther Stend, former chairman of the molecular and cell biology department at UC Berkeley. “In some instances, people who couldn’t hack it in other fields moved to AIDS, where they could get funding, and forced out the good scientists.
It all comes down to money and who has it: The group that controls the purse strings controls the direction of research. But “the larger issue is the drug industry’s influence on the scientific process, says Peter Arno, a health economist at the Albert Einstein College of Medicine in New York and co-author of “Against the Odds: The Story of AIDS Drug Development, Politics and Profits. “And it’s a very corrupting influence.
“Academics receive industry funding all the time, and it doesn’t necessarily bias their results, counters Kenneth Kaitin, assistant director of the Center for the Study of Drug Development at Tufts.
One of the richest and most influential drug companies is Burroughs Wellcome, an American subsidiary of a British pharmaceutical, headquartered in North Carolina. It is an oddity in the rarefied world of billion-dollar multinational companies: a medical philanthropy with a corporate arm. In 1936, after its founder, Henry S. Wellcome, died, all of the company’s stock was deposited into a charitable trust, which is now the second-largest source of funds for biomedical research in Great Britain (the largest being the government.) In 1955, the Burroughs Wellcome Fund, similar in structure to its London-based parent, was set up in the United States.
Most of the company’s profits--from dozens of drugs, including Actifed and Sudafed cold remedies and the antidepressant Wellbutrin--finance biomedical research and drug development. Burroughs Wellcome endows chairs at Johns Hopkins and other medical schools, funds scholarships and awards, and provides grant to hundreds of scientists. Both here and in Great Britain, the Wellcome Trust has become a quiet but potent force in biomedical science.
In the early ‘80’s, Burroughs Wellcome resynthesized AZT from a public-domain formula, saw that it prevented HIV from making an enzyme critical to its reproduction, and decided to throw its weight behind the drug. It was perhaps inevitable that AZT would become a pharmaceutical front-runner, but no one expected it to go unchallenged for so long. Some observers claim that most of the major pharmaceutical companies weren’t initially interested in AIDS because the patient populations were too small to justify the research expense. Plus, viruses are wily foes--witness science’s inability to conquer the common cold.
“AZT was seen as a temporary stopgap, says John James, editor of AIDS Treatment News. “Ideally, we should have gone on to fundamentally better drugs--which we have not done.
IN 1985, AFTER AZT SHOWED THAT IT was able to thwart HIV in test tubes, Burroughs Wellcome, with the blessing of the FDA, moved quickly to test the drug in people with AIDS. From the start, the tests were problematic. Patients were already desperately ill, and the drug seemed to make them even sicker. To be admitted to the tests, they had to have had pneumocystic carinii pneumonia, the No. 1 killer of people with AIDS, and their T-cell counts--the number of immune cells--had to have dropped below 200.
The study began in early 1986 with 282 patients at 12 medical sites around the country. The first step in this process was to hire principal investigators, or PI’s--researchers at leading medical schools and hospitals who designed the AZT trial as a double-blind, placebo-controlled trial: Give half the patients the drug, the other half a placebo, and see which group fares best. Not even the doctors know who gets the real thing.
But the AZT trials in which 145 people with AIDS were on AZT and 137 on a placebo, were unblinded almost immediately. Patients knew right away who was getting what. The AZT pills tasted bitter, and the side effects tore up the gastrointestinal tract, causing nausea, vomiting and a loss of appetite; a severe atrophy made their muscles feel like wet spaghetti. Not to mention acne, pounding migraines, impotence and high fevers.
The People With AIDS Coalition in New York set up a hotline to analyze patients’ pills. If patients weren’t receiving AZT, they often bought the drug on the black market. According to Michael Callen, one of the founders of the PWA, some patients shared their pills with those on placebos out of a sense of solidarity.
Within a month, doctors also knew who was on what. According to FDA reports, nearly half the people taking AZT developed such severe anemia that they needed blood transfusions, so patient care was hardly identical. The AZT was devouring their bone marrow, which produces the immune-system cells that HIV attacks, so it was accelerating the very process it was supposed to stop. Some patients were so weak they couldn’t get out of bed. Twenty-seven were taken off the drug temporarily, another 21 altogether.
Every week, researchers at the 12 centers around the country waited for word to halt the painful tests. They heard nothing. However, after the initial reaction to the drug, some patients seemed to get better--they put on weight, and symptoms such as night sweats, fatigue and neurological problems eased or disappeared. “It became apparent some people were doing better, recalls Paul A. Volberding, a professor of medicine at the UC San Francisco Medical Center who was the PI for the test at San Francisco General Hospital.
Suddenly, the trials were halted after only 16 weeks, two months earlier than planned, because officials felt that it was unethical to withhold a potentially lifesaving drug. Although patients using AZT had suffered horribly at first, their survival rate was astonishing. Nineteen people in the placebo group had died versus one in the group receiving AZT. An NIH press release proclaimed that AZT “showed great promise in prolonging life in AIDS patients.
The FDA jumped on the available data, because, an agency official says, “it suggested that AZT was the best hope at the time. Still pressured by activists’ demands for action, the agency moved at warp speed to approve it.
But in the meantime, there were reports of problems at one of the test sites. The understaffed FDA relies primarily on the honor system when testing new drugs, but the agency does do audits when there are complaints. In this instance, it dispatched an investigator, Patricia Spitzig, to Massachusetts General Hospital.
Spitzig discovered “serious violations of the protocols. People received the wrong medications. One patients who died was listed as part of the placebo group, but he may have been getting AZT. At least 84 vials of medication had disappeared. But after the FDA analyzed her report, officials decided that, despite the violations, the Mass General data was strong enough to include in the final test results.
On the morning of Jan. 16, 1987, an FDA panel convened in the agency’s Rockville, Md., headquarters to decide whether to approve the commercial sale of AZT for treating AIDS. The group included a panel of advisers; the approval panel; a contingent from Burroughs Wellcome led by David Barry, the company’s vice president in charge of research; half a dozen of the AZT trial’s principal investigators and several government officials led by Samuel Broder, who had come to be known around the NIH as “Mr. AZT because of his promotion of the drug.
Everyone expected to rubber-stamp this. After all, this was Burroughs Wellcome. Their drug applications were always clean and thorough--no discrepancies or anomalies. By the time a drug had overcome all the regulatory hurdles to reach this stage of the approval process--and only 20% do--it was usually ready to be marketed. Itzak Brook, who chaired the FDA panel, had even alerted the agency’s public-affairs officer to prepare a press release.
Brook, a spare man with delicate features, is a professor of pediatrics and surgery at the Uniformed Services University of the Health Sciences in nearby Bethesda. He had chaired the FDA’s Anti-Infective Drug Advisory Committee for two years. But he had never seen anything quite like this. There wasn’t an empty seat in the large room. AIDS activists were patrolling the grounds and buttonholing panelists whey they went to the bathroom, pressuring them to approve the drug. Brook and the 10 other members of the approval panel felt a tremendous burden of responsibility to do the right thing.
But as the morning wore on, Brook became increasingly uneasy. According to the testimony given that day, more patients in the AZT group had died since the study was halted. And the many blood transfusions given to patients on AZT could have accounted for the difference in survival rates.
The FDA’s anti-viral chief, Ellen Cooper, a cool professional, was sharply critical of the study during her testimony. She had little more than a month to review the data--normally FDA medical officers have several months to digest this information and do a meaningful analysis--but what she found was troubling. The study had been unblinded, leaving open the possibility of biases in patient management. It alarmed her that long-term toxicity studies on animals weren’t completed, so there was no telling what the consequences of AZT would be in humans over time. “Will efficacy last? Will toxicity accumulate to intolerable levels with longer exposure? Prolonged administration of an anti-retroviral agent, such as AZT, may be of more harm than benefit, she concluded. To approve this drug would represent a “significant and potentially dangerous departure from our normal toxicology requirements.
Perhaps the initial results were a statistical fluke, Brook thought. Perhaps the study was stopped prematurely. At the lunch break, he discovered other panelists shared his misgivings, agreeing that they needed more data. After lunch, Brook recalls, the FDA brought in the heavy artillery.
In an unusual move, Paul Parkman, the FDA’s acting director of the Center for Drugs and Biologics, came to plead AZT’s case and assured everyone that the government would work out a post-approval monitoring system with Burroughs Wellcome. It became clear to everyone, says Brook, that the FDA wanted this drug approved.
“The real issue for the FDA, recalls one knowledgeable source close to the process, “was whether the government had the right to prevent patients from taking a drug when they are desperately ill and dying.
“I speak for myself, but I think others as well, said PI Dr. Paul Volberding at the hearing. “We would like this drug to be available to people with AIDS. I have become convinced, using the drug and seeing the data, that it does have a clinical benefit in this patient population.
But Brook remained unswayed. “My gut feeling was the drug company was pushing very hard for approval even though they knew the drug wasn’t ready, Brook recalls. “Something just didn’t click. I think someone behind the scenes was pulling strings to get the drug approved.
Others discount political pressures, pointing out that there simply were no other drugs. “The expeditious action was warranted, says the source, “by the national concern for any type of medication to treat people who are desperately ill and afflicted with AIDS.
It was a Friday afternoon, everyone was weary, and people had planes to catch, so they took a vote at 4:05. Brook was shocked at the outcome: 10-1 for approval. He was the lone dissenter. “Once a drug is approved, it is impossible to control how it is used, he warned them, in a parting shot. “We may release a genie out of the bottle, and it may be something that we may regret.
Once AZT was approved--just as Brook feared--there was a runaway effect. Because it was the only drug available for AIDS patients, many doctors prescribed it for all of their HIV-infected patients, including those who were otherwise healthy.
The wholesale price that Burroughs Wellcome initially set for AZT was staggering: $188 for a bottle of 100 capsules, which, at the then-recommended dosage--12 capsules a day--translated into a retail price of about $10,000 a year per patient, making it one of the most expensive drugs in history. “The price was based on the usual factors, says Kathy Bartlett. “Cost of research and development, production, marketing, the need to maintain an ongoing R&D; program, the uncertain market for the drug and the possibility of other new therapies.
When the price was announced, AIDS activists charged Burroughs Wellcome with price gouging and profiteering on a drug originally invented by government researchers at taxpayer expense. The price of AZT dropped twice, first because of manufacturing improvements, and again in 1989 when it became clear the drug would be used in the early stage of the disease, making a substantially larger patient base. AZT now costs $2,200 a year because of the reductions and because dosage has been cut in half.
With the approval of AZT, federal money gushed into the testing of AIDS drugs--except there really weren’t many drugs ready for testing in humans. So scientists tested AZT on infants and children with AIDS, on pregnant women and on HIV-positive people with no symptoms. The PI’s on the original AZT trial dominated the trials group and served on the core committees where key decisions about spending and resource allocation were made. Burroughs Wellcome officials had access to these committee meetings. “This is unusual for a drug company, particularly when other companies weren’t given the same opportunity, says Karl Johnson, director of the operations office of the trials group before he retired in 1992. “It is a matter of public record that David Barry was always at the table--and I don’t mean just in the room--whenever the original AIDS clinical gang were getting together. He was a member of Tony Fauci’s advisory group. Fauci, the director of the national Institute for Allergies and Infectious Diseases and the official who spearheads the was on AIDS, was unavailable for comment.
But, according to Bartlett, “there’s nothing unusual about representatives of pharmaceuticals attending these meetings.
“The idea that the ACTG was dominated by Burroughs Wellcome PIs, that PIs are contaminated by an association with a company, is simplistic thinking that is dangerous for society, says Stanford’s Tom Merigan, a member of the trials group. “The fact is, there’s only a certain number of people who have experience doing these types of studies. If you cut experience out of the loop, you lose a lot.
What is not disputed, though, is that the few drugs then ready for pre-approval testing on humans were tested only in combination with AZT, making it virtually impossible to determine if their success or failure was due to their essential effectiveness or their interaction with AZT. In any case, they were not subsequently approved.
“Granted, AZT was studied a lot because it was the first drug that showed some efficacy--it’s like the advantage of incumbency, says health economist Peter Arno. “But a big part of the reason why the overwhelming number of drug trials (80%) were on AZT is because of Burroughs Wellcome’s influence. And it is often very subtle. It has to do with support scientific conferences and of research, with publications in special issues of journals the drug companies support--all of which are helpful in promoting one’s own career. You can’t go to a conference, a symposium, anything remotely related to the pharmaceutical industry without seeing sponsorship by Burroughs Wellcome--and a few other companies.
Since 1986, the value of Burroughs Wellcome stock has jumped from $1.4 billion to $10 billion, augmented by sales of AZT, which total 12% of Burroughs Wellcome 1992 revenues, as well as two other drugs used to control AIDS-related infections: Septra, a sulfa drug that prevents pneumocystic carinii pneumonia, and Zovirax, an antiviral also used to combat herpes.
Burroughs Wellcome is not the only manufacturer of AZT. The NIH recently signed a non-exclusive licensing agreement with Barr Laboratories to market AZT in competition with Burroughs Wellcome. The NIH contends that its scientists not only first synthesized AZT but also were instrumental in discovering its anti-HIV properties, so the agency should receive some royalties from the drug’s sale. Burroughs Wellcome has filed suit--scheduled for trial this month--to block Barr Laboratories’ production. If Burroughs Wellcome loses, the government could lose millions in royalties.
While profits were soaring, Wellcome’s philanthropic arm was also swinging into action. In August, 1989, the NIH announced AZT significantly slowed the progression to AIDS in HIV-positive people with T-cell counts below 500 but who had not yet developed AIDS. Suddenly, the market for AZT expanded exponentially, from the 40,000 people with AIDS to the 650,000 who were HIV-positive.
Burroughs Wellcome says it gave more than $7 million to hundreds of AIDS groups ranging from guerrilla clinics to research centers and hospices. When Burroughs Wellcome approached AIDS Project Los Angeles, it triggered a heated debate. “We wondered: It this smart? Are we taking guilt money here? recalls Stephen Bennett, APLA’s chief executive officer at the time. “But the next thing we knew, they were giving money to all the small organizations who were desperate for money, desperate.
When the tiny, cash-starved agencies accepted Burroughs Wellcome’s largess, the bigger, more visible groups soon followed. Among the more notable recipients are Project Inform, a San Francisco-based education and lobbying group, which got $149,000; AIDS Project Los Angeles, $55,000, and $1 million to the American Foundation for AIDS research to support community-based research.
As part of Burroughs Wellcome’s campaign, posters jointly sponsored by the company and various AIDS group appeared on billboards and buses, urging people to get tested for HIV because “new treatments could “put time on your side.
For desperately ill people who have nothing else, the brief reprieve offered by AZT--the “AZT honeymoon--is worth any price. It gives them renewed mental clarity and a few more month to settle their affairs and say goodby to loved ones. “We’ve had staff members (at San Francisco General) who got so sick they couldn’t work, says Paul Volberding. “Then they started on AZT, and now they’re back at work.
But opinion is sharply divided over using AZT before symptoms appear. Even among people who take AZT, there doesn’t seem to be any consensus. Some, like Nicholas (a pseudonym), 42, an unemployed Las Vegas hotel worker who’s used AZT for more than five years, experience few or no side effects. “I’ve been HIV positive for eight years without any side effects whatsoever, he says. “I don’t know if that’s because of AZT or the fact I’ve always been in great health. But I’m not willing to take a chance and stop taking the drug.
Others, though, like patient Robert Bowers in Los Angeles, who tested positive for HIV about nine years ago, have been debilitated by AZT. Bowers was put on an AZT regimen about 4+ years ago when his T-cell counts dropped below 400. “The pain was excruciating, Bowers recalls. Afterward, he was chronically with low-grade fevers, aching muscles, lightheadedness, nausea, piercing headaches and an overwhelming fatigue that made it almost impossible to do the simplest chores. A year and a half ago, after experimenting with different dosages, he went off AZT--and his symptoms vanished. “I had forgotten what it was like to feel good, says Bowers.
“Taking AZT, says Michael Callen, author of “Surviving AIDS and a long-term AIDS patient who refuses to take AZT, “is like aiming a thermonuclear warhead at a mosquito.
These concerns crystallized by 1990, when evidence began to trickle out that AZT wasn’t so terrific, that only half the people with AIDS could tolerate the drug, that it caused vaginal cancer in laboratory animals. One study, conducted by Samuel Broder at the National Cancer Institute, revealed that people who took AZT for two to three years had a 49% incidence of lymphoma, a cancer of the lymph glands, compared to about 2% of AIDS patients who didn’t take AZT.
Another study, conducted by researchers at the Veterans Administration on asymptomatic patients, was even more alarming. “Our study showed AZT didn’t make you live longer, says John D. Hamilton, of the VA Medical Center in Durham, N.C., and principal investigator or the study. “It delayed the symptoms due to AIDS. But it carried with it adverse side effects. Our thinking was that if you don’t get any survival benefit, what it boils down to is deciding whether you want to have symptoms of HIV or symptoms of AZT.
It’s also interesting to take a closer look at 1989 studies that, according to Volberding, “show an absolutely monotonously consistent halving of the progression rate. So progression rates go from 7.6% (for those on placebo) to 3.6% (for those taking AZT), or in that range. “That means that 7.6 HIV patients out of every 100 progress to AIDS if they don’t take AZT; 3.6 patients progress to AIDS if they do take it. So doctors are administering a toxic chemotherapy to 100 people in hopes that four of them will progress more slowly to AIDS.
What’s more, after several years of treatment, HIV becomes resistant to AZT.
Richard Beltz is a professor of biochemistry at Loma Linda University. In 1961, working on a grant from the National Cancer Institute, he synthesized the compound that came to be known as AZT.
Beltz never published his results, so bragging rights for discovering AZT belong to Jerome Horowitz, another cancer researcher who formulated the compound independently in 1964 but did not patent it. But Beltz never forgot about his creation. “I thought about patenting it, he said. “But I finally decided against it because resistance developed so fast. Anybody who works with AZT for even a short time can see that.
At the FDA hearings in January, 1987, when AZT was approved, panel members did voice concerns about the possibility of resistance. But Burroughs Wellcome’s scientists stoutly denied seeing any evidence of it. Studies had been done in the early 1980’s in Burroughs Wellcome’s labs on AZT, in hopes of finding a use for it as an antibacterial drug. “You don’t find resistance in toxicology studies, says Bartlett. “The first reports of viral resistance were in 1988.
“I don’t see how anyone who works with AZT as an antibacterial drug could not know that resistance develops to this drug within a few days in certain bacteria, says Beltz. “Cripes, I found it within a year (working with bacteria). So why wouldn’t they find it with greater resources?
FDA adviser Michael Lange agrees. “If the 1986 study at the 12 medical centers had been permitted to go on as planned, the fact that AZT benefits were exceedingly transient would have shown up, he says.
Counters Bartlett: “There is resistance with a lot of medications. It’s one of the limitations of the drug, but there’s nothing unusual about it. Resistance is less of a problem when the medication is used early in the disease.
The debate on how soon to start taking AZT may ultimately be settled by the Concorde study, which has been going on for the past three years in France and Great Britain. When the preliminary results were released in April, it sent shock waves through the AIDS establishment. “There was a very small, early benefit (from taking AZT), but that effect was not maintained, says Ian Weller, who was the PI for the Concorde in the United Kingdom. “After three years, we detected no difference between those on placebo and those taking AZT in terms of final outcome. The concorde study, however, may have skewed results, since 32% of the placebo group received AZT.
Today, things are changing in AIDS research. Fifteen of the world’s top drug companies announced a groundbreaking collaborative agreement in April. They agreed to pool information and share experimental compounds to speed up the search for a cure. A number of promising drugs, such as protease inhibitors, which stop the HIV virus from producing an enzyme key to its replication, are being developed. Ribavirin and Peptide T are now being tested in humans.
But for people like Michael Callen, it is too little, too late. A struggling musician found to have AIDS in 1982, he has nimbly defied death, one of the longest of the long-term survivors. But time is running out. His right leg is swollen to several times its normal size by Kaposi’s lesions. He has lesions all over his lungs, as well, and the pain is unremitting.
“I have managed to survive for 11 years with AIDS, and we’re still nowhere, says Callen. “While they were frittering away billions of dollars, while they were dallying with AZT, they were not pursuing treatments that could have saved my life. And I will pay for their stupidity with my life.