The Future of AIDS Drugs
In 1985, a scientist working for Burroughs Wellcome made what he thought was a stunning breakthrough. In test-tube experiments, a substance called Compound S was killing the virus that causes AIDS. At the time, AIDS researchers still believed a cure - a so-called "magic bullet" - was within their grasp. And the pharmaceutical company was ready to fire with Compound S, later called AZT. The following year, some 280 subjects enrolled in the first clinical trial of AZT. But after less than five months, researchers halted the study. The results had been so dramatic that they decided it wouldn't be fair to keep giving half the participants a placebo (usually a sugar pill) when AZT was working medical wonders. The US Food and Drug Administration, fighting accusations at the time of wrapping too much red tape around the approval of drugs for people with the AIDS virus, approved AZT in 1987 based only on such preliminary research.
Although toxic at high doses, AZT remains the most common drug for treating people with AIDS (PWAs). According to the congressional Office of Technology Assessment, domestic sales of AZT have totaled $200 million so far. But new research suggests the compound is not only useless to patients in the long run, it could actually harm them if taken too soon. In fact, of the original participants in the 1986 AZT trial, half died within two years of taking the drug. Not only that, but those who received AZT earlier in their treatment died sooner than those who received it in the later stages of the disease. Ultimately, the study ended too soon to determine Compound S's true impact on survival. And over time, death overruled the initial results. The fallout from these early AZT trials is changing the way AIDS activists feel about clinical studies, and causing them to tone down their demands for speedier drug approvals.
Today, a so-called fast track moves AIDS drugs from the lab to local drugstores in record time - something activists once staged die-ins and barricaded factory doors to accomplish. Now, some fear their activism may have backfired. Many AIDS drugs on the market have no proven benefit because the clinical trials testing their effectiveness were either rushed or too small to be significant. PWAs must take the drug company's word on what a prescription will do. But since some drugs are highly toxic, activists wonder whether the treatments are always worth the risks. Observes Spencer Cox, who chairs the Antiviral Project for the Treatment Action Group (TAG) in New York City, "At a certain point in AZT therapy, a patient is only getting toxicity."
But even as they grow increasingly cautious about the claimed benefits of new drugs, activists are by no means advocating a slowdown in experimentation. As Mike Immel, manager of HIV information for Boston's AIDS Action Committee, points out, if patients are informed of the risks of newly approved or experimental drugs, they have nothing to lose. Ultimately, PWAs must decide between taking a possibly ineffective, even harmful, drug or doing nothing to fight a deadly disease. More important, many more people will die, says Immel, without a fast track to new drugs. The average rate of survival from the time of AIDS diagnosis to death has increased in the last decade from a year to two years, and doctors credit that longer life span to a fairly new drug that treats pneumocystis pneumonia, a leading cause of death among people with full-blown AIDS. Immel maintains that today's experimental treatments could prolong - and perhaps even save - not only the lives of future generations, but also those of existing PWAs.
Powerful new weapon
PWAs receiving treatment today constantly need new kinds of drugs (or combinations of them) to fight the disease effectively. That's because within six months to a year of beginning drug treatment, patients often grow resistant to antiretrovirals like AZT and ddI (which interfere with HIV's ability to replicate) as the virus mutates and conquers the drug. "What'll we do - studies for 40 years?" asks Immel.
"We desperately need that access." Robert Zackin, a PWA who works as an AIDS statistician for a program operated out of Harvard School of Public Health, is a case in point. Before he began taking an experimental drug known as a protease inhibitor late last spring, Zackin's T-cell count was zero. (T cells, measured per cubic millimeter of blood, help stimulate the immune system to attack the AIDS virus.) His system had also become intolerant of every drug available, a condition that had forced him to stop drug treatment altogether. At the end of his pharmaceutical rope, Zackin joined the new drug trial and was ecstatic when his T-cell count jumped to 150. A normal level is around 1000.
Dr. Cal Cohen is research director at the Community Research Initiative of New England, a community-based AIDS research group in Brookline. He believes the protease inhibitor, which acts like chemical scissors by snipping out parts of the viral core, will become a powerful weapon in the war against AIDS. Prior to its discovery, researchers "felt helpless," says Cohen. Many PWAs, particularly those with low T-cell counts, had gone through all the other antiretrovirals and become resistant.
Cohen is one of many researchers conducting the international trial Zackin is enrolled in for Abbott, a drug manufacturer. The results have been so promising, he says, that the company is switching to an "open-label" study. That means all of the approximately 1000 patients currently enrolled in the trial will receive the protease inhibitor. (Generally, a certain number of subjects in a trial are given a placebo so researchers can compare the results of the two groups.) In addition, the drug will reportedly be made available to 2000 more PWAs. The results of any study are less reliable without a control group, but, as in the case of AZT, researchers working with the Abbott drug don't want to deny a potentially beneficial treatment to patients. Once again, the preliminary evidence is strong enough to run a risk. For Zackin, who is seven months into the trial, the protease inhibitor may be a lifesaver. But as an AIDS statistician and a veteran of clinical trials, he remains skeptical. "I'm thankful for what I can get," he says, "but I know it's not a cure."
Improving drug trials
Such skepticism is healthy when approaching drug trials. Immel, who was an early member of ACT UP/Boston, says AIDS activists always remained wary of AZT, even as they pushed for its distribution. "From the start, everyone knew it was a mediocre drug," he says. After it was approved, "we yelled and screamed for several more years to get something else." A common ACT UP chant was, "Ten billion dollars - one drug. Big deal." Many activists are now refocusing their efforts not on slowing down trials but on making them less risky to subjects without sacrificing accuracy.
In most studies, AZT has now been substituted for sugar pills as a placebo, to ensure at least some medication for patients not receiving the trial drug. And the New York-based TAG, a major AIDS lobby, is pushing further, to allow placebos to be replaced with a research subject's own medication. "That gives control back to patients, allowing them to take whatever is best for them during a trial," says Cox. Such a protocol will discourage people from dropping out of trials, he suggests. And researchers will be comparing the results of the new drugs to a more relevant standard: the best treatments available today.
Perhaps more controversial is TAG's proposal to change the way drugs are evaluated. In the rush to find new treatments, scientists have scrapped the traditional and more deliberate process of measuring a drug's usefulness by its ability to extend life or stave off disease. Today, they consider indirect evidence, like a rise in the subject's T-cell count. TAG is calling for a return to the old standards. Even Dr. Gail Skowron, a prominent AIDS researcher in Providence, Rhode Island, acknowledges that "after learning so much about HIV, we realize [T cells] ... don't tell a whole lot." In other words, such measurements don't necessarily translate into health benefits or lives saved.
Some AIDS activists argue, however, that replacing "surrogate markers" like T cells with mortality rates will have the effect of lengthening drug trials. Researcher Cohen, of CRI, says that isn't necessarily true if the trial tests the sickest of patients. "If you take people with less than 100 T cells, you unfortunately can determine much more quickly whether you're saving people," he says.
Taking into account the concerns of groups like TAG, the trial Cohen is helping conduct for Abbott will follow PWAs on its protease inhibitor right up until the drug is approved in April or May. That way, Cohen says, the drug company can determine whether death is being delayed, as Abbott hopes. That type of follow-up didn't happen with saquinavir, another protease inhibitor, approved by the FDA last December in a record-breaking 97 days. "Researchers merely saw a change in T cells and viral loads," says Cohen. "The question is, so what?"
A matter of self-preservation
Swept up in the constant flow of scientific setbacks, some PWAs are beginning to wonder whether the medical community is simply spinning its wheels. They fear that lost among the hundreds of trials and various combinations of drugs is a cure - or maybe just a more effective treatment. The most bitter among them fear that drug companies are more concerned with making a buck than with helping people.
Paul, a PWA from Providence who doesn't want his last name published for fear of losing his job, is part of an experimental trial for Delavirdine, an antiretroviral discovered and developed by Upjohn. When he first looked into the study last spring, researchers for Upjohn told him he qualified because his T cells were below 500. That was news to Paul, who, even after he signed up, continued to get readings above 500 at another clinic. Researchers told him that "they were using a different standard of absolutes," he says. "They said, 'You need, you need, you need [this drug].' And guess what they got? A new patient."
Paul's cynicism is understandable - his T cells are dropping on Delavirdine. He has also suffered severe side effects - a rash, chronic fatigue, stomach aches, and excruciating headaches - with no relief. "[Researchers] said it wasn't from the Delavirdine," Paul says. "You're taking pills and having side effects, and they say it can't be the pills." Fed up, Paul recently threatened to quit the trial, but the researchers sweetened the pot, promising to give him a lifetime's supply of Delavirdine, AZT, and possibly ddI if he stuck it out until the June 1 end date. For Paul, whose last employer canceled his health insurance a few weeks ago, the deal was too good to refuse. He knows there is probably a better treatment out there for him, but, like many PWAs, he feels helpless against the powerful drug companies. "I'm talking about the way very, very big business treats people with HIV," he says. "I mean, we're fighting for our lives."
Survival is always the chief motivation for entering a drug trial, and it remains so throughout. Thus, even those PWAs who stick with a trial wind up cheating to better their odds. The practice is more common than researchers would like to admit. To gain access to a promising new treatment, research subjects have been known to lie about their medical history, making it conform to the requirements of a trial. Others violate the rules of a "blind" study (meaning they're not supposed to know what they're taking) and send the experimental drug to a private lab to be analyzed. If it turns out to be a placebo, they drop out of the trial. What such patients may not take into consideration is that cheating skews the results of a study so critically that it could mean the difference between approval and rejection of an experimental drug.
No one knows how rampant patient misconduct is, partly because many researchers turn their backs to it, not wanting to stop a trial or admit their results could be wrong. And the sloppy procedures in some studies don't help: it's often easy for PWAs to distinguish between the drug and the placebo. Cathy Delianedis, a 36-year-old mother of two from Worcester, was recently part of a study testing different combinations of three drugs: ddI, ddC, and AZT. Some patients got all three drugs; others got one drug and two placebos, or two drugs and one placebo. Delianedis immediately figured out which of the three she was given by comparing an old prescription of AZT with the new AZT, which tasted sweet. A placebo, she concluded. Then she tried the alleged ddC - also sugary. Only the ddI tasted bitter. Convinced, therefore, that only the ddI was real, Delianedis stopped taking the other two medications. She continued to refill all three prescriptions, however, knowing researchers would check. The pills began to pile up. "I literally had garbage bags filled with prescriptions," she says. "I wasn't going to go through the regimen of taking that crap." As it turned out, Delianedis was right: the AZT and ddC were fake. Still, if she'd been wrong, her participation in the trial would have done more harm than good.
Humans vs. guinea pigs
Skowron, who works as the associate director and clinical-trials coordinator at the Brown University AIDS Program (BRUNAP), acknowledges that patient misconduct is a problem, but says there is no way to stop it. "If people want to lie, they lie," she says. Rather than devising ways to catch cheaters, Skowron says, researchers need to win the trust of their subjects. To do this, they should test only those drugs that have the potential to help. That way, participants won't feel like they're part of a futile experiment - or a scientist's vain curiosity. "Do I think every drug I test is a cure?" asks Skowron. "Well, I like to think there's a rationale behind it. There needs to be some evidence that it inhibits the virus." Researchers stand a better chance of diffusing mistrust among PWAs if they themselves are honest.
Skowron has personal experience with the dangers involved in a trial and says she would never minimize those risks to coerce PWAs into participating. She was one of the initial researchers to test ddC, which later proved to cause a disorder of the nervous system called neuropathy. Skowron has "a lot of respect for the potential of drugs to do harm," she says. Skowron also encourages patients to tell her if they're not following the rules. "Instead of having people lie to us, we need to know whether they're skipping doses because of a stomach ache," she says. Ultimately, PWAs need to feel like human beings - not guinea pigs, says Delianedis, who has worked as a peer counselor at AIDS Project Worcester. Three years ago, she participated in a study testing two drugs that did seem to help her condition. During the trial, Delianedis's T-cell count jumped from less than 500 to 800 and stayed there. But overall, the combination was a failure, so the manufacturer stopped supplying it.
Delianedis eventually convinced the drug company to give her another six months' worth. After that ran out, though, her T cells skidded back into the 300s. "For a while, I was very angry," she says. "I just couldn't cope with their handing me a carrot and then pulling it back. I felt like just another statistic, like I'd lost all control." Next time, says Delianedis, she will ask whether a drug will still be available if a trial is discontinued. Despite the drawbacks to drug trials, Jim Voltz, executive director of AIDS Project Worcester, says every trial has a purpose, even if it is to rule out a drug.
He and other AIDS activists will be "forever grateful to those clients who have gone through trials and have since died," he says. "We are making progress. It may seem slow for people with AIDS and those who love them, but we are moving forward." As Jeff Getty, a 38-year-old PWA who received a highly controversial and experimental bone-marrow transplant from a baboon in December, told the New York Times,<> "I know I could die from this treatment. But I am certain that I will die if I do nothing."