The Big 'Tease: Are Protease Inhibitors the Miracle Drugs?

The headlines were straightforward enough. "New AIDS therapies prolonging lives," "Triple-drug therapies are changing patterns, costs of AIDS treatment," "The end of AIDS? Not yet, but new drugs offer hope." This front-page coverage in newspapers and magazines throughout the country came in conjunction with the Fourth Conference of Retroviruses and Opportunistic Infections, which met in Washington, D.C. from Jan. 22 to 26. The therapies heralded at the conference involve combinations of old AIDS drugs with a new, experimental type of drug termed "protease inhibitors." Despite the bold, auspicious headlines, however, protease inhibitors have proven to be some of the most controversial as well as the most expensive AIDS drugs yet concocted. First put on the marketplace in late 1995 after the fastest and least stringent approval process in the history of the Food and Drug Administration, protease inhibitors have a mixed clinical record at best -- one that most AIDS clinicians have overlooked for the time being in favor of the increased treatment options the drugs offer. The story of protease inhibitors parallels the story of the HIV virus they were designed to trammel. Both have inspired considerable dissent within the AIDS research community. (Although that dissent has inspired surprisingly scant coverage in the mainstream media.) And both have subverted the traditional route of disseminating information through peer-reviewed scientific journals in favor of the unmediated forum of press conferences and press releases. Of the two, though, HIV takes top honors for breaking rules, standards and precedents. Big-budget science, even in the age of hype, has never seen its like before. Without having published a single paper to back up his claims, cancer researcher Robert Gallo held a press conference at the National Institutes of Health in April 1984 announcing that the newly discovered retrovirus LAV/HTLV-III -- later renamed HIV -- was the "probable cause" of AIDS. Before his announcement, Gallo had spent 20 years in the failed search for a viral cause of cancer and at one point claimed to have discovered a sexually transmitted retrovirus that causes leukemia -- after an absurdly untenable 45 year latency period. It was later revealed that more than half of Gallo's AIDS patients had in fact tested HIV-negative, and a Congressional investigation uncovered fraudulent data in the papers Gallo did eventually publish. To this day, Gallo's hypothesis -- that HIV causes AIDS -- remains unproven. More than 100,000 papers have been published on HIV, and yet even the outlines of a proof that the virus causes AIDS are lacking. In fact, virologist Dr. Stefan Lanka wrote an article for the AIDS dissident journal "Continuum" in May 1995 arguing that no one has even proven that the HIV virus itself exists. In conjunction, Continuum posted a £1,000 [one-thousand pound] "Missing Virus" reward for anyone who can locate a paper establishing the independent existence of HIV. To date, two leading researchers have submitted claims to the reward. Neither succeeded. ("Continuum"'s contest follows the criteria for isolating any retrovirus, established at the Pasteur Institute in 1973.) As of 1997, HIV-AIDS dissidents have coalesced around two groups, the Group for the Scientific Reappraisal of the HIV-AIDS Hypothesis and the Health Education AIDS Liaison. The former consists of more than 450 scientists, including two Nobel Prize winners, while the latter is a rapidly growing activist organization with 23 chapters around the world. In the past two months alone, chapters have formed in Atlanta and Philadelphia. Then there's Dr. Peter Duesberg, a widely vilified virologist who is nonetheless considered among the world's leading experts on retroviruses -- the class of viruses to which HIV belongs. Last year he released the book "Inventing the AIDS Virus" to considerable harrumphing from the AIDS research orthodoxy. In it he argues that AIDS is a syndrome of 30 previously existing illnesses and conditions brought on by a combination of factors, including recreational drug use (an idea first proffered by the U.S. Centers for Disease Control and Prevention), the use of clotting factor given to hemophiliacs (already known to suppress immunity), and the AIDS treatments themselves (such as AZT, which was shelved as a cancer chemotherapy in 1964 because of its extreme toxicity). Other scientists, including the French researcher whom Gallo was found to have stolen his data from, now argue that HIV is only one cause among many possible factors leading to AIDS. Press coverage of protease inhibitors, however, typically omits this background. Instead, it begins here: In a virus -- such as HIV -- protease is an enzyme that helps the virus make copies of itself inside infected cells. A protease inhibitor is a synthetically created drug that "gums up" the copying process, preventing the virus from replicating and infecting other cells.AIDS patients who take these drugs -- or more likely their private and/or public insurance underwriters -- can expect to spend upwards of $10,000 a year on the therapy. And yet there is precious little scientific evidence to suggest that AIDS patients who use these drugs feel any better or live any longer than those who donÍt. That may be for a good reason too. One expert in the field sees HIV protease inhibitors as a miracle drug, but not because he thinks theyÍll cure AIDS. He argues instead that protease inhibitors are the ultimate test of Gallo's hypothesis. Yes, these drugs appear to stop HIV, and that's precisely the problem. Ultimately, he argues, protease inhibitors may prove the unpopular stance he and a growing number of dissident scientists have taken: that HIV does not cause AIDS and that in its urgent search for effective treatment -- and ultimately a cure -- mainstream science is rushing down a dead-end street. DROP/ Dr. David Rasnick is a visiting scientist at the University of California, Berkeley and a pioneer in protease research and protease inhibitor development. Rasnick has studied proteases and protease inhibitors since the mid-1970s, researching those related to HIV since 1984. He has also followed the AIDS epidemic since its initial days in late 1980. After founding a bio-tech company in the San Francisco area, he and his colleagues began to hear about a strange "cancer" that was afflicting a subset of the city's gay community. Later called GRID (for Gay-Related Immune Deficiency), the syndrome of diseases was eventually given what is now one of the most ubiquitous acronyms in the English-speaking world: AIDS. And then came the watershed moment in AIDS history. "In 1984 Robert Gallo had his press conference, and I'll never forget that," Rasnick recalled. "I was just as tickled as I could be, because he claimed that it was a virus that was the probable cause of AIDS. I knew viruses had all sorts of proteases. I had been interested in them for many years. Then I said, 'Wow! It's a retrovirus. I'm a protease inhibitor guy. I'm going to jump in on this.' This was within days or weeks of Gallo's press conference."Since then, he's become much more skeptical of Gallo's claims, harboring doubts about the HIV-causes-AIDS hypothesis since 1987. But now he sees his area of expertise as providing a key test to check the validity of the claims of Duesberg et al. His thesis is that HIV protease inhibitors work so outstandingly in stopping the virus that they provide an effective "toggle" in turning off the virus' contribution to a patient's symptoms. If protease inhibitors show no long-term clinical benefits in AIDS patients, then farewell to the assumed direct correlation between HIV and AIDS. (Of course, the solution could be more complex than a "yes" or "no" answer. That is, HIV could be one of several "co-factors" that by themselves are benign but together lead to AIDS -- a position that some AIDS researchers have now taken in favor of the original Gallo model.)So what do the data say? Recent media coverage of protease inhibitor studies have been largely positive -- some even playing it like a victory at sea or a Babe Ruth shot out of the ballpark. ("There's no toxicity. It's a home run!" Crowed one "Newsday" article.) But did anyone actually see the ball in the air? Or is the catcher holding it? "This is research by press release," Rasnick cautions. "People are making all these conclusions from the studies. But there's nothing published on this ƒ . The only thing that matters to an AIDS patient is whether he feels better, he does better and he lives longer. And that isn't published anywhere in the scientific literature." Indeed, combing through the journals and conference abstracts, one finds hundreds of references to protease inhibitors and protease inhibitor research. But tracking down a study that actually finds protease inhibitors providing patients with a longer life or better health is like trying to find a passenger pigeon in midtown Manhattan. Accept anything that looks like a pigeon and there are flocks upon flocks to choose from; stick to the task at hand and ƒ well ƒ good luck. One recent National Institutes of Health study, for instance, was publicized as part of the protease inhibitor success stories from the recent Retroviruses Conference. AIDS Clinical Trials Group 315 studied the consequences of putting AIDS patients on a "cocktail" of zidovudine (AZT), lamivudine (3TC) and the protease inhibitor ritonavir. The first two drugs are known as "reverse transcriptase inhibitors" and are in general much more toxic than protease inhibitors. The study, like so many of the headline-grabbing studies of late, considered a mere three-month trial period. "You can't determine anything in three months," Rasnick noted. "It's within the background noise. Yet people are drawing tremendous, unwarranted conclusions from this stuff." And the bottom line -- if the patients on the drug cocktails lived longer or felt better -- was nowhere to be found. Dr. Michael M. Lederman of Case Western Reserve University was the protocol chairman and author of ACTG 315. He says the study was never designed to consider how the patients fared as a result of the therapy. Instead, his team measured the popular "surrogate markers" CD4 count and viral load (see sidebar). However, Lederman does think the extrapolation to a patient feeling better and living longer (morbidity and mortality, in clinical-speak) is a reasonable one. "We believe that changes in viral load measurements in response to these therapies do predict a response in morbidity and mortality," he noted. But belief is something entirely different from proof. AIDS researchers never seem to be short on the former. Without the latter, though, the clinician is left with no solid foundation on which to stand -- other than the hallowed ground of the faith healer. DROP/ On the front lines of AIDS care today, physicians -- under pressure by AIDS activists and a population living with a reputed "death sentence" -- have of necessity offered the treatment options that researchers say offer the greatest hope. Despite the expense, the controversy or the potential down side of the therapies, most American AIDS patients have access to protease inhibitors if they and their doctors deem them necessary. The drugs' extreme costs have led to an unprecedented raiding of public funding coffers. As Lawrence Fox from the National Institutes of Health Division of AIDS noted, "From a public health point of view, the cost of protease inhibitors is enormous. In states that provide assistance [such as Massachusetts], their budgets have been gobbled up by the costs of the drugs." Dr. Gary Reiter is the founder of the River Valley HIV Clinic in Holyoke, Mass. and has been treating people with AIDS since 1981, when he was based in San Francisco. "I see that we have really come a long, long way since the early days," he said. "I've found protease inhibitors in general to be an extremely effective therapy -- and remember what he have now is just the first generation of these new drugs."Closer to the frontlines, Dr. Donald Abrams is the Assistant Director of the AIDS Program of San Francisco General Hospital, one of the most prominent AIDS care facilities in the world. Abrams does prescribe protease inhibitors, but he is cautious in holding out too much hope for the drugs. "I do wonder exactly what it means in the long run for the patients," he noted. "People can get into the mindset of 'It's the virus, stupid' without remembering that it's the patient's well-being that should be foremost."He's also wary of the claims that the introduction of protease inhibitors is somehow related to the recently announced decline in AIDS rates in New York City. "Let's not forget that the epidemic peaked in 1993," he observed. "That predates the introduction of protease inhibitors, which were released to the public in 1995." In addition to running NIH studies, Lederman runs an AIDS clinic at the University Hospitals of Cleveland, where he prescribes protease inhibitors for his patients. Like Rasnick, he doesn't know of any clinical studies that show protease inhibitors' reported efficacy in helping an AIDS patient live a longer or better life. "There have been none published to date," he said. The problem, he asserted, is that studies to determine the so-called "clinical endpoints" take too long when, as he put it, "people are dying." "Presently, I'm persuaded that benefits of these therapies are important, and I'm not going to wait for clinical trials to use them," he said.DROP/ In early 1996, one study did trumpet an impressive decrease in mortality rates for patients on protease inhibitors over a six month period. Abbott Laboratories -- which makes the protease inhibitor ritonavir -- announced a 50 percent survival rate of protease inhibitor patients over the placebo controls. The study was front-page news, but one year later it still has yet to be released for any outside scrutiny or peer review. (If Phillip Morris or RJR-Nabisco came out with an unreviewed study debunking the cigarette-lung cancer link, would it even make the evening news?) More important, after Abbott had collected data for six months more, the study did not make headlines. And in the final analysis, that may be more newsworthy than the preliminary presentation. Rasnick was at the 11th International Conference on AIDS in Vancouver where Abbott gave the rundown on its year-long study-in-progress. "If there was anything to it, we should have heard about how the percentages are really holding up: 50 percent saved and all that," Rasnick noted. Instead, the cause for celebration six months earlier was all but forgotten -- morbidity and mortality rates weren't even addressed. Even if Abbott's initial spike in the first six months on the drug turns out to be real, some longer clinical studies indicate that patients on protease inhibitors end up doing no better than the placebo controls, if that. For instance, Rasnick was at a 1994 conference where one pharmaceutical company had funded 18 months of a protease inhibitor clinical trial -- with the drug saquinavir, in this case -- and a scientist on the team was presenting the results. "About the third sentence out of his month after he introduced the study was 'There was no clinical difference between the treated and the controls,'" Rasnick marveled. "No morbidity and mortality difference between them. They were also looking at surrogate markers [i.e. "viral load" and CD4 count], but nobody gives a damn about surrogate markers if the clinical endpoints aren't there."This study got published too," he continued. "But they didn't include the clinical data, only the surrogate marker data. And that's not uncommon in the drug world: Everybody publishes the favorable stuff and leaves all the other stuff out."In some cases, protease inhibitor patients who stay as healthy as the placebo controls are lucky indeed. One new phenomenon that protease inhibitors appear to have heralded is a precipitous decline in health without any warning -- as documented in the Dec. 6 "Newsweek" cover story on protease inhibitors. The origins of this sudden downturn syndrome, also known as "crashing," are unknown. The combined toxicity of the drug cocktails are certainly a source of concern. As Rasnick observed, "Crixivan from Merck crystallizes out the kidney and causes kidney stones. You can have renal failure with these things. Ritonavir stops the liver enzymes so the heightened toxicity of all the other drugs mount up and patients can die in a couple of days. You can save them if they're in a hospital at the time when they have these effects. Then you take them off the drugs, you take them off of everything, and you treat them for the toxicity of the liver. And you hope that the liver hasn't been destroyed to the point that it's irreversible. This is the dark side of protease inhibitors."Seeing the "dark side" firsthand was only one of a host of circumstances that made Rasnick first begin to question Gallo's HIV-causes-AIDS hypothesis. "Nothing made sense," he recalls. "It was just one thing after another," he said. For instance, the virus could scarcely be found -- let alone in levels sufficient to cause disease: "You try to ask people how many viral particles you find in the infected patients -- you can't find any in them. The virus isn't active." Furthermore, "HIV tests" have never been specific to HIV. That is, they have been shown to give false positive readings for people with the flu, arthritis, lupus or with exposure to diseases such as tuberculosis, hepatitis and malaria. Even pregnancy or prior pregnancy has produced "HIV positive" responses. To top it off, the test actually indicates the presence of antibodies, which with every other virus has been the sign of a healthy immune system responding to infection. As Rasnick put it, "AIDS is the only disease where if you have antibodies to the virus it's a death sentence. I've got antibodies to smallpox -- I'm happy about that. That means I won't get smallpox. I've got antibodies to measles -- I'm happy about that. That means I won't get measles."Rasnick has found the climate for addressing these concerns, however, to be anywhere from unfriendly to downright hysterical. He has co-authored papers with Duesberg and says he is disgusted by the response of the scientific community to Duesberg's research: "Peter Duesberg is one of the premier scientists in the world. He was a hair's breadth from getting a Nobel Prize. Yet as a result of his stand on HIV, all of a sudden overnight he's a fool, he's incompetent. "It's almost like clinical McCarthyism," Rasnick observed. "It's a system completely out of kilter. AIDS is a sociological phenomenon. It's not a scientific issue, it's not a medical issue. I mean, we are looking at mass hysteria here. A train without breaks going down a mountain. And if you try to put rationality to it, you won't find it. It ain't there."The entirely unscientific response to HIV-AIDS dissidents was in fact one of the reasons Rasnick began to suspect that the doubters may be onto something after all. "All of a sudden, we can't do what scientists do anymore," he noted. "Scientists raise Cain. We're skeptical. We're critical. In the days of AIDS, though, skepticism is gone. Now it's to the point where you could get hurt professionally or financially or your career could be in jeopardy if you challenge the HIV hypothesis."It's almost like a religious thing. There are some things that you just can't talk about anymore. And that's not science. That's something else." nSIDEBARAIDS Dissent OnlineFor more information on AIDS dissidents, visit the following sites on the worldwide web:Rethinking AIDS Homepage's AIDS Dissident Virtual Library Group for the Scientific Reappraisal of the HIV-AIDS Hypothesis Education AIDS Liaison Fact or Fraud? Authorityhttp://www.aidsauthority.orgInfectious AIDS: Have We Been Misled? Causes AIDS: A Second Look MarkedThe term "surrogate markers" crops up a lot when discussing HIV-AIDS research and the status of HIV infection in a patient. In short, surrogate markers are benchmarks for doctors to monitor the hypothesized progress from HIV to AIDS and the efficacy of the drug treatments they prescribe. The two AIDS surrogate markers now in use are the "viral load" test and CD4 cell count -- also known as the T4 or T-cell count. The first uses new biochemical techniques like the polymerase chain reaction (PCR) to measure the activity of the virus. (Ironically, the inventor of PCR, Nobel Prize winner Kary Mullis, is an outspoken opponent of the HIV-causes-AIDS hypothesis.) The second tracks one type of cell in the body's immune system that often falls to dangerously low levels in AIDS patients. However, the tests rely on as many unproven assumptions as the experimental drug therapies they purport to measure. It is often assumed, for instance, that introduction of a therapy followed by a rise in CD4 count means that the therapy is successful. But, as Dr. David Rasnick of the University of California, Berkeley cautions, that same phenomenon happens all the time outside of AIDS-related medicine: "The CD4 cells are not being produced as a result of killing any virus. They're being squeezed out as the result of an assault to the circulatory system. It has nothing to do with the theory of HIV. It's a common phenomenon. You don't have to have AIDS or anything. If you get an injection, this will happen. If you take a pill this will happen. It happens to people who are healthy. If you have a drug, you will get a boost of CD4 cells."The assumption that HIV kills CD4 cells, let alone that it causes AIDS, hasn't even been proven. (Three Australian researchers wrote a definitive critique of the hypothesized link between HIV and CD4 counts, which can be found on the worldwide web on the "Rethinking AIDS Homepage.")Finally, the "viral load" test is still unproven in providing any useful clinical information about an AIDS patient. And yet it's frequently used in conjunction with protease inhibitors, the class of drugs now being touted as a major advancement in the treatment of AIDS. "Researchers are using an unproven test -- the 'viral load' thing -- to assess an unproven drug -- HIV protease inhibitors," Rasnick noted. "And they used HIV protease inhibitors in the same study to validate the test. It's a dog chasing its tail. Or as Don Abrams [Assistant Director of the AIDS Program at San Francisco General Hospital] says, it's like an M.C. Escher print. It's two hands drawing each other."


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