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A Wall Street Journal Article about drug holidays.
      #2413 - 04/05/00 01:32 AM

I believe that this is something everyone on these drugs should talk to their doctors about.

The Wall Street Journal, Monday, January 25, 1999 Cocktail Break: HIV Patients Who Quit Drug Combo and Thrive Offer Researchers Clues --- Studies Will See if 'Holidays' Allow the Immune System To Work on Its Own --- No Cure, but Hope for Vaccine By Michael Waldholz and Elyse Tanouye , Staff Reporters of The Wall Street Journal AIDS scientists have stumbled across a surprising new avenue of research, one that holds hope for a future vaccine and, for at least some patients, a respite from the daily doses of cumbersome and expensive drug cocktails that allow them to keep the AIDS virus in check. In a flurry of experiments begun in the past few weeks, several prominent AIDS researchers are allowing a selected few patients to do what, until recently, was believed to be extremely dangerous: suspend the powerful drug therapy that has put HIV, the virus that causes AIDS, in remission. The goal is to determine whether these patients' own disease-fighting immune systems can keep the virus harmlessly under control without the help of the multidrug therapy that has revolutionized treatment of HIV/AIDS since early 1996. The currently accepted dogma in AIDS treatment is that "drug holidays," periods when patients skip a day or more of their combination-drug regimen, are dangerous because they allow a previously suppressed virus to rise up anew in large numbers, perhaps in a mutant form that will be resistant to all drugs. But many patients have already quit the drugs on their own, either because of the cost, which can run $12,000 a year or more for a dozen-plus pills a day, or because of debilitating side effects. And while some patients have relapsed, doctors have been surprised to find that others are staying healthy. As a result, reports from researchers in the U.S. and abroad are now suggesting that brief or prolonged drug vacations for certain patients "may be OK; in fact, it may be preferable," says Michael Saag of the University of Alabama at Birmingham, who plans a study over the next few months. In one of the more influential reports, researchers at the Aaron Diamond AIDS Research Center in New York City say they are following two patients who ended drug therapy on their own and, nonetheless, have kept the virus at low levels for 21 months without any signs of illness. In two other patients, however, the virus rebounded to dangerous levels within 10 days to a few months. Scientists have discovered that although HIV usually reappears when a patient stops taking the drugs, this brief spike in viral levels may actually rev up the immune system in some people. This may be because the reappearance of HIV gives certain dormant scout cells in the immune system a glimpse of their viral enemy, allowing them to signal legions of other cells to mount a constant assault on the virus. Yet even the most hopeful of researchers say they don't believe stimulating such an immune response will be a useful treatment for the vast majority of the world's estimated 34 million HIV-infected people. For one thing, from what they can tell so far, the immune response occurs only in patients who had started drug treatment soon after infection and had successfully beaten back the virus to undetectable levels with the drug cocktails. Scientists hope that by analyzing even just a few successes they will identify, finally, the kind of immune-system cells that must be triggered by a future vaccine. Such a vaccine, scientists muse, wouldn't have to wipe out all virus but would allow a low level of virus to survive without exploding into a full-blown deadly disease. "Many viruses that infect us are kept in check, not totally wiped out, by the immune system after a first-time exposure," says Bruce Walker of Massachusetts General Hospital in Boston, who already is studying one patient who has gone off the drugs and who plans to enroll a total of 10 in his study by the summer. "This scenario may be possible under some circumstances for HIV." [Note: This is exactly what the immune system was believed to do with HIV, before the researchers adopted the Ho-Shaw theory. After an initial brief period of viral activity the immune system neutralized the virus, after which there was an average latency period of 10 years (highly variable) before the virus mysteriously caused AIDS. – Phil] Independently of one another, clinical investigators at several facilities around the country will be enrolling as many as 100 HIV-infected people in various studies. The patients will go off their antiviral drugs voluntarily and knowingly, rather than be given placebos. In addition to the Boston and Alabama studies, government scientists outside Washington have ended drug therapy for three men and plan to enlist 50 more in the next few months. Scientists in New York will undertake similar research, also with about 10 patients. The studies haven't yet been publicly announced, and will probably gain their first attention at a large AIDS conference next week in Chicago. "It's wild; I really feel like I have a normal life back for the first time in 10 years," says Richard Shaw, a 39-year-old construction-project estimator in New Hope, Pa., who is one of the first three test subjects enrolled in the study at the National Institutes of Health in Bethesda, Md. Two weeks ago, Mr. Shaw voluntarily stopped taking a combination of three anti-AIDS drugs, after researchers last fall found no evidence of the virus in his bloodstream following two years of continuous drug therapy. Since quitting the medicine, he says, "my energy has increased dramatically. I'm really excited." At this early stage, there is no sign that HIV has re-emerged, but Mr. Shaw will be closely monitored every month and put back on the drugs immediately if the virus surges back to dangerous levels. The researchers say that by later this year, they should begin to see if the immune systems of Mr. Shaw and several dozen other volunteers can successfully restrain the virus without drugs, at least for a few months and perhaps much longer. "For a long time, we thought the only way to prevent illness was to give antiviral drug therapy continuously to suppress levels of the virus in the bloodstream," says Dr. Walker, the HIV researcher at Massachusetts General. "But what has many of us excited and hopeful is new evidence showing that under certain circumstances, the immune system can keep the virus under control." He adds: "If that's possible, we may be onto a whole new way to fight HIV." "We believed this was theoretically possible," says David Ho, director of the Aaron Diamond Center. "Now we know it is, and now we need to study this phenomenon in a more controlled way." Dr. Ho cautions, however, that "this is all very, very early research," adding that, "I would not suggest this as a treatment direction for doctors or their patients. But as a research avenue, this has got a lot of promise." Nobody is suggesting that HIV can be conquered without the drug cocktails. Indeed, the prospect of taking patients off the drugs, either for short or long duration, is possible precisely because the drugs have been so effective in driving down the AIDS virus to undetectable levels in many infected people. This feat, first accomplished three years ago when researchers combined new so- called protease-inhibitor medicines with older anti-HIV drugs like AZT, is changing the face of AIDS throughout the U.S. and in other developed nations where the drugs' high cost isn't a barrier to access. Most remarkably, between 1996 and 1997 AIDS deaths in the U.S. declined 45% and the incidence of full- blown AIDS dropped 15%. [Note: the decline in deaths began before the introduction of the cocktails and has not been shown to be caused by their introduction. – Phil] But because of side effects and a demanding dosing regimen, many patients are having difficulty adhering to the therapy, often discontinuing treatment despite doctor warnings. There is growing evidence that not complying with the daily regimen is why 40% to 50% of patients eventually fail on therapy. [A convenient excuse. If the drugs don't work, it's the patients' fault. – Phil] When the new drugs were first introduced, some scientists, especially Dr. Ho, made the bold and controversial prediction that administering the medicines early in infection and continuing without fail for three or more years might actually eradicate the virus in some people. But last January, researchers reported that even after the virus is driven below detection in the bloodstream, tiny reservoirs of virus remain hidden in some cells unreachable by the drugs. "It was disappointing but not totally surprising," says Anthony Fauci, head of the National Institute of Allergies and Infectious Diseases. "It was now apparent that drug therapy alone wasn't likely to defeat the virus. Something more was needed." The something more, Dr. Fauci and others believe, is the body's own powerful, germ-fighting immune system. HIV thwarts the body's ability to ward off infection because it targets and kills precisely those white blood cells needed to signal and carry out combat against the virus. "All along many of us have believed that somehow we had to help reignite a powerful immune response to HIV," Dr. Fauci says. With the virus's attack on the immune system significantly disabled by the drugs, it finally seemed feasible that the immune system might be able to get the upper hand in its battle against HIV, he says. In fact, new research emerging in the months following the hidden-reservoir report led scientists to believe that in certain people, the immune system already was effectively combating the virus. For years, scientists have been curious about a small number of HIV-infected people who-without ever taking drugs-were disease-free for years and able to keep the virus under control. Last year, Dr. Walker and others reported that these so-called "long-term, nonprogressors" had very high levels of an important type of white-blood T-cell that has an ability to recognize HIV in the bloodstream and alert the rest of the immune system to launch an assault on the virus; in most people who progress to AIDS, these T-cells are killed early on by the virus. [SMALL number of HIV-infected people who stay healthy for years? Baloney. Remember that average 10-year asymptomatic period that somehow gets forgotten whenever the researchers don't want to think about it. -- Phil] Then in June, just before a giant worldwide gathering of AIDS researchers and doctors in Geneva, came news that a Berlin man had terminated drug therapy yet remained disease-free for almost 18 months, even though he still had a tiny residue of virus in his blood. News of the "Berlin patient," as he was identified by researchers, was first reported by Mark Schoofs in a story for the New York Times Magazine. In analyzing the Berlin patient, researchers found that his blood contained the same T-cell profile that Dr. Walker had found in the nonprogressors. "That was key," Dr. Walker says. "It suggested to us that something this patient had done had been able to trigger the kind of immune response needed for a person to control the virus without medicine." Franco Lori, director of Project Right, an AIDS research program at both Georgetown University and Pavia, Italy, thinks he knows what it is, and what scientists now believe may be a key to the new research. Soon after the Berlin patient went on therapy in 1996, his virus levels dropped precipitously. But then he stopped therapy for two weeks while he was hospitalized for a testicular infection. The virus re-emerged, and the patient went back on therapy, until a bout of severe nausea a few months later forced him to suspend drug treatment altogether. Now, more than two years later, "he still is keeping the virus controlled" without drugs, says Dr. Lori, who has been studying the Berlin patient. "It's as if by allowing the virus to come back briefly, the patient was teaching his immune system to mount an attack strong enough to keep the virus controlled." The Berlin patient would have been considered a rare curiosity, except that following news of his experience, several other research groups, including the Diamond Center in New York, said they too were quietly following a few patients who on their own had briefly suspended therapy, gone back on the drugs and then stopped taking them completely -- and were now disease-free. In a presentation to a small gathering of AIDS scientists earlier this month in Colorado, which will be made public next week in Chicago, researchers Doug Nixon and Marty Markowitz of the Diamond Center said they are studying two patients who, after driving the virus down to undetectable levels with drugs, suspended therapy on their own for 10 to 30 days, went back on the drugs, and then stopped treatment completely. Both patients have had only low, seemingly benign levels of virus in their bloodstream for 21 months, the Diamond Center investigators reported. "It is as if the brief return of the virus acted like a vaccine, providing the immune system with a limited dose of the virus that triggered a full-blown and powerfully protective immune response. Anyway, that's what we think is going on," says Dr. Ho, the Diamond Center director. Researchers call the theory "self-inoculation." These scientists now hope they may have found a way for some patients to live long lives with a low-level HIV infection. Virologists point out that humans often survive disease-free with virus infections, such as chicken pox or mononucleosis, that only cause illness anew if the immune system weakens. In each of these cases, the immune system controls the virus because it was able to generate a powerful response following exposure to the infectious agent. It is this theory that scientists will be testing with patients like Mr. Shaw, of the NIH study. Last autumn, while Mr. Shaw was still on medication, studies of his blood and cells removed from his lymph nodes showed no residue of virus. "It was then I asked my doctors if I could simply stop the drugs," he says. He says he had been on the drugs continuously since 1996, and before that had been in numerous clinical trials since first being diagnosed with HIV in 1988. Moreover, he wanted to get off the drugs because they were causing a common side effect in which pockets of fat were mysteriously accumulating in his gut. Still, it was a high-risk request, Mr. Shaw admits. Richard Davey, one of his physicians at NIH, says he expects that many test subjects may relapse. Yet researchers say they hope that if just a few patients are as successful as the Berlin and Diamond Center patients, scientists can begin to understand what in their immune response is different. "People keep asking me if I believe it's gone, will it come back," Mr. Shaw says of his HIV. "I think it's gone. But, if nothing else, it's been nice having a sanctioned drug holiday."

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