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Are New Drug Treatments Responsible for Declines in AIDS?

Government officials, AIDS organizations and the media unanimously agree that the recent decline in AIDS cases and deaths is an unprecedented occurrence due to a new combination of drugs that include protease inhibitors, chemicals said to block the replication of HIV. However, a careful look behind the headlines reveals that there is no medical evidence to support these popular claims about the protease inhibitor "combo cocktails."

The declines in AIDS deaths attributed to combination therapies actually began several years before protease inhibitor drugs became available for general use. (72) Since the first protease inhibitor received Food and Drug Administration (FDA) approval in December of 1995, a more likely explanation for decreased deaths would be the change in the official AIDS definition adopted in 1993 which allows HIV positives with no symptoms or illness to be diagnosed with AIDS. Since 1993, more than half of all newly diagnosed AIDS cases are counted among people who are not sick. (73)

CDC data also show that decreases in AIDS cases commonly ascribed to "AIDS cocktails" preceded the introduction of the new drug treatments by three full years. According to the CDC's HIV/AIDS Surveillance Report, AIDS diagnoses peaked in the third quarter of 1991, increased once in the first quarter of 1993 as a result of the 1993 expanded AIDS definition, and have dropped each year since. (75)

News stories of AIDS patients who rise from their death beds to run marathons after taking the drug cocktails, are just that -- stories. In science, such unverified accounts are dismissed as anecdotal, a term that comes from the Greek word anekdotos, meaning unpublished. None of the anecdotal tales of recoveries attributed to new drug combinations have been substantiated by controlled studies published in peer-reviewed medical journals, a fact acknowledged in the fine print of pharmaceutical advertisements:

"At this time there is no evidence that Ziagen will help you live longer or have fewer of the medical problems associated with HIV or AIDS."

"It is not yet known whether Crixivan will extend your life or reduce your chances of getting other illnesses associated with HIV."

"At present, there are no results from controlled clinical trials evaluating the effects of Viramune [on] the incidence of opportunistic infections or survival."

"There have been no clinical trials conducted with Combivir." (76)

Incomplete and inconclusive data from one 1997 study are used to claim that mortality rates are lower among HIV positives treated with protease inhibitors. (77) This particular trial was prematurely terminated before statistically significant results could be obtained, and no placebo control comparing unmedicated HIV positives was used, no recurrent AIDS-defining illnesses that appeared among participants were recorded (except recurrent pneumonia), and the results mentioned in the final report are for only a small fraction of the patients enrolled in the study. (78) Current pharmaceutical ads use this study to declare that their new drugs are "proven to help people with HIV live longer, healthier lives" while simultaneously admitting that "because the study ended early, there was insufficient data to determine [the drug's] statistical impact on survival." (79)

While there is no evidence that cocktail therapies produce clinical health benefits, well-documented side effects include headache, fever, nausea, vomiting, diarrhea, oral lesions, abdominal pain, severe fatigue, sexual dysfunction, general ill feeling, skin rashes, a hypersensitivity reaction that can result in sudden death, nervous system damage, enlarged liver, liver failure, kidney stones, kidney sludge, physical deformities including hunchbacks, sunken cheeks, and "stick-like limbs," diabetes, heart disease, "unmasking" of various opportunistic infections including CMV retinitis (a viral infection which can lead to blindness), and spontaneous bleeding in hemophiliacs. (80)

Media reports attributing declines in AIDS to protease inhibitor cocktails often neglect to mention the high rate of drug failure or the considerable number of HIV positives who either quit the new combinations because of intolerable side effects or have never taken them at all. Recent studies place drug failure rates at 50% while others note that as many as 40% of participants drop out of protease inhibitor drug trials due to adverse effects, and as AIDS expert Dr. James Curran laments, "fewer than 10% of US AIDS patients have access to and are on the new wonder drugs." (81) For more information on the chemotherapy/protease inhibitor drug combinations known as HAART, please see A Sobering Report on AIDS Cocktails and What's Up with Viral Load? on pages 32 and 36.

 

AZT: A Drug in Search of a Disease

AZT is not a new drug. It was not created for the treatment of AIDS and is not an antiviral. AZT is a chemical compound that was developed -- and abandoned -- over 30 years ago as a potential chemotherapy treatment for cancer. (108) Prior to the first AIDS drug trials in 1986, AZT had never been administered to human beings.

Chemotherapy works by killing all growing cells in the body. Many cancer patients do not survive chemotherapy due to its destructive effects on the immune system and intestines. Because of the damage it causes, chemotherapy is never used as a prevention for cancer, and is only administered for very limited amounts of time.

This label has appeared on bottles containing as little as 25 milligrams, a small fraction (1/20 to 1/60) of a patient's daily prescribed dose of 500 to 1,500 mg. (109)

Since cancer is a condition of persistently growing cells, AZT was designed to prevent the formation of new cells by blocking development of DNA chains. In 1964, experiments with AZT on mice with cancer showed that AZT was so effective in destroying healthy growing cells that the mice died of extreme toxicity. (110) As a result, AZT was shelved and no patent was ever filed. Twenty years later, the pharmaceutical company Burroughs Wellcome (now Glaxo-Wellcome) began a campaign to remarket AZT as an anti-HIV drug based on the idea that AZT would block the formation of HIV DNA chains. Glaxo-Wellcome won FDA approval for AZT as an AIDS treatment after one highly flawed study of only four months duration. (111)

Approval of this extremely toxic chemotherapy for use by AIDS patients was based on information that suggested AZT raised levels of T cells and therefore delayed the onset of AIDS indicator diseases. The rise noted in T cells was interpreted as evidence that AZT eradicated HIV in T cells, a concept for which there is no scientific proof. Although the study was halted before any long-term effects of AZT were known, proponents established that standard treatment with AZT should be continuous and lifelong.

A multitude of independent studies conducted before and after FDA approval, including the Concorde study -- the largest (1,749 subjects) and longest (three years in duration) study on AZT -- determined that AZT increases T cell counts only moderately and briefly without improving health and that it does not delay onset of AIDS indicator diseases. (112)

The brief rise in T cells noted when AZT use is initiated is due to the toxic nature of the drug and to the blood system's response to the destruction of bone marrow. (113) As AZT destroys bone marrow, the blood system attempts to correct this depletion by overproducing T cells, often creating more new T cells than the number found in a patient's blood prior to beginning treatment. But as the source of these new T cells -- the bone marrow -- is killed off by AZT, the level of T cells drops lower, ultimately causing complete destruction of the immune system. Individual tolerance to, and absorption of AZT determine length of survival on this toxic compound.

Following recommendations for "early intervention," one-third to one-half of HIV positives who develop AIDS do so only after taking AZT. Independent studies have shown that AZT actually accelerates clinical decline and decreases quality of life, at times even causing death before any AIDS-defining illnesses appear -- an occurrence officially described as "death without any preceding AIDS-defining event." (114)

The concept of "HIV mutation" has become a popular explanation for the fall in T cells observed in patients treated with AZT. Promoters of the mutation hypothesis assert that the positive effects of AZT are diminished by mutant strains of HIV that become resistant to the drug. There is, however, no scientific evidence to substantiate their claim.

In addition to destroying T cells, B cells and the red blood cells that carry oxygen throughout the body, AZT and other nucleoside analog drugs destroy the kidneys, liver, intestines, muscle tissue, and the central nervous system. Nucleoside analog drugs also interfere with the activities of mitochondria, the subcellular particles that are the energy factories of every living cell in the body. Mitochondria contain their own DNA which makes them vulnerable to the effects of nucleoside analogs.

Epivir (3TC), Zerit (D4T), Hivid (ddC) and Videx (ddI) are all nucleoside analog drugs prescribed to HIV positives as "antivirals." All are modeled after AZT, and all work in the same manner.

Defined Terms

Granulocytopenia: Loss or reduction of the number of granulocytes, a group of white blood cells that fight infection. These white blood cells contain a variety of enzymes used to destroy infectious agents.

Pancytopenia: Generalized loss or reduction of white blood cells.

B cells: One of two principle types of lymphocytes (white blood cells). B cells are transformed into plasma cells that secrete immunoglobulins or antibodies that destroy invading microorganisms. The protective effect of immunoglobulins is called humoral immunity.

Nucleoside analog: A synthetic compound similar to one of the components of DNA or RNA. Nucleoside analogs such as AZT act as artificial caps to DNA chains which prevent real DNA units from being added. For this reason these drugs are often referred to as DNA chain terminators.

 

A Sobering Report on Protease Inhibitors and "Combo Cocktails"

Protease inhibitors are a new class of AIDS drugs used in conjunction with older chemotherapy compounds such as AZT and ddI. The mixture of these treatments is called a "combination cocktail" or "highly active antiretroviral therapy" (HAART). The formula is usually two parts nucleoside analog to one part protease inhibitor. According to popular belief, this mix brings new power to the old chemotherapies, and achieves what press reports and AIDS groups characterize as unprecedented and amazing results.

Approved after the fastest and most lenient review process in FDA history and immediately hailed as miraculous by mainstream media, the clinical benefits of protease inhibitor drugs remain unproved. More than four years after being released for use, there are still no reports in scientific journals that provide evidence of health improvement in patients taking these powerful drugs.

Claims of victory for protease inhibitors are based entirely on changes in surrogate markers, laboratory measurements of unsubstantiated accuracy and value in assessing actual health. In the only published report alleging higher survival rates for patients treated with protease inhibitors, the study used no unmedicated placebo controls, did not allow reporting of any recurrent AIDS-defining events except pneumonia, included no patient data, cited outcomes for less than 10% of overall participants, and was prematurely terminated after an average follow-up of 38 weeks when emerging mortality statistics favored the protease inhibitor treated patients.115 The survival outcomes between the two groups1.4% mortality among those on the new drugs, 3.1% for the old drugs have no statistical significance, a fact that forces the drug advertisements to admit "because the study was ended early, there was insufficient data to determine the statistical impact of Crixivan on survival."117

One National Institutes of Health study of protease inhibitors, ACTG315, is portrayed as a success even though its conclusions are drawn from a trial of only 12 weeks.118 Dr. Michael Lederman, protocol chairman and author of ACTG 315 acknowledged that the study was never designed to consider a patient's health. Instead, results were determined by changes in the surrogate marker of "viral load," a test that does not diagnose illness, quantify active virus or measure health.

The absence of data on long-term effects of protease inhibitors has not prevented orthodox AIDS organizations who promote or provide the drugs from becoming uncritical advocates. Following the lead of the media, their focus has been on securing widespread access to the treatments rather than on examining evidence to insure they are safe and effective. AIDS doctors have also overlooked the remarkable lack of documentation in favor of the options for treatment offered by protease inhibitors. And while boldface headlines continue to assign lifesaving properties to these drugs, the tiny type in pharmaceutical ads, the ever-growing list of side effects, and the increasing number of unsuccessful experiences ranging from physical deformities to sudden death tell an entirely different story.

Protease inhibitors are assumed to work by disrupting an enzymatic link in the reproduction of HIV. Enzymes are proteins that join together or cut apart other molecules. Like all retroviruses, HIV has three enzymes: reverse transcriptase, integrase, and protease which cut proteins apart, an essential step in the reproductive process of a retrovirus. Protease inhibitors block proteases by acting as dysfunctional molecules that take the place of functional ones and inhibit the cutting apart of proteins. All retroviral enzymes are similar to various human enzymes and there are numerous human proteases, including ones required for digestion of food.

Protease inhibitors are like nucleoside analog drugs such as AZT in that they produce dysfunctional substitutes that interrupt or prevent normal processes of enzymes. While manufacturers of protease inhibitors claim that the drugs specifically target HIV protease, the growing list of side effects contradicts their assertions. Nucleoside analogs such as AZT, once promoted as specifically targeting HIV, have been shown to block the construction of vital human DNA as effectively as they block the formation of HIV DNA. It is now known that AZT, ddI and other nucleoside analogs block the DNA inside mitochondria, the subcellar particles that produce the energy required for the life of all cells.

The necessity for lifelong therapy with protease inhibitor cocktails is described as absolute, although drug manufacturers clearly state that "the long-term effects of protease inhibitors are unknown." The need for rigorous compliance with combo therapy is a popular subject of news reports and AIDS organization seminars. Patients are required to pop as many as 30 pills a day on a 24 hour schedule some taken with food, others on an empty stomach, many that cannot be taken together and warned that without strict adherence to the dosages and times, their virus will mutate into new, drug resistant strains.

According to Dr. David Rasnick, a protease expert working outside the AIDS system, the theory of resistant HIV protease is completely unfounded. Rasnick, a pioneer in the development of protease inhibitors points out, "no one has ever published data on a resistant HIV protease found in any patient. The only inhibitor-resistant HIV proteases ever examined have been produced in the lab using genetic engineering."119

Nevertheless, warnings about drug-resistant HIV proteases are emphasized in media reports that also speculate about new epidemics that will arise when unstoppable forms of HIV are introduced into the population. As announced by AIDS researcher Dr. Bruce Walker on a recent segment of ABC News' Nightline, "That's going to be the next epidemic that we're dealing with, the transmission of drug resistant HIV viruses."120 Such reports reinforce the notion that no matter how unbearable the side effects, a patient who quits the drugs becomes a public health menace. This science-fiction scenario has even inspired some health officials and legislators to consider mandatory treatment laws for HIV positives.121

Perhaps the greatest achievement of protease inhibitors is the new life they have given to AIDS advertising campaigns. An epidemic of posters, billboards, and full-page magazine ads urge HIV positives to "be smart about HIV" by "hitting early and hard" with medicines "proven to help people live longer, healthier lives."122 However, many staunch supporters of AIDS pharmaceuticals are less certain. Top AIDS scientist Dr. Anthony Fauci expressed serious reservations about the use of protease inhibitors by "otherwise healthy people" in a recent article in the Journal of the American Medical Association, "We do not know whether early intervention in asymptomatic individuals will result in a long-term clinical benefit or whether the cumulative toxicity over years of drug administration will outweigh the potential benefits."123 Even Dr. Robert Gallo has warned that "these drugs are toxic...the longer you take the drugs, the greater the toxicity."124 Dr. Jay Levy, another mainstream AIDS specialist, maintains that "these drugs can be toxic and can be directly detrimental to a natural immune response to HIV."125

A careful examination of the small print in protease inhibitor ads puts the promises made by smiling models into perspective: "Since Crixivan has been marketed, other side effects have been reported including rapid breakdown of red blood cells, kidney stones and kidney failure. In some patients with hemophilia, increased bleeding has been associated with protease inhibitor use."126 Pre-marketing side effects like diarrhea, nausea, fungal infections, bloody urine, weakness, headaches and liver inflammation were all but ignored by AIDS activists who pressured the FDA for fast-track approval.127 The list of post-marketing side effects continues to grow and contradicts earlier reports on the cocktails that proclaimed, "It's unbelievable. There's no toxicity. It's a home run!"128

Documented adverse reactions presently include CMV retinitis (a viral infection that often results in blindness), diabetes, liver failure, physical deformities, renal failure, kidney sludge, skin rashes, severe exhaustion, loss of appetite, pancreatitis, diarrhea, nausea and vomiting, muscle and joint pain, neuropathy, sexual dysfunction, fever, chills, dizziness, abdominal pain, depression, sleep disorders, and sudden death.129

Other than anecdotal tales of miraculous recoveries trumpeted in the press, the lower levels of "viral load" found in some patients taking protease cocktails seem to be the only and highly questionable result of these treatments. But even "undetectable" viral loads are not an unprecedented occurrence in HIV treatment. AZT has lowered those levels for many years without resolving AIDS. A POZ magazine article recalls that "in the European Delta study, fully 40% of participants became 'undetectable' [for viral load] on AZT/ddI; another 5% did so on AZT alone. We have been reducing viral load to undetectable levels for a decade. But if becoming 'undetectable' on nucleoside combos hasn't prevented progression to disease and death, why is 'undetectable' on protease combinations impervious to failure except for the fact that we haven't followed patients long enough to see it?"130

Although the media credits "AIDS cocktails" with recent decreases in AIDS cases and deaths, CDC surveillance reports clearly show that AIDS cases and mortalities have been steadily declining since 1993 almost three years before the cocktails were approved for use.131 Some experts like David Rasnick attribute the drop in AIDS deaths that began in 1993 to the fact that over half of all AIDS cases reported since that year are among people who test HIV positive but have no illness or symptoms.132 The same reports show that AIDS cases had leveled off in 1991 and increased only once since, in the first quarter of 1993 when more conditions and illness were added to the definition of AIDS.

For some, the chorus of enthusiastic press reports about protease inhibitors recalls the release of AZT twelve years ago. "Once again, all we have are researchers talking to reporters about incomplete studies that haven't been scrutinized by the scientific review process," remarks Dr. Rasnick. "And the researchers involved are funded by the companies that make the drugs in question. There is no justification for the claims coming from these sources, particularly when we've seen it all before."133

Declarations of success and improved survivability for AZT were based on abbreviated trials of less than six months duration that were sponsored by the drug's manufacturer who selected for publication only those trials with seemingly favorable outcomes. Success was measured by the surrogate marker of that day, increased T cell counts, which have proved to be a temporary phenomenon at best and of questionable clinical value. As with AZT, the elation unleashed over protease inhibitors is based on unpublished manufacturers' studies so brief they are usually measured in weeks rather than months, and on the surrogate marker of reduced "viral load," a measurement that has not been correlated with actual health benefits. While the media persists with stories of the miraculous achievements of protease inhibitors making believers out of the concerned public and desperate AIDS patients, only time and independent research will reveal the truth about the latest "great hope" in the war on AIDS.

Defined Terms

Pancreatitis: Inflammation of the pancreas; chronic pancreatitis often causes diabetes.

Neuropathy: Any disease or disorder of the nervous system.

Surrogate Marker: A laboratory test result that takes the place of or substitutes for a clinical indication or diagnosis.

 

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