DEBATING
AZT


AZT: A Medicine from Hell

October 1998

The more ignorant, reckless and thoughtless a doctor is, the higher his reputation soars, even amongst powerful princes.

Praise of Folly

Desiderius Erasmus (c. 1466 -1536), Dutch humanist.

National Health Minister Nkosazana Zuma has been condemned by just about everyone recently for her heartless decision not to make a drug called AZT available at State expense to HIV-positive pregnant women. It reduces the risk, so it’s said, of the transmission of HIV from mother to child. Politicians and journalists from left to right have joined moist-eyed, hand-wringing doctors in pleading for the free provision of AZT to these women, their babies cruelly deprived and doomed to die, they say.

In all the fuss about the minister’s decision on AZT, no one, it seems, has stopped to ask, “So what the hell is this stuff anyway?”

In 1964, a chemist called Jerome Horwitz synthesised a sophisticated experimental cell poison for the treatment of cancerous tumour cells (1). It was called Suramin, or Compound S. Its formal title is 3’-azido-3’-deoxythymidine - zidovudine for short - but everyone knows it by its nickname, AZT.

It works like this. Thymidine is one of the four nucleotides (building blocks) of DNA, the basic molecule of life. AZT is an artificial fake, a dead ringer for thymidine. As a cell synthesises new DNA while preparing to divide in order to spawn another, AZT either steals in to take the place of the real thing, or else disrupts the delicate process by interfering with the cell’s regulation of the relative concentrations of nucleotide pools present during DNA synthesis. That’s the end of the cell line. Cell division and replication, wrecked by the presence of the plastic imposter, comes to a halt. Chemotherapeutic drugs such as AZT are described as DNA chain terminators accordingly (2). Their effect is wholesale cell death of every type, particularly the rapidly dividing cells of the immune system and those lining our guts. Horwitz found that the sick immune cells went, but with so many others that his poison was plainly useless as a medicine. It was akin to napalm-bombing a school to kill some roof-rats. AZT was abandoned. It wasn’t even patented. For two decades it collected dust, forgotten - until the advent of the AIDS era.

As soon as Dr Robert Gallo made his famous announcement at a press conference on 23 April 1984 that his virus was the probable cause of AIDS, the race was on to find a pharmaceutical weapon against it. The stratospheric profit potential (since borne out) of being the first past the post was on everybody’s mind. Obviously, if an already synthesised drug could be applied to the malady, it would short-cut most of the road-race there. AZT was fished off the shelf, along with numerous other abandoned brews, and put to some in vitro tests. It demonstrated a bright alchemical sparkle. On the basis of a reassuring but fallacious assertion that AZT was specifically antagonistic to HIV, and a thousand times more toxic to the latter than human cells generally, the drug went to clinical trials. The chaos into which the trials degenerated is a tale too long to tell here. It wouldn’t be extravagant to call them fraudulent (3). (Subsequent trials consistently turned in opposite results.) At best, they were so incompetently staged that the data gathered under them were useless, save to note that one in five of its subjects taking AZT needed repeated blood transfusions to keep going. Small surprise, since the label on bottles of AZT supplied to laboratories bears a skull and cross-bones and cautions, “Toxic by inhalation, in contact with skin and if swallowed. Target organ(s): Blood, bone marrow…Wear suitable protective clothing.”

Four months after the trials started, they were called off prematurely, on an interpretation of provisional results deemed positive for the drug by the trial overseer. Which is odd for a drug claimed to be on double-blind test, with neither doctor nor patient supposed to know who was on what, but there we are. Next, it went before the FDA, to be approved in record time under huge political pressure from the gay lobby. Strong reservations were expressed at the hearing about its dreadful toxicity. The chairman’s vote against it was defeated. As the most poisonous drug ever licensed by the FDA for indefinite use, and with the conviction apparently that the terrible new disease needed a terrible medicine, AZT was approved for use in extreme AIDS cases only - for which you might want to read, in cases of people very ill with their presenting AIDS indicator disease, fungal pneumonia or what have you. Scarcely a year later, in the orgy of stupidity that characterises the AIDS age, AZT was officially recommended for administration to entirely healthy people, whose misfortune it was to register positive to an HIV antibody test. Since the drug destroys the very immune cells allegedly attacked by HIV, the introduction of AZT as a treatment regimen for asymptomatic HIV-positive people saw the AIDS mortality rate among the previously well take off like a rocket. Five years and countless deaths later, and only after the disastrous results of the European Concorde and St Mary trials, was this murderous treatment recommendation reversed. AZT, it was found, did no good. Of course not. On any intelligent consideration of its pharmacological action, AZT could never be ‘antiviral’, any more so than arsenic could have cured the scurvy for which it was administered to sailors, and later, to troops in the trenches in the First World War.

In Europe and the US, HIV-positive ‘long term survivors’ quietly gather to form groups, having sloughed off the terror of the death sentences imposed on them by their doctors. Here’s the strangest thing. Without exception, what they find they all have in common is that they all eschewed (or quickly gave up) AZT, related nucleoside analogues like 3TC, and protease inhibitors. Some have pondered the unthinkable: that nearly all medically managed AIDS cases, always terminal, represent that balefully familiar phenomenon in the history of medicine, iatrogenocide - to be killed by the cure. Their reasoning becomes less obscure when one reads the AZT package insert. To do so might tempt one to wonder impertinently whether AZT isn’t AIDS by prescription. Indeed, such perverse conjecture is actually confirmed in capitals: AZT use “MAY BE ASSOCIATED WITH HEMATOLOGIC TOXICITY INCLUDING GRANULOCYTOPENIA AND SEVERE ANEMIA” (destruction of white and red blood cells respectively), and “PROLONGED USE OF RETROVIR HAS BEEN ASSOCIATED WITH SYMPTOMATIC MYOPATHY (gross atrophy of muscle tissue) SIMILAR TO THAT PRODUCED BY HUMAN IMMUNODEFICIENCY VIRUS”. As to the latter claim, history will judge whether the thousands of healthy HIV-positive people who embarked on their metabolic poison treatment and wasted away (just as the AZT insert predicted) would have died had they ignored doctor’s orders and thrown their pills away. Here the syphilis story is instructive.

Before the introduction of mercury and arsenic salts as a treatment for this clap, the organic brain damage and dementia that signalled ‘tertiary-’ or ‘neuro-syphilis’ was quite unknown to medicine. When penicillin replaced the older decoctions, it then disappeared. The moral is hard to miss.

One sane notion in that otherwise mad dance with death that chemotherapy for cancer involves is that you stop before you drop. Since healthy cells are always killed in the crossfire, the idea is to rescue the patient from going over the cliff along with the target bad cells, by taking him off the drug in the nick of time. That iron rule is broken in AIDS treatment. You’re going to die, you’re told, so better take the bitter medicine to the bitter end, to stave off the evil day. But as AZT heads like a heat-seeking missile for one’s immune and energy transporting cells (“target organs: blood, bone marrow”, remember?) dying of AIDS on AZT is a racing certainty. No one has ever been cured by AZT, but it sells like hot cakes all the same, still the most widely prescribed AIDS drug, and it reaps profits counted in billions.

Ever irrepressible as a medicine following one failure after another, in 1994 AZT was proposed as a treatment for pregnant women to prevent the transmission of HIV from mother to child, or so it was touted. Until then, it had been staunchly contraindicated during pregnancy. Generously underwritten by the drug’s manufacturer, the study, ACTG 076, in which this startlingly novel use of AZT was tried, epitomises the junk-science that characterises so much AIDS research. Of 477 babies born to HIV-positive mothers in the trial, 13 in the AZT-treated group were born antibody-positive, against 40 in the placebo group. Apart from the lunacy of basing a decision to dose HIV-positive mothers with a cell-toxin as lethal as AZT on such feeble numbers, the underlying assumption that an HIV-positive test result predicts inevitable illness and death is a canard of modern medicine which, surprisingly, wants for evidence. Most babies ‘seroconvert’ to HIV-negative in any event, medicated or not. The other overarching myth is that the mere presence of antibodies in one’s bloodstream signifies an active infection. Isn’t it elementary that we carry antibodies to all sorts of pathogens that we have met and defeated? Isn’t this first-year stuff? Advocates of AZT confess to being completely in the dark to account for the vaunted HIV blocking effect they claim. The reason why administering vitamin A instead works precisely the same magic might be a pointer to something less interesting: stressed health, thanks to chronic poor nourishment and living conditions. As for the positive immune signals a ‘short course of AZT’ can generate, poison ingestion provokes an immune reaction as the body rises to the insult. This is old hat.

Thrown to the wind have been all the safeguards set up to ensure that the Diethylstilbestrol and Thalidomide tragedies would never happen again. Before the hysteria of the AIDS age, women were enjoined even to avoid drinking beer during pregnancy. A recently reconfirmed active carcinogen, and teratogen too - cells not killed outright are nastily maimed - AZT freely crosses the placental barrier, so the package insert tells us cheerfully. Has anyone here paused to question whether a growing foetus comprising rapidly dividing cells should be exposed to a random terminator of DNA chain synthesis? Apparently not. Certainly not the recipients of GlaxoWellcome’s largesse from its slush fund of millions for those who make AIDS their business in this country. Nor our doctors carrying out bold medical experiments on the foetuses of pregnant black women - whose unlucky dice gives them a positive registration to the irredeemably and hopelessly non-specific ‘HIV-antibody’ test. Of course anyone in the game crying foul, and drawing attention to the reams of literature in the medical journals about the harm caused by AZT, especially to the young, is going to find himself sent off and defunded, for keeps. Were it not for the amazing collapse of critical intelligence in the AIDS age, GlaxoWellcome’s heart-warming contributions to ‘the fight against AIDS’, with its research grants and cut-prices - described by the Mail and Guardian as a “bouquet of assistance” - might have been seen less as philanthropy than commerce, pure and simple. As it has achieved so successfully abroad, what better way to fix its local market than by buying off our medical establishment and ‘AIDS activist’ crowd with lolly aplenty to fund their dumb projects? And by enticing our government with current discounts for its rancid wares, in order to hook longer-term contractual commitments.

The AIDS Law Project at Wits currently busies itself with plans to sue the minister in the High Court for an order compelling her to respect ‘pregnant women’s rights to AZT’, and dole it out on the house. Then again, its ‘AIDS activist’ lawyers gratefully take junkets to AIDS conferences in holiday cities overseas at GlaxoWellcome’s expense. The ‘human rights’ they pursue might be better served were these legal crusaders to call off their foolish case and think of ways best to bite the hand that feeds them. Several actions for loss of support have been launched against GlaxoWellcome in England and the USA, arising out of the deaths of family members killed by their doctors’ prescriptions of AZT (5).

Although she has justified her perplexing decision on AZT on the basis of financial considerations exclusively, saying she would rather spend her money on ‘AIDS education’, one day Health Minister Nkosazana Zuma will be praised for her great prescient wisdom in keeping AZT away from pregnant women and their foetuses. A bit like much-lauded Dr Francis Kelsey, whom Kennedy honoured for her wise perspicacity in sparing the USA the European Thalidomide calamity, when in truth her only notable trait was her fortuitously inefficient foot-dragging in obstructing the start of the FDA approval process.

It’s high time that everyone involved in this nightmarish mess went off to do some basic homework in the subject in which they have so much to say for themselves.

(1) Horwitz, J.P., Chua, J. and Noel, M: Nucleosides. V. The monomesylates of 1-(2’-Deoxy-beta-D-lyxofuranosyl)thymine, Journal of Organic Chemistry 29: 2076-2078 (1964). However, an American biochemistry professor with whom I have corresponded privately makes a documented prior claim to the first synthesis of AZT in the autumn of 1961. He prefers both to remain anonymous and not to upset the settled history - based on the first to publish. He mentioned to me that he employed AZT as an experimental cell-poison against leukaemic blood cells, and against the bacteria Salmonella Potsdam and E. coli. (Studies in the ‘90’s have confirmed AZT’s activity against all three.) He pointed out that after publishing his paper, Horwitz investigated the activity of AZT against Jensen tumour cells, and not against leukaemic blood cells as I reported originally in line with the conventional history. He also criticised my repetition of the claim that Horwitz abandoned AZT because of its toxicity (see for example the excerpt from Radford’s article immediately below). He said the reason was its inactivity against target cancer cells, while the acute toxicity of AZT emerged only later. Actually, Horwitz has made contradictory statements about this. Reviewing this essay, he remarked, “…you are justified in sounding a warning against the long-term therapeutic use of AZT, or its use in pregnant women, because of its demonstrated toxicity and side effects. Unfortunately, the devastating effects of AZT emerged only after the final level of experiments were well underway, that is, the experiments which consisted of giving AZT to large numbers of human patients over a long period of time. Your effort is a worthy one… I hope you succeed in convincing your government not to make AZT available...”

In an enthusiastic article about the pharmaceutical industry in the UK, Tim Radford wrote in the Guardian on 30 March 2000, “They settled on an anti-cancer drug which had proved too toxic to use against cancer: It was AZT… Since DNA is a ubiquitous part of life, compounds that act against it can potentially stop life forms like bacteria, like viruses, like humans. Of course, they can cause cancer as well, so balancing the risks is an essential part of the fascination.” The fascinating risks for the development of cancer posed by the administration of AZT are examined extensively in my reply to Dr Martin, AZT and Heavenly Remedies.

(2) DNA chain formation termination - described in this paragraph - is generally understood to be the basic pharmacological action of AZT. GlaxoWellcome asserts in its PRODUCT INFORMATION release about AZT, “In vitro, zidovudine triphosphate has been shown to be incorporated into growing chains of DNA by viral reverse transcriptase. When incorporation by the viral enzyme occurs, the DNA chain is terminated.” In a glitzy CD dished out at the 13th International AIDS Conference in Durban, GlaxoWellcome claims similarly: “Nucleoside Reverse Transcriptase Inhibitors – NRTIs – [like AZT are] phosphorylated by cellular enzymes… competitively inhibit viral DNA synthesis [and are incorporated] into the DNA thus terminating DNA synthesis.”

This conventional model of AZT pharmaco-kinetics is accepted by a vociferous critic of the drug, Dr Peter Duesberg, professor of molecular biology at the University of California at Berkeley. His criticisms go principally to the unacceptable toxicology profile of AZT, and do not take issue with its manufacturer’s claims about its mode of action. Accordingly, in Inventing the AIDS Virus he writes, “While on AZT, Bergalis once told a reporter she hoped to also get dideoxyinosine (ddI), another experimental AIDS drug. This drug and ddC, two products of cancer chemotherapy research, work in precisely the same way as AZT. Chemically altered building blocks of DNA, they enter the growing chain of DNA while a cell is preparing to divide and abort the process by preventing new DNA building blocks from adding on… So, like AZT, ddI and ddC kill dividing cells and have similar toxic effects. They destroy white blood cells and therefore can cause AIDS.” Jay Levy, professor of medicine and director of the Laboratory for Tumor and AIDS Virus Research at UCSF (and unlike Duesberg, a vocal protagonist of the orthodox HIV-AIDS model) said in Newsday on 12 June 1990, “AZT can only hasten the demise of the individual. It’s an immune disease and AZT only further harms an already decimated immune system.” Duesberg’s most recent and most detailed critique of AZT, co-authored with pharmacology biochemist David Rasnick Phd, is contained in The AIDS Dilemma: Drug diseases blamed on a passenger virus, published in Genetica in mid-1998. It can be read on the internet.

As Mycek et al put it in their text Pharmacology (2nd ed), it is trite that before the drug can be incorporated into DNA, “AZT must be converted to the corresponding nucleoside triphosphate by mammalian thymidine kinase in order for it to exert its antiviral activity.” Recognising this, GlaxoWellcome claims, “Within cells, zidovudine is converted to the active metabolite, zidovudine 5’triphosphate (AztTP), by the sequential action of cellular enzymes.” But numerous investigations since AZT was approved by the FDA in the US have found that AZT is triphosphorylated in vivo very inefficiently, and at least one order of magnitude lower than necessary for its claimed anti-HIV effect. Consequently viral DNA chain termination by the incorporation of metabolically altered AZT into DNA in place of natural thymidine is insignificant in relation to other activities of the drug, inter alia as a potent oxidising agent. This subject will get a close look in my reply to Dr Martin, AZT and Heavenly Remedies. AZT also disrupts cell division by perturbing the relative levels of natural nucleotide pools, with the drug acting as a ‘sink’ and sponging up phosphate molecules essential to the process. Starved of these molecules and denied the energy they provide, dividing cells die.

This pivotal criticism of the conventional model of the pharmacology of AZT - namely that AZT is not in fact triphosphorylated as GlaxoWellcome claims it is - is made and elaborated extensively in a paper discussed in my reply to Dr Martin, A Critical Analysis of AZT and its Use in AIDS by Papadopulos-Eleopulos et al, published in mid-1999 as a special supplement to the academic medical journal Current Medical Research and Opinion. Like Duesberg and Rasnick’s paper mentioned above, it is archived on the website http://www.virusmyth.com/ . Librapharm also has it posted at: http://www.librapharm.co.uk/cmro/vol_15/supplement/main.htm

(3) The way in which AZT was approved and reached the market as an AIDS drug has been closely researched and reported by John Lauritsen (Poison by Prescription: The AZT Story, and The AIDS War), Celia Farber (Sins of Omission, The AZT Scandal), Bruce Nussbaum (Good Intentions), Elinor Burkett (The Gravest Show on Earth), Peter Duesberg (‘With therapies like these who needs disease’ in Inventing the AIDS Virus) Martin Walker (Dirty Medicine and HIV, AZT, Big Science & Clinical Failure) and Steven Epstein (Impure Science: AIDS, Activism, and the Politics of Knowledge). It’s an amazing story, and is certain to haunt GlaxoWellcome in litigation sooner or later. Some of this writing can be read on the website mentioned above.

(4) In his address to the National Council of Ministers on 28 October 1999, during which he ordered an investigation into the safety of AZT, President Mbeki mentioned these lawsuits. GlaxoWellcome’s representatives in South Africa immediately denied them. A few days later, the President’s office asked me for details. I referred to the English cases of Threakall and others, and the American Nagel and McDonnell cases, all of which had been reported in the press. A month later however, in a telephone call from Susan Threakall’s English solicitor Graham Ross, I was informed that her action, his lead case, had been withdrawn a couple of months earlier. In March 2000, Paul Headlund, the American attorney who had handled the Nagel and McDonnel cases, told me that the claims had not been pursued. GlaxoWellcome was therefore technically correct in disputing Mbeki’s statement that there were cases concerning AZT pending against it at that time. What GlaxoWellcome omitted to mention was that a month earlier a court in Maine in the US had dismissed a bid by health authorities to compel Valerie Emerson to administer AZT to her son after her daughter had died on the drug, and held, “She feels that she has willingly and in good faith surrendered up the life of one child to the best treatment medicine has to offer and does not want to do the same with the next. Nikolas has made significant strides recently in gaining weight and overcoming developmental deficits, and appears happy and healthy. She does not want to see this child take on the pallor and pain of a sick and dying child.”

I am currently briefed in a claim against GlaxoWellcome for the widow and minor son of an attorney killed by a single month’s course of AZT and 3TC treatment. The action will be the first world-wide in which the integrity of GlaxoWellcome’s claims about the molecular pharmacology of AZT and the adequacy of the information provided about its hazards will be examined by a trial court in the light of the Papadopulos-Eleopulos et al review paper and others canvassed in my reply to Dr Martin. It will be the plaintiffs’ case that AZT is an unreasonably dangerous drug with no therapeutic or palliative value as an ‘antiretroviral’ whatsoever. This action is my lead case. I have since been instructed to represent two other plaintiffs, one who suffered permanent leg muscle damage and another liver damage after treatment with the drug. For another action I am handling involving AZT poisoning, but brought on a different basis, see An AIDS Case in the appendices to this debate.

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AZT: A Medicine from Heaven

Desmond J Martin

31 March 1999

THE Southern African HIV/AIDS Clinicians Society responds to an article AZT: A Medicine from Hell, by Anthony Brink, published in The Citizen on March 17.

Human Immunodeficiency Virus (HIV) disease is a major global health problem and is associated with a significant morbidity and mortality.

The number of people infected with HIV is rapidly increasing; recent estimates indicate more than 30 million adults and 1,1 million children are infected worldwide. In South Africa it is estimated that in excess of three million people are infected. It has been predicted that 40 million persons, including four to five million children, will have acquired the infection by the year 2000. Mother-to-child transmission, the major cause of HIV infection in infants, has led to a 30 percent increase in the mortality rate of infants and children in recent years.

The introduction of highly active anti-retroviral therapy (HAART) has been good news. In the US the age-adjusted death rate among people with HIV in 1997 was less than 40 percent of what it was in 1995. This experienced was mirrored in other Western nations where dramatic declines in morbidity and mortality as a result of the increasing use of combination anti-retroviral therapy has occurred; many of these regimens contain AZT.

When AZT and other nucleoside analogues were first introduced they were used as monotherapy (a single drug was used). Clinical experience quickly showed that the effect of a single drug was short-lived, as resistance to the drug developed. It was then shown that by using a combination of drugs, a more lasting effect was obtained.

BENEFICIAL

An added advantage of combination therapy was that the drugs acted at different stages of the replication cycle of the virus. This option therefore made sense; the risk of drug resistance was drastically reduced and long-lasting beneficial effects have been recorded. AZT together with 3TC and a protease inhibitor is a combination that has been found to be highly effective.

Impaired quality of life associated with the progression of HIV disease has a profound effect on the patient and leads to an increase in the direct medical and non-medical costs of illness. Published studies have shown that patients on combination therapy with AZT and 3TC have been able to maintain or more importantly improve their quality of life.

So effective are combination anti-retroviral regimens in reducing the complications of the disease that there are anecdotal reports emanating from the US that Aids wards are being emptied of their patients and in some instances wards have been closed. Clinicians are now treating patients in out-patient settings and the status of the disease has changed to that of a chronic manageable disease.

It is however, in the arena of prevention of HIV infection that AZT has produced dramatic results.

Worldwide, approximately 500 000 infants become infected each year as a result of mother-to-child transmission. In some African countries 25 percent of pregnant women are infected with HIV. Without preventative therapy up to a third of their babies may become infected; many of these children will die in their early years.

In 1994 a clinical trial conducted in the US and France (ACTG 076) demonstrated that AZT given to mothers during their pregnancies, intravenously during labour and orally to their babies for six weeks reduced the risk of mother-to-child transmission by 67 percent. This regimen has been adopted as the "standard of care" in the US.

However, it is unsuitable for developing countries because of its complexity and cost.

To address the problem the Ministry of Health in Thailand introduced a trial of simpler and less expensive regimens of AZT to prevent mother-to-child transmission. This trial showed that a simpler regimen of AZT given orally to mothers in the last weeks of pregnancy reduced the risk of transmission by 50 percent. This short course AZT regimen (so-called Thailand regimen) is much more suitable for developing countries than the US-protocol because it is much easier to administer and less costly ($50 v $800).

Preliminary data from United Nation Aids Programme (UNAids)- sponsored studies have also demonstrated that even more abbreviated, affordable, AZT-containing regimens may be equally effective.

Another instance where preventative AZT therapy is commonly used is in the event of a health-care worker (HCW) sustaining an occupational exposure to blood or body fluids from an HIV infected person (eg. needle-stick injury).

These occurrences are usually charged with much emotion and HCW’s are, quite justifiably, entitled to appropriate post-exposure prophylaxis to be commenced as soon as possible after the injury. A multinational study conducted among occupationally exposed HCW’s demonstrated a 79 percent reduction in the risk of acquiring HIV infection when AZT was used as post-exposure prophylaxis.

TOXICITY

The toxicity of AZT is a very real issue however, the toxicity (particularly bone marrow toxicity) is usually noted in patients with advanced HIV disease whose bone marrow function may already be impaired by HIV disease. Toxicity does not appear to be a problem during short-term use (post exposure prophylaxis or mother-to-child transmission prevention).

Nevertheless vigilance and monitoring on the part of the clinician is necessary. If toxicity occurs the drug should be stopped and other drugs substituted and any appropriate management should occur. Toxicity in most cases is reversible. In addition, careful monitoring of babies whose mothers took AZT during pregnancy has failed to show any significant abnormal findings.

Thus AZT in combination with other drugs has proved to be invaluable for the treatment of those already infected with HIV and has also proved to be a potent preventative agent in the mother-to-child setting and for occupational exposures. For these very reasons the drug AZT deserves the accolade: AZT: a medicine from heaven.

Desmond J Martin is president of the Southern African HIV/Aids Clinicians Society.

Note: Dr Martin has no conflict of interest and has not received financial sponsorship from GlaxoWellcome.

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AZT and Heavenly Remedies

What can you do against the lunatic...who gives your arguments a fair hearing and then simply persists in his lunacy?

Winston Smith, in Nineteen Eighty-Four

George Orwell

[1] AZT - pure poison? Nonsense, retorts Dr Martin, with the avuncular bedside reassurance of doctor who knows best. AZT, he proclaims, is God’s own medicine.

[2] In his letter covering his response to my essay AZT: A Medicine from Hell, Martin rebukes the editor of the Citizen for his “gross irresponsibility” in publishing my piece without having first obtained the views of “the established experts.” In this reply, we’ll have a look at what experts from the top drawer of the AIDS research establishment have to say about AZT, the kind of guys who get to publish in the world’s most splendid medical and scientific journals.

[3] The first clinical report from practising doctors that something was terribly wrong with Dr Martin’s Heavenly Medicine was filed by Dr Laura Bessen and her colleagues in March 1988. In a letter to the New England Journal of Medicine headed Severe Polymyositis-like Syndrome Associated with Zidovudine Therapy of AIDS and ARC, they reported, “All patients had an insidious onset of myalgias, muscle tenderness, weakness, and severe muscle atrophy favouring the proximal muscle groups. Physical examinations revealed varying degrees of muscle weakness and grossly apparent atrophy. Weight loss due to muscle loss was uniformly noted; in one patient, the loss was a striking 18kg.” Bessen et al noted, “We did not observe this illness before zidovudine was available…” It sure wasn’t the HIV, because fortunately for the patients they were treating, the doctors found that “the syndrome was ameliorated after the drug was stopped.” But the patient doesn’t always recover: In their review paper Mitochondrial toxicity of antiviral drugs in Nature Medicine in 1995, Lewis and Dalakis noted, “In some cases, reversal of symptoms corresponds to cessation of therapy; in others toxicity persists…” They also drew the important distinction: “It is self-evident that ANAs [antiviral necleoside analogues] like all drugs have side-effects. However the prevalent and at times serious ANA mitochondrial toxic side-effects are particularly broad ranging…”

[4] Two months after Bessen’s letter, Gorard et al reported their observation of Necrotising myopathy and zidovudine in the Lancet: “A 24-year-old woman presented in January 1988 with a 2-week history of progressive leg weakness and difficulty in walking. She had been found to be HIV antibody positive in April 1986, and in October 1986, Pneumocystis carinii pneumonia developed. After the pneumonia she had been on zidovudine 200 mg 4-hourly and had required three blood transfusions for consequent myelosuppression [white blood cell depletion]. On examination there was proximal weakness but no wasting of the upper and lower limbs, tenderness of the shoulders and thighs, and preserved deep tendon reflexes. Her gait was waddling and she was unable to rise out of a chair without using her arms...7 days after zidovudine withdrawal, her proximal weakness and muscle tenderness had improved significantly, and muscle force was clinically normal at follow-up 2 months later.” In September in the same journal, Helbert et al published their findings on Zidovudine-associated myopathy: “A severe proximal myopathy, predominantly affecting the legs, seems to be a significant complication of long-term zidovudine therapy, even at reduced doses; it affected 18% of our patients who had received treatment for more than 200 days. Other drugs could not be implicated. The pathogenesis is obscure; the myopathy resolves on cessation of zidovudine, but not on dose-reduction…” For some people anyway. After just a month’s course of AZT treatment, a colleague of mine lost most of his muscle mass and died several months later weighing 42kg. A client has suffered permanent leg muscle damage and can no longer walk more than short distances without experiencing the fall-down fatigue of a marathon runner at the end of his race.

[5] Bessen, Gorard, Helbert and their colleagues’ clinical observations were investigated and reported by Dalakas et al in 1990 in the New England Journal of Medicine. Comparing the myopathy caused by AZT with that presumed to be caused by HIV, they concluded that “long-term therapy with zidovudine can cause a toxic mitochondrial myopathy, which...is indistinguishable from the myopathy associated with primary HIV infection... Before 1986, when zidovudine (formerly called azidothymidine) was introduced, the number of patients with HIV-associated myopathy was small, and myopathy was considered a rare complication of HIV infection. During the past two years, an increasing number of patients receiving long-term zidovudine therapy have had myopathic symptoms such as myalgia (in up to 8 percent of patients), elevated serum creatine kinase levels (in up to 15 percent), and muscle weakness. These symptoms generally improve when zidovudine is discontinued.” In 1994, Dalakas et al elaborated on this in their paper in Annals of Neurology with the title summing it up, Zidovudine-Induced Mitochondrial Myopathy is Associated with Muscle Carnitine Deficiency and Lipid Storage: “The use of zidovudine (AZT) for the treatment of acquired immunodeficiency syndrome (AIDS) induces a DNA-depleting mitochondrial myopathy, which is histologically characterized by the presence of muscle fibres with ‘ragged-red’-like features, red-rimmed or empty cracks, granular deterioration, and rods (AZT fibres)… We conclude that the muscle mitochondrial impairment caused by AZT results in (1) accumulation of lipid within the muscle fibres owing to poor utilization of long-chain fatty acids, (2) reduction of muscle carnitine uptake by the muscles, and (3) depletion of energy stores within the muscle fibres.” In Clinical Pharmacology (1997, 8th ed.) Laurence, Bennet, and Brown say about AZT, “A toxic myopathy (not distinguishable from HIV-associated myopathy) may develop with long term use.” In fact whether muscle wasting ever occurs among HIV-positives who avoid AZT and related drugs is doubtful: Coker et al mentioned in AIDS in 1991 that “A clinically significant myopathy that precedes the development of zidovudine associated mitochondrial myopathy has been a rarity in our experience.” In February 1999, in Neurotoxicology, Waclawik et al published their investigation of whether the direct muscle cell toxicity of AZT is aggravated by retroviral infection. And found in the negative, as the conclusion in the title tells: Zidovudine [AZT] myotoxicity: quantitative separation of AZT effects on proliferation and differentiation of muscle cells in vitro. Lack of myotoxicity potentiation by retrovirus.

[6] Till et al reported their investigation of AZT-muscle damage in Annals of Internal Medicine in 1990 under the pointed title Myopathy with Human Immunodeficiency Virus type 1 (HIV-1) infection: HIV-1 or zidovudine?: “Results of quadriceps muscle biopsies done on our patients who responded to zidodvudine withdrawal showed severe myopathic changes without evidence of inflammatory infiltrates. Electron microscopy revealed many ultrastructural changes, including destruction of the sarcomere profile with z-band change in the form of streaming and rod bodies. Muscle mitochondria showed wide variation in size, swelling, degeneration and laminar bodies…There have been 40 case reports of patients who have developed while taking zidovudine (including our 5 symptomatic patients). Zidovudine therapy was discontinued in 34 of these patients and 26 improved.” Arnardo et al reported their comparison of muscle biopsies from HIV-positive patients treated with AZT and those who had not in the Lancet in 1991. In the AZT exposed tissues they observed “inflammatory myopathy with abundant ragged-red fibres (RRF)… No abnormal mitochondria were noted histologically in samples from the HIV-positive patients who had not received zidovudine.” Pezeshkpour et al reported a similar comparison in Human Pathology in the same year, “…muscle biopsy specimens from [HIV-positive] patients show a variety of features, including phagocytosis, degeneration or necrosis of muscle fibres, endomysial or perimysial inflammation, cytoplasmic bodies, and nemaline (rod) bodies. Following the introduction of zidovudine (AZT) for the treatment of the acquired immunodeficiency syndrome (AIDS), the number of HIV-positive patients with myopathic symptoms has increased. Zidovudine has been implicated as the cause of the myopathy because these symptoms generally improve when AZT is discontinued.” Upon a comparative analysis they found “specific structural changes [to muscle tissue] associated only with AZT, but not with HIV [and that] mitochondrial abnormalities are unique to AZT-treated patients. Since mitochondrial DNA is specifically reduced, the structural changes [to AZT-exposed muscle tissue] noted on electron microscopy are probably associated with mitochondrial dysfunction. Zidovudine, a DNA chain terminator that inhibits the mitochondrial y-DNA polymerase is toxic to muscle mitochondria.” Any doubts were settled by Mhiri et al in Annals of Neurology, also in 1991. Their comparative study “identified a distinct clinicopathological picture of zidovudine-induced myopathy associated with mitochondrial dysfunction”, hence the title: Zidovudine Myopathy: A Distinctive Disorder Associated with Mitochondrial Dysfunction.

[7] In their paper Massive Conversion Of Guanosine To 8-Hydroxy-Guanosine In Mouse Liver Mitochondrial DNA By Administration Of Azidothymidine published in Biochemical and Biophysical Research Communications in 1991, Hayakawa et al confirmed, “Recently, acquired mitochondrial myopathy caused by AZT therapy in patients with AIDS was reported: typical ragged red fibres and paracrystalline inclusions in mitochondria were seen in biopsied muscle specimens from such patients. As there is ample evidence indicating that mitochondrial myopathy is phenotypic expression of mutant mtDNA, the authors intended to establish an animal model of the disease as well as to elucidate the mechanism of mtDNA mutation by examining mouse liver mtDNA after administration of AZT.” They found that “oral administration… for four weeks converted dG [deoxyguanosine, another nucleotide, i.e basic building block of DNA] in liver mtDNA [mitochondrial DNA] hydrolysate massively to 8-OH-dG [the oxidised, destroyed form of the DNA nucleotide]. Even below 1/10th the dose given to patients (AZT 1mg/kg/day) 25.2% of the total dG was converted to be 8-OH-dG. 38.1% of the total dG was converted to 8-OH-dG by AZT, 5mg /kg/day [half the human equivalent dose]. …This suggests that orally administered AZT interrupts mtDNA replication. Another possible cause is that mis-terminated mtDNA would result in impaired mitochondrial inner membrane, leading to production of OH which induces formation of a DNA-protein cross-link involving cytosine and tyrosine. Such cross-link disturbs the extraction of mtDNA resulting in its low recovery from mitochondria… Recently it was reported that a single 8-OH-guanine residue inserted in a viral genome induced a G.A mispair during replication leading to the G.C to T.A transversion mutation, reflecting structural and conformational changes imposed by the adducted purine within the DNA helix. MtDNA exists in the matrix of mitochondria, so that the leak of oxygen radicals from impaired respiratory chain with AZT attacks guanine residue converting to 8-OH-guanine, leading to further mtDNA mutation. There is a general consensus that mitochondria are less efficient in repairing DNA damage and replication errors than the nucleus. For example they lack excision repair and recombinational repair mechanisms. The higher steady state of oxidative damage in mtDNA than in nuclear DNA is most likely due to a copious flux of oxygen radicals, inefficient repair, and the nakedness of mtDNA. Thus oxidative damage of mtDNA can be accumulated during even short periods of AZT administration. Several point mutations found in mtDNA of patients with mitochondrial myopathy could be originated from the oxygen damage of mtDNA. Conformational changes in the DNA helix by the adducted purine would promote deletion of mtDNA which is common in degenerative neuro-muscular diseases. The animal model of mitochondrial myopathy with AZT administration reported here seems to be useful for elucidating the mechanism of mtDNA mutations leading to myopathy. However, for AIDS patients, it is urgently necessary to develop a remedy substituting this toxic substance, AZT.” In 1991, in Neuromuscular Disorders, Chariot and Gherardi published a supporting paper Partial Cytochrome c Oxidase Deficiency and Cytoplasmic Bodies in Patients with Zidovudine Myopathy, “Long term therapy with [AZT] can induce a toxic myopathy associated with mitochondrial changes.” Most recently, in their paper Zidovudine-induced experimental myopathy: dual mechanism of mitochondrial damage in the Journal of Neurological Science in July 1999, Masini et al “investigated the in vivo effect of AZT in an animal model species (rat) not susceptible to HIV infection. Histochemical and electron microscopic analyses demonstrated that, under the experimental conditions used, the in vivo treatment with AZT does not cause in skeletal muscle true dystrophic lesions, but rather mitochondrial alterations confined to the fast fibers. In the same animal models, the biochemical analysis confirmed that mitochondria are the target of AZT toxicity in muscles” particularly “mitochondria energy transducing mechanisms.” Do you think the manufacturer paid any heed to any of this? With all that money rolling in, you must be joking.

[8] The burden of these reports is plain: AZT rots your muscles. As it does so, the patient enjoys Martin’s “quality of life” while he inexorably slips away with the wasted appearance of a concentration-camp victim. Compounding this is the fact that at the same time that his muscle tissue is being poisoned and is dying off, the patient literally starves to death, thanks to the decimation of the cells that line his gut walls. This hampers the digestion of what food is retained in the gut following intense biliousness and diarrhoea after AZT ingestion. (A client of mine reported, “The worst experience of my life.”) Throw a protease inhibitor into the ‘cocktail’, and protein digestion is fouled into the bargain, by inhibiting cathpepsin, an essential digestion enzyme. When the patient dies, as he inevitably must, the image of the gaunt white AIDS patient who horribly and mysteriously wastes away is reinforced in the popular consciousness. Another AIDS case for the statistical tally. And to add to the quilt. Of course nobody cared much about disease-caused wasting in Africa, commonplace from time immemorial where poverty-linked tuberculosis, malaria and gut illnesses are endemic, until its opportunities for research grants popped up when this wasting was renamed ‘slim disease’ or AIDS. In the AIDS age, rural poor don’t die of the privations of poverty any more, they die of promiscuity. The ‘AIDS experts’ shift the cause of disease from outside to inside. How convenient in the age of the ‘global economy’.

[9] How rapid a poison is AZT? Some people last a couple of years. On the other hand my colleague was killed by a single month’s course of AZT (stretched over two because he found it so unbearable). This is no mystery in the light of numerous investigations of how quickly the poison sets in. In February 1999, in Free Radical Biological Medicine, Szabados et al looked at the Role of reactive oxygen species and poly-ADP-ribose polymerase in the development of AZT-induced cardiomyopathy in rats: “The short term cardiac side-effects of AZT (3'-azido-3'-deoxythymidine, zidovudine) was studied in rats to understand the biochemical events contributing to the development of AZT-induced cardiomyopathy. Developing rats were treated with AZT (50 mg/kg/day) for 2 wk and the structural and functional changes were monitored in the cardiac muscle. AZT treatment provoked a surprisingly fast appearance of cardiac malfunctions…” In 1991 in Laboratory Investigations, Lamperth et al reported Abnormal skeletal and cardiac muscle mitochondria induced by zidovudine (AZT) in human muscle in vitro and in an animal model within three weeks of experimental exposure to “AZT at doses equivalent to the total daily dose used in acquired immunodeficiency syndrome patients. After 19 days, the AZT-treated myotubes in tissue culture exhibited abnormal mitochondria characterized by proliferation…, enlarged size, abnormal cristae and electron-dense deposits in their matrix. The changes were partially reversible after AZT withdrawal. Rats treated with AZT developed weight loss, 100-fold elevation of creatine kinase, and increased serum lactate and glucose.” Corcuera-Pindado et al reported Histochemical and ultrastructural changes induced by zidovudine in mitochondria of rat cardiac muscle in the European Journal of Histochemistry in 1994: “We carried out an ultrastructural and histoenzymatic study in rat cardiac muscle. Groups of animals (3 rats per group) were given drinking water with or without AZT (1 or 2 mg AZT/ml). After 30, 60 and 120 days, the hearts were studied by light and electron microscopy... The ultrastructural study showed a disruption of cristae and an increased size of mitochondria in rats treated with AZT for 30- and 60-days.” Lewis et al reported that Zidovudine induces molecular, biochemical, and ultrastructural changes in rat skeletal muscle mitochondria in the Journal of Clinical Investigations in 1992: “Molecular changes in a rat model of AZT-induced toxic myopathy in vivo helped define pathogenetic molecular, biochemical, and ultrastructural toxic events in skeletal muscle and supported clinical and in vitro findings. After 35 d of AZT treatment, selective changes in rat striated muscle were localized ultrastructurally to mitochondria, and included swelling, cristae disruption, and myelin figures. Decreased muscle mitochondrial (mt) DNA, mtRNA, and decreased mitochondrial polypeptide synthesis in vitro were found in parallel. Mitochondrial molecular changes occurred in absence of altered abundance of cytosolic glyceraldehyde-3-phosphate dehydrogenase, or sarcomeric mitochondrial creatine kinase mRNAs.”

[10] In his answer to my essay, Martin admits that AZT destroys bone marrow, but then hedges: HIV “may” be the real culprit. This is a tired old tale rehashed. Mercury and arsenic salts - doctors’ favourites for ages - poisoned the patient, whose death was then blamed on unbalanced humours or germs. That AZT destroys bone marrow is frankly declared by its manufacturer. So let’s not fudge. In 1987 in Annals of Internal Medicine, Gill et al reported Azidothymidine Associated with Bone Marrow Failure in the Acquired Immunodeficiency Syndrome (AIDS): “Four patients with [AIDS], and a history of Pneumocystis carinii pneumonia developed severe pancytopenia [marked decrease in all types of blood cells]…12 to 17 weeks after the initiation of azidothymidine therapy… Partial bone marrow recovery was documented within 4 to 5 weeks in three patients, but no marrow recovery has yet occurred in one patient during the more than 6 months since AZT treatment was discontinued.” In the same year in the New England Journal of Medicine Richman et al reported The Toxicity of Azidothymidine (AZT) in the Treatment of Patients with AIDS and AIDS-Related Complex: “Anemia…developed in 24% of AZT recipients and 4% of placebo recipients (P<0.001). 21% of AZT recipients and 4% of placebo recipients required multiple red-cell transfusions (P<0.001). Neutropenia (<500 cells per cubic millimeter) occurred in 16% of AZT recipients, as compared with 2% of placebo recipients (P<0.001).” The next year, Walker et al followed up in Annals of Internal Medicine reporting Anemia and erythropoiesis in patients with the acquired immunodeficiency syndrome (AIDS) and Kaposi sarcoma treated with zidovudine: “In the current study, transfusion-dependent anemia occurred in 6 of 15 patients with AIDS and Kaposi sarcoma who were receiving zidovudine therapy. All 6 affected patients required their first blood transfusion between 3 and 9 weeks after starting zidvoudine therapy, and each required 4 to 14 units of packed erythrocytes to maintain a hemoglobin level above 100 g/L over a 12-week study.” Consistent with this, Costello reported in the same year, in the Journal of Clinical Pathology that, “Blood transfusion is often necessary in patients with AIDS, especially in those receiving AZT, a drug which produces severe anaemia in a proportion of recipients. Forty nine (36%) of 138 patients treated with AZT required blood transfusion at least once.” For AIDS doctors slow to the point, Harrison’s Principles of Internal Medicine spells it out: “[AZT], used for treating [HIV], often causes severe megaloblastic anemia…caused by impaired DNA synthesis.” Even in the modern age where AZT dosing levels are now hugely reduced, in 1998, in the New England Journal of Medicine, Hymes et al investigated and reported The Effect of Azidothymidine on HIV-related Thrombocytopenia, and found again: “The hematocrit [red blood cell count] decreased in the same patients...with three of eight patients requiring red-cell transfusion by the fourth week of treatment.” So did Mocroft et al in their paper in AIDS in 1999: Anaemia is an independent predictive marker for clinical prognosis of HIV-infected patients from across Europe: “We found that 78.2% of the [HIV-infected] patients with mild or severe anaemia at baseline had received zidovudine”.

[11] In their 1988 paper in the British Journal of Haematology, entitled, 3’-Azido-3’-deoxythymidine inhibits proliferation in vitro of human haematopoietic progenitor cells, Dainiak et al reported their investigation of “the mechanism by which cytopenias develop [i.e. cell depletion, which is]…a serious, dose limiting toxicity of AZT therapy…” Observing that “Anaemia [during AZT therapy] appears to be due to bone marrow suppression [and] nearly one half of patients treated with AZT for [HIV]-associated disease develop transfusion-dependent anaemia due to bone marrow depression”, they concluded from their study that “AZT is a potent inhibitor of haematopoiesis in vitro, and that erythroid progenitors are particularly sensitive to its action. These results may explain the marrow hypoplasia that occurs during AZT administration in vivo.”

[12] AZT reaches and can destroy foetal bone marrow too. In the May 1998 issue of the Pediatric Infectious Diseases Journal, Watson et al at the University of Rochester Medical Center in New York reported the case of an HIV-negative baby born to a positive mother who had been treated with a HAART cocktail of AZT, 3TC and a protease inhibitor, suffering “high output congestive heart failure secondary to profound anemia.” The paediatricians excluded “infection, nutritional deficiencies, congenital leukemia and congenital red blood cell aplasia in the child” and considered the “cause of the life-threatening anemia in our infant…to be in utero erythroid marrow suppression by one or more of the antiretroviral agents administered to the mother.”

[13] Martin alleges that “toxicity in most cases is reversible.” This optimistic jive was flatly contradicted by Mir and Costello just a year after AZT was approved. They reported their concern in the Lancet in 1988 that “bone marrow changes in patients on zidovudine seem not to be readily reversed when the drug is withdrawn. These findings have serious implications for the use of zidovudine in HIV positive but symptom-free individuals.”

[14] Writing in AIDS in 1997, Kelleher et al noted, “Lack of strong evidence exists for sustained immune reconstitution by current therapies [comprising AZT and other drugs, and AZT may] unmask silent opportunistic infections.” Not only can AZT “unmask silent opportunistic infections”, it can exacerbate clinically conspicuous ones. Havlir and Barnes reported in February 1999 in the New England Journal of Medicine that HIV-positive tuberculosis patients treated with [AZT-based] ‘antiretroviral therapy’ developed “paradoxical worsening of disease…in up to 36 percent of [them], characterized by fever, worsening chest infiltrates on radiograph, and peripheral and mediastinal lymphadenopathy…[whereas] only 7 percent of patients who received antituberculosis therapy but not antiretroviral therapy had paradoxical reactions.” On 18 September 2000, Reuters released a report Doctors describe AIDS patients’ medical paradox. It could have been written by a deadpan standup comedian: “Some AIDS patients whose ravaged immune systems have been boosted by taking cocktails of powerful medicines [not even the manufacturers claim this] have been suffering a surprising increased susceptibility to infections, researchers said on Monday. Scientists at Thomas Jefferson University in Philadelphia labeled as a medical paradox their discovery that AIDS patients whose conditions had been improving [according to surrogate markers, not actual health] thanks to treatment with drug cocktails had been coming under attack from opportunistic infections that ordinarily should not have been much of a problem. In a study published [in September] in the journal Annals of Internal Medicine, the researchers said the sometimes-fatal ‘immune reconstitution syndrome’ stemmed from an inflammatory reaction by the newly strengthened immune system to bacteria or viruses already present in the patient. The researchers said the causes of the syndrome were unknown. The researchers said they were startled by the fact that the infections were affecting patients who had been benefiting from so-called highly active antiretroviral therapy (HAART) involving the use of combinations of powerful anti-HIV (human immunodeficiency virus) medicines. The doctors described learning of patients with a typical infection suffered by those with HIV - mycobacterium avium infection… ‘No one is exactly sure what to do against this syndrome yet,’ DeSimone said... More than a year ago, researchers began to see patients with HIV, the virus that causes AIDS, developing infections at times that caught them off guard. The Jefferson doctors said they decided to search the medical literature and speak with colleagues to learn whether others had seen similar developments. They said doctors at other hospitals mentioned infections such as CMV retinitis, an AIDS-related blindness...” A subject to which we will return later. In the case of children, apart from being poisonous to their blood cells, McKinney et al found that AZT didn’t alleviate their secondary infections. In their paper A multicenter trial of oral zidovudine in children with advanced human immunodeficiency virus disease published in the New England Journal of Medicine in 1991, they reported, “Although no control group was available for direct comparison, the improvement in the children in this study closely paralleled the observations in controlled studies of adults receiving zidovudine… Children treated with zidovudine continued to have bacterial and opportunistic infections.” Of the eighty eight children in the study, “One or more episodes of hematologic toxicity occurred in 54 children (61 percent) and neutropenia (neutrophil count, <0.75X10^9 per liter) in 42 (48 percent).” So why prescribe it?

[15] Martin’s happy claim that AZT cocktails afford “long-lasting beneficial effects” was refuted in November 1997, when Lemp et al reported in the Journal of Acquired Immune Deficiency Syndrome and Human Retrovirology that with HAART (Highly Active Antiretroviral Therapy), “the treatment benefit is temporary and confers no long-term survival advantages.” Obviously. How could it possibly? Would you nurse your wilting pot-plant with weed-killer? In the clever age, whatever happened to common sense? At last some lay folk are waking up; Steven Gendin wrote an article in the January 1999 issue of the AIDS-drugs-promoting rag POZ, candidly entitled If the virus doesn’t get you, the drugs you take will. He’s seen enough of his friends fade away on AZT to know. In July 2000 he went himself at the age of 34, dead of heart failure - which we will examine below.

[16] That AZT is entirely ineffective as a therapy was borne out clearly by the large-scale Concorde trials in Europe, reported by the Coordinating Committee in the Lancet in April 1994: “A total of 172…participants died [169 while taking AZT, 3 while on placebo] …The results of Concorde do not encourage the early use of zidovudine in symptom-free HIV-infected adults.” Embarrassingly for Wellcome, and disastrously for its share prices, the fabulous results of the chaotic American study that had preceded FDA approval of AZT couldn’t be reproduced. The drug was found to have no clinical benefits. Predictably, “Representatives of the Wellcome Foundation who were also members of the Coordinating Committee…declined to endorse this report” and insisted on gerrymandering the reach of its grim conclusions. Even so, the adverse implications of the trial for AZT could not be avoided. One glaring finding was that AZT’s “severe side-effects”, even in cases of patients on low doses quashed any apparent therapeutic value as suggested by raised CD4 cell-counts - about which the Committee noted that the results “also call into question the uncritical use of CD4 cell counts as a surrogate endpoint for assessment of benefit from long-term antiretroviral therapy.” Emphasising the worthlessness of CD4 cell counting in Annals of Internal Medicine in 1996, Fleming and DeMets described it as being “as uninformative [an indication of immune status] as a toss of a coin.” Not that anyone took any notice. Today, patients terrified by their doctors’ mournful announcements of their low cell counts - still taken as a signal of collapsing health and imminent demise - are urged to start with ‘antiretrovirals’ like AZT, following which the prophesy will be faithfully fulfilled. For example, Harrigan et al reported in AIDS in July 2000 that “Triple therapy for HIV-infected patients… do not have any unique effects on CD4 cell counts independent of reductions in plasma viral load”, according to Reuters; “The data appear to contrast with recent evidence suggesting that such regimens are able to maintain an immunologic benefit even after plasma viral rebound… The team examined the correlation between CD4 cell counts and plasma viral load over 52 weeks using data from 3 randomized clinical trials… The studies compared dual nucleoside therapy with triple combination therapy that included a protease inhibitor, with or without a nonnucleoside reverse transcriptase inhibitor. The data presented in these randomized double-blinded trials suggest that the specific antiretroviral regimen used neither increases nor decreases the strength of the correlation between the change in CD4 cell count and the change in plasma viral load.” CD4 cell counting continues to the present day, as if it means anything. And the evidence mounts against multi-drug therapy, a topic deferred for a later look.

[17] Notwithstanding the dark clouds looming over AZT at the end of the Concorde trials, Wellcome released ebullient press statements quite at variance with the negative findings that the trial overseers were later to report in the Lancet. But the company could hardly endorse a finding and broadcast to the world that a flagship money-spinner didn’t live up to its billing. To obfuscate the drug’s demonstrated therapeutic irrelevance, and keep a good thing going for the company’s bottom line, Wellcome pulled a sharp move. To protect its delinquent product, it immediately threw its support behind a new gimmick called ‘combination therapy’. Henceforth the dose was slashed in half or more, and AZT was to be marketed as a drug combined with others - all equally ineffective on their own, as if to mix two or three toxic duds would be to conjure them miraculously into a medicinal marvel. It’s a treatment approach that is now falling to pieces, as we’ll see when we review the recent literature about HAART cocktails later on. But before we leave the subject of mixing your drinks, just in is a paper by Havlir et al in the July 2000 issue of the Journal of Infectious Diseases warning for heaven’s sake don’t take AZT and 4TC together. Reuters Health reported: “Combination treatment with zidovudine and stavudine results in worse outcome than treatment with stavudine alone, according to the results of a 48-week multicenter study…The researchers conclude that stavudine and zidovudine should not be used together in any antiretroviral regimen.” Now you tell us.

[18] In fact, not only was AZT found to be useless at the end of the Concorde trials, it turned out to be positively harmful: Phillips et al reported in a letter to the New England Journal of Medicine in March 1997 that “Extended follow-up of patients in one (AZT) trial, the Concorde study, has shown a significantly increased risk of death among the patients treated early.” In another paper in that year, Impact of treatment changes on the interpretation of the Concorde trial, White et al highlighted in AIDS that “participants of open-label ZDV [AZT] still had four to five times the incidence of ARC/AIDS/death of participants on blinded therapy [of which approximately half were on AZT and half on placebo] … The unadjusted hazard of ARC/AIDS/death was 4.6 times higher for participants [in the deferred group] who had received ZDV...after adjustment for latest CD4 this became 1.6 … There was a suggestion of a benefit in terms of [slower] progression to ARC, AIDS or death [with AZT], no effect on progression to AIDS or death, and a suggestion of an increase in mortality.” Walker summed it up in his essay HIV, AZT, big science & clinical failure, “…the Concorde trial results showed conclusively that asymptomatic antibody-positive individuals who took AZT, died more quickly and in greater number than those simply affected by AIDS-defining illnesses.” As Marginal structural models to estimate the causal effect of zidovudine on the survival of HIV-positive men in the September 2000 issue of Epidemiology by Hernan et al suggested too: “Our analysis included the 2,178 men who attended at least one visit between visits 5 and 21 while HIV positive, and who did not have an AIDS-defining illness and were not on antiretroviral therapy at the first eligible visit. By the end of the follow-up (media duration-69 months), 1,296 men had initiated zidovudine treatment and 750 had died”, from which the researchers drew the dazzling conclusion of “a detrimental effect of zidovudine.”

[19] The negative Concorde trial results were entirely on par with those of an earlier French trial. In 1988 in the Lancet, Dournon et al had published a study of AZT, conducted at the Claude Bernard Hospital in France. It was wider and longer than the American Fischl trial that had preceded FDA approval, and at the end of it the researchers found AZT to be “disappointing.” They noted, “The bone marrow toxicity of AZT and the frequent need for other drugs with haematological toxicity meant that the scheduled AZT regimen could be maintained in only a few patients… by six months, these values [i.e. initial modulation of p24 antigen levels] had returned to their pretreatment levels and several opportunistic infections, malignancies and deaths occurred” - by nine months, about a third dead, another third very sick. But most significantly for the idea that AZT exerted an anti-HIV effect, “full-dose AZT for 2 months did not eliminate antigenemia in patients with pretreatment p24 levels of 200 U/ml or higher...[so] in AIDS and ARC patients, the rationale for adhering to high-dose regimens of AZT, which in many instances heads to toxicity and interruption of treatment, seems questionable.” It bears emphasising that the dose was 200mg every four hours, the standard officially recommended dose, and the same as the dose given during the pre-approval Fischl trial in the US, yet the reported outcome was completely different.

[20] It is worth quoting at length from the Claude Bernard Hospital AZT trial report because it is very illuminating: “AZT was started at full dose in 260 patients, 64 with ARC and 196 with AIDS. In 58 of these patients, AZT had to be stopped at least once for a minimum of 7 days. In 142 other patients, dosage was reduced by half because of leucopenia (79), leucopenia and (32), anaemia (20), rash (3), vomiting (3), headaches and insomnia (2), myalgia (2), or hepatitis (1). 3 patients reduced the dose with no medical reason. Later on, progression of toxicity led to suspension of AZT (for at least 7 days) in 85 of the 142 patients whose treatment had been reduced to half dose. Thus AZT was stopped at least once in 143 (55%) patients who began the full-dose regimen. Because of their initial haematological status 105 (28.8%%) patients were treated from the start with half-dose AZT – toxicity led to cessation of treatment in 71 (67.6%) cases.”

[21] One can’t help wondering whether the fact that the French trial was performed independently, and beyond the reach and control of the drug’s manufacturer, might not have had something to do with it. Indeed, Professor David Warrell, UK chairman of the Concorde trials, commented on Wellcome’s efforts to skew the final Concorde report as follows: “What we learnt I suppose, and we shouldn’t have been surprised, is that when the wrong result is produced for a famous and flourishing company on which a great deal of financial expectation rests, the company’s representatives are going to be under a great deal of pressure, and the interpretation of those results is going to be ‘stressed’; there is going to be an attempt perhaps to blunt the message, to modify, to make a more mellow conclusion from results which seem to be inescapable in their implications.”

[22] Martin’s absurd statement that AZT and 3TC “improves quality of life” is just stale advertising propaganda quoted mindlessly from some glossy ad. The trouble that doctors have with patient ‘non-compliance’ is notorious, due to the intolerable, excruciating ‘side effects’ that most people experience on these drugs. Numerous papers have detailed these problems, most recently for example, Nicholson: Managing side-effects: practical advice on dealing with side-effects of antiretroviral therapies in AIDS Treatment Update, October 1998. In 1994, Lenderking et al of the Harvard School of Public Health, reporting their Evaluation of the Quality of Life Associated With Zidovudine Treatment in Asymptomatic Human Immunodeficiency Virus Infection in the New England Journal of Medicine, found “a reduction in the quality of life due to severe side effects of therapy” and the “severe adverse events” it caused, which were “life-threatening in some cases.” Without intended irony, AIDS expert Dr. Lori Swick pointed out in The Toronto Star in September 1999 that “One of the major barriers to effectively treating HIV is that most people do not feel sick at the time they are offered anti-HIV medications. In fact, it is only after starting the medications that they begin to feel sick.” Well, of course. Jerry Cade MD, who serves on the US Presidential Advisory Council on HIV/AIDS agrees. In the April 2000 edition of A+U, an AIDS magazine in the US, he stated, “In the face of extreme drug side effects, some patients … are becoming extremely ill from the medications.” On 12 July 2000 Business Today quoted AIDS don Anthony Fauci, director of the US National Institute for Allergies and Infectious Diseases telling the 13th International AIDS Conference in Durban about the desirability of interrupting the ‘antiretroviral’ treatment with ‘drug holidays’: “The patients in the study are absolutely delighted to spend half their time off therapy… Clearly, even our most vigorous efforts to eradicate (the virus) had been unsuccessful.” The report went on, “Most patients have a difficult time staying on their anti-HIV drugs because the effect wears off or the side effects become intolerable. Side effects can include everything from fever to headaches, from nausea to anemia. Many patients therefore cannot take the drugs... A separate study reported Tuesday by Scott Holmberg of the U.S. Centers for Disease Control and Prevention shows how intolerable treatments can be.” GlaxoWellcome however would prefer you sick without a break until you go. Its PRODUCT INFORMATION release for Combivir (AZT and 3TC) states, “Patients should be advised of the importance of taking COMBIVIR as it is prescribed” i.e. “One COMBIVIR tablet…twice a day.”

[23] The truth of the matter is that AZT makes you feel like you’re dying. That’s because on AZT you are. How can a deadly cell-toxin conceivably make you feel better as it finishes you, by stopping your cells from dividing, by ending the vital process that distinguishes living things from dead things? Not for nothing does AZT come with a skull and cross-bones label when packaged for laboratory use.

[24] These are some of AZT’s ‘side effects’ listed by its manufacturer: Body as a Whole: abdominal pain, back pain, body odor, chest pain, chills, edema of the lip, fever, flu syndrome, hyperalgesia; Cardiovascular: syncope, vasodilation; Gastrointestinal: bleeding gums, constipation, diarrhea, dysphagia, edema of the tongue, eructation, flatulence, mouth ulcer, rectal hemorrhage; Haemic and Lymphatic: lymphadenopathy; Musculoskeletal: arthralgia, muscle spasm, tremor, twitch; Nervous: anxiety, confusion, depression, dizziness, emotional lability, loss of mental acuity, nervousness, paresthesia, somnolence, vertigo; Respiratory: cough, dyspnea, epistaxis, hoarseness, pharyngitis, rhinitis, sinusitis; Skin: acne, changes in skin and nail pigmentation, pruritus, rash, sweat, urticaria; Special senses: amblyopia, hearing loss, photophobia, taste perversion; Urogenital: dysuria, polyuria, urinary frequency, urinary hesitancy.

[25] A typical encounter with “A world of antiretroviral experience” promised children in an AZT advertisement in the Lancet in 1991 was described in an article by Gayle Melvin, KIDS WITH AIDS, run in several newspapers in the US and Canada in September 1998: “Robert Swanson’s medicines came with horrible side effects: nausea, diarrhea and blinding headaches… Robert would secretly skip a dose of medicine. ‘I’d find his pills all over the place, in his room, in the dirty clothes’, Britten says… ‘When you think of medicine, you think of something that makes you better, but I don’t feel better when I take it,’ Robert says. ‘I’d rather feel good and let the virus take over than feel bad and take the medicine.’ …Tina [takes] AZT,…ddC and Viracept, a protease inhibitor…three times a day. Then she waits to get sick. ‘My head will start to hurt all over, like a pounding. I get dizzy. Sometimes I throw up,’ she says in her sweet, girlish voice. She gets sick every time? ‘Every time’, says Tina… As they go through their teens, these children face [the] challenges [of] taking responsibility for their…often debilitating medical regimen.”

[26] Gay playwright Larry Kramer, founder of prominent AIDS-activist group ACT-UP, was interviewed on WebMD on 7 January 2000. As he made plain, he’s not opposed in principle to drug treatment for AIDS diseases; on the contrary he said, “I have felt it…important, … to concentrate all my energy on fighting for a cure, fighting for drugs.” He had many revealing observations from the ground about current therapies, mostly AZT-based ‘cocktails’: “I think, for those of us who follow the literature, the medical literature…what’s appearing more and more, is terribly frightening reports that the proteases, the cocktails simply are not working in a larger and larger percentage of people, and that these new drugs that are coming out right, left, and centre have such horrendous side effects that people simply are beginning to refuse to take them…We’re finding out, for instance, that 50 percent of people who take certain drugs die from liver disease rather than AIDS, because the drugs are so harsh on the liver… unfortunately, …most of the activists, the AIDS activists, who speak for us now are so in the pockets of the bureaucracy of the drug companies …, that they have become almost fascist in ramming their treatment notions down the rest of us. The research that is done today is pretty much dictated by a small handful of pea brains called Treatment Action Group, TAG, which has a stranglehold on what is researched, what the drug companies release, how it’s tested, and … the guidelines [for] all of this poison… we really must start putting pressure on the pharmaceutical companies to make us drugs that don’t have such horrible side effects... And more and more people I know are refusing to take drugs at all, which is very interesting. They’d rather just not feel that sick. …And the other thing that nobody pays any attention to is that we simply do not have any data - sufficient data - to know which of these drugs works and in which combination. The drug company makes the drug, unleashes it on the world, goes on to merrily develop another poison without continuing to test the stuff that’s out there. There is no database that is worth anything… If after only two years, the combination therapies are beginning to make people so sick and kill them, how are you supposed to take them for the rest of your life? Get real… I said to a friend of mine, David Sanford, who’s editor of the Wall Street Journal, who has AIDS, and who just feels so awful from all of these drugs, and I said ‘why don’t you get out there and say I feel awful from all these drugs?’ …I think it’s very interesting that I am hearing about more and more patients who are simply stopping taking the medicine. They’re just too uncomfortable.” Also participating in the interview was Dr. Richard Marlink, senior research director and lecturer at the Department of Immunology and Infectious Diseases at the Harvard School of Public Health, and executive director of the Harvard AIDS Institute. He heartily agreed with Kramer’s concern that “the fact that that database does not exist anywhere” and thought it was “a national crime.”

[27] The extreme liver toxicity of AZT mentioned by Kramer has long been observed, and it has recently been formally acknowledged again. In 1989, in Annals of Internal Medicine, Dubin et al found Zidovudine-induced hepatotixicity: “We report a patient who experienced acute cholestatic hepatitis on initial exposure to and rechallenge with zidovudine and, as a result, was unable to receive further therapy with the drug... Seven days [after starting AZT therapy] the patient presented with a 2-day history of intermittent fevers and abdominal discomfort... Seven days [after re-starting AZT therapy once the initial symptoms resolved] the patient again experienced fever, right upper quadrant pain, nausea, and headache... One month later [after discontinuing AZT] the liver function tests had almost completely returned to normal and remained without significant abnormalities.” In 1990, during a stint at Mount Sinai School of Medicine, Professor Allen Arieff reported several cases of fatal lactic acidosis among patients treated with AZT. Reports of AZT-generated liver disease were also fielded by the National Institutes of Health. The numerous cases turned up by FDA epidemiologist Joel Freiman led to the FDA demanding that Burroughs Wellcome issue an advisory to leading infectious disease specialists in the US about the danger that AZT treatment posed to the liver. Which it did in 1993. It went unheeded. Perhaps because the AZT PRODUCT INFORMATION advisory still says, “There are insufficient data to recommend dose adjustment of Retrovir in patients with impaired hepatic function.”

[28] On 19 November 1999 Reuters Health reported that “Liver disease has become the leading cause of death among HIV patients at a Massachusetts hospital, [according to] a report issued on Friday...[by] Dr. Barbara McGovern, a professor at Tufts University School of Medicine and a member of staff at Lemuel Shattuck Hospital in Jamaica Plains, Mass. The findings were reported…at the annual meeting of the Infectious Diseases Society of America in Philadelphia. McGovern said HIV patients who take a powerful combination of AIDS drugs called highly active antiretroviral therapy (HAART) were at particular risk because of the drug’s potential toxicity to the liver. One-third of HIV patients with underlying liver disease at Lemuel Shattuck have had to stop taking HAART.” In the same month, in their paper HIV Treatment-Associated Hepatitis, Orenstein and LeGall-Salmon reported in The AIDS Reader that “Severe hepatitis has been reported with all of the currently available classes of antiretroviral agents.”

[29] In a case report published in August 2000 in Infections in Medicine entitled Lactic Acidosis Secondary to Nucleoside Analog Antiretroviral Therapy, Khouri and Cushing explain why drugs in the AZT class hammer the liver: “There are several reports of lactic acidosis and microvesicular steatosis-associated nucleoside analog toxicity in HIV-infected patients… The patients were treated with zidovudine and had a high mortality rate… Seven reports have described the syndrome of lactic acidosis in 25 patients with HIV/AIDS… Of the total, 21 were receiving treatment with zidovudine, and 1 was receiving treatment with stavudine, lamivudine, and indinavir. Sixteen (64%) of the patients were female, and 18 (72%) died… The nucleoside analog antiretroviral agents…inhibit mitochondrial DNA (mtDNA) polymerase in cell culture…. Zalcitabine, stavudine, zidovudine, and didanosine all have an effect on mtDNA synthesis… Inhibition of mtDNA can lead to a variety of metabolic abnormalities. These are largely the result of a derangement in pyruvate metabolism. After formation by glycolysis, pyruvate is metabolized in the mitochondria by pyruvate dehydrogenase (PDH) to acetyl coenzyme A (CoA). Pyruvate may be reduced to lactate by lactate dehydrogenase, and it may also be used in gluconeogenesis… Inhibition of mtDNA causes a disorder of oxidative phosphorylation by making the mitochondrial respiratory chain dysfunctional and unable to break down acetyl CoA. This dysfunction shifts pyruvate metabolism toward the other pathways, reduction to lactate and gluconeogenesis. The lactate cannot be cleared as rapidly as it is being produced, and the resultant excess causes an acidosis. The increased gluconeogenesis causes hyperglycemia. Even though the inhibition of polymerase g makes the respiratory chain dysfunctional, PDH is fully functional and makes acetyl CoA. The overproduction of acetyl CoA, without utilization in the respiratory chain complex, pushes it out of the mitochondria and into the cytoplasm, where it serves as a substrate for fat production… Inability to metabolize acetyl CoA also leads to increased circulating levels of the ketones acetoacetate and b hydroxybutarate… Suggested mechanism and manifestations of mitochondrial dysfunction. (A) The nucleoside analog antiretroviral agents inhibit mitochondrial DNA (mtDNA) polymerase g in cell culture. Inhibition of mtDNA makes the mitochondrial respiratory chain dysfunctional and unable to break down acetyl coenzyme A (CoA). This shifts pyruvate metabolism toward the other pathways, reduction to lactate and gluconeogenesis. The lactate cannot be cleared as rapidly as it is produced and the resultant excess causes an acidosis. (B) The increase of pyruvate leads to increased gluconeogenesis in the liver, resulting in secondary diabetes mellitus. The gluconeogenesis stimulates insulin production. (C) The overproduction of acetyl CoA without utilization in the respiratory chain complex pushes it out of the mitochondria to the cytoplasm, where it serves as a substrate for fat production. (D) The overproduction of lactate causes lactic acidosis. The gluconeogenesis causes the secondary diabetes mellitus and hyperinsulinemia, the hyperinsulinemia causes insulin resistance, and fat synthesis causes fatty liver and weight gain…. The predicted clinical manifestations of mitochondrial dysfunction are fatigue from decreased levels of adenosine triphosphate production, lactic acidosis, ketoacidosis, secondary diabetes mellitus, and fatty liver and weight gain caused by hyperglycemia.”

[30] As for the fabled power to prevent pregnant women transmitting HIV to their foetuses that Martin claims for AZT, Bennet warned in Mandatory testing of pregnant women and newborns: a necessary evil? in AIDS/STD Health Promotion Exchange 1998 that “At present, data regarding the effects of ZDV (AZT) use on vertical transmission rates are inconclusive and incomplete. In addition, the long-term effects of ZDV use during pregnancy and after birth on the woman and any resulting child are yet to be discovered. The possibility has not yet been ruled out that this ‘risk-reducing’ measure may not be effective and may prove detrimental to the health of both mother and child.”

[31] Bennet’s caveat has moved from the hypothetical to the tragically real. In February 1999, French researcher Stephane Blanche announced at the Sixth Conference on Retroviruses and Opportunistic Infections that the drug had apparently killed two babies in an AZT trial that he and colleagues were conducting. Both had fallen sick at four months and had died of mitochondrial dysfunction and neurological defects - conditions ordinarily very rare. In September 1999, in his research team’s paper in the Lancet entitled Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues, he reported: “We analysed observations of a trial of tolerance of combined zidovudine and lamivudine and preliminary results of a continuing retrospective analysis of clinical and biological symptoms of mitochondrial dysfunction in children born to HIV-1-infected women in France.... Eight children had mitochondrial dysfunction. Five, of whom two died, presented with delayed neurological symptoms (epilepsy, massive cortical necrosis, cortical blindness, spastic tetraplegia, cardiomyopathy and muscle weakness) and three were symptom-free but had severe biological or neurological abnormalities. Four of these children had been exposed to combined zidovudine and lamivudine, and four to zidovudine alone. No child was infected with HIV-1... Our findings support the hypothesis of a link between mitochondrial dysfunction and the perinatal administration of prophylactic nucleoside analogues… Further assessment of the toxic effects of these drugs is required.” On the same theme, in the same issue of the Lancet, Dutch researchers Brinkman et a