VIRUSMYTH HOMEPAGE
OPEN LETTER TO GLAXO-SMITH-KLINE
By Anthony Brink
March 2001
Following is an Open Letter to John Kearney, CEO of Glaxo-Smith-Kline, South Africa.
President Mbeki's directive on 28 October 1999 that the safety of AZT be investigated on the basis that "there is a large volume of scientific evidence...that [AZT] is harmful to health" alerted the South African public to the fact that AZT is dangerously poisonous. Which shouldn't have surprised anyone, since it was synthesised in 1961 and tried out for a couple of years thereafter as an experimental cell toxin. The reams of horrifying medical literature to which the President was referring are summed up in light style in my little book Debating AZT: Mbeki and the AIDS drug controversy (*). But apart from being very poisonous, your company is sitting on an even darker secret about AZT: It doesn't work. It cannot and does not have the antiretroviral effect you claim for it. Here's why.
You allege in the package insert supplied with AZT that it's converted by enzymes inside human cells from its parent form as a pro-drug into its active form, AZT triphosphate. By which we understand you to imply the rider, "to a level in vivo equal to or above its minimum effective concentration." You allege too that AZT triphosphate terminates HIV replication by being incorporated into growing proviral DNA chains during reverse transcription of HIV RNA. But these claims are not true and your company knows it.
In November 1986, Furman and others, including researchers from Wellcome Research Laboratories (a division of your company in an earlier incarnation), reported their finding in the American scientific journal Proceedings of the National Academy of Sciences of the United States of America 1986; 83: 8333-7 that the minimum concentration of AZT triphosphate in cells required to inhibit proviral HIV DNA chain synthesis significantly, in other words have an antiretroviral action, is 0.7 micromolar i.e. 0.7 micromoles per litre. That's in the most ideal artificial conditions in vitro, never mind the much tougher real world in vivo, in which AZT triphosphate has to compete with natural nucleotides for binding to growing DNA chains, and in which a massively higher concentration of the drug would be necessary for that and other reasons. A concentration your company has never got around to determining. We'll pretend just for now that the entirely synthetic RNA template employed by Furman and your researchers to determine the drug's IC50 value (i.e. minimum inhibition concentration to block HIV retrotranscription to a significant extent) was a valid substitute for real HIV RNA - accepting for present purposes that there is such a thing. We'll also close our eyes and make believe that immune cells in our blood will triphosphorylate AZT just like the cell lines cultured in Furman's petri dishes.
In your company's rush to market the drug in 1987, after ramming it through FDA approval following completely botched and corrupted clinical trials, it didn't bother ascertaining whether the cells of people given AZT are able to triphosphorylate it to the minimum effective level that Furman established. The first investigation of this only took place four years later, followed by a dozen further published studies.
Every single study of the extent to which patients' cells metabolise AZT into its active triphosphorylated form has returned findings which reveal that they are unable to do so. Or to be more precise, that they do so at utterly negligible levels (see table below). Excluding the first Toyoshima study (unvalidated and slightly out of scale with all the rest), the average finding in all these studies is 0.14 picomoles of AZT triphosphate per million cells. Since the volume of eukaryotic cells is about 1 picolitre, a million of them has a volume of 1 microlitre. So 0.14 picomoles of AZT triphosphate per microlitre amounts to 0.14 micromolar. That's five times too little - one fifth of the minimum level of AZT triphosphate determined by your own company (even in the most ideal artificial in vitro conditions) to be necessary for the drug to work as a nucleoside analogue reverse transcriptase inhibitor by terminating proviral HIV DNA chain synthesis. In fact the best executed studies of the bunch reveal AZT to be triphosphorylated in vivo at levels one, even two orders of magnitude below the minimum effective concentration that Furman reported.
If the drug really stops HIV replication by inhibiting proviral HIV DNA chain synthesis as your package insert alleges, one would expect AZT ingestion to result in a consistent, sustained and simultaneous fall over time in all direct markers conventionally considered to indicate HIV infection levels - namely HIV DNA ("viral burden"), HIV RNA ("viral load"), detection of p24 and reverse transcriptase ("viral isolation") and p24 antigenaemia. But all studies of the effect of AZT on these parameters show that the drug has no such anti-HIV effect. None at all on HIV DNA synthesis (viral burden), which flatly refutes your basic claim that the drug blocks it. And consequently a completely insignificant effect on HIV RNA (viral load) - see graph below. Etc. All of which is perfectly predictable since AZT isn't triphosphorylated in vivo enough to stop HIV retrotranscription, as we've seen. So the drug is all risk and no benefit. The studies are surveyed and discussed, together with the triphosphorylation data, in a seminal 30,000-word review of the molecular pharmacology of the drug by Papadopulos-Eleopulos et al, published in mid-1999 as a special supplement to the academic medical journal Current Medical Research and Opinion Vol. 15 (#). You were given a copy a couple of months after it came out. You've never responded to it.
Would you please explain then why you claim in your AZT package insert that "Zidovudine [AZT] is phosphorylated in ... cells to ... the triphosphate (TP) derivative... " - by implication to virustatic levels in vivo - when this has been disproved over and over again?
And why you claim that "Zidovudine-TP acts as an inhibitor of, and substrate for, the viral reverse transcriptase", that "The formation of further proviral DNA is blocked by incorporation of zidovudine-TP into the chain and subsequent chain termination (sic)", and that AZT is thus "an antiviral agent ... active against ... the Human Immunodeficiency Virus", when the results of all published investigations of the effects of AZT in vivo, as indicated by the direct markers mentioned above, give the lie to these claims.
Also why you claim AZT has been shown to be "effective", when the only long term, large scale, prospective, randomised, double-blind, placebo-controlled, clinical AZT study yet conducted - the Concorde trials in England, Ireland and France involving 1749 symptom-free HIV-infected individuals - found that AZT administration has no therapeutic benefits when initiated early (The Lancet 1994; 343:871-81), and the extended results of the study a year later showed "a significant increased risk of death among the patients treated early" (New England Journal of Medicine 1997; 336:958-9)?
The families and other survivors of the thousands of people poisoned by AZT would love to know. Their lawyers too, I'm sure.
In your reply addressing the triphosphorylation and efficacy issues that I've raised, you can leave out the effect of AZT on T4 cell counts or antibody levels - these indirect markers modulated by cell poisons like AZT independently of any antiviral activity. And if you don't mind, please spare us the "AZT has brought quality of life to AIDS sufferers around the world" spiel. The one your company pumped so successfully with some of its $4.7 billion marketing budget last year - generating AZT and 3TC sales in the same year of $1.1 billion. Save it for the widow and young son of a legal colleague of mine who in good health embarked on a course of AZT and 3TC treatment on the strength of your company's promises, immediately took very ill on it, and then steadily wasted to a skeleton in diapers with his muscle and gut tissue poisoned off, uncontrollably vomiting his life away into a bucket.
Thanks.
Anthony Brink
Pietermaritzburg
arbrink@iafrica.com
* Debating AZT: Mbeki and the AIDS drug controversy (paperback R60-00) can be obtained at most good bookshops in South Africa, ordered directly from the author (arbrink@iafrica.com ; 0836260945) or read online at: http://azt.aidsmyth.com or www.virusmyth.net/aids/data/abdebating.htm
# A Critical Analysis of AZT and its Use in AIDS by Papadopulos-Eleopulos et al, Current Medical Research and Opinion Volume 15 (special supplement) is posted online at:
www.librapharm.co.uk/cmro/vol_15/supplement/main.htm and at www.virusmyth.net/aids/data/epazt2.htm
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Please forward it in rich text to retain my formatting. You might also like
to ask Mr Kearney
to 'please explain'. His telephone number locally is 011- 313 60 77 and his
telefax number
011-3156951. From abroad dial your international code for South Africa,
+27, and drop the
zero before the local area code.
If you can't get any sense from him, try GlaxoSmithKline's British and
American CEO's,
Sir Richard Sykes and William Morrow. Their telefax numbers (from within
South Africa)
are 0944 181 9668330 and 091 919 315 3330 respectively.
But keep your eye on the ball. Don't be distracted by any obfuscating
explanations
about the effect of AZT on T4 cell counts or antibody test reactivity.
These are indirect
markers which are modulated by cell toxins like AZT independently of
whether the
drug has any antiviral activity. Just ask how AZT can possibly work as a
chain terminator
of proviral HIV DNA synthesis if it's not triphosphorylated within cells in
vivo - contrary to
GlaxoSmithKline's false claim that it is. And why AZT is marketed as an
antiretroviral
medicine when it doesn't reduce 'HIV infection' levels according to all
direct markers
for this action.
VIRUSMYTH HOMEPAGE