An Open Letter to John Kearney,
CEO of GlaxoSmithKline,
South Africa

March 2001

Dear Mr Kearney

AZT

In the package insert supplied with AZT you allege that it's converted by enzymes inside human cells from its parent form as a pro-drug into its active agent, AZT triphosphate. And that AZT triphosphate stops HIV replication by being incorporated into growing proviral DNA chains during the reverse transcription of HIV RNA.

In November 1986 Furman and others including researchers from Wellcome Research Laboratories (a division of your company in an earlier incarnation) reported their finding that in the most ideal artificial conditions in vitro, the minimum concentration of AZT triphosphate necessary to inhibit proviral HIV DNA chain synthesis significantly, i.e. have an antiretroviral effect, is 0.7mM (1).

But sixteen studies conducted since then have found that in the real world in vivo, our cells can’t triphosphorylate AZT to anything like that level, with the best of the studies reporting AZT to be triphosphorylated in cells in vivo at levels one, even two orders of magnitude below the drug’s minimum effective concentration (2).

Would you please explain then why you persist in claiming that "Zidovudine [AZT] is phosphorylated in ... cells to ... the triphosphate (TP) derivative... " - by implication to effective virustatic concentrations in vivo - when study after study has consistently shown that it isn’t?

If AZT prevents HIV replication by terminating proviral HIV DNA chain synthesis as you claim, one would expect the medicine 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 reported studies of the effect of AZT on these parameters in vivo show that the drug has no such anti-HIV effect (3). None at all on HIV DNA synthesis (viral burden), which flatly refutes your key claim that the drug blocks it. An insignificant effect on HIV RNA (viral load) (4). And none on the rest. All of which is perfectly predictable, since AZT is triphosphorylated by our cells negligibly, as we’ve seen.

So why do you still 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 ... HIV", when all studies of the effect of AZT on direct markers for HIV infection levels in vivo have demonstrated these claims to be untrue?

And why do you continue to claim that AZT is “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 reported in 1994, involving 1749 symptom-free HIV-positive individuals - found that AZT has no therapeutic benefits when administered early (5), and the extended results of the study a year later showed “a significant increased risk of death among the patients treated early” (6) ?

In your reply addressing the triphosphorylation and efficacy issues that I’ve raised, please leave out the effect of AZT on T4 (CD4+) cell counts - a non-specific, indirect marker modulated by cell poisons like AZT independently of any antiviral activity (7). The same goes for antibody levels.

Thanks.

ANTHONY BRINK
PIETERMARITZBURG

TO REPLY

FOOTNOTES:

(1) Proceedings of the National Academy of Sciences of the United States of America 1986; 83: 8333-7.
(2) See table below.
(3) Current Medical Research and Opinion, 1999; Volume 15; Special Supplement - posted online at:
www.librapharm.co.uk/cmro/vol_15/supplement/main.htm and
www.virusmyth.net/aids/data/epazt2.htm
(4) See graph below.
(5) Lancet 1994; 343:871-81
(6) New England Journal of Medicine 1997; 336:958-9
(7) AIDS 1996; 10:1444-1445.

TABLE:




GRAPH:


a) Eron JJ et al. NEJM 1995;333:1662-9
b) De Jong MD, et al. PNAS 1996;93:5501-6
c) Katlama C, et al. JAMA 1996;276:118-25
d) Katlama C, et al. JAMA 1996;276:118-25
e) Staszewski S et al. JAMA 1996;276:111-7
f) Carr A, AIDS 1996;10:635-41
g) O'Brien WA, et al. NEJM 1996;334;426-31
h) O'Brien WA, et al. NEJM 1996;334;426-31
i) Katzenstein D, et al. NEJM 1996:1091-8
j) Bakshi SS, et al. J Infect Dis 1997;175:1039-50
k) Bruisten SM et al. AIDS Res & Hum Retr 1998;12:1053-8
l) Delta Committee. AIDS, 1999:57-65
m) Delta Committee. AIDS, 1999:57-65
n) Lillo FB, et al. AIDS 1999;13:791-6


1. According to American HIV experts Saag, Shaw and Coombs and their associates in their article HIV viral load markers in clinical practice in Nature Medicine 1996; 2(6): 625-9: “A three-fold or greater sustained reduction (>0.5 log) of the plasma HIV RNA levels is the minimal response indicative of an antiviral effect... [R]eturn of HIV RNA levels to pre-treatment values (or to within 0.3 - 0.5 log of the pre-treatment value), confirmed by at least two measurements, is indicative of drug failure”.

2. According to the 1997 British HIV Association guidelines for antiretroviral treatment published in The Lancet 1997; 349:1086-1092: “If the viral load has not fallen by about 1 log 8-12 weeks after treatment initiation consideration should be given to modify therapy”.

3. All studies in which the effect of AZT on HIV viral load in patients has been investigated, have consistently established that AZT taken alone or in combination with other drugs is not able to induce a sustained decrease in the “plasma HIV RNA level” of >0.5 log (the American criterion for anti-HIV drug efficacy), much less 1 log (the British criterion).

4. By both the American and British criteria mentioned above, AZT fails to achieve “the minimal response indicative of an antiviral effect” and is therefore a “drug failure” i.e. ineffective as an antiviral medicine against HIV.

TO GLAXO ANSWER