Zidovudine

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Zidovudine (aka 3'-azido-3'-deoxythymidine, azidothymidine, or simply AZT) is an analog of thymidine in which the 3' hydroxyl group is replaced by an azido group. For this reason, AZT is considered a chain terminator of DNA synthesis. It was synthesized in 1964 by Jerome Horwitz.

AZT belongs to a class of chemical compounds known as nucleoside analog reverse transcriptase inhibitors, commonly called NRTI's. It is sold under the names Retrovir® and Retrovis®, and as an ingredient in Combivir® and Trizivir®. It was the first drug approved for the treatment of AIDS in 1987, and it was the first drug approved for "preventative" treatment of HIV/AIDS in 1990.

Molecular structure of AZT

AZT

3'-Azido-3'-deoxythymidine

Empirical Formula C10H13N5O4
Molecular Weight 267.24
Half-life Approx. 3.3 hours
Excretion Renal
Pregnancy category FDA Pregnancy category C

Contents

Proposed mode of action

Once HIV infects a cell, it uses an enzyme called reverse transcriptase to copy its RNA into DNA, which is then integrated into the host cell's genome. At some point in the future, this integrated proviral DNA is synthesized into viral RNA and viral proteins which are used to assemble new viruses.

AZT is an analog of thymidine, a DNA nucleoside. When it takes the place of thymidine in a growing DNA chain, the chain stops because it then lacks the hydroxyl group necessary for additional nucleotides to be attached to the growing DNA chain. Thus, AZT is a "chain terminator of DNA synthesis".

AZT is proposed to interfere with the transcription of proviral DNA. For this reason, AZT and drugs with a similar proposed mode of action are called antiretroviral nucleoside analog reverse transcriptase inhibitors. The "nucleoside analog" part of this label is explained above, but the "antiretroviral" and "reverse transcriptase inhibitor" part are really misnomers, due to the following points:

  1. For AZT to be effective against HIV by inhibiting the synthesis of proviral DNA, it must first be triphosphorylated (addition of 3 phosphate groups) from its unphosphorylated form. This process of triphosphorylation must take place inside the cell, because triphosphorylated AZT cannot penetrate the cell membrane. In other words, it is required that the cell itself is capable of triphosphorylating a sufficient amount of AZT to break the cycle of infection in the cell. This has been shown not to be the case.
  2. Considering the fact that few T-cells are infected with HIV, this gives AZT a very high toxicity index. So, it is also required that AZT be very specific in its inhibition of viral DNA compared to cellular DNA. However, AZT significantly inhibits cellular DNA polymerase used in the DNA replication process required for cell division, as AZT is readily converted into its monophosphate form, inhibiting the phosphorylation of cellular constituents, including cellular nucleotides. In other words, AZT does not specifically inhibit reverse transcriptase, and hence AZT does not specifically inhibit proviral DNA.
  3. Reverse transcriptase enzyme is not specific to retroviruses. Thus, even if AZT acted as a "reverse transcriptase inhibitor", there is no justification for calling it an "antiretroviral".
  4. AZT inhibits mitochondrial DNA (mtDNA) replication, and this inhibition of mtDNA has been posited as an explanation for the severe cellular toxicity of AZT.

All of these points severely undermine the proposed "anti-HIV" mechanism of AZT.

History

Development as cancer drug

Zidovudine was the first drug approved for the treatment of AIDS and HIV infection. Jerome Horwitz finished finalizing the method of synthesis of AZT in 1964, as well as indicates it this publication in J. Org. Chem, when he describes the best method to obtain the intermediary 5, under a US National Institutes of Health (NIH) grant (Horwitz 1964). Its synthesis is inexpensive and easily performed:

Image:AZT_synthesis.png

AZT was originally intended to treat cancer, but failed to show efficacy and had an unacceptably high toxicity profile. (Note: There is some dispute over whether a high toxicity profile contributed to the shelving of AZT. Horwitz himself appears to have given conflicting testimony in various interviews.)

The choice is AZT

"Enjoy AZT": artwork created by the activist art group Gran Fury
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"Enjoy AZT": artwork created by the activist art group Gran Fury

The drug then faded from view until February 1985, when Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan, three scientists in the National Cancer Institute (NCI), collaborating with Janet Rideout and several other scientists in Burroughs Wellcome Co., started working on it as an AIDS drug.

Fraud and incompetence from the FDA

New York Native, 1 June 1987
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New York Native, 1 June 1987

A placebo-controlled randomized trial of AZT was subsequently conducted by Burroughs-Wellcome (now GlaxoSmithKline), in which it was allgedly shown that it could prolong the life of patients with AIDS. However, as John Lauritsen has documented based on information obtained under the Freedom of Information Act, the trials quickly became unblinded and the studies which subsequently formed the basis of approval for AZT were marked by sloppiness, incomplete and incoherent methodologies, and false data:


The multi-center clinical trials of AZT are perhaps the sloppiest and most poorly controlled trials ever to serve as the basis for an FDA drug licensing approval. Conclusions of efficacy were based on an endpoint (mortality) not initially planned or formally followed in the study after the drug failed to demonstrate efficacy on all the originally intended endpoints. Because mortality was not an intended endpoint, causes of death were never verified. Despite this, and a frightening record of toxicity, the FDA approved AZT in record time, granting a treatment IND in less than five days and full pharmaceutical licensing in less than 6 months. — Martin Delaney ("AZT on Trial", John Lauritsen, New York Native 19 October 1987)


Burroughs Wellcome Co. filed for a patent on AZT in 1986. The Food and Drug Administration (FDA) approved the drug (via the then-new FDA accelerated approval system) for use against HIV, AIDS, and AIDS Related Complex (ARC, a now-defunct medical term for pre-AIDS illness) on March 20, 1987, and then as a preventive treatment in 1990. It was initially administered in much higher dosages than today, typically one 400mg dose every four hours (even at night). One of AZT's "side-effects" includes anemia, a common complaint in early trials.

AZT for healthy people and babies

"Living With HIV"

Concorde trials

"Twilight Zone" virology and the rise of protease inhibitors

President Mbeki and the AIDS drug controversy

Patent issues

AZT is easy to produce in bulk, costing about USD $0.63 per daily dose (pdd), but due to the patent protection, GlaxoSmithKline is able to sell it for about $8 pdd.

In 1991, Public Citizen filed a lawsuit claiming that the Zidovudine patent was invalid. The United States Court of Appeals for the Federal Circuit ruled in 1994 in favour of GlaxoSmithKline. In 2002, another lawsuit was filed over the patent by the AIDS Healthcare Foundation.

However, the patent expired in September 2005, allowing other drug companies to manufacture and market generic AZT without having to pay GlaxoSmithKline any royalties. The FDA has since approved four generic forms of AZT for sale in the US.

Biological critiques of AZT's alleged mode of action

According to Murad F [1], [2] , sodium azide acts in the same way as hydroxylamine and nitrites (poppers), by activating the guanylyl cyclase. Better, they noticed that all these compounds led to the forming of nitrogen monoxide, the famous EDRF. The alkylazides (AZT) may even much more than the sodium azide to behave as NO, because they are more reactive. Moreever, according to Sherk & al., the hydrolysis of alkyl or arylazide in hydroxylamine is frequent in the presence of an acid catalysis.

Hydroxylamine is a strong mutagenic agent.

When we learn that the nitrogen monoxide is a regulator of the apoptosis, either favoring it, or preventing it, we can ask the question of the double action of AZT, allowing the increase of the CD4 + at the beginning of the treatment, and their drop afterward. The Frost diagramm of nitrogen gives the solution: azides react spontaneously with peroxynitrites to give dinitrogen, nitric oxid...

e.g. : the Gibbs enthalpy of this reaction :

RN3 + 2 H+ + 2 ONOO- -> 4 NO + RNHOH + H2O

is ~ - 800 kJ/mol.

image:Nitrogen_frost_diagramm.png

But nitric oxid needs glutathione not to be reoxidized in peroxynitrite... and azides ( AZT) destroys slowly the glutathione (see Reardon & al.).

Kim & al.write p 254 :

The induction of apoptosis often requires exposure to high levels of exogenous NO donors.

Therefore, NO donors such as alkylazides (AZT) and nitrites (poppers) are capable, in theory, if they are absorbed in great quantities, of provoking a decline in the CD4 +.

These considerations lead to the understanding that AZT and others (the NRTI, NNRTI or PI) do not invariably act as antiretrovirals, but that their chemical properties alone can explain why they might be effective and why resistances appear :

Initially, as long as the rate of glutathione is good, AZT will allow an increase of the TH1 (CD4 +), then, as the rate of glutathione decreases, it is the inverse effect which takes place.

Proven toxicities of AZT

"TOXIC. Toxic by inhalation, in contact with skin and if swallowed. Target organ(s): Blood bone marrow. If you feel unwell, seek medical advice (show the label where possible). Wear suitable protective clothing."
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"TOXIC. Toxic by inhalation, in contact with skin and if swallowed. Target organ(s): Blood bone marrow. If you feel unwell, seek medical advice (show the label where possible). Wear suitable protective clothing."

Common "side effects" of AZT include nausea, headache, changes in body fat, and discoloration of finger and toenails. More severe side effects include anaemia and bone marrow suppression. These might be caused by the sensitivity of the γ-DNA polymerase in the cell mitochondria.

Here are a few examples from the medical literature that dissidents cite as evidence AZT harmed AIDS patients:

1) The observation that among male homosexuals, "HIV dementia among those reporting any antiretroviral use (AZT, ddI, ddC, or d4T) was 97% higher than among those not using this antiretroviral therapy" is interpreted by its authors with little concern for percentages: "This effect was not statistically significant" (117[3]).

2) The stunning results that HIV-positive hemophiliacs on AZT have 4.5-times more AIDS and have a 2.4-times higher mortality than untreated HIV-positive hemophiliacs, is excused by the NIH researcher James Goedert, the former proponent of the nitrite-AIDS hypothesis (see 3.), with the casual explanation, "probably because zidovudine was administered first to those whom clinicians considered to be at highest risk" (204[4]). But, although AZT apparently increased the morbidity and mortality of hemophiliacs significantly, Goedert et al. did not question the appropriateness of AZT therapy.

3) Darby et al. report in Nature in 1995 that the mortality of HIV-positive British hemophiliacs increased 10-fold since the introduction of AZT in 1987 (183[5]). The authors acknowledge that "treatment, by prophylaxis against Pneumocystis carinii pneumonia or with zidovudine [AZT] has been widespread" in HIV-positive hemophiliacs. But instead of even considering that these drugs could play a role in accelerating the deaths of hemophiliacs, they argued that "HIV-associated mortality has not been halted by these treatments" (183[6]). They failed to explain why HIV-associated mortality would have risen 10-fold only after the introduction of AZT and other anti-AIDS therapies in 1987, rather than in the two decades before 1985 when HIV was unknowingly transfused into hemophiliacs together with clotting factor (24[7]).

4) Saah et al. explain their observation that male homosexuals on AZT have a two- to four-fold higher risk of Pneumocystis pneumonia than untreated controls as follows: "Zidovudine was no longer significant after T-helper lymphocyte count was considered, primarily because nonusers had higher cell counts..." (201[8]). The fact that an inhibitor of DNA synthesis designed to kill human cells would reduce lymphocyte counts was not mentioned.

5) An evaluation of AIDS prophylaxis with AZT produced in 1994 the following results: "the average time with neither a progression of disease nor adverse event was 15.7, 15.6, and 14.8 months for patients receiving placebo, 500 mg zidovudine, and 1500 mg zidovudine, respectively. …After 18 months, the 500-mg group gained an average of 0.5 month without disease progression, as compared with the placebo group, but had severe adverse events 0.6 month sooner." On this basis the authors concluded that, "…a reduction in the quality of life due to severe side effects of therapy approximately equals the increase in the quality of life associated with a delay in the progression of HIV disease" (202[9]). It remains unclear, however, how one gains 0.5 months "without disease progression" while one has "severe adverse effects" 0.6 months sooner.

In view of this one wonders why since 1994 at least 220,000 mostly healthy, HIV-positive people continue to receive AZT, either by itself or combined with other drugs like protease inhibitors, all of which have no therapeutic value and cost the patient or tax payer over $12,000 per year (26[10]).

6) The blunt result that AZT prophylaxis reduced survival from 3 to 2 years, and caused "wasting syndrome, cryptosporidiosis, and cytomegalovirus infection ... almost exclusively" in AZT-treated AIDS patients, was interpreted like this: "The study of patients who progress from primary HIV infection to AIDS without receiving medical intervention gives insights into the effects of medical intervention on presentation and survival after developing an AIDS defining illness". But the nature of these "insights" was not revealed by the authors (203[11]).

7) The largest test of AIDS prophylaxis with AZT of its kind, the Concorde trial, found no prophylactic value, but instead revealed a 25% higher mortality in AZT recipients than in untreated controls (343[12]). In view of these awkward results Seligmann et al. reached the patronizing conclusion: "The results of Concorde do not encourage the early use of zidovudine [AZT] in symptom-free HIV-infected adults" (160[13]).

8) A study that treated HIV-positive, intravenous drug users from New York with AZT observed: "The rate of CD4 lymphocyte depletion did not appear to slow after the initiation of zidovudine therapy….". This led to the conclusion: "Our data failed to provide evidence for an effect of zidovudine on the depletion of CD4+ lymphocytes, but the direction of the modeling results suggested that zidovudine users in this sample may have experienced more rapid CD4+ cell depletion" (87[14]).

9) As of 1994 the American NIAID and the CDC promoted the prevention of maternal HIV transmission with AZT (45, 184, 185, 344). But the costs of the hypothetical triumph of reduced HIV transmission in terms of birth defects and abortions were omitted from the reports of the original trial (184[15], 185[16], 344-347[17]). However a study from outside the US reported 8 spontaneous abortions, 8 therapeutic abortions and 8 serious birth defects, including holes in the chest, abnormal indentations at the base of the spine, misplaced ears, triangular faces, heart defects, extra digits and albinism among the babies born to 104 AZT-treated women. But these bewildering results were interpreted as just "not proving safety, thus lending tenuous support to the use of this drug" (200[18]).

Indeed, "spontaneous" or therapeutic abortion as a result of AZT was not an unforseeable accident. A review in The Lancet on "non-surgical abortion" documents that chemotherapeutic drugs, like methotrexate, have been used to abort normal and ectopic pregnancies since 1952 (188[19]). The article concedes early "concerns over teratogenicity, but concludes: used correctly, the method could bring great benefits" (188[20]).

10) In 1996, the American National Institute of Child Health and Human Development reported the consequences of AIDS prophylaxis with AZT for HIV-positive babies: "In contrast with anecdotal clinical observations and other studies indicating that zidovudine favorably influences weight-growth rates, our analysis suggests the opposite. Because our analysis of zidovudine effect on standardized growth outcomes was based on limited numbers of patients (no more than 10 at any one visit with prior zidovudine use) and because we could not control for stage of HIV disease in the study design, the result indicating no effect or a negative effect of zidovudine on growth should be interpreted with caution. Presumably, zidovudine use is confounded by progression of HIV disease. The observation that standardized LAZs [length for age scores] were lower after the start of zidovudine therapy than before may suggest merely that sicker infants received zidovudine. However, our findings suggest that the widely held view that antiretroviral treatment improves growth in children with HIV disease needs further study" (205[21]). Thus AZT toxicity was shifted to HIV.

But if the lower health standards of AZT-treated babies were due to prior "HIV disease", it would have been necessary to conclude that AZT failed to reverse or even maintain the "HIV disease" of these babies. But that possibility was not mentioned nor apparently even considered by the AZT-doctors. Moreover, the likelihood that AZT was the cause of the babies’ diseases was obscured by averaging the diseases of AZT-treated with those of untreated HIV-positive babies (see 7.7.). The same arguments are used in the conclusions of this study [22] , while an individual thinking normally should have put a stop.

11) The disquieting observation that AZT increases the annual lymphoma risk of HIV-positives 50-fold, from 0.3 to 14.5%, per year was resolved by the NCI director, Samuel Broder and his collaborators, by claiming a victory for AZT: "Therefore, patients with profound immunodeficiency are living longer [on AZT], theoretically allowing more time for the development of non-Hodgkin lymphoma or other malignancies" (198[23]).

Documents

Poison by Prescription by John Lauritsen

Good Intentions by Bruce Nussbaum

Debating AZT by Anthony Brink

Films

Credit

Wikipedia
This page uses content from the AIDS_reappraisal article on Wikipedia, captured on 30 January 2006. The list of authors can be seen in the page history. As with the AIDS Wiki, the text of Wikipedia is available under the GNU Free Documentation License.
Wikipedia
This page uses content from the Zidovudine article on Wikipedia, captured on 20 March 2006. The list of authors can be seen in the page history. As with the AIDS Wiki, the text of Wikipedia is available under the GNU Free Documentation License.

References

  1. Horwitz, JP, Chua, J, Noel, M, 1964. J. Org. Chem. 1964, 29, 2076.