Commentary to Nature on AZT

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Last updated: Apr 01, 2024
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The following is the email rejecting this correspondence

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From: "Clarke, Maxine" <M.Clarke@nature.com>
To: "'vturner@cyllene.uwa.edu.au'" <vturner@cyllene.uwa.edu.au>
Subject: from Nature (Turner/Papadopulos-Eleopulos)
Date: Thu, 25 May 2000 15:06:45 +0100
X-Mailer: Internet Mail Service (5.5.2650.10)

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Dear Dr Turner

Thank you for your article about various AIDS issues. I am afraid we are unable to offer to publish it as a Commentary, or anywhere in Nature at its present length. Your article is a review/hypothesis rather than a Nature-style Commentary. Many of the papers you cite are 10-15 years old, and as such your article is not suitable in principle to be considered as a Review in a topical, weekly journal like Nature, particularly as there are many more recent papers in the field that come to different conclusions to those that you report, that are not cited.

Naturally we are happy to consider comments on our News and Opinion articles for our Correspondence section. The phrase to which you object in Michael Cherry's News story is his statement that you "claimed that the drug was unacceptably toxic". If the papers mentioned in that News report did not claim that AZT is unacceptably toxic, and if you in fact believe that the drug is not unacceptably toxic, we would be happy to print a short letter of

a couple of sentences from you making these two specific points. Please send us a suggested text if you would like to take this course. If, however, you did not state in these particular papers that AZT is unacceptably toxic but you have stated this elsewhere, or believe it to be the case, we do not see any purpose in publishing a clarification from you.

You go on to comment on the peer-review system. We cannot offer to publish this part of your letter as you do not make any points in it that have not been made before. Nature is, of course, in general happy to consider disinterested contributions that provide novel perspectives on this issue.

The rest of your article concentrates on work that you say contradicts the observations by virtually all workers in the AIDS field that HIV is the causative agent. It does not seem to us to serve a constructive purpose to revisit old history when there are many papers in the more recent literature on the effects of HIV in vitro and in vivo, and hence that have superseded

the older work.

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Yours sincerely

Maxine Clarke

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----------------------------------------------------------------------

Dr Maxine Clarke
Executive Editor
Nature
4-6 Crinan St
London N1 9XW, UK
m.clarke@nature.com
tel +44 (0)20 7843 4537
fax +44 (0)20 7843 4596/7
www.nature.com

Ā 

Eleni Papadopulosā€‘Eleopulos1 Valendar F.Turner2 John M Papadimitriou3 Todd Miller4 Sam Mhlongo5 Christian Fiala6 Helman Alfonso7 Barry Page8, David Causer8

1Corresponding author, Department of Medical Physics, Royal Perth Hospital, Wellington Street, Perth Western Australia 6001; Consultant Emergency Physician, Department of Emergency Medicine, Royal Perth Hospital; 3 Department of Pathology, University of Western Australia; 4Department of Molecular and Cellular Pharmacology, University of Miami Medical School Florida, USA 5Department of Family Medicine Medunsa South Africa 6General Public Hospital Department of Gynecology and Obstetrics Wiener Ring 3-5 2100 Korneuburg Austria

7Department of Research, Unversidad Metropolitana Barranquilla, Colombia 8Department of Medical Physics, Royal Perth Hospital.

In a recent issue (Nature April 27th) Michael Cherry claimed that a paper published by our group in 1999 ā€œappeared to be a major influence in [President] Mbeki's refusal to sanction state provision of this drug [AZT] to prevent mother-to-child transmission of HIV because we ā€œclaimed that the drug was unacceptably toxicā€. In fact the aim of our paper was not to examine the degree of AZT toxicity (its toxicity is acknowledged by everybody including Cherry himself) but to:

(i) determine if AZT, the pro-drug given to patients, is metabolised to its antiretroviral active form, triphosphorylated AZT;

(ii) determine if AZT has anti-HIV effects;

(iii) evaluate the mechanism of its toxicity and suggest methods, by which its toxicity may be decreased.1

As stated in "An open letter to the president of South Africaā€ in the same issue, it is true that the peer-review system, like the ballot box, parliamentary debate and constitutional law in politics, has been designed to sort ā€œout those ideas which have a greater chance than others of surveying intellectual scrutiny and testing through experimentā€, and that editors of scientific journals have no other option but to submit all the papers for reviewing by specialists in the field. However, it is also true that:

(i) The peer-review system does not always guarantee ā€œdemocratically endorsed proceduresā€. ā€œIf in a subject there was initially a diversity of opinions, the review system will assure a very short life for that condition, and soon the field will be closed to all but those who are in the center. Once a herd is established, by whatever historical evolution this has come about, it obtains such firm control that it is extremely difficult to do anything about it. And even if it were appreciated that that is the situation, one just doesnā€™t know how to interfere. Where then is the right to free speech if every journal has to send each article out to a number of people to review, and the bulk of people are with the herd? Usually with just one-third of the reviewers very negative, the paper does not get published. So there is no free speech in the sense that you cannot publish diverse viewpointsā€.2Ā  (Note added June 2005:Ā  ClickĀ  HEREĀ  to read the editor of Medical Hypotheses paper on the peer review process).

(ii) At present there is evidence that studies with ā€œnegativeā€ findings, that is studies with findings at odds with what is expected, are difficult to publish. ā€œNegative studies suffer a substantial time lag. With some exceptions, most of this lag is generated after a trial has been completedā€¦Typical examples in HIV disease include the use of early zidovudine monotherapy in asymptomatic patients, acyclovir, ditiocarb (Imuthiol), and oral graniclovir prophylaxis, where positive and negative trials started at about the same time, but negative studies appeared later or are still unpublishedā€.3

It is true ā€œthe idea that there is a direct, causal relationship between infection with the human immunodeficiency virus (HIV) and the onset of AIDSā€, has survived the peer-review system. However, it is also true that ā€œintellectual scrutiny and testing through experimentā€ show that:

(1) The HIV hypothesis of AIDS was put forward to account for the high frequency of some clinical and laboratory phenomena in gay men, IV drug users and haemophiliacs, none of which were new. The main clinical phenomena were Kaposiā€™s sarcoma (KS) and Pneumocystis carinii pneumonia, the former constituting the basis for a relationship between AIDS and retroviruses. At present everybody including the CDC acknowledge that HIV plays no role, either directly or indirectly in the development of KS.4, 5

(2) The laboratory phenomenon was a decrease in T4 cells, determined by the use of antibodies, in blood (Acquired Immune Deficiency). Destruction of the T4 cells by HIV was said to be the ā€œhallmarkā€ of HIV infection.6 However, one year after the acceptance of the HIV theory, Weiss, Ludlam et al wrote (concerning patients with haemophilia): ā€œOur findingā€¦supports our previous conclusion that the abnormal T-lymphocyte subsets are a result of the intravenous infusion of Factor VIII concentrates per se not HTLV-III infectionā€.7 One year later researchers from CDC claimed, ā€œ...factor concentrate (Factor VIII) itself may be immunosuppressive even when produced from a population of donors not at risk of AIDS.8 In 1985 Montagnier wrote: ā€œThis syndrome [the AIDS diseases] occurs in a minority of infected persons, who generally have in common a past of antigenic stimulation and of immune depression before LAV [HIV] infectionā€.9 More importantly, at present there is evidence that the decrease of T4 cells in blood is not due to their destruction by HIV or any other factor. ā€œThis article discusses the importance of alterations in the CD4+ and CD8+ cell migration in regulating blood lymphocyte levels and questions the extent of virus-mediated CD4+ cell destructionā€,10 ā€œCD4+ T-cell lymphopenia is due to both shortened survival time and a failure to increase the production of circulating CD4+ T-cellsā€,11 or to the down-regulation of the CD4 molecule.12

(3) It was accepted that no single infectious agent could possibly be the direct cause of the multiple diseases seen in AIDS patients. It was postulated then that the destruction of T4 cells (the immune deficiency) inevitably led to the appearance of KS and the opportunistic infections. At present, evidence exists which proves that T4 decrease is neither necessary nor sufficient for the syndrome to develop. ā€œCD4 [T4] cell counts were not significantly associated with the risk of progressionā€ to disease.13 ā€œAlong with other recent analyses and experimental developments these conditions also suggest a need to re-evaluate current concepts about HIV pathogens including the concept that a systemic depletion of CD4 T-cells is the hallmark of the diseaseā€.14

(4) Although as the proponents of the HIV theory predicted many drugs have been developed to treat HIV infection, the beneficial clinical effects of these, if any, cannot be due to their anti-HIV effect. With no exception, all the anti-HIV drugs presently used, by design can only prevent the synthesis of HIV DNA. Once the DNA is formed they cannot prevent the transcription of the DNA into RNA. In other words the drugs can decrease HIV RNA only indirectly, by decreasing the HIV DNA. The presently available data shows that no drug, and no drug combination, including Highly Active Antiretroviral Therapy (HAART) decreases the ā€œviral burdenā€, that is HIV DNA.1, 15, 16. In fact, HAART can lead to ā€œa significant increase in PBMC proviral DNAā€.17

(5) According to the HIV theory of AIDS, haemophiliacs acquire HIV via contaminated factor VIII. Yet CDC data show that this is not possible. Their data shows that HIV ā€œdoes not spread or maintain infectiousness outside its host. Although these unnatural concentrations of HIV can be kept alive under precisely controlled and limited laboratory conditions, CDC studies have shown that drying of even these high concentrations of HIV reduces the number of infectious viruses by 90 to 99 percent within several hours. Since the HIV concentrations used in laboratory studies are much higher than those actually found in blood or other body specimens, drying of HIV-infected human blood or other body fluids reduces the theoretical risk of environmental transmission to that which has been observed-essentially zero".18

(6) The main prediction of the HIV theory of AIDS was, that although AIDS was first diagnosed in gay men, because AIDS was caused by a sexually transmitted agent, which like all other such agents, is bidirectionally transmitted, AIDS, would rapidly spread throughout the heterosexual population. One of the first scientists to publish data that this could not be the case, at least in gay men, was Robert Gallo and his associates. In 1984 he wrote: ā€œOf eight different sex acts, seropositivity correlated only with receptive anal intercourseā€¦.ā€.19 In 1986 Gallo wrote: ā€œData from this and previous studies have shown that receptive rectal intercourse, for example, is an important risk factor for HTLV-III [HIV] infectionā€¦We found no evidence that other forms of sexual activity contributed to the riskā€.20 This was confirmed in many other studies including the Multicenter AIDS Cohort Study, (MACS) the best, largest (about 5,000 men), and longest study which commenced in 1984 and is ongoing.21 In this, as well as other studies, it was shown that it is the frequency of passive anal passive intercourse, not the number of partners which is important in the development of a positive antibody test and AIDS.22-24 In a 1994 review of most, if not all the epidemiological studies conducted in gay men, the authors concluded: ā€œit can be said that the cited reports yield convincing evidence that (1) unprotected ano-genital receptive intercourse poses the highest risk for the sexual acquisition of HIV-1 infection; (2) ano-genital insertive intercourse poses the highest risk for the sexual transmission of HIV-1 infection; (3) there is mounting epidemiological evidence for a small risk attached to oro-genital receptive sex, biologic plausibility, credible case reports and some studies show a modest risk, detectable only with powerful designs; (4) sexual practices involving the rectum and the presence of (ulcerative) STD facilitate the acquisition of HIV-1; (5) no or no consistent risk for the acquisition of HIV-1 infection has been reported regarding other sexual practices such as ano-genital insertive intercourse and oro-anal sexā€¦.(8) the association of substance use with HIV infection is probably the result of interaction, because substance use increases the likelihood of practising ano-genital receptive intercourseā€.25 Unquestionably, to date, the best designed and executed study in heterosexuals was conducted by Nancy Padian and her associates. In 1987 they reported: ā€œThe total number of exposure to the index case (sexual contacts with ejaculation) and the specific practice of anal intercourseā€ were associated with the development of a positive antibody test. The results from their long (ten years) prospective study of heterosexual couples of whom only one partner of either sex was antibody positive were published in 1997 where they reported that ā€œno seroconversions occurred among exposed partnersā€.26 According to one of the best known HIV/AIDS experts, Jaap Goudsmit, for heterosexual ā€œHIV transmissionā€ anywhere in the world, including Haiti, Africa, Thailand, ā€œa homosexual or anal factor seems to be requiredā€.24 In other words, at present there is ample evidence that sex plays an important role in the acquisition of a positive antibody test and AIDS and the practice of safe sex should form the basis for any effort in prevention. However, there is no proof that AIDS is a bidirectionally sexually transmitted disease. Unlike any other sexually transmitted disease, AIDS and a positive antibody test, like pregnancy, can be sexually acquired but not sexually transmitted. The difference is that while pregnancy can be acquired by a single sexual intercourse, for AIDS to appear a very high frequency of receptive anal intercourse over a long period is necessary. AIDS is more like anal 27, 28 and cervical cancer.29 The effect is not the result of the act itself but its high frequency. However, as with pregnancy, cervical and anal cancer, other factors may promote or militate against the development of AIDS and a positive antibody test.

If a hypothesis cannot account for the phenomena for which was put forward, and if its predictions are not fulfilled, then scientists have no choice but to reappraise it.

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