Current Medical Research and Opinion and ‘medical publication ethics’: The curious case of the Perth Group’s missing AZT pharmacology paper
(But see postscript)
On 1 July 2010 Brink wrote to CMRO publisher (at the time) Jay Magrann:
Dear Mr Magrann
I write to you about a paper you published in the form of a special supplement to Current Medical Research and Opinion 1999;15 Suppl 1:S1-45: ‘A critical analysis of the pharmacology of AZT and its use in AIDS’ by Papadopulos-Eleopulos et al. [original PDF, 227 KB]
Although indexed by MEDLINE at http://www.ncbi.nlm.nih.gov/pubmed/11594171 under the citation given above, I’m unable to find any mention of the paper in your CMRO ‘ISSUE ARCHIVE’ online. [Papadopulos-Eleopulos et al. had discovered the paper was missing and made enquiries; see below.]
A feature article published in Nature 405;105 on 11 May 2000 under the title ‘[CMRO] editor defends publishing key AZT paper’ reported that ‘South African president Thabo Mbeki has referred to this paper … in support of his reluctance to endorse the use of AZT – for example, to prevent the transmission of HIV from pregnant mothers to their babies … Peter Clarke, the journal’s managing editor … who at the time was also in charge of editorial decisions [said the] paper was refereed over an “extended period of time” … Clarke adds that he took many months to reach a decision.’
Indeed, under ‘Peer Review’ on your website you record that ‘All manuscripts … undergo rigorous specialist peer review. The basic criterion for acceptance is that the work described must be clinically relevant and medically and scientifically accurate, demonstrating methodological rigour, clarity, balance and objectivity.’ This applies equally to ‘Supplements … on specific drugs’, for ‘Supplements undergo the same rigorous peer review that is used for regular CMRO articles.’
Papadopulos-Eleopulos’s et al. conclusion based on an exhaustive review of all the available data is that AZT is not triphosphorylated intracellularly to anywhere remotely approaching its inhibition concentration – rather to levels one or more orders of magnitude below it. (The abstract of the paper is copied below.) To the best of my knowledge this conclusion has never been refuted.
The paper obviously has gargantuan ramifications for AZT manufacturer GlaxoSmithKline in multi-billion-dollar toxic tort exposure, and I accordingly wondered whether in the decision to omit any mention of the paper from your ‘ISSUE ARCHIVE’ any influence had been brought to bear by any of those numerous members of your Editorial Board and/or International Advisory Board who have disclosed that they are in the corporation’s pay as researchers, clinical trial investigators and consultants/ advisors, besides holding its stock and being married to its employees. In other words, by persons enjoying direct ‘financial relationships with industry’, as your ‘Transparency Policy’ puts it, which is to say having ‘relevant financial or other relationships with commercial entities [that] may lead to a real or perceived conflict of interest.’
In your editorial ‘Re-commitment’ in the current issue of CMRO June 2010, Vol. 26, No. 6, page 1247, you emphasize your ‘strong re-commitment to CMRO’s long-term involvement in medical publication ethics’, and record that ‘CMRO has undergone a major transformation over the past 18 months focused on a re-commitment to the core principle of the journal: to provide ethical, unbiased and rapid publication of quality content that is validated by rigorous peer review. We have enacted a Transparency Policy to ensure the openness of potential conflicts of interest, joined the Committee on Publication Ethics (COPE), re-designed our journal to make it easier to navigate and read, and expanded our web site to provide more features and options for accessing our content.’
In view of your ‘strong re-commitment’ to ‘medical publication ethics’ and your provision of ‘more features and options for accessing our content [on CMRO’s] web site’ I was surprised to find Papadopulos-Eleopulos’s et al. extraordinarily important review, ‘A critical analysis of the pharmacology of AZT and its use in AIDS’ inaccessible.
Could you throw any light on this?
I’d be grateful.
Advocate of the High Court of South Africa
CC: Executive Managing Editor (New York): Dorothy Pennachio
The triphosphorylated form of the nucleoside analogue 3’-azido-3’-deoxythymidine (Zidovudine, AZT) is claimed to interrupt the HIV replication cycle by a selective inhibition of viral reverse transcriptase, thereby preventing the formation of new proviral DNA in permissive, uninfected cells. Given that initial HIV infection of an individual instigates abundant HIV replication from inception until death, and that the life of infected T-cells is only several days, the administration of AZT should lead both in vitro and in vivo (i) to decreased formation of proviral DNA; and thus (ii) to decreased frequencies of ‘HIV isolation’ (detection of p24 or reverse transcription or both) in stimulated cultures/cocultures of T-cells from seropositive individuals; (iii) to decreased synthesis of HIV p24 and RNA (‘antigenaemia’, ‘plasma viraemia’, ‘viral load’) ultimately resulting in low or absent levels of all three parameters; and (iv) to a perfect and direct correlation between all these parameters. A critical analysis of the presently available data shows that no such evidence exists, an outcome not unexpected given the pharmacological data on AZT. HIV experts all agree that only the triphosphorylated form of AZT (AZTTP) and not the unphosphorylated form administered to patients, nor its mono- or diphosphate, is the active agent. Furthermore, the mechanism of action is the ability of AZTTP to halt the formation of HIV-DNA (chain termination). However, although this claim was posited from the outset, AZT underwent clinical trials and was introduced as a specific anti-HIV drug many years before there were any data proving that the cells of patients are able to triphosphorylate the parent compound to a level considered sufficient for its putative pharmacological action. Notwithstanding, from the evidence published since 1991 it has become apparent that no such phosphorylation takes place and thus AZT cannot possess an anti-HIV effect. However, the scientific literature does elucidate: (i) a number of biochemical mechanisms which predicate the likelihood of widespread, serious toxicity from use of this drug; (ii) in vitro data proving that AZT has significant antibacterial and antiviral properties which confound interpretation of its effects when administered to patients. Based on all these data it is difficult if not impossible to explain why AZT was introduced and still remains the most widely recommended and used anti-HIV drug.
The Perth Group followed up on 30 July 2010:
Dear Mr Magrann,
In 1999 CMRO published a review on AZT as a supplement to the Journal .
I am writing on behalf of all the authors of this paper, of which I am one, to point out that our paper is not listed in the Journal archive. We note that other supplements on other topics by other authors are present at the Journal website.
We would be grateful if you could enlighten us as to why our paper has been omitted.
Valendar F Turner
1. Papadopulos-Eleopulos, E., V. F. Turner, et al. (1999). “A critical analysis of the pharmacology of AZT and its use in AIDS.” Current Medical Research and Opinion 15 (Supplement 1): 1s-45s .
On 2 August 2010 CMRO’s ‘Risk & Compliance Manager’ responded, copying Turner and Magrann in:
Dear Mr Brink,
I have been asked by my colleague, Mr Magrann, to look into the question raised in your email of Thursday, July 01.
Informa acquired CMRO from LibraPharm in 2006. At that time, we were supplied with a pre-existing archive of materials relating to past volumes of the Journal. As would be clear from any review of this archive, it is not and does not purport to be a complete record of all historic articles that appeared in this publication.
As you point out, Informa and CMRO currently adhere to accepted codes of industry practice regarding editorial integrity, transparency and ethics and I can assure you that we are not aware of anything related to this article’s omission from the archive that would indicate a breach of any such codes.
I trust this clarifies the matter for you.
Risk & Compliance Manager
Informa Business Information
Tel: +44 (0)20 3377 3605
Mob: +44 (0) 78 2569 6444
69-77 Paul Street
London, EC2A 4LQ
Turner replied on 3 August 2010, copying Magrann and Pennachio:
Dear Mr. Angel,
Thank you for including me in the reply to Mr. Brink. I assume your email is in place of a direct reply from Mr. Magrann, to whom I addressed my enquiry.
My fellow authors and I share the frustration Informa must feel purchasing a new Journal and then discovering the archive is missing copies of published material. Especially since CMRO is held in such high regard and is so clinically orientated. But we confess we did not realise the CMRO archive is incomplete. In fact to the contrary. The archive page has an impressive list of papers going as far back as far as 1972 and at first sight appears anything but incomplete. In hindsight we should have taken a look at every year’s papers rather than randomly picking half a dozen or so when we discovered our paper was missing. Perhaps it would assist readers if you inserted a note on your website that certain papers are missing and listing those that are. PubMed has all the titles, including our own paper.
We are sure you would welcome any opportunity to obtain missing files from authors who have been published at CMRO. In that light we attach the original pdf of our paper which was kindly provided to us by Dr. Clarke. We would be most appreciative if you could insert our paper into your archive where it belongs.
We trust there will be no hard feelings over this episode.
Valendar F Turner
Turner wrote Angel again on 11 August 2010
Dear Mr. Angel,
I sent the email below just over a week ago but have not heard back. In case you did not receive it I am resending it within this email. My apologies if you already have this communication.
My colleagues and I would appreciate a response in regard to installing our AZT paper at the CMRO archive.
Valendar F Turner
According to the ‘cmroStaff’ page:
Mr Magrann has disclosed that that he served as a consultant to the Medical Publishing Insights and Practices (MPIP) Roundtable Workshop, which was jointly sponsored by the International Society of Medical Publication Professionals (ISMPP), Leerink Swann Strategic Advisors, Amgen, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline and Pfizer Inc. (emphasis added)
On 5 February 2012 Turner wrote to new CMRO publisher Malavika Legge:
Dear Ms Legge,
Re: Papadopulos-Eleopulos, E., V. F. Turner, et al. (1999). “A critical analysis of the pharmacology of AZT and its use in AIDS.” Current Medical Research and Opinion 15 (Supplement 1): 1s-45s.
This review paper was published as a Supplement to CMRO in 1999 but is not listed at the Journal’s website. It appears other special issues are listed and are available for other years.
The paper is listed at PubMed.
Would it be possible to include this paper (attached) at the Journal’s website archive?
Thanking you for your attention to this matter.
Valendar F Turner
So much for CMRO's ‘strong re-commitment to CMRO’s long-term involvement in medical publication ethics’, ‘re-commitment to the core principle of the journal: to provide ethical, unbiased and rapid publication of quality content that is validated by rigorous peer review’, ‘Transparency Policy to ensure the openness of potential conflicts of interest’, membership of ‘the Committee on Publication Ethics (COPE)’, and ‘re-design.. [of] our journal to make it easier to navigate and read, and expan[sion of] our web site to provide more features and options for accessing our content.’
When there’s certain content we don’t want people to see.
In early 2013 we found it back online, for subscribers or $50 purchase.