A Critical Analysis of the Pharmacology of AZT and its Use in AIDS

Abstract

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.

Fully-spliced HIV-1 RNAs are reverse transcribed with similar efficiencies as the genomic RNA in virions and cells, but more efficiently in AZT-treated cells

“…AZT, after conversion to AZT-5'-triphosphate by cellular enzymes, inhibits RT through a competition with the natural dTTP [6]. To further investigate the RTion of spliced RNAs, we examined its sensitivity to AZT (Fig.…”

Expertise and Inauthentic Scientific Controversies: What You Need to Know to Judge the Authenticity of Policy-Relevant Scientific Controversies

“…Looking through the abstracts of those that do, the vast majority either recommend the use of AZT for MTCT prevention explicitly or do not offer an explicit opinion. Only one article, a literature review by Papadopulos-Eleopulos et al (1999), seems to outright reject the possibility of using AZT as an antiretroviral drug.…”

“…Unfortunately, Mbeki never properly elaborated what literature he had actually read nor did he specify where found it. Mbeki himself only ever mentioned one article directly and this was the aforementioned literature review by Papadopulos-Eleopulos et al (1999), published in Current Medical Research and Opinion (Robertson, Hartley, & Paton, 2000;Myburgh, 2007Myburgh, , 2009Cherry, 2009). In contrast to the above assessment by the author, Mbeki attributed great significance to the article.…”

“…Instead he appears to have accessed a variety of "critical" websites, among them websites such as virusmyth.com which contain a number of popular, non-peer-reviewed or otherwise unpublished texts disputing, among other things, the safety of antiretroviral drugs (Cherry, 2009). The only peer-reviewed scientific article on virusmyth.com with limited relevance for the use of AZT for MTCT prevention is the aforementioned Papadopulos-Eleopulos et al (1999) review.…”

Paediatric special interest group in medicine Haematometra and haematocolpus in a teenage girl Lies, damned lies and EDIS data: Statistics built on sand Lies, damned lies and EDIS data: Statistics built on sand: Reply Emergency sedation intubation Emergency sedation intubation: Reply Emergency physicians roles in managing HIV seroconversion illness: Take stock or take HAART? Emergency physicians roles in managing HIV seroconversion illness: Take stock or take HAART? Reply

“…Among the many consequences are suicide 26 and the administration of disproven, unproven and toxic 'antiretroviral' medications. [27][28][29][30][31][32][33][34] On the other hand, because emergency physicians are more likely than non-AIDS specialists to be involved with HIV/AIDS cases, especially needlestuck patients, they should insist on a full, urgent and open debate in order to resolve these matters while guarding their patients' wellbeing and their own reputations. seroconversion illness, argues that definitive diagnosis of acute HIV infection and subsequent management of such patients is complex and beset by controversy, and that emergency physicians have no role in this setting.…”