The discipline of medicine has changed. Its traditional cohesion and leadership have fractured into multiple disconnected specialty groups, allowing powerful commercial and political forces to increase control over both structure and function of medical practice. The COVID era burst through boundaries long taken for granted.
A major driver of opinion about COVID has been the World Health Organisation (WHO). Its Health Emergencies Programme in its proposed form, designed to strengthen disease-specific systems and capacities, including for vaccines, pharmaceuticals and other public health interventions, may be a serious threat to independent local health systems. Given it is an unelected body responsive to powerful lobbies, and a with a performance short of wide approval in its overarching role in the recent pandemic, there is reason to tread carefully.
I have practised as a physician in Australia for half a century. I recall when we knew (and revered) the name of the President of the Royal Australasian College of Physicians, while living in fear of their Chief Examiner as we sought qualification! They were great men and women and were the exemplars for ethical practice. Today they only occasionally question imperfect narratives or challenge the ethics of prevailing medical practice, risking being part of the problem rather than a solution.
Recently I was invited to speak at a symposium “Medicine at the Crossroads in the COVID Era”. I sought a topic that illustrates contemporary challenges to Western medicine. Few topics could be more relevant than threats to the doctor-patient relationship, and to science-based medicine seen in the COVID-19 pandemic. So I chose “The curious tale of hydroxychloroquine (HCQ)” as a metaphor for the distortion COVID imposed on clinical practise, driven by misinformation aimed at supporting a flawed narrative originating from the highest sources of medical influence.
I am a clinical immunologist. I have a special interest in chronic inflammatory disease and the immunology of the airway. Among the valuable drugs in my clinical practice was HCQ, for which I wrote approximately 20,000 prescriptions without any observed major side effect. It proved to be a safe and effective medication that blocked antigen-promoting pathogenic immune responses in patients with autoimmune or hypersensitivity diseases.
COVID made HCQ a household name. No medication attracted more brutal and remorseless assault. It was subjected to derision and negativity by medical professionals and the public alike. HCQ presents the dilemma that embodies the extremes of the narrative and science of COVID. In this context and over the last three years, popular narrative and science have gone down quite different paths.
First, a little about hydroxychloroquine. At the molecular level, the drug retains the quinoline ring structure of its parent, quinine, an alkaloid secondary metabolite derived from bark of the cinchona tree, native to Peru. Known as an allelochemical, meaning that it interacts with other organisms, quinine is a highly evolved anti-oxidant and free radical scavenger component of the defence network of host plants. Quinine shares with other allelochemicals multiple intracellular targets. Advantages for allelochemicals used as therapeutics in treating disease include modification of the cell response to infection in order to dampen the hijacking of its metabolic machinery to produce pathogen.
Quinine differs from synthetic antivirals that block specific biochemical steps essential for viral replication. Advantages that come with multiple cell targets include resilience to mutant escape, protection against mutated variants resistant to both natural and vaccine-induced immunity, long biological half-lives, and activity over a wider disease cycle, with value in both prevention and therapy. Quinine and its derivatives have a long track record in treating infectious disease, most notably malaria. Chloroquine was effective in vitro against SARS-CoV-1. So it was no surprise that Chinese scientists included chloroquine in a panel of repurposed drugs testing for anti-Covid activity within weeks of the pandemic being announced. In vitro anti-viral activity in micromolar concentrations was confirmed in several centres.
Numerous small clinical studies appeared through the first half of 2020, supporting drug benefit. Two studies were influential, shaping the immediate future for HCQ, but in unintended ways. First came reports from the infectious disease group in Marseille, led by the controversial Professor Didier Raoult. A successful trial including 24 patients, published in mid-March, that combined the antibiotic azithromycin with HCQ gained attention with Sanofi, a French multinational pharmaceutical and healthcare company, offering large supplies, and President Macron consulting Raoult.
The second was a family doctor Vlad Zelenko, in 2020 in upstate New York who noted in an open letter to President Trump a dramatic change in outcomes from COVID-19 infection when early disease was treated with HCQ, azithromycin and zinc. His data were later published as a case series of 2,200 patients, claiming 95 per cent protection against both admission to hospital and death. Trump’s enthusiasm for Zelenko’s approach led to worldwide publicity and controversy.
Blowback against HCQ was immediate and without precedent.
In France, Raoult was an easy target. By November 2020 he faced a disciplinary hearing for “spreading false information” and eventually lost his job. The mainstream press aimed to quell “disinformation”. It had meshed gears to continue an attack on Raoult which pre-dated COVID and centred on studies in tuberculosis. Opposition became focussed around complaints made by a Dr Bik, identifying procedural problems, ethics irregularities and methodology variations (but never fraudulent HCQ claims). Legal proceedings brought by Raoult made him a public talking point. The science of HCQ was lost in the fray.
The ongoing furore ensured the rejection of HCQ as a COVID therapy in France. In the US, Zelenko suffered a similar fate – incomplete patient data combined with the curse of support from President Trump generated widespread condemnation. Comments such as “where a jumble of facts, falsehoods, and rumours—-collides with our fragile information ecosystem” characterised the public and medical response.
Several events in late 2020 combined to stifle any chance of HCQ survival. Three large randomised controlled trials (RCT) failed to support HCQ, causing the WHO to distance itself from the drug. In its place the narrative became “support vaccines at any cost”. Trials of a second repurposed drug with anti-Covid activity and the imminent launch of the genetic vaccines further shaped the narrative.
The Surgisphere Trial was published in The Lancet (22/5/20), the Solidarity Trial, sponsored by the WHO, in the New England Journal of Medicine (NEJM:15/10/20), and the Recovery Trial involving a collaborative UK group (5/6/20) in the NEJM. Each study included thousands of hospitalised patients with late and serious disease, with high mortality of 10-25% in both study and control arms. The Surgisphere Study was withdrawn by The Lancet, with claims of fraud because of data manipulation, while numerous inconsistencies were noted in the other studies. High doses used in sick patients were linked to cardiac arrhythmias. The results of these studies stopped further research. The WHO withdrew support for HCQ, and the Cochrane Review (considered an arbiter of “best practice”) advised against further studies.
The demonstration from Monash University in June of 2020 that ivermectin had anti-viral activity in vitro followed by positive clinical studies, immediately shifted disinformation claims from HCQ to another repurposed drug that threatened the imminent release of the COVID vaccines. Results from phase 3 trials for a series of genetic vaccines appeared in late 2020 amongst a fanfare of support, with political, media and medical commitment combining to suppress any treatment option that may hinder vaccine uptake.
FAST forward to 2023. Six discoveries have changed the playing field to give a better understanding of HCQ in management of Covid-19.
The first is identification of a target for HCQ early in viral replication. It was known that HCQ increased pH within lysosomes to reduce lysosomal protein degradation and early autophagy, key events in later aspects of viral replication. However, recent proteomic studies using cloned and tagged viral proteins identified specific protein-protein interaction on cell surfaces that required a Sigma1R molecule as a chaperone to enable viral entry across the cell membrane. Many drugs were assessed for their capacity to block the action of Sigma1R. HCQ was the most potent of this group, signalling its potential for effective early treatment.
The second insight came from an analysis of clinical studies concentrating on high-risk subjects with early disease. Despite clear evidence from early 2020 that HCQ had maximum benefit early in disease (as was the case with most anti-viral therapies) and in high-risk patients, detractors of HCQ continued to include hospitalised patients with advanced disease in meta-analyses. It was these inappropriate assessments that influenced official advice.
Professor Harvey Risch, in an evidence-brief of June 2021, included a meta-analysis of nine controlled outpatient studies in high-risk subjects. Every study showed protection with the meta-analyses revealing highly significant protection against hospitalisation (at 44%, and death at 75%). Regional studies in India and Brazil found a close temporal relationship between dosing and a reduction in mortality.
The third insight came from a concern over conflict of interest (COI) created by grants and payments from pharmaceutical companies to investigators. Where authors had no COI, success for HCQ treatment was 86 per cent, while in those with a COI, only 5% had positive outcomes.
Fourth, was a retrospective analysis of the experience of the Marseille group, previously directed by Professor Raoul. Data on 30,400 subjects treated to the end of 2021 were included. Sensitivity to earlier criticism about accuracy and objectivity led to the study including an external judicial officer in the study. Amongst this treated group, subjects treated with HCQ had a mortality of 0.1%. When those treated with HCQ were compared with those not treated with HCQ, the HCQ-treated subjects had a significant advantage with respect to mortality (70% protection in outpatients, and 45% in in-patients), providing strong support for the inclusion of HCQ in early therapeutic regimens.
Fifth, was the registration of the specific antiviral drugs molnupiravir and Paxlovid based on scanty and controversial data. Molnupiravir is a powerful mutagen with untested toxicity in humans and little evidence of clinical value. Paxlovid reduces both admission to hospital and mortality, but to a lesser extent than does HCQ. It has age restrictions, drug incompatibilities and a high relapse rate.
Accusation of undue influence over regulatory assessment of both drugs despite concerns, and costs in excess of $1000 per course, may have contributed to both HCQ and IVM being recently released by the Australian Therapeutic Goods Administration for off-label use. Just 12 months ago, a doctor in Queensland could be jailed for prescribing HCQ, while others across Australia faced being deregistered. The data have not changed.
A sixth reason was concern that the vaccine narrative, which drove the suppression of repurposed drugs, had become tarnished with repeated boosters failing to protect – even promoting infection – amidst growing alarm over severe adverse events.
THE curious tale of HCQ is a story of tension between a narrative to protect pharmaceutical interests, and science. It should never have happened because long established clinical practice involves informed consent and decisions based on what may work within the doctor-patient relationship. This includes judicious use of off-label drugs of known safety and mechanism of action.
As a clinical immunologist whose patients often have rare diseases, and are all different, I need to individualise the therapy I prescribe. In the COVID era HCQ came to symbolise a change in the order of medical business — of denying patients best-practice medicine and ridiculing individuals and institutions who promoted it.
The WHO has moved a long way from its founding principles in 1948 to keep the world safe by connecting nations, partners and people to promote health. COVID laid bare an agenda to manipulate world-best practice and centralise its control. Suppressing HCQ was a rehearsal. By controlling major clinical trials and using their influence on regulatory bodies, with supportive propaganda, the WHO and its partners shifted decision-making from grass-roots medicine to international forces driven by power and financial reward.
The WHO is a complex organisation, subject to many political and economic influences. It is vulnerable to manipulation because of chronic underfunding and the crossfire of conflicting national agendas. Its support for expensive, potentially dangerous, and variably effective patented antiviral drugs (Remdesivir, molnupiravir and Paxlovid), alongside its negativity with respect to safe, cheap and effective repurposed drugs such as HCQ and ivermectin, may, regrettably, reflect the influence of massive pharmaceutical companies and their host nations on its fragile agenda.
Things started to go wrong in mid-2020 with the Solidarity Study mentioned above recruiting more than 3,550 hospitalised patients with advanced Covid-19 in 35 countries and 400 hospitals. They were unlikely to respond to any therapy. Unless initiated within 24-48 hours anti-viral treatment is rarely beneficial. On the basis of results from this study, WHO posted on December 31, 2020, a release recommending against HCQ as a dangerous and ineffective drug likely to cause ventricular arrhythmias. That posting remains, supported by “30 trials with more than 10,000 patients”. Again, all were in late-stage infection and, as usual, evidence that HCQ works well in early disease was pointedly ignored.
A review of all studies provides perspective. This web site maintains an updated and annotated compendium of meta-analyses, including every study on every drug tested against COVID. Current data on early treatmentwith HCQ gives 62% protection in 36 studies with 56,000 patients. Mortality following early treatment was 72% less in the treated group, according to a meta-analysis including 15 studies and 52,000 patients. This data source includes a review of 39 published Physician Case Series of early treatment in 237,000 subjects. The mean protection against hospitalisation and mortality, was 94%. While these real-life data sets are subject to bias, include different drug combinations and lack patient details, they are consistent with more formal studies.
This essay has followed the science, arguing that HCQ has a pivotal role in early treatment of high-risk individuals with COVID-19 infection. The argument has had to battle alternative stories, espoused by much of the mainline press, that vaccines and expensive antiviral drugs are the exclusive key to controlling Covid.
The handling of HCQ in COVID has two major elements. First, given that HCQ was an approved pharmaceutical whose safety profile and mechanism of action were well known, it could be argued that the physician operating with informed consent within the doctor-patient relationship should be free to determine whether the off-label use of HCQ would benefit that patient.
Second, the fate of HCQ is a story about switching decision-making in medicine around a core of experienced clinicians familiar with local needs, to powerful global political and commercial interests.
The “Curious Tale of HCQ in the COVID Era” raises questions about how best to make clinical decisions for our patients. Traditional Australian confidence in the doctor-patient relationship, and science, have served us well. We should be careful to defend and strengthen them. The WHO has an important role in monitoring disease, providing advice and coordinating programmes that otherwise are beyond local resources. However, these essential activities must not conflict with sovereign authorities in domains equipped with quality health services based on local knowledge, strong science infrastructure and a tradition of medical practise based on personal responsibility.
(I thank Professor Stephen Leeder AO for his editorial skills)
Robert Clancy is Emeritus Professor of Pathology at the University of Newcastle Medical School. He is a member of the Australian Academy of Science’s Covid-19 Expert Database. He also wrote on aspects of the Covid pandemic in Quadrant’s July-August and October issues