Eighteen months ago, the first in a series of articles on the management of COVID-19 was published in Quadrant. The constant in these articles was that optimal management combined spaced vaccine administration with effective early drug treatment to cover breakthrough infections. This article compares two groups of drugs promoted as effective in the early treatment of COVID-19: recycled anti-viral drugs that target specific replication and re-purposed drugs of biological origin that render target cells hostile to viral infection.
Background: Those who have followed this series and perhaps others, will recognise how a “vaccine narrative” and its ideology, promoted by the pharmaceutical industry, led to the cancellation of non-patented drugs. These re-purposed drugs had an extensive data base supporting prevention and early treatment of COVID-19. Opposition to their use was unprecedented, denying both science and the established practise of the doctor-patient relationship. This opposition threatened use of “off-label” drugs regularly prescribed with benefit by most doctors. Governments also banned the use of these drugs for treatment of COVID-19, threatening and enacting the deregistration of doctors who opposed the narrative and prescribed ivermectin (IVM) or hydroxychloroquine (HCQ) for early treatment of COVID-19 infection. The Therapeutic Goods Administration (TGA), the Australian licensing body, succumbed to pressure by banning use of IVM for treatment of COVID-19, not because it was ineffective but because “it may interfere with vaccine uptake; it may deprive indigenous patients use for scabies; and there may be confusion re appropriate dosage regimen”. This win for Big Pharma was a loss for thousands of Australians who would benefit, including many at risk of developing serious disease.
Even worse, several weeks later Merck, a company that has publicly derided IVM, its own off-patent product, announced as front-page news its new “wonder” drug, molnupiravir. This drug and another, Pfizer’s Paxlovid, were rapidly given TGA’s provisional approval for use in Australia despite limited supporting evidence of efficacy and less on safety. These triumphs for the pharmaceutical industry came on the heels of remdesivir, an antiviral drug given to hospitalised patients, which remains in use despite a distinctly disappointing clinical record and an even less impressive safety profile. Bear in mind these three drugs have strong patents and cost over A$1000 per course. Pfizer’s anticipated annual earnings of US$100 billion, including US$22 billion from Paxlovid and US$32 billion from its mRNA vaccine, Comirnaty, are greater than the annual budget of Pakistan, the world’s fifth-most populous country.
The drugs: Two groups of drugs have been proposed as early treatment for COVID-19. These are the recently available specific anti-viral agents, developed and tested with variable effect in different viral infections. This group includes molnupiravir and Paxlovid which target mechanisms related to viral replication and assemblage. In addition, there are repurposed drugs, including HCQ and IVM, neither of which retain patent protection but are readily obtained and inexpensive. HCQ and IVM, with a long history of efficacy and safety, are derived from biological sources and act on multiple targets within infected cells.
MOLNUPIRAVIR: The molnupiravir story is extraordinary. Heavily promoted by Merck, the mainstream media hailed it as “the wonder drug for COVID”. The Federal government immediately committed to buying 300,000 doses, with the TGA immediately listing molnupiravir on the Pharmaceutical Benefits Scheme (PBS) as of March 1, 2022, for early treatment of mild/moderate COVID-19 in high-risk groups.
Know that molnupiravir is not a new drug. In a slightly modified form it was planned to be trialled, in 2003 for hepatitis C. The trial was cancelled due to concerns that the drug may cause mutations in host DNA, risking cancer or transgenerational pathology. Molnupiravir acts as a mutant nucleotide base, leading to an “error catastrophe” due to accumulated mutations in the viral DNA. It is known in medicine that mutation of a single base is sufficient to cause disease, sickle cell anaemia being one example. The potential for creating viral mutants that could spread through the community and cause mutations in host cell DNA has been demonstrated, although the significance of these findings remains unclear. Confusing clinical data in studies used to register molnupiravir failed to show more rapid reduction in infectious virus. Trial results submitted to the FDA were an interim analysis of half the planned recruitment. The key finding was that serious outcomes (admission to hospital or death) in the treated group were half that of the placebo controls. No concerning adverse events were noted. However, a full analysis of the completed trial found that protection fell to 30 per cent. A separate study of those not included in the interim analysis showed the placebo group saw less admissions to hospital and fewer deaths than in the study’s treated arm. Two failed studies in India with 2,000 subjects were not included in the FDA submission.
Concern regarding safety and efficacy led to the independent Panoramic Study, conducted in the UK. More than 20,000 subjects have been recruited and analysis is keenly awaited. France cancelled its order for molnupiravir and India refused to register the drug because of toxicity concerns. Most countries are awaiting the Panoramic Study’s outcome. Follow this link to the Great Molnupiravir Swindle for references and further comment.
PAXLOVID: Paxlovid shared its listing on the PBS with molnupiravir on March 1, 2022. It has been the drug of choice for prescribing doctors because of concerns in regard to efficacy and safety with molnupiravir. There are strict criteria for Paxlovid use.
One component of Paxlovid, nirmatrelvir, inhibits the viral protease, an enzyme which cuts the string of viral proteins produced by RNA-dependent ribonuclease, into separate functional protein units. A second drug, ritonavir, inhibits cytochrome P450 pathways responsible for inactivation of many drugs, including nirmatrelvir, thus increasing its half-life.
Clinical studies concluded that Paxlovid does reduce serious COVID-19 outcomes, including admission to hospital and deaths. A primary study claimed an 89 per cent reduction in admission to hospital and deaths, with few concerning side effects. However, a second study showed Paxlovid to be less efficient, with a 60 per cent reduction in serious outcomes. Concerns have since appeared.
The first concern was that no relief of sustained symptoms was observed — surprising given apparent protection against more severe outcomes.
Second was that, despite a reduction in viral load, duration of infectivity was less affected. This is a clinical issue, as about 10-20 per cent of treated patients develop recurrence of symptoms and infectivity. President Biden, with rebound infection, provides a recent and well know example. One explanation may be that Paxlovid dampens infection without eliminating the virus, thus buying time for natural immunity to eradicate it. Delayed eradication for any reason predisposes to rebound infection.
Third, Paxlovid appears to be less effective in immunised subjects (who were not included in clinical trials). This may be due to protracted viral excretion in vaccinated individuals. A study in Israel of 110,000 subjects failed to show benefit in those under the age of 65 who had been immunised. In those treated with Palovid who were over 65, both those who had been vaccinated and those without vaccination showed benefit. However the level of benefit was less in the vaccinated group (60% protection compared to 86% in the unvaccinated). In the younger vaccinated subjects there was a trend towards more serious outcomes in those treated with Paxlovid, than in the control group.
Fourth, toxicity concerns remain. Ritonivir is known to be toxic to liver and kidneys from its use in HIV infection. It blocks the P450 pathway in the liver, used to inactivate protease drugs and many other medications. While ritonivir’s value in Paxlovid is to increase duration of the protease activity of nirmatrelvir, the same mechanism causes drug interactions with many drugs sharing the P450 metabolic pathway. The slow washout time for statins, taken by about 60 per cent of the elderly for control of cholesterol levels, make it unsafe to stop taking a statin to enable use of Paxlovid.
Fifth, in a large study testing post-exposure prophylaxis, Paxlovid failed to protect. Despite uncertainties and complexities it is continues to be used extensively in the elderly. The question is whether it has been released prematurely. This link includes references to issues raised with respect to Paxlovid.
HYDROXYCHLOROQUINE (HCQ): Many reading this article will be surprised to see HCQ mentioned as an effective therapeutic agent for COVID-19, for such is the force of opinion against the value of HCQ in early COVID-19 treatment or for prevention, that I doubt anything written here will change opinion. No medication has been subjected to more hostile and vigorous rejection based on narrative rather than science. The spurious methods used by detractors range from a focus on failed outcomes of late treatment (no anti-viral therapy is effective when given late in disease), to a bias in publishing negative trial results. The prestigious medical journal, The Lancet, was forced to withdraw the Surgisphere Study, widely quoted by naysayers as “proving” HCQ was ineffective. When the authors of the study failed to provide details of a suspect database, suspicions of outright fraud abounded.
In common with other products with anti-COVID-19 activity derived from biological sources, HCQ has numerous intracellular sites of activity with the net effect of a reduction in viral replication. Its mechanism, raising pH (or alkalinity) within intracellular vacuoles, affects protein breakdown within lysosomes, antigen processing and assembly of macromolecules (and virus particles) within endosomes.
The complete data set for HCQ includes 349 studies, 460,000 patients and 5,500 authors and is reviewed in detail here.
Highlights of this comprehensive review include importance of early treatment (62 per cent improvement) compared to late treatment (19 per cent improvement). Given the “negative noise” surrounding HCQ treatment, the authors of this meta-analysis applied strict exclusion criteria to exclude controversial studies. In the 33 included studies there was 63 per cent improvement of the main outcome measure over controls. Protection against admission to hospital was 41 per cent and against death 72 per cent in these studies, which included 56,000 subjects.
None whom I meet expressing strong opinion against the use of HCQ for COVID-19 treatment had knowledge of this database and nor were they interested!
IVERMECTIN (IVM): Following the early focus on HCQ, studies appeared supporting the value of IVM for treatment of COVID-19. Many mechanisms of action have been identified. An important one is the blocking of “docking” of the spike protein with its ACE receptor. Additional mechanisms include inhibition of the protease targeted by Paxlovid, blocking nucleocytoplasmic shuttling needed for viral replication and viral inhibition of the host’s innate immune response and inhibition of the host’s inflammatory response.
What may emerge as the main advantage of IVM is its diversification across molecular targets, buffering against the emergence of viral evolutionary escape. The narrow target of the protease inhibitor included in Paxlovid (niratrelvir) predicts emergence of resistant mutations. Mutant escape was found with similar protease inhibitors in HIV, another RNA virus with high mutation rates. The outcome was that protease inhibitors were “rendered obsolete” in HIV treatment (Int. J. Mol. Sci 23(2022)3507).
High level safety of IVM in the dose range used to treat COVID-19 follows observation over many millions of patients treated for other parasitic infections such as river blindness. That the extensive data validates clinical benefit in using IVM in the treatment of COVID-19 can be seen in a real time meta-analysis of 88 studies. Statistic improvements for mortality, ventilation, hospital admission, incidence of infection, profile of disease and viral clearance are documented. Given criticism of some studies with methodological defects a meta-analysis of 31 randomised controlled trials was performed after excluding all studies of concern. Significant outcomes were found for prophylaxis (84 per cent effective); protection following early treatment at 66 per cent; and late treatment 29 per cent. These data came from study of 6,967 patients with 382 authors.
An important and dramatic observation following IVM therapy was the significant reversal of hypoxia due to COVID pneumonia within 24 hours of treatment (Hazan et al: Future Microbiol Jan 2022: 10.2217/fmb-2022-0014). Dr Tess Lawrie, a leading international epidemiologist, described the IVM data base as “in excess of data usually submitted for a regulatory drug approval”.
Increasingly IVM is used in combination with an antibiotic, to minimize inflammation resulting from “virus-bacteria” co-stimulation, and zinc which is toxic to virus. IVM and HCQ act as ionophores to enhance uptake of zinc. The value of adding broad-spectrum antibiotics to anti-COVID-19 therapy was demonstrated in Brazil. In addition to significant reduction in hospitalisation and deaths, it was noted that combining azithromycin with either IVM or HCQ reduced post-COVID symptoms (“Long Covid”) (p<0.0001). This critical observation urgently needs confirmation, as Long Covid has become a major health challenge, little reduced by vaccines (Cadegiani et al in “New Microbes and New Infections” 43(2021)100915).
The data base supporting IVM for safe and effective control of COVID-19 goes beyond the clinical trials discussed above. Public health measures in countries, states and regions across the world — including India, Mexico, regions of Peru and Argentina, Japan, Dominican Republic, and Brazil — have made IVM freely available as uncontrolled studies, with consistent and dramatic reductions in COVID-19 infections, hospitalisations, and deaths within weeks of widespread availability. Professor Philip Morris has compiled an excellent summary of IVM in COVID, with references:
COMMENT: This article draws together for the first time, comparative data of drugs for the early treatment of COVID-19. The two anti-viral drugs, molnupiravir and Paxlovid, are available on the Pharmaceutical Benefits Scheme in Australia for older high-risk patients, while prescribing HCQ or IVM is banned (note is made that IVM for COVID-19, could be prescribed by some physicians in Queensland, until 4/8/22. Perhaps a beginning?).
The impact of the “narrative” on assessment of re-purposed drugs, can be seen with different responses to effective, compared to (apparent) failed, IVM studies. Here is an example from Brazil.
First, a study involving the complete population of the city of Itajai showed a dose-related effect for prophylactic use of IVM (100 per cent less admissions to hospital, P<0.001; 86 per cent less deaths, P<0.006). By contrast, those not using IVM had a sevenfold higher mortality. This high-quality study was not reported in the mainline media. It attracted no comment amongst the “experts” who inform us on all things COVID. How relevant is this study to the current crisis facing Australia and its health care systems — very much so, one would think.
Second is a study published in the prestigious New England Journal of Medicine (NEJM) and known as the Together Trial examined the efficacy of IVM in preventing the same serious outcome measures in patients attending ten public clinics. It was concluded, as stated in the abstract, that IVM treatment was associated with an 11 per cent non-significant protection. A failure for IVM! This news was widely published in the Australian press as the “death-knell for IVM”, reinforced by comments from “the experts”. No such critic could have read the article or understood the data. If they had, they would have noted that more than half of the control group failed to complete the study (possibly due to them not wanting to take a placebo, with IVM readily available in the community). When the study is analysed “per protocol” (that is counting those who completed the trial), protection against admission to hospital was a statistically significant 60 per cent! (This calculation was omitted in the NEJM but done by hundreds of concerned doctors and scientists). Over 50 additional faults are discussed in the http://ivmmeta.com link. The authors refused to provide patient data, and the NEJM has not answered requests for information, including ignoring a letter signed by 100 senior international physicians and scientists. David Scheim (US), who initiated the 100-signatory letter, wrote
If we allow the Together trial to report a negative conclusion as to IVM efficacy against COVID-19 without disclosing any outcomes of key interest or any underlying data, then we have entered a brave new world of scientific research in which pesky generic competition to new patented drugs can be declared ineffective by fiat.
But the damage had been done in the public arena, where it appears only “the narrative” counts. For more of David Scheim on IVM watch the video below
The silence of the usual IVM naysayers over the grossly deficient “Together” study is par for the course. They are vocal in hailing randomised control trials (RCT) as the holy grail of drug acceptance for re-purposed non-patented drugs (without seeming to appreciate how many exist) but are without comment on the way pharmaceutical companies manipulate RCT to attain registration, using strategies such as excluding subjects unlikely to respond (note the Paxlovid RCT included only “un-immunised” subjects who have subsequently been shown to respond poorly, if at all). Failure of the Merck RCT to accurately position molnupiravir led to “conditional marketing” approval by the UK government within a month of Merck’s press release of its interim analysis. The British Medical Journal questioned whether registration was premature, yet not a word from the “usual” outspoken critics of unpatented drugs (BMJ 2022.376:0443). (http://ivmmeta.com ).
Experienced epidemiologists agree on the importance of considering a range of analytic instruments including RCT, meta-analyses, observational trials with propensity score matching, and population studies, while recognising the strengths and weaknesses of each modality. Published “physician experience” has been neglected. It is one of the three planks of Dave Sackett’s ground- breaking idea of Evidence Based Medicine. This experience documented in 32 studies has been summarized in a meta-analysis of observational trials that included 219,000 patients (https://ivmmeta.com): a mean protection of 95 per cent and 93 per cent respectively for hospitalisation and death was calculated, using propensity score matching (that is the use of constructed matched controls to reduce confounding bias).
Several specific negative critiques require comment. The most public of these have been by Popp et al and its recent “update” (for the Cochrane Database), and an article sponsored by the BBC (UK). In the same mould is a remarkable “Letter to Andrew Hill” by Dr Tess Lawrie. In supporting IVM, she questioned his reversal of a positive meta-analysis. Each of these critiques has been critically reviewed, to identify bias, methodological faults, and selective cherry-picking of studies. The reader is referred to the following references for detailed comment:
(i) “The Uses and Abuses of Systematic Reviews: the case of ivermectin in Covid-19“. Fordham et al(10.31219/osf.io/pcqcj) : (Cochrane Report by Popp et al).
(ii) Letter to Andrew Hill – By Tess Lawrie (https://ivmmeta.com)
(iii) BBC article – (https://ivmmeta.com )
CONCLUSION: Molnupiravir is a drug waiting for evidential support. Mutant toxicity as a potential cause of cancer and transgenerational defects, must be excluded. Production of mutant virus in the community has not been excluded. Results from the Panoramic Oxford trial will be critical to the future of molnupiravir.
Paxlovid has value, particularly in those over 65, irrespective of vaccine status. The Israel data showing no benefit in younger subjects needs further study, while rebound infection and safety require clarification. Production of viral mutants into the community is a concerning longer term threat.
Objective assessment of HCQ is too much to expect — an unfortunate outcome of an over-heated narrative with apparently unstoppable momentum. The vigour of the reaction to its use in treating COVID-19 and the bureaucratic and political consequences defies the universal principal of the doctor-patient relationship. This not only denies patients a valuable medicine but also threatens the principles upon which medical practice has evolved.
IVM also has been subject to “narrative lore” in unprecedented fashion. Efficacy in treating COVID-19 is supported by over 30 RCT’s involving 7,000 patients. Valid concern with respect to the quality of some studies has been addressed. Experience in regions and countries making IVM freely available, and numerous observational studies using propensity score matching, add to the evidence base. IVM has advantages over the currently available anti-viral drugs: a broader therapeutic window allows effective use in prophylaxis and later in infection; infectious viral production is shortened; its solid safety record means it is not age restricted; the remarkable reversal of hypoxia; evidence of significant reduction in Long COVID and its multi-loci anti-viral targets, give advantages over current specific anti-viral drugs. And it is cheap and available!
Of particular relevance to the immediate threat within Australia, are the numerous regional studies showing benefit across a community, not possible with any alternate medication or vaccination strategy.
This science-based review of drugs used to treat COVID-19 infection includes links to reference sources. Australians struggling with an unprecedented burden of COVID-19 infection (NSW on July 23 listed 160,000 active cases, 2,200 in hospital and 14 deaths) are being deprived of the cheapest, safest and most effective drugs.
The cheapest, safest, most effective, and science-based way to blunt the anticipated COVID-19 surge would be provision of IVM-based packages to households, those supplied with rapid antigen detection kits and clear instructions. The never-answered question, one that goes to the essence of traditional Western medicine, is that given a number of cheap TGA-accredited re-purposed drugs with extraordinary safety records, each with a substantial body of data supporting efficacy in treating COVID-19, “What is there to lose?”
(Thanks to the numerous doctors and scientists, both national and international, who proof-read this article, making many helpful suggestions and comments. Particular thanks to Christine.)
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 has also written on aspects of the Covid pandemic in the July-August and October issues