Covid-19: Ivermectin’s politicisation is a warning sign for doctors turning to orphan treatments
BMJ 2021; 373 doi: https://doi.org/10.1136/bmj.n747 (Published 01 April 2021) Cite this as: BMJ 2021;373:n747Read our latest coverage of the coronavirus outbreak
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Re: Covid-19: Ivermectin’s politicisation is a warning sign for doctors turning to orphan treatments
Dear Editor,
The gathering enthusiasm for ivermectin in both prophylaxis and treatment exposes some interesting, somewhat understandable biases in both the professional and lay communities. Caution is nonetheless perfectly justified. While I have no strong opinion regarding clinical use - risk/benefit is a matter for the clinician - I am a little concerned about the concept of mass prophylaxis without specific trials evaluating safety against efficacy. It seems rather too good to be true that a neurotoxin effective both topically and orally against a range of animal phyla should also be a completely safe antiviral (and anti inflammatory)! In a world where we are recommending against a vaccine due to possible adverse effects of the order of 1 in several hundred thousand, the admittedly rare neurotoxic effects in hosts may need a closer look [1] .
Typically, the drug is administered for a short course; safety in such a setting is no guarantee when levels remain elevated over the longer term. Additionally, mutations in the MDR1 gene may render the blood-brain barrier 'leaky' in some populations, as is the case for several dog breeds in a veterinary setting [2]. Prolonged widespread use may select for resistant strains of its primary targets. And finally, we have no data on the possibility of an effect on ecosystems from excreted doses or their metabolites.
[1] R E Chandler
Serious Neurological Adverse Events after Ivermectin—Do They Occur beyond the Indication of Onchocerciasis?
The American Journal of Tropical Medicine and Hygiene 2018
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929173/
[2] K L Mealey 1, S A Bentjen, J M Gay, G H Cantor
Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene
2001
https://pubmed.ncbi.nlm.nih.gov/11692082/
Competing interests: No competing interests
Dear Editor
It is disgraceful to refer to a hormone with a 500 million year evolutionary history as an "orphan drug".
"Vitamin" D3 supplementation is now being advised by a cross-party group of parliamentarians in Eire, following discussions with D3 experts.
https://www.rte.ie/documents/news/2021/04/2021-04-07-report-on-addressin...
It appears that politicisation is necessary to inform the public of the most important contribution to health, inlcuding covid-19, that they lack. Unfortunately the Eire politicians need to revise dosage upwards, towards 4000 IU pd, the dose taken by most of the 200+ signatories belonging to the international group the author referred to as the "Vitamin D for All Coalition". D3 has had 500 million years to refine our defences against microbes, vaccines a mere 400 days for C-19. We need both, so a big cheer for the politicians in Dublin.
Competing interests: No competing interests
Re: Covid-19: Ivermectin’s politicisation is a warning sign for doctors turning to orphan treatments
Dear Editor
Concerns about the politicisation of Ivermectin, in the treatment of covid infections, and the disputed ‘orphan’ status of vitamin D are made more topical by a recent decision of the Westminster government to provide free vitamin D to all care home residents in England, for four months only , from February 2021. (1)
The dose is that recommended by NICE, 400iu daily. This is far too little to raise blood levels significantly, to boost immunity to viral infections, as many of your contributors have pointed out.
It is not clear if this move is a political response, albeit an inadequate one, to the case for vitamin D, made by your contributors the past year.
Eight weeks ago the Welsh government were asked if they were taking similar action. They have not replied.
1 https://www.gov.uk/government/publications/vitamin-d-for-vulnerable-grou...
Competing interests: No competing interests
Re: Covid-19: Ivermectin’s politicisation is a warning sign for doctors turning to orphan treatments
Dear Editor
There is no reference in Bibi Aisha-Wadvalla’s article to the British Ivermectin Recommendation Development Panel headed by Dr Tess Lawrie in Bath, and its metaanalysis of the human trials, as well as its response to the EMA assessment of the drug.
Or to its approval under varying conditions for covid by the governments of Belize, Honduras, Colombia, Panama, Czechia, Hungary, Bulgaria, Slovakia, Macedonia, South Africa, and the Indian states of Uttar Pradesh, Bihar, Odisha, Goa, Uttarakhand and Punjab.
Of the more populous states, UP and Bihar have the best per capita figures in India.
There is the study of the nine Peruvian states that adopted it, and there are two studies now showing that African countries who mass use it for parasites are also doing better with covid.
Competing interests: No competing interests
Re: Covid-19: Ivermectin’s politicisation is a warning sign for doctors turning to orphan treatments
Dear Editor,
Ivermectin is not the first, and won’t be the last medication that we prescribe off-label, when we believe, right or wrong, it will be beneficial to our patients. What is unusual, instead, is the worldwide opposition by health agencies to its use in COVID-19, in spite of 35 years of favorable pharmacovigilance records, and the many signals of efficacy (and dare say effectiveness) although not from formally perfect trials – see Bryant et al. preprint https://doi.org/10.31219/osf.io/k37ft .
While science cannot take shortcuts, medical practice has to bet its odds against time, risk of death or lasting disability, and unaffordable or unavailable cures. Today we are fighting a virus that in a mere year has killed almost 3 million humans, and chances are we will have to fight its lifelong sequelae in a much larger population for years to come; and in addition it is rapidly mutating. Given the low risk of adverse events and the yet to ascertain, but generally favorable outcomes of ivermectin prophylaxis and treatment in COVID-19, the most humane and ethical conduct, in my opinion, is to issue a temporary authorization to general practitioners for its use, collecting the relative data, and urgently fund and perform those missing well-designed clinical trials that WHO, EMA and FDA, among others, advocated for.
Competing interests: No competing interests
Dear Editor
I believe Helga Rhein has it right [1]. In my personal experience as a member of the public GPs have hitherto treated Vitamin D deficiency where detected with benefit to health. I do not understand why all this sudden disdain from public health/government. Improving Vitamin D levels would surely be a lot less speculative than the products in which they are so heavily invested.
[1] Helga M Rhein, ‘ It is wrong and misleading to call vitamin D an orphan treatment. Better would be to call it a neglected prophylactic: UK chief medical officers appear to neglect the population’s need for sufficient vitamin D, tolerating widespread deficiency’, 5 April 2021, https://www.bmj.com/content/373/bmj.n747/rr-3
Competing interests: AgeofAutism.com, an on-line daily journal, concerns itself with the potential environmental sources for the proliferation of autism, neurological impairment, immune dysfunction and chronic disease. I receive no payment as UK Editor. I also moderate comments for the on-line journal ‘The Defender’ for which I am paid. I am also a member of the UK Medical Freedom Alliance
Dear Editor
Vitamin D is a nutrient, functioning as powerful immune modulator in the innate and adaptive immune system (1,2), as well as facilitating calcium absorption. Suboptimal supply (serum 25(OH)D below 75 nmol/l) predisposes people to become infected with SARS-CoV-2 as Kaufman et al. (3) clearly showed in a large US study with 191,779 participants. Many other studies have confirmed this, including a meta-analysis of 39 studies (4) and a UK BioBank study (5) who suggested “habitual use of vitamin D supplements is related to a lower risk of COVID-19 infection”.
On the other hand, after decades of similar reports, Sutherland et al (6) recently confirmed amongst 440,581 UK adults widespread vitamin D deficiency, worst in people with melanin-rich skin types (BAME) and those living in socio-economic deprivation.
Advocating sufficient vitamin D intake is therefore an easy to implement preventative measure, urgently needed in the UK, where deficiency is widespread. It will provide the population with knowledge how best to keep one’s own immune health well and this should have become an urgent matter during a pandemic. This was called for in the open letter, signed by 220 scientists, doctors and leading authorities (not 110, as Wadvalla reported) (7). A number of other groups of physicians have given similar statements in the past few months, from Italy, France, UK and Ireland (8).
Unfortunately up until now those calls have largely been ignored, and even ridiculed for instance by the author calling it “orphan treatment”.
In contrast, it appears to me incomprehensible that NICE dismisses the existing evidence of the UK population’s high prevalence of vitamin D deficiency, and that public health physicians are not advising widespread vitamin D testing and supplementation.
(PS haven’t we been there before with the decades-long denial of a link between tobacco and lung cancer?)
1. Bishop E, Ismailova A, Dimeloe S, Hewison M, White J. (2020). Vitamin D and Immune Regulation: Antibacterial, Antiviral, Anti‐Inflammatory. JBMR Plus. https://asbmr.onlinelibrary.wiley.com/doi/full/10.1002/jbm4.10405
2. Charoenngam N., Holick MF. Immunologic Effects of Vitamin D on Human Health and Disease. Nutrients 2020, 12, 2097; doi:10.3390/nu12072097
3. Kaufman HW, Niles JK, Kroll MH, et al. (2020) SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels. PLoS ONE 15(9): e0239252. https://doi.org/10.1371/journal.pone.0239252
4. Kazemi A, Mohammadi V, Aghababaee SK, et al, Association of Vitamin D Status with SARS-CoV-2 Infection or COVID-19 Severity: A Systematic Review and Meta-analysis, Advances in Nutrition, 2021;, nmab012, https://doi.org/10.1093/advances/nmab012 https://academic.oup.com/advances/advance-article/doi/10.1093/advances/n...
5. Ma H, Zhou T, Heianza Y, Qi L. Habitual use of vitamin D supplements and risk of coronavirus disease 2019 (COVID-19) infection: a prospective study in UK Biobank. Am J Clin Nutr. 2021 Jan 29:nqaa381. doi: 10.1093/ajcn/nqaa381. https://pubmed.ncbi.nlm.nih.gov/33515005/
6. Sutherland J.P., Zhou A., Leach M.J., Hypponen E. Differences and determinants of vitamin D deficiency among UK biobank participants: A cross-ethnic and socioeconomic study (2020) Clinical Nutrition, https://www.clinicalnutritionjournal.com/article/S0261-5614(20)30639-7/fulltext
7. Over 200 Scientists & Doctors Call For Increased Vitamin D Use To Combat COVID-19. VitaminDforAll
8. Roll Call of Credible Experts Advocating Vitamin D for COVID-19. VitaminDforAll
Competing interests: No competing interests
Re: Covid-19: Ivermectin’s politicisation is a warning sign for doctors turning to orphan treatments
Dear Editor
There are more than a dozen RCTs on Ivermectin, almost all of them positive, but the author chose to mention the only two seemingly negative, but very poorly conceived trials*, one of them a preprint. Could the author explain his peculiar choice? To an informed reader, this appears to be deceptive. Could the editor of this letter explain why they did not insist on a balanced review of the existing evidence?
Thanks, Evan Larson PhD
*The Colombian trial had to change endpoints during the study as disease remained so mild, later it turned out the control group also took ivermectin. The Mexican trial was a risible late-stage single-dose regimen, designed to fail.
Competing interests: No competing interests
Re: Covid-19: Ivermectin’s politicisation is a warning sign for doctors turning to orphan treatments
Dear Editor
Clinical medicine takes place in hospitals, not in offices. Clinical doctors need to make decisions that might lead to survival rather than to the deaths of their patients. Sometimes the luxury of a perfectly structured, performed, and analysed controlled trial might not be available, and this is especially likely to be the case during a pandemic with a novel virus. More than 4 million Covid-19 cases in the UK and more than 125,000 deaths does give a sense of urgency, especially when hospitals and their ICUs have been overwhelmed.
The treatments that we have been using are obviously inadequate. Despite the hard and dedicated work of our health professionals, 125,000 deaths indicate that an additional form of treatment has been required.
We have known since before the pandemic that vitamin D deficiency is common within the UK, and especially among the elderly, the obese, and those with ethnically-determined dark skins. It became obvious very early that death from Covid-19 was associated with and predicted by serious vitamin D deficiency. It should not require an RCT to enable doctors to undertake their clinical responsibility to detect and correct a vitamin or hormone deficiency, but this is what NICE demanded.
NICE has now published a disclaimer that it only provides advice and that the responsibility of the doctors to their patients might over-ride this advice. NICE is passing the legal responsibility to doctors. Watch this space.
For doctors to prescribe vitamin D, especially in its rapidly acting activated form 25(OH)D, to patients very ill with Covid-19 pneumonia cannot be criticised. With a treatment that is very cheap and that would have potential benefit and no risk, the greatest utility would be to accept Pascal's wager and use vitamin D.
The worst utility would be that of NICE and the government to withhold vitamin D. There would be no benefit from doing so, and with the weight of evidence available the effect would be likely to result in a great many avoidable deaths. The same applies to Ivermectin.
I would hope that doctors will do their best to prevent their critically ill patients from dying by using all treatments with potential benefit, as long as they do not put these patients at undue risk.
And what about patient participation? How many of the 125,000 Covid-19 dead would have refused vitamin D or ivermectin? Were they informed of the potential benefits that might have made the difference between life and death? This is the real world of a hospital, not the offices of NICE or the WHO.
Competing interests: No competing interests
Re: Covid-19: Ivermectin’s politicisation is a warning sign for doctors turning to orphan treatments
Dear Editor
Zoonotic diseases are on the rise due to exponential rise in the global population causing man to encroach on new ecological habitats in search of space, food, and resources as well as improved opportunities for rampant wildlife trade causing inter-species virus jumps. The fact that the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) virus has been thought to have originated from wildlife and may have “jumped” into humans, not only highlights future risks from animal-borne diseases but also provides an important clue to its resolution.
In unusual times likes these, when the world is battling with a virus, drug repurposing can be possible solution to avoid needless deaths. It is concerning that few drugs (Remdesivir, tocilizumab) were given emergency approval for use against COVID-19 without adequate trials on their safety profiles, Ivermectin, on the other hand has been withheld in spite of 35 years of favorable pharmacovigilance records, and many well designed Randomized controlled trials on its efficacy. [1]
Secondly, recent studies have shown Vitamin D to play a role in COVID-19 and to call it an "orphan treatment" would be incorrect. [2]
The hospitals are overwhelmed and the doctors are overworked. They depend on health authorities to carry out meta-analyses and come up with guidelines that need to be followed. In the present circumstances, what seems unusual is the focussed intentional systematic suppression, forbidding and censoring of a cheap, widely available, life-saving therapeutic, Ivermectin, in the middle of a pandemic.
There have been various groups that are creating awareness around Ivermectin for COVID-19, including the frontline covid-19 critical care alliance [3] created by highly published critical care specialists from major academic medical centers and the British Ivermectin Recommendation Development (BIRD) Panel headed by Dr Tess Lawrie. The BIRD is an evidence based consultancy collaboration of 75 researchers, specialists, patient representatives [4] that follow the W.H.O “evidence to decision framework” to conduct metanalyses and systematic reviews of Randomised Controlled Trials (RCT) of Ivermectin on COVID-19. As per this group, Ivermectin is recommended strongly for all phases of COVID-19.
A Review Article: Global trends in clinical studies of ivermectin in COVID-19 published in March 2021 in The Japanese Jpurnal of Antibiotics has been co-authored by Dr. Satoshi Ōmura. In the article they have described the benefits of ivermectin in COVID-19 as: " Ivermectin may even turn out to be comparable to the benefits achieved from the discovery of penicillin—said to be one of the greatest discoveries of the twentieth century. Here, one more use for ivermectin, which has been described as “miracle” or “wonder” drug, is being added. History has demonstrated that the existence of such natural product-derived compounds with such diverse effects is exceedingly rare. " [5]
Satoshi Ōmura is known for the discovery and development of various pharmaceuticals originally occurring in microorganisms. He was awarded the 2015 Nobel Prize in Physiology or Medicine jointly with William C. Campbell and Tu Youyou for discoveries concerning a novel therapy against infections caused by roundworm parasites. More precisely, his research group isolated a strain of Streptomyces avermitilis that produce the anti-parasitical compound avermectin. This lead to the discovery of ivermectin. [6]
In the end, we need to also realise that Ivermectin is not a replacement to social distancing, masks and personal protection equipment. To achieve post-pandemic phase globally, large scale vaccination programmes have already begun in full swing all over the world. The vaccines are developed keeping the S proteins in mind, i.e they are virus-directed, and some "vaccine escape strains " have been a cause of worry. [7] Ivermectin, on the other hand, targets the virus as well as the host and could work on these strains as well. [8]
While several countries and some sections of the population need to wait for their turn to get vaccinated, Ivermectin could act as a safety bridge, in saving human lives, while we get there.
References:
1. https://ivmmeta.com/
2. Cutolo M, Paolino S, Smith VEvidences for a protective role of vitamin D in COVID-19RMD Open 2020;6:e001454. doi: 10.1136/rmdopen-2020-001454
3. www.flccc.net
4. https://www.francesoir.fr/sites/francesoir/files/media-icons/bird-procee...
5. http://jja-contents.wdc-jp.com/pdf/JJA74/74-1-open/74-1_44-95.pdf
6. "Satoshi Omura PhD". Retrieved 5 October 2015. https://en.wikipedia.org/wiki/Satoshi_%C5%8Cmura#cite_note-Gairdner-1
7. Garcia-Beltran et al., Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity, Cell (2021), https://doi.org/10.1016/j.cell.2021.03.013
8. Abhigyan Choudhury, Nabarun C Das, Ritwik Patra, Manojit Bhattacharya, Pratik Ghosh, Bidhan C Patra, and Suprabhat Mukherjee. Exploring the binding efficacy of ivermectin against the key proteins of SARS-CoV-2 pathogenesis: an in silico approach. Future Virology 0 0:0
Competing interests: No competing interests