Hydroxychloroquine – Is it safe or not?
Quinine was isolated from the Chinchona Officialis tree bark in Peru. It has been used in the past for treatment of malaria. In 1825, a British Army officer in India discovered that the bitter medication was more palatable if mixed with gin and so, the gin and tonic was born. Now, this article has nothing to do with quinine but it seemed like a less dry lead–in to discuss the track record of hydroxychloroquine safety. We shan’t discuss whether or not to use it for COVID but just the fact that it is almost as old as Methusalah. So, let’s mix a G and T with a wedge of lime and read on…
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Spoiler alert
This article addresses a medical and political hot potato, namely studies on the safety of hydroxychloroquine (HCQ). It does not presume to comment on its efficacy as an antiviral. Reasons for topic selection are threefold: members have asked about the issue, it remains very germane, and it piqued my own interest after having come across some medical literature. Our club is blessed with a smart membership that can think independently and this is offered with respect for your consideration. As an aside, this is not my area of medicine but I have been fortunate to have written a number of medical articles and book chapters to the literature and know my way around PubMed and literature searches.
Your Fleet Sturgeon’s short answers based on available literature:
1. Is hydroxychloroquine safe? Short answer: yes, based upon years of experience and recommendations/reviews by the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) 1,2 The WHO has it on its list of essential medicines as well. 3 2. Some COVID studies have shown toxicity of HCQ; were these studies well–done? It turns out that some of these appear to have been designed to show side effects of hydroxychloroquine. 4,5 3. Cardiac concerns (discussed below) are the main issue and patients should avoid higher doses used in some studies.
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Origins of chloroquine (CQ) and hydroxychloroquine (HCQ)
The bitter bark from a high altitude tree from S outh American was known to have curative qualities back in the 1600s. French chemists identified quinine and its use for periodic fever diseases. 6 Bayer Dye Works, Germany identified chloroquine (CQ) in 1934. The WHO was established to deal with malaria. It selected chloroquine and dichlorodiphenyltrichloroethane (DDT) as their program to eradicate the disease. 6 The latter had the disastrous wildlife effect of thinning bird eggshells and its use ceased. Hydroxychloroquine (HCQ) was identified in 1946 and found to have 40% less toxicity than chloroquine. 7
Past findings on safety of CQ and HCQ
Fortunately, these medications have a long history of use with much data on their safety profile. HCQ was over–the–counter in France until a decree in 2020. 8 The WHO commissioned a review of safety and toxicity of CQ after its first thirty years of use. 1 Their report found: “With the doses recommended for malaria suppression or treatment, side effects are rare, and, when they do occur, they are usually slight. They generally consist of gastrointestinal disturbances (nausea, vomiting, abdominal pain, anorexia) dizziness, headache, and occasionally pruritus (itching). Though unpleasant, these symptoms tend to be mild, of short duration, and without adverse consequences. Their incidence can be reduced to a very low level by avoiding excessive doses and by not taking chloroquine on an empty stomach but always with some food or after a meal.” As with any medication, the greatest concern lies in administration during pregnancy. The paper went on to comment:
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“Taking into account the very wide use of chloroquine as an antimalarial for some 30 years, it can reasonably be assumed that any increased incidence of congenital malformation following the use of chloroquine for treatment or suppression of malaria would certainly have been noticed, and sooner or later would have been reported.” Other sources similarly indicate the safety of CQ and HCQ during pregnancy. 9 The manufacturer-listed contraindications for its use are allergy to similar medications, existing retinal disease, and pregnancy. 10,11 In contrast, some studies have shown improved outcome in pregnant women with systemic lupus erythematosus (SLE) with the suggestion that HCQ be continued during gestation. 11 Caution should be used with known liver and renal disease, with oral medications that lower blood sugar, and some cardiac medicine. 9 The current CDC website advice on travelling to malaria – endemic regions agrees with the above suggested safety profile and states: 2 “Hydroxychloroquine can be prescribed to adults and children of all ages. It can also be safely taken by pregnant women and nursing mothers.”
With regard to side effects, the site reports:
“Hydroxychloroquine is a relatively well tolerated medicine. The most common adverse reactions reported are stomach pain, nausea, vomiting, and headache. These side effects can often be lessened by taking hydroxychloroquine with food. Hydroxychloroquine may also cause itching in some people.”
Standard dosage and side effects for HCQ
Drugs.com is a common online reference for medications. 12 It lists the common use indications as malaria prophylaxis (prevention), malaria treatment, rheumatoid arthritis, and systemic lupus erythematosus. Recommended doses are:
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• Malaria prophylaxis: 400 mg weekly • Malaria treatment per CDC: 800 mg initially and then 400 mg at 6, 24, and 48 hours thereafter for a total dose of 2,000 mg • Lupus: 200 mg - 400 mg daily • Rheumatoid arthritis: 400 mg – 600 mg daily While staying out of the debate regarding efficacy against COVID-19, a brief mention of some protocol doses suggested by hydroxychloroquine advocates seems worthwhile. These are both intended for use early on as outpatients: 13,14,15 • Vladimir Zelenko protocol: 200 mg HCQ twice daily for 5 – 7 days • America’s Front Line Doctors: Zelenko protocol • Front Line COVID Critical Care Alliance I-MASK+ protocol: 400 mg HCQ on day 1, then 200 mg twice daily for the subsequent two days
What serious side – effects occur with hydroxychloroquine?
The above paragraphs describe common side effects. Retina damage can occur with long–term use, mainly above the recommended doses. The main concern relates to potentially lethal heart rhythms: ventricular tachycardia and torsades de pointes. 16 The cardiac electrical activity of a normal heartbeat consists of several parts labelled P through U as below. The upper chambers of the heart (atrium) contract first and then, after a delay to allow blood to flow into the lower chambers, the ventricles contract. The P wave is associated with the electrical activity of the atrium and the T wave with the ventricle. The concern relates to the distance between the Q and T waves – i.e. the QT interval and when it is elongated or, prolonged (red arrow, below left). A “vast” number of medications can prolong the QT interval, including hydroxychloroquine, azithromycin, other antibiotics, psychiatric medications, and others. 17 This can disrupt the normal rhythm and cause the ventricle to rapidly and repeatedly contract with very high heart
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rates and poor pumping of blood (ventricular tachycardia). The other dysrhythmia is torsades de pointes , from the French , to twist around a point as the pattern appears to do. This results in cardiac arrest.
Normal ECG
Tachycardia
Prolonged Q T interval degenerating into torsades de pointes
So what about recent trials that show HCQ to be unsafe?
Two main problems arose with the HCQ safety trials: falsification of data (and retraction by the publishing journal a month later) and excessively high trial dosages. Anthony Fauci, the Bill and Melinda Gates Foundation (BMGF), and the WHO funded around 20 HCQ studies using unusually high doses. The Alliance for Human Research Protection identified several of these in a June 2020 report. 18 Mehra et al published the 2020 Lancet Surgisphere report on over 96,000 patients that demonstrated 25% excess mortality. This was the study that halted HCQ studies underway at that time including those done by the WHO. 19,20 However, Lancet
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retracted the article a month later due to fraudulent data. Three of these same authors published another COVID article in the prestigious New England Journal of Medicine the same month which was similarly retracted. Interestingly, NEJM has blocked the link to that article. 21 The FDA had approved an emergency use authorization (EUA) for hydroxychloroquine and chloroquine on March 28, 2020 but revoked it in June after publication of the Lancet article. 22 With regard to dosage safety, one study in Brazil treated COVID–19 compared high dose versus low dose HCQ with either 1200 mg of chloroquine daily for 10 days (12 grams total) versus a mix of chloroquine and placebo for a total of 2.7 grams. Excess lethality in the high – dose group caused cessation of that part of the study and prompted recommendation to use lower doses. 23 On e large review reported increased mortality for patients receiving hydroxychloroquine (7.7%) versus those not receiving it (7.1%) in 26 studies. This increase, although statistically significant, was obviously pretty minimal. 24 No statistically significant difference was noted with chloroquine (which, curiously, has the 40% higher toxicity). They noted that most (67%) of these patients were enrolled in the large RECOVERY and WHO SOLIDARITY trials. 25,26 Oddly, the raw data on the 10,012 patients calculate to 14% mortality for HCQ and 17% not receiving the medication. 23 The Cochrane Collaboration publishes very well – respected, authoritative reports on many medical topics. Their 2021 review of studies involving a total of 8,569 patients reported that that HCQ, “clearly did not affect how many people died . ” 27 The RECOVERY trial enrolled 4,716 patients. 25 1,561 patients received 2 grams of hydroxychloroquine within the first 24 hours and then 800 mg daily for the next 9 days. A non–statistically difference in death within 28 days of 27% HCQ and 25% for controls (no HCQ). 62.9% of controls and 59.6% of HCQ patients were discharged alive within 28 days. Mechanical ventilation or death was noted in 30.7% HCQ and 26.9% control. The
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latter two sets of data show a negligible difference. No difference in major cardiac arrhythmia was noted for hydroxychloroquine. The WHO S OLIDARITY trial involved 405 hospitals with 954 patients receiving hydroxychloroquine and 906 controls who did not. 26 Patients receiving HCQ were dosed at 2,000 mg over the first 24 hours, then 400 mg twice daily for 10 days. This failed to demonstrate increased mortality from hydroxychloroquine. However, on July 4, 2020 the WHO announced cessation of the hydroxychloroquine portion of the study. They noted, “associated safety signals in the clinical laboratory findings,” but also that those interim results, “do not provide solid evidence of mortality.” This cessation would not affect used of HCQ in non–hospitalized patients. It is worth noting the SOLIDARITY and RECOVER trial both used large first–day doses without noting adverse cardiac effects. A PubMed medical literature search yielded a number of large studies using hydroxychloroquine with or without azithromycin. 28-31 These showed some minor side effects such as gastrointestinal distress or headache. Some did show QT prolongation but no cardiac dysrhythmias. Summary Hydroxychloroquine has been around a long time and felt safe enough by the WHO to give to everyone, including children and pregnant or breast-feeding women. Available studies show patients experiencing minor side effects. Although QT prolongation may occur, there has not been a concurrent issue with arrhythmias and death. And, for some reason, the fabricated (and promptly retracted) 2020 Lancet Surgisphere article was the basis for cancellation of ongoing HCQ studies.
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References
1. Weniger, H & World Health Organization. (1979). Review of side effects and toxicity of chloroquine / World Health Organization. https://apps.who.int/iris/handle/10665/65773; WHO_MAL_79.906.pdf 2. Centers for Disease Control and Prevention, Medicines for the Prevention of Malaria While Traveling Hydroxychloroquine (Plaquenil), https://www.cdc.gov/malaria/resources/pdf/fsp/drugs/hydroxychloroquine.pdf 3. WHO Model Lists of Essential Medicines. https://www.who.int/groups/expert- committee-on-selection-and-use-of-essential-medicines/essential-medicines- lists... 4. Risch H. Early outpatient treatment of symptomatic, high – risk COVID – 19 patients that should be ramped up immediately as key to the pandemic crisis. American Journal of Epidemiology 2020; 189: 1218-1226. https://pubmed.ncbi.nlm.nih.nih.gov/32458969 5. Kennedy R. The Real Anthony Fauci. Bill Gates, Big Pharma, and the Global War on Democracy and Public Health. New York: Skyhorse Publishing. 2021. ISBN: 9781510766808. The Real Anthony Fauci (skyhorsepublishing.com) 6. Arrow K, Panosian C, and Gelband H, Editors. Saving lives, buying time: economics of malaria drugs in an age of resistance. Washington DC, National Academies Press. 2004 ISBN: 0-309-53233-7. P. 125 - 132 7. McChesney E. Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate. American Journal of Medicine 1983; 75: 11-18 8. Paley- Vincent C, Boudet-Gizardin N. Is the prescription of hydroxychloroquine legal in France to treat patients with COVID – 19? 2020. Covid 19: Can hydroxychloroquine be legally prescribed in France? (ginestie.com)
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9. Rainsford KD, Parke AL, Clifford-Rashotte M, Kean WF. Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. Inflammopharmacology . 2015; 23: 231-69. doi: 10.1007/s10787-015-0239-y. Epub 2015 Aug 6. PMID: 26246395. 10.Electronic medicines compendium. https://www.medicines.org.uk/emc/product/11516/smpc 11.Yusuf IH, Sharma S, Luqmani R, Downes SM. Hydroxychloroquine retinopathy. Eye 2017; 31: 828-845. doi:10.1038/eye.2016.298 12.Drugs.com HCQ information: Hydroxychloroquine Dosage Guide + Max Dose, Adjustments - Drugs.com 13.Vladimir Zelenko protocol: https://vladimirzelenkomd.com/treatment-protocol/ 14.America’s Front Line Doctors: https://americasfrontlinedoctors.org/covid/hydroxychloroquine/treatment- protocols/ 15.Front Line COVID Critical Care Alliance: https://covid19criticalcare.com/covid-19- protocols/i-mask-plus-protocol/ 16.Silva J, Silva M, Skare T. Chloroquine and QTc interval. Clinical Experimental Rheumatology 2007; 25: 795 17.Farzam K, Tivakaran VS. QT Prolonging Drugs. [Updated 2022 May 15]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan- . Available from: https://www.ncbi.nlm.nih.gov/books/NBK534864/ 18.Nass M. Alliance for human research protection. Covid – 19 has turned public health into a lethal, patient – killing experimental endeavor . June 2020. https://ahrp.org/covid-19-has-turned-public-health-into-a-lethal-patient-killing- experimental-endeavor
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19. Mehra M, Desai S, Ruschitzka F, Patel A. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID – 19: a multinational registry analysis. Lancet 2020 electronic publication. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31180- 6/fulltext 20. World Health Organization News. WHO discontinues hydroxychloroquine and lopinavir / ritonavir treatment arms for COVID – 19. https://www.who.int/news/item/04-07-2020-who-discontinues- hydroxychloroquine-and-lopinavir-ritonavir-treatment-arms-for-covid-19 21. Mehra M, Desai S, Kuy S, Henry T, Patel A. Cardiovascular disease, drug therapy, and mortality in COVID – 19. New England Journal of Medicine 2020 electronic publication. https://www.nejm.org/doi/full/10.1056/NEJMe2020822 22. Office of the Commissioner. Coronaviris (COVID-19) update: FDA revokes emergency use authorization for chloroquine and hydroxychloroquine. U.S. Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Revokes Emergency Use Authorization for Chloroquine and Hydroxychloroquine | FDA 23. Borba M, Val F, Sampiano V, et al. Effect of high vs low dose of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial. Journal of the American Medical Association Open 2020. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2765499 24. Axfors C, Schmitt A, Janiaud P, et al. Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta – analysis of randomized trials. Nature Communications 2021; 12: 2349 – 2361 https://www.nature.com/articles/s41467-021-22446-z
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25. WHO Solidarity Trial Consortium. Repurposed antiviral drugs for covid – 19 interim solidarity trial results. New England Journal of Medicine 2021; 384:497- 511 https://pubmed.ncbi.nlm.nih.gov/33264556/ 26. RECOVERY Collaborative Group. Effects of hydroxychloroquine in hospitalized patients with COVID – 19. New England Journal of Medicine. 2020; 383: 2030 - 2040 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556338/pdf/NEJMoa2022926.pd f 27. Singh B, Ryan H, Kredo T, Chaplin M, Fletcher T. Chloroquine or hydroxychloroquine for the prevention and treatment of COVID – 19. Cochrane Library 2021 https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD013587.pub2/ep df/full 28. Skipper C, Pastick K, Engen N. Hydroxychloroquine in nonhospitalized adults with early COVID – 19 a randomized trial. Annals of Internal Medicine 2020; 173: 623- 631. doi: 10.7326/M20-4207. https://pubmed.ncbi.nlm.nih.gov/32673060/ 29. Cavalcanti, Zampieri F, Rosa R. Hydroxychloroquine with or without azithromycin in mild to moderate COVID 19. New England Journal of Medicine 2020; 383: 2041 – 2052 doi:10.1056/NEJMoa2019014 30. Johnston C, Brown E, Stewart J, et al. Hydroxychloroquine with or without azithromycin for treatment of early SARS – CoV-2 infection among high – risk outpatient adults. A randomized trial. EClinicalMedicine 2021 33:100773. Doi:10.1016/j.eclinm.2021.100773 31. Mitjà O, Corbacho-Monné M, Ubals M, et al. Hydroxychloroquine for Early Treatment of Adults With Mild Coronavirus Disease 2019: A Randomized, Controlled Trial. Clinical Infectious Disease . 2021 6: e4073-e4081. doi: 10.1093/cid/ciaa1009. PMID: 32674126; PMCID: PMC7454406.
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