ABSTRACT

Chloroquine (CQ) and its analog hydroxychloroquine (HCQ) were recently included in several clinical trials as potential prophylactic and therapeutic options for SARS-COV-2 infection/covid-19. However, drug effectiveness in preventing, treating, or slowing the progression of the disease is still unknown. Despite some initial promising in vitro results, rigorous pre-clinical animal studies and randomized clinical trials have not been performed yet. On the other hand, while the potential effectiveness of CQ/HCQ is, at best, hypothetical, their side effects are factual and most worrisome, particularly when considering vulnerable groups of patients being treated with these drugs. in this comment, we briefly explain the possible mechanisms of action of CQ/HCQ for treating other diseases, possible actions against covid-19, and their potent side effects, in order to reinforce the necessity of evaluating the benefit-risk balance when widely prescribing these drugs for SARS-COV-2 infection/covid-19. We conclude by strongly recommending against their indiscriminate use.

Coronavirus Infections; Chloroquine, toxicity; Hydroxychloroquine, toxicity; Contraindications, Drug

INTRODUCTION

SARS Cov-2 infection and Coronavirus disease (covid-19) brought the world to an unimaginable halt. Nevertheless, there is a strong need for up-to-date information about the evolution of the pandemic and the disease, the viability and testing of new antiviral therapies, and any drugs in consideration for prophylaxis and treatment of SARS-CoV-2/covid-19. Among several alternatives, Chloroquine (CQ) and its analog Hydroxychloroquine (HCQ) gained special attention from governments after the publication of in vitro studies¹1. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-71. https://doi.org/10.1038/s41422-020-0282-0
https://doi.org/10.1038/s41422-020-0282-... followed by limited clinical results²2. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial [published online ahead of print, 2020 Mar 20]. Int J Antimicrob Agents. 2020;105949. https://doi.org/10.1016/j.ijantimicag.2020.105949
https://doi.org/10.1016/j.ijantimicag.20... , with vast news dissemination, particularly in the US and Brazil.

CQ and HCQ are antimalarial agents and have been prescribed for treatment of autoimmune diseases (e.g. rheumatoid arthritis and lupus) for almost 70 years³3. Sandhu VK, Weisman MH. Hydroxychloroquine - how much Is too much? J Rheumatol. 2019;46(4):340-2. https://doi.org/10.3899/jrheum.180639
https://doi.org/10.3899/jrheum.180639... _. The prescription of CQ/HCQ in malaria is for prophylaxis and/or for when drugs accumulate in malaria-infected erythrocytes and interfere with the toxic heme formation during the parasite growth. In rheumatic diseases, CQ/HCQ might exert multiple anti-inflammatory effects, which are associated with the drug affinity to the autophagosomes and lysosomes of leukocytes³3. Sandhu VK, Weisman MH. Hydroxychloroquine - how much Is too much? J Rheumatol. 2019;46(4):340-2. https://doi.org/10.3899/jrheum.180639
https://doi.org/10.3899/jrheum.180639... . CQ/HCQ could affect the autoantigen presentation of leukocytes along the lysosomal pathway in autoimmune diseases, by disrupting the MHCII pathway⁴4. Schaer CA, Laczko E, Schoedon G, Schaer DJ, Vallelian F. Chloroquine interference with hemoglobin endocytic trafficking suppresses adaptive heme and iron homeostasis in macrophages: the paradox of an antimalarial agent. Oxid Med Cell Longev. 2013;2013:870472. https://doi.org/10.1155/2013/870472
https://doi.org/10.1155/2013/870472... . In addition, CQ and HCQ alter the production of potent pro-inflammatory cytokines, such as TNFα and IL6, by interfering with the endosomal pH during the activation of Toll-like receptors³3. Sandhu VK, Weisman MH. Hydroxychloroquine - how much Is too much? J Rheumatol. 2019;46(4):340-2. https://doi.org/10.3899/jrheum.180639
https://doi.org/10.3899/jrheum.180639... ,⁴4. Schaer CA, Laczko E, Schoedon G, Schaer DJ, Vallelian F. Chloroquine interference with hemoglobin endocytic trafficking suppresses adaptive heme and iron homeostasis in macrophages: the paradox of an antimalarial agent. Oxid Med Cell Longev. 2013;2013:870472. https://doi.org/10.1155/2013/870472
https://doi.org/10.1155/2013/870472... .

Mechanisms of Action of CQ/HCQ on SARS-CoV-2/covid-19 Infection

In the context of the new SARS-CoV-2 infection and covid-19 pathogenesis, Figure shows possible mechanisms of action based on SARS (Severe Acute Respiratory Syndrome)⁵5. Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: an old drug against today’s diseases? Lancet Infect Dis. 2003;3(11):722-7. https://doi.org/10.1016/s1473-3099(03)00806-5
https://doi.org/10.1016/s1473-3099(03)00... . For SARS-CoV-2, both CQ and HCQ perform antiviral activity in entry and post-entry stages of the 2019-nCoV in kidney epithelial cells (Vero E6 cell, ATCC-1586)¹1. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-71. https://doi.org/10.1038/s41422-020-0282-0
https://doi.org/10.1038/s41422-020-0282-... ,⁶6. Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6:16. https://doi.org/10.1038/s41421-020-0156-0
https://doi.org/10.1038/s41421-020-0156-... . SARS-CoV-2 uses the ACE2 (Angiotensin-converting enzyme-2) receptor for cell entry by receptor-mediated endocytosis, similarly to SARS-CoV. The entry of coronavirus into cell cytoplasm and the release of virus content depend on the endocytic machinery, which CQ/HCQ could disrupt due to its ability to neutralize the pH in these compartments⁶6. Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6:16. https://doi.org/10.1038/s41421-020-0156-0
https://doi.org/10.1038/s41421-020-0156-... (Figure A). The immunomodulatory activity of CQ/HCQ might interfere with the strong inflammatory response triggered by SARS-Cov-2 during development of the infection, but these ideas are hypothetical and not confirmed in pre-clinical or clinical studies. In fact, a recent gold standard, randomized, double-blind, placebo-controlled trial across the United States and parts of Canada tested hydroxychloroquine as post exposure prophylaxis in 821 subjects. This trial reported that hydroxychloroquine did not prevent illness compatible with covid-19 or confirmed infection when used as post exposure prophylaxis within 4 days after exposure⁷7. Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. N Engl J Med. 2020:1-9. https://doi.org/10.1056/NEJMoa2016638
https://doi.org/10.1056/NEJMoa2016638... . It has been demonstrated that the rapid virus infection and replication leads to a dysregulated immune response that progress to a cytokine storm response in severe covid-19, followed by the development of ARDS, septic shock, and eventual multiple organ failure⁸8. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507-13. https://doi.org/10.1016/S0140-6736(20)30211-7
https://doi.org/10.1016/S0140-6736(20)30... . Since CQ/HCQ might act through the inhibition of cell signaling mechanisms resulting in blunting of pro-inflammatory cytokines⁹9. Zhang W, Zhao Y, Zhang F, Wang Q, Li T, Liu Z, et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): the perspectives of clinical immunologists from China. Clin Immunol. 2020;214:108393 https://doi.org/10.1016/j.clim.2020.108393
https://doi.org/10.1016/j.clim.2020.1083... (Figure B), it might be tempting to propose that both drugs would reduce the immunopathological tissue damage caused by viral infection¹⁰10. Li H, Liu SM, Yu XH, Tang SL, Tang CK. Coronavirus disease 2019 (COVID-19): current status and future perspectives. Int J Antimicrob Agents. 2020;55(5):105951. https://doi.org/10.1016/j.ijantimicag.2020.105951
https://doi.org/10.1016/j.ijantimicag.20... .

Toxic Effects of CQ/HQC

The major problem is that no rigorous pre-clinical cell-based, animal, nor randomized clinical studies were conducted to investigate these potential new mechanisms for antimalarial drugs or their clinical effectiveness to treat covid-19. However, there is bounteous evidence of their very detrimental side effects, and non-appropriated prescription can cause acute poisoning and even death. This is especially important when, in face of the recent spread of news for supposed benefits of CQ and HCQ against SARS-CoV-2/covid-19, individuals can self-medicate to prevent SARS-CoV-2 infection with off-label medicines, or obtain prescriptions from unethical practitioners. On March 31, 2020, The World Health Organization published specific guidance about the use of “off-label” drugs for covid-19 in clinical trials, especially concerning the use of CQ and HCQ without proper medical prescription¹¹11. World Health Organization. Solidarity clinical trial for COVID-19 treatments. Geneva: WHO; March 2020 [cited 2020 Apr 12]. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments
https://www.who.int/emergencies/diseases... . On April 22, 2020, the National Institutes of Health published a strong rebuttal against their use for the treatment of covid-19¹²12. US National Institutes of Health. COVID-19 Treatment Guidelines. Overview and spectrum of COVID-19: summary recommendations. Bethesda, MD: NIH; 2020 [cited 2020 April 22]. Available from: https://covid19treatmentguidelines.nih.gov/overview/
https://covid19treatmentguidelines.nih.g... . On May 26, 2020, the World Health Organization temporarily suspended CQ and HCQ use in the Solidarity Trial¹³13. World Health Organization. Q&A: hydroxychloroquine and COVID-19. Geneva: WHO; May 2020 [cited 2020 May 29]. Available from: https://www.who.int/news-room/q-a-detail/q-a-hydroxychloroquine-and-covid-19#
https://www.who.int/news-room/q-a-detail... .

Due to their lysosomal affinity, CQ and HCQ accumulate in cells from several tissues with consequent tissue injury in the liver¹⁴14. Abdel Galil SM. Hydroxychloroquine-induced toxic hepatitis in a patient with systemic lupus erythematosus: a case report. Lupus. 2015;24(6):638-40. https://doi.org/10.1177/0961203314561667
https://doi.org/10.1177/0961203314561667... , retina¹⁵15. Yusuf IH, Sharma S, Luqmani R, Downes SM. Hydroxychloroquine retinopathy. Eye (Lond). 2017;31(6):828-45. https://doi.org/10.1038/eye.2016.298
https://doi.org/10.1038/eye.2016.298... , skeletal¹⁶16. Casado E, Gratacós J, Tolosa C, Martínez JM, Ojanguren I, Ariza A, et al. Antimalarial myopathy: an underdiagnosed complication? Prospective longitudinal study of 119 patients. Ann Rheum Dis. 2006;65(3):385-90. https://doi.org/10.1136/ard.2004.023200
https://doi.org/10.1136/ard.2004.023200... , and cardiac muscle cells¹⁷17. Yogasundaram H, Putko BN, Tien J, Paterson DI, Cujec B, Ringrose J, et al. Hydroxychloroquine-induced cardiomyopathy: case report, pathophysiology, diagnosis, and treatment. Can J Cardiol. 2014;30(12):1706-15. https://doi.org/10.1016/j.cjca.2014.08.016.
https://doi.org/10.1016/j.cjca.2014.08.0... . As announced by the FDA on April 7, 2020, side effects of HCQ include irreversible cardiac effects (including cardiomyopathy and QT prolongation), proximal myopathy and neuropathy¹⁸18. US Food and Drug Administration. Coronavirus (COVID-19) Update: Daily Roundup April 7, 2020. Silver Spring, MD: FDA; 2020 [cited 2020 April 10]. Available from: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-daily-roundup-april-7-2020
https://www.fda.gov/news-events/press-an... . Importantly, CQ and HCQ have long half-lives after oral administration (40-50 days)³3. Sandhu VK, Weisman MH. Hydroxychloroquine - how much Is too much? J Rheumatol. 2019;46(4):340-2. https://doi.org/10.3899/jrheum.180639
https://doi.org/10.3899/jrheum.180639... . The resolution of cardiac and skeletal muscle symptoms is frequently slow after HCQ or CQ discontinuation¹⁹19. Stein M, Bell MJ, Ang LC. Hydroxychloroquine neuromyotoxicity. J Rheumatol. 2000;27(12):2927-31.. Patients with CQ- or HCQ-induced myopathy frequently present progressive proximal muscle weakness, dyspnea, absent leg reflexes, and ventilator failure in severe cases¹⁶16. Casado E, Gratacós J, Tolosa C, Martínez JM, Ojanguren I, Ariza A, et al. Antimalarial myopathy: an underdiagnosed complication? Prospective longitudinal study of 119 patients. Ann Rheum Dis. 2006;65(3):385-90. https://doi.org/10.1136/ard.2004.023200
https://doi.org/10.1136/ard.2004.023200... ,¹⁹19. Stein M, Bell MJ, Ang LC. Hydroxychloroquine neuromyotoxicity. J Rheumatol. 2000;27(12):2927-31.,²⁰20. Azimian M, Gultekin SH, Hata JL, Atkinson JB, Ely KA, Fuchs HA, et al. Fatal antimalarial-induced cardiomyopathy: report of 2 cases. J Clin Rheumatol. 2012;18(7):363-6. https://doi.org/10.1097/RHU.0b013e31826852db
https://doi.org/10.1097/RHU.0b013e318268... . Specifically for HCQ-induced cardiotoxicity, higher risk groups are older adults, cardiovascular patients, and patients with renal insufficiency³3. Sandhu VK, Weisman MH. Hydroxychloroquine - how much Is too much? J Rheumatol. 2019;46(4):340-2. https://doi.org/10.3899/jrheum.180639
https://doi.org/10.3899/jrheum.180639... . Moreover, reported side effects of CQ/HCQ on skeletal and cardiac muscles are abundant for patients suffering from rheumatic diseases receiving these medications³3. Sandhu VK, Weisman MH. Hydroxychloroquine - how much Is too much? J Rheumatol. 2019;46(4):340-2. https://doi.org/10.3899/jrheum.180639
https://doi.org/10.3899/jrheum.180639... . The US Center for Diseases Control and Prevention (CDC) recently updated the nine key symptoms for SARS-CoV-2/covid-19, and among these, three are related to the musculoskeletal system. Therefore, to prescribe prophylactic drugs that can trigger these problems in populations such older adults or obese/diabetic patients that have sub-optimal musculoskeletal health²¹21. Marrelli MT, Brotto M. The effect of malaria and anti-malarial drugs on skeletal and cardiac muscles. Malar J.2016;15:524. https://doi.org/10.1186/s12936-016-1577-y
https://doi.org/10.1186/s12936-016-1577-... defies scientific reasoning.

Final Considerations

The concept of using CQ/HCQ as prophylactic or therapeutic alternatives for SARS-Cov-2 infection is, at best, hypothetical, but their side effects are factual. In fact, CQ/HCQ could contribute to the exacerbation of musculoskeletal diseases in older adults at risk for developing severe covid-19²²22. Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, et al. Cardiovascular implications of fatal outcomes of patients with Coronavirus Disease 2019 (COVID-19) [published online ahead of print, 2020 Mar 27]. JAMA Cardiol. 2020:e201017. https://doi.org/10.1001/jamacardio.2020.1017
https://doi.org/10.1001/jamacardio.2020.... . Also, some of the characteristics of rheumatic patients at risk for developing CQ- and HCQ-induced myopathies are old age and other remarkable underlying medical conditions³3. Sandhu VK, Weisman MH. Hydroxychloroquine - how much Is too much? J Rheumatol. 2019;46(4):340-2. https://doi.org/10.3899/jrheum.180639
https://doi.org/10.3899/jrheum.180639... ,²³23. Joyce E, Fabre A, Mahon N. Hydroxychloroquine cardiotoxicity presenting as a rapidly evolving biventricular cardiomyopathy: key diagnostic features and literature review. Eur Heart J Acute Cardiovasc Care. 2013;2(1):77-83. https://doi.org/10.1177/2048872612471215
https://doi.org/10.1177/2048872612471215... , which are also found at the higher-risk patients for developing severe covid-19²2. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial [published online ahead of print, 2020 Mar 20]. Int J Antimicrob Agents. 2020;105949. https://doi.org/10.1016/j.ijantimicag.2020.105949
https://doi.org/10.1016/j.ijantimicag.20... . Thus, we end this comment by invoking the foundation of medical ethical treatment for over 2,500 years: primum non nocere– first do no harm!

REFERENCES

Publication Dates

History