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VOLUME 25 , ISSUE 4 ( April, 2021 ) > List of Articles

REVIEW ARTICLE

Evidence for Chloroquine/Hydroxychloroquine in the Treatment of COVID-19

Rajesh M Shetty, ArunKumar Namachivayam

Keywords : Acute hypoxemic respiratory failure (AHRF), Chloroquine, Coronavirus disease 2019, COVID-19 drug treatment, Hydroxychloroquine

Citation Information : Shetty RM, Namachivayam A. Evidence for Chloroquine/Hydroxychloroquine in the Treatment of COVID-19. Indian J Crit Care Med 2021; 25 (4):441-452.

DOI: 10.5005/jp-journals-10071-23773

License: CC BY-NC 4.0

Published Online: 01-04-2021

Copyright Statement:  Copyright © 2021; Jaypee Brothers Medical Publishers (P) Ltd.


Abstract

Introduction: Given the current lack of an approved and effective treatment or vaccine for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), repositioning old drugs for use as an antiviral treatment is an interesting strategy because knowledge about these drugs’ safety profile, posology, and drug interactions is already known. Chloroquine and hydroxychloroquine, widely used as antimalarial and autoimmune disease drugs, have recently been reported as a potential broad-spectrum antiviral drug. Background: The in vitro antiviral activity of chloroquine has been identified since the late 1960s. However, antiviral mechanisms of chloroquine remain speculative. Several clinical trials have been conducted to test the efficacy and safety of chloroquine or hydroxychloroquine in the treatment of COVID-19-associated pneumonia. The quality of the studies and the outcomes are evaluated in this systematic review and meta-analysis. Review results: Literature review revealed 23 clinical studies. Only 9 of 23 studies were randomized controlled trials. Of nine randomized controlled trials, only study by Skipper et al. was deemed to be at low risk of bias. All studies evaluated variedwith different outcomes. Mechanical ventilation and virological clearance were the only common outcomes evaluated in more than two studies. Virological clearance odds ratio (OR) was 1.25 (95% confidence interval [CI] of 0.57–2.73; Chi2 = 0.83; I2 = 0%). GRADE quality of evidence was downgraded by three levels to very low due to concerns about the risk of bias, inconsistency, and imprecision. For mechanical ventilation, OR was 1.09 (95% CI 0.80–1.50; Chi2 = 0; I2 = 0). GRADE quality of evidence was downgraded by two levels to low due to concerns about the risk of bias and imprecision. There was no statistically significant difference between the groups for these two outcomes. Conclusion: As per the available evidence, based on our review, we conclude that hydroxychloroquine/chloroquine has not shown to be beneficial when used for the treatment of patients with COVID-19 pneumonia.


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  1. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395(10223):497–506. DOI: 10.1016/S0140-6736(20)30183-5.
  2. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020;382(8):727–737. DOI: 10.1056/NEJMoa2001017.
  3. Chen J, Liu D, Liu L, Liu P, Xu Q, Xia L, et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease 19 (COVID-19). J Zheijang Univ 2020 Mar;49(1):0–0. DOI: 10.3785/j.issn.1008-9292.2020.03.03.
  4. Coronavirus Disease (COVID-19) pandemic. World Health Organization (cited 2021 January 03). Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019.
  5. Devaux CA, Rolain JM, Coloson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID 19? Int J Antimicrob Agents [Forthcoming]. DOI: 10.1016/j.ijantimicag.2020.105938.
  6. Gao J, Tian Z, Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. BioScience Trends 2020;14(1):72–73. DOI: 10.5582/bst.2020.01047.
  7. 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. Int J Antimicrob Agents [Forthcoming]. DOI: 10.1016/j.ijantimicag.2020.105949 [in press].
  8. Dong L, Hu S, Gao J. Discovering drugs to treat Coronavirus disease 2019 (COVID-19). Drug Discov Ther 2020;14(1):58–60. DOI: 10.5582/ddt.2020.01012.
  9. Zumla A, Chan JF, Azhar EI, Hui DS, Yuen KY. Coronaviruses-drug discovery and therapeutic options. Nat Rev Drug Discov 2016;15(5):327–347. DOI: 10.1038/nrd.2015.37.
  10. Haladyj E. Sikora M, Felis-Giemza A, Olesinska M. Antimalarials- are they effective and safe in rheumatic diseases? Reumatologia 2018;56(3):164–173. DOI: 10.5114/return.2018.76904.
  11. Savarino A, Di Trani L, Donatelli I, Cauda R, Cassone A. New insights into the antiviral effects of chloroquine. Lancet Infect Dis 2006;6(2):67–69. DOI: 10.1016/S1473-3099(06)70361-9.
  12. Yan Y, Zou Z, Sun Y, Li X, Xu KF, Wei Y, et al. Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model. Cell Res 2012;23(2):300–302. DOI: 10.1038/cr.2012.165.
  13. Inglot AD. Comparison of the antiviral activity in vitro of some non-steroidal anti-inflammatory drugs. J Gen Virol 1969;4(2):203–214. DOI:10.1099/0022-1317-4-2-203.
  14. Miller DK, Lenard J. Antihistaminics, local anesthetics, and other amines asantiviral agents. Proc Natl Acad Sci USA 1981;78(6):3605–3609. DOI: 10.1073/pnas.78.6.3605.
  15. Shimizu Y, Yamamoto S, Homma M, Ishida N. Effect of chloroquine on thegrowth of animal viruses. Arch GesamteVirusforsch 1972;36:93–104. DOI: 10.1007/bf01250299.
  16. Keyaerts E, Vijgen L, Maes P, Neyts J, RanstMV. In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem Biophys Res Commun 2004;323(1):264–268. DOI: 10.1016/j.bbrc.2004.08.085.
  17. McChesney EW. Animal toxicity and pharmacokinetics of hydroxychloroquinesulfate. Am J Med 1983;75(1A):11–18. DOI: 10.1016/0002-9343(83)91265-2.
  18. 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):722–727. DOI: 10.1016/s1473-3099(03)00806-5.
  19. Keyaerts E, Li S, Vijgen L, Rysman E, Verbeeck J, Ranst MV. Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice. Antimicrob Agents Chemother 2009;53(8):3416–3421. DOI: 10.1128/AAC.01509-08.
  20. Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J 2005;2:69. DOI: 10.1186/1743-422X-2-69.
  21. Hu TY, Frieman M, Wolfram J. Insights from nanomedicine into chloroquine efficacy against COVID-19. Nat Nanotechnol 2020;15(4):247–249. DOI: 10.1038/s41565-020-0674-9.
  22. Mauthe M, Orhon I, Rocchi C, Zhou X, Luhr M, Hijlkema KJ, et al. Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy 2018;14(8):1435–1455. DOI: 10.1080/15548627.2018.1474314.
  23. Pallister J, Middleton D, Crameri G, Yamada M, Klein R, Hancock TJ, et al. Chloroquine administration does not prevent Nipah virus infection and disease in ferrets. J Virol 2009;83(22):11979–11982. DOI: 10.1128/JVI.01847-09.
  24. Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, et al. Hydroxychloroquine is a less toxic derivative of chloroquine, is effective in inhibiting SARS CoV-2 infection in vitro. Cell Discov 2020;6:16. DOI: 10.1038/s41421-020-0156-0.
  25. 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):269–271. DOI: 10.1038/s41422-020-0282-0.
  26. Mackenzie AH. Dose refinements in long term therapy of rheumatoid arthritis with antimalarias. Am J Med 1983;75(1): 40–45. DOI: 10.1016/0002-9343(83)91269-X.
  27. Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Res 2020;177:104762. DOI: 10.1016/j.antiviral.2020.104762.
  28. Higgins JPT, Spiegelhalter DJ. Being sceptical about meta-analyses; a Bayesian perspective on magnesium trials in myocardial infarction. Int Immunol J Epidemiol 2002;31(1):96–104. PUBMED 11914302.
  29. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P et al. GRADE: an emerging consensus on rating quality of evidence and strength recommendations. BMJ 2008;336(7650): 924–926. DOI: 10.1136/bmj.39489.470347.AD.
  30. Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv [Forthcoming] DOI: 10.1101/2020.03.22.20040758.
  31. Molina JM, Delaugerre C, Le Geoff J, Mela-Lima B, Ponscarme D, Goldwirt L, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Med Mal Infect [Forthcoming]. DOI: 10.1016/j.medmal.2020.03.006.
  32. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Sevestre J, et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: a pilot observational study. Travel Med Infect Dis 2020;101663 [Forthcoming]. DOI: 10.1016/j.tmaid.2020.101663.
  33. Geleris J, Sun Y, Platt J, Zucker J, Baldwin M, Hripcsak G, et al. Observational study of hydroxychloroquine in hospitalized patients with COVID-19. N Engl J Med 2020;382(25):2411–2418. DOI: 10.1056/NEJMoa2012410.
  34. Rosenberg ES, Dufort EM, Udo T, Wilberschied LA, Kumar J, Tersoreiro J, et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York state. JAMA 2020;323(24):2493–2502. DOI: 10.1001/jama.2020.8630.
  35. Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, et al. Hydroxycholoroquine in patients with mainly mild to moderate Coronavirus disease 2019: open label, randomised controlled trial. BMJ 2020;369:m1849. DOI: 10.1136/bmj.m1849.
  36. Mahevas M, Tran VT, Roumier M, Chanbrol A, Paule R, Guillaud C, et al. Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data. BMJ 2020;369:m1844. DOI: 10.1136/bmj.m1844.
  37. Magagnoli J, Narendran S, Pereira F, Cummings T, Hardin JM, Sutton SS, et al. Outcomes of hydroxycholoroquine usage in United States Veterans hospitalized with Covid-19. medRxiv 2020 [Forthcoming]. DOI: 10.1101/2020.04.16.20065920; 10.1016/j.medj.2020.06.001.
  38. Arshad S, Kilgore P, Chaudhry Z, O’Neill, Zervos M. Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19. Int J Infect Dis 2020;97:396–403. DOI: 10/1016/j.ijid.2020.06.099.
  39. The RECOVERY Collaborative Group. Effect of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med 2020;383(21):2030–2040. DOI: 10.1056/NEJMoa.2022926.
  40. WHO Solidarity Trial Consortium. Repurposed Antiviral drugs for Covid-19-Interim WHO Solidarity trial results. NEJM December 2, 2020. DOI: 10.1056/NEJMoa2023184.
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