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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 2  |  Issue : 1  |  Page : 5-7

Chloroquine/hydroxychloroquine in the treatment and prophylaxis of COVID-19 disease


Department of Microbiology, Al-Amiri Hospital, Kuwait City, Kuwait

Date of Submission10-Apr-2020
Date of Acceptance16-Apr-2020
Date of Web Publication16-Jun-2020

Correspondence Address:
Dr. Deepthi Nair
Department of Microbiology, Al-Amiri Hospital, Kuwait City
Kuwait
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ACCJ.ACCJ_5_20

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  Abstract 


COVID-19 is a zoonotic viral infection caused by severe acute respiratory syndrome coronavirus-2. Although the management of COVID-19 infection is mainly supportive, the arena of infective therapy now also includes drugs such as chloroquine and its substitute, hydroxychloroquine, which are believed to have antiviral properties in addition to their antimalarial and immunomodulating effects. The objective of this review article is to focus on the antiviral effect of chloroquine/hydroxychloroquine in the treatment and prophylaxis of COVID-19 disease.

Keywords: Chloroquine, COVID-19, hydroxychloroquine, severe acute respiratory syndrome coronavirus-2


How to cite this article:
Nair D. Chloroquine/hydroxychloroquine in the treatment and prophylaxis of COVID-19 disease. Ann Clin Cardiol 2020;2:5-7

How to cite this URL:
Nair D. Chloroquine/hydroxychloroquine in the treatment and prophylaxis of COVID-19 disease. Ann Clin Cardiol [serial online] 2020 [cited 2020 Sep 27];2:5-7. Available from: http://www.onlineacc.org/text.asp?2020/2/1/5/284926




  Introduction Top


Corona virus disease 2019 (COVID-19), a zoonotic viral infection, believed to have originated from Wuhan in the Hubei Province of China, has crippled the global health and economy in the 21st century. The infection caused by a novel strain coronavirus (CoV) called severe acute respiratory syndrome (SARS)-CoV-2, has infected 487,452 persons and caused 22,026 deaths as per the World Health Organization (WHO) report on March 26, 2020. Several symptomatic as well as asymptomatic persons have tested positive for the disease. Although the main target of SARS-CoV-2 is the respiratory system, the virus has potential effects on the cardiovascular system too.[1]


  Chloroquine and Hydroxychloroquine in Relation to Severe Acute Respiratory Syndrome-Coronavirus-2 Top


The treatment and prophylaxis of SARS-CoV-2 infection pose a challenge due to the nonavailability of Food and Drug Administration-approved drugs that are specific for the treatment of COVID-19 disease. Infection prevention and control measures along with supportive treatment remain the basic strategy in the management of this infection. Mild cases recover, but moderate-to-severe cases, especially those with underlying diseases of the heart and lungs, and the immune-compromised, may need more specific treatment in addition to the supportive measures.

Interestingly, the global mega trial called “SOLIDARITY,” launched by the WHO, has included chloroquine/hydroxychloroquine in its drug trial for the treatment of COVID-19 disease, with the other drugs in the trial being lopinavir-ritonavir combo, remdesevir, and combination of lopinavir-ritonavir with interferon-beta. Trials on the use of convalescent plasma therapy for COVID-19 disease are being undertaken in a few countries.

Chloroquine and hydroxychloroquine are 4-aminoquinoline drugs used to treat malaria and autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. However, these drugs were also shown to have antiviral effect when a few studies earlier reported their ability to inhibit the replication of human CoV (HCoV)-229E, SARS-CoV, and HCoV OC43.[2],[3],[4] In various countries, chloroquine and hydroxychloroquine are currently recommended in the treatment and prophylaxis of COVID-19 patients, althoughin vitro and clinical data are sparse.


  Severe Acute Respiratory Syndrome-Coronavirus-2 Cell Entry and Replication Top


SARS-CoV-2 enters the body via nose or mouth and replicates in the ciliated epithelial cells of the nasopharynx, producing both direct degeneration of the ciliated cells and an outpouring of chemokines and interleukins.[5] The spike protein (S) in the virus binds to the host cell receptor, angiotensin-converting enzyme 2 (ACE2), which is in abundance in the heart and lungs.[6] While some viruses fuse with the plasma membrane, many viruses are endocytosed prior to fusion.


  Antiviral Action of Chloroquine and Hydroxychloroquine Top


Chloroquine and hydroxychloroquine are weak bases and are believed to raise the pH of acidic vesicles. When administered, they get concentrated in acidic, low-pH organelles such as endosomes, Golgi vesicles, and lysosomes and raise the endosomal pH required for virus host cell fusion.[7] They also interfere with the glycosylation of host cell ACE2 receptors of SARS-CoV-2 and viral envelope glycoprotein.[7],[8]

Chloroquine and hydroxychloroquine suppress the production and release of cytokines such as tumor necrosis factor-alpha and interleukin-6, which mediate the inflammatory complications of various viral infections.[9] They, therefore, also act as immunomodulants. The ability of the drugs to reduce the production of cytokines helps in the “cytokine storm” phase of COVID-19 disease, which is an uncontrolled release of cytokines by immune cells observed in a subgroup of patients with SARS-CoV-2 infection.

A recent study describes how the COVID-19 virus attacks the 1-Beta chain of hemoglobin and captures the porphyrin to inhibit human heme metabolism. This leads to insufficient hemoglobin for the transport of respiratory gases, oxygen and carbon dioxide, leading to respiratory insufficiency. It was found that chloroquine could prevent the viral surface glycoproteins from attacking the heme to form the porphyrin and inhibit the binding of the glycoproteins to porphyrins to some extent, effectively relieving the symptoms of respiratory distress.[10]


  Review of Recent Studies on Chloroquine/hydroxychloroquine in Relation to Covid-19 Disease Top


According to a study in China, COVID-19 patients treated with chloroquine had clinical and virological benefit when compared to a comparison group, and chloroquine was added as a recommended antiviral drug for the treatment of COVID-19 in China.[11]

In a study conducted in France, twenty COVID 19 patients treated with hydroxychloroquine showed significant reduction in viral load in the nasal swabs tested on day 6 of treatment, thereby indicating a favourable response to hydroxychloroquine therapy. However, the study was not a randomized clinical trial, the sample size was small, and clinical outcomes were not assessed.[12],[13]

In the USA, hydroxychloroquine is more frequently used in the therapy of COVID-19 patients based on itsin vitro activity against SARS-CoV-2.

One small study reported that hydroxychloroquine alone or in combination with azithromycin reduced the detection of SARS-CoV-2 RNA in upper respiratory tract specimens compared with a nonrandomized control group, but did not assess clinical benefit.[13]

A study from China evaluated the antiviral effect of hydroxychloroquine against SARS-CoV-2 infection in comparison to chloroquine in vitro. The cytotoxicity of hydroxychloroquine and chloroquine in African green monkey kidney vero E6 cells (ATCC-1586) was measured by standard cell counting kit-8 assay, and the results did not show any significant difference. Next, they determined the dose–response curves of the two molecules against SARS-CoV-2 at four different multiplicities of infection by quantification of viral RNA copies in the cell supernatant at 48 h post infection. It was noticed that the differences in the maximal effective concentration (EC50) for chloroquine were lower than that for hydroxychloroquine, and the result was statistically significant. The results were corroborated by immunofluorescence microscopy, which again showed that hydroxychloroquine can effectively inhibit SARS-CoV-2 in comparison to chloroquine.[14] This study is again anin vitro study.In vivo evidence is lacking.

Randomized clinical trials to navigate clinicians on the use, dosing, or duration of hydroxychloroquine for the prophylaxis or treatment of SARS-CoV-2 infection are lacking.[15]


  Benefits and Adverse Effects of Chloroquine/hydroxychloroquine Top


Both chloroquine and hydroxychloroquine have relatively few adverse effects at standard doses, with the main concerns being retinopathy and cardiotoxicity (QT prolongation) on prolonged use, and when used in high doses.[16] Both drugs are considered safe to use during pregnancy and breastfeeding.[17] They have a high volume of distribution and a prolonged half-life.[18] Both have a high oral bioavailability.[19],[20]

Chloroquine and hydroxychloroquine are cost-effective drugs. Hydroxychloroquine is less toxic than chloroquine and is said to have an effective potency against SARS-CoV-2 when compared to chloroquine.[21],[22] Oral absorption of both drugs is excellent, and the drugs achieve high concentration in lungs.[23] The high affinity of the drug for the lung tissue is an advantage in the treatment of SARS-CoV-2 pneumonia.


  Conclusion Top


Chloroquine and hydroxychloroquine are affordable and available drugs with proven antiviral effects. However, more virological and clinical data are needed to assess the efficacy of these drugs in the treatment and prophylaxis of COVID-19 infection. Dose of hydroxychloroquine needs to be controlled. Overdose can lead to poisoning. Vigilant monitoring of drug-induced cardiotoxicity should be practiced during COVID-19 therapy with chloroquine/hydroxychloroquine. Self-medication should be avoided. Clinicians should consider these drugs on a case-by-case basis. Wider availability and lower cost may prompt the unlimited use of these drugs. Their therapeutic benefits need to be assessed via various drug trials and molecular studies, in order to cope with the treatment challenges faced during the ongoing SARS-CoV-2 pandemic. Genetic analysis will favor the identification of virus-specific processes which may be appropriate targets for the development of antiviral therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Madjd M, Safavi Naeini P, Solomon SD, Vardeny O. Potential effects of coronaviruses on the cardiovascular system: A review. JAMA Cardiol. Published online March 27,2020. [doi: 10.1001/jamacardio.2020.1286].  Back to cited text no. 1
    
2.
Keyaerts E, Vijgen L, Maes P, Neyts J, Van Ranst M.In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem Biophys Res Commun 2004;323:264-8.  Back to cited text no. 2
    
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Kono M, Tatsumi K, Imai AM, Saito K, Kuriyama T, Shirasawa H. Inhibition of human coronavirus 229E infection in human epithelial lung cells (L132) by chloroquine: Involvement of p38 MAPK and ERK. Antivir Res 2008;77:150-2.  Back to cited text no. 3
    
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Keyaerts E, Li S, Vijgen L, Rysman E, Verbeeck J, Van Ranst M, et al. Antiviral Activity of chloroquine against human coronavirus OC43 infection in newborn mice. Antimicrob Agents Chemother 2009;53:3416-21.  Back to cited text no. 4
    
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McIntosh K, Anderson LJ. Coronaviruses, including severe acute respiratory syndrome (SARS) – Associated corona virus. In: Bennett JE, Blaser MJ, editors. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, PA, USA: The Curtis Center; 2005. p. 1994-5.  Back to cited text no. 5
    
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Turner AJ, Hiscox JA, Hooper NM. ACE2: From vasopeptidase to SARS virus receptor. Trends Pharmacol Sci 2004;25:291-4.  Back to cited text no. 6
    
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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;14:1435-55.  Back to cited text no. 7
    
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Savarino A, Di Trani L, Donatelli I, Cauda R, Cassone A. New insights into the antiviral effects of chloroquine. Lancet Infect Dis 2006;6:67-9.  Back to cited text no. 8
    
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Jang CH, Choi JH, Byun MS, Jue DM. Chloroquine inhibits production of TNF-alpha, IL-beta and IL-6 from lipopolysaccharide – Stimulated human monocytes/macrophages by different modes. Rheumatology 2006;45:703-10.  Back to cited text no. 9
    
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Liu W, Li H. COVID-19: Attacks the 1 beta chain of haemoglobin and captures the porphyrin to inhibit human heme metabolism. ChemRxiv. 2020 March 27 Preprint [doi.org/10.26434/chemrxiv. 11938173.v5].  Back to cited text no. 10
    
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CDC. Therapeutic Options for COVID-19 Patients; 2020.  Back to cited text no. 11
    
12.
Raoult D, Hsueh PR. COVID-19 therapeutic and prevention. Int J Antimicrob Agents. (In press). [Last accessed on 2020 Mar 07]. Doi :10.1016/j ijantimicag.2020105937 PMID:32151714 PMCID:PMC7135736.  Back to cited text no. 12
    
13.
Gautret P, Lagier J, Parola P, Hoang V, 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. Doi :10.1016/j.ijantimicag.2020.105949 [pubmed] (In press).   Back to cited text no. 13
    
14.
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.  Back to cited text no. 14
    
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Information for Clinicians on Therapeutic Options for COVID-19 Patients. Centers for Disease Control and Prevention. Available from: https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html.2020March21. [Last accessed on 2020 Mar 29].  Back to cited text no. 15
    
16.
Al-Bari AA. Chloroquine analogues in drug discovery: New directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases. J Antimicrob Chemother 2015;70:1608-21.  Back to cited text no. 16
    
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Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation A reference guide to fetal and neonatal risk. 5th ed. Baltimore, MD: Williams and Wilkins;1998.  Back to cited text no. 17
    
18.
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.  Back to cited text no. 18
    
19.
Furst DE. Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases. Lupus 1996;5:S11-5.  Back to cited text no. 19
    
20.
Tett SE, Cutler DJ, Day RO, Brown KF. Bioavailability of hydroxychloroquine tablets in healthy volunteers. Br J Clin Pharmacol 1989;27:771-9.  Back to cited text no. 20
    
21.
McChesney EW. Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate. Am J Med 1983;75:11-8.  Back to cited text no. 21
    
22.
Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al.In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [published ahead of print, 2020 Mar 9] Clin Infect Dis 2020 pii: ciaa237. [doi: 10.1093/cid/ciaa237].  Back to cited text no. 22
    
23.
Tripathi KD. Antimalarial drugs. In: Essentials of Medical Pharmacology. 5th ed, ch. 57:740. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2003.  Back to cited text no. 23
    

Editor's note: After accepting this article for publication many new developments have taken place regarding chloroquine prophylaxis of COVID-19. On June 1, 2020, ClinicalTrials.gov listed a remarkable 203 Covid-19 trials with hydroxychloroquine, 60 of which were focused on prophylaxis. The Lancet[1] issued a statement on June 4, 2020 regarding an article published in their journal on "hydroxychloroquine was associated with higher rates of ventricular arrhythmia and death in COVID-19 patients". This led to several global hydroxychloroquine trials being halted. This study was retracted as three of the authors "can no longer vouch for the veracity of the primary data sources." The authors Mandeep R Mehra, Frank Ruschitzka, Amit N Patel said that "several concerns were raised with respect to the veracity of the data and analyses conducted by Surgisphere Corporation and its founder and our co-author, Sapan Desai, in our publication." Later another report was published by Boulware et al.[2] in NEJM. An editorial noted that the findings are more provocative than definitive, suggesting that the potential prevention benefits of hydroxychloroquine remain to be determined. 1. Mehra MR, Desai SS, Ruschitzka F, Patel AN. RETRACTED: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. The Lancet [Internet]. 2020 May [cited 2020 Jun 12]; Available from: https:// linkinghub.elsevier.com/retrieve/pii/S0140673620311806 2. 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. New England Journal of Medicine [Internet]. 2020 Jun 3 [cited 2020 Jun 12]; Available from: http:// www.nejm.org/doi/10.1056/NEJMoa2016638




 

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