Review: Hydroxychloroquine and Chloroquine for Treatment of SARS-CoV-2 (COVID-19)

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging viral infection causing coronavirus disease 2019 (COVID-19). Hydroxychloroquine and chloroquine have garnered unprecedented attention as potential therapeutic agents against COVID-19 following several small clinical trials, uncontrolled case series, and public figure endorsements. While there is a growing body of scientific data, there is also concern for harm, particularly QTc prolongation and cardiac arrhythmias. Here, we perform a rapid narrative review and discuss the strengths and limitations of existing in vitro and clinical studies. We call for additional randomized controlled trial evidence prior to the widespread incorporation of hydroxychloroquine and chloroquine into national and international treatment guidelines.

[1]  Jacques Fantini,et al.  Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection , 2020, International Journal of Antimicrobial Agents.

[2]  Yuan Wei,et al.  A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19 , 2020, The New England journal of medicine.

[3]  N. Seidah,et al.  Chloroquine is a potent inhibitor of SARS coronavirus infection and spread , 2005, Virology Journal.

[4]  Parag H Mehta,et al.  Life Threatening Severe QTc Prolongation in Patient with Systemic Lupus Erythematosus due to Hydroxychloroquine , 2016, Case reports in cardiology.

[5]  A. Barbaud,et al.  [Prevalence of hydroxychloroquine-induced side-effects in dermatology patients: A retrospective survey of 102 patients]. , 2018, Annales de dermatologie et de venereologie.

[6]  Jiyuan Zhang,et al.  Pathological findings of COVID-19 associated with acute respiratory distress syndrome , 2020, The Lancet Respiratory Medicine.

[7]  G. Pond,et al.  A randomized, double-blind, window of opportunity trial evaluating the effects of chloroquine in breast cancer patients , 2019, Breast Cancer Research and Treatment.

[8]  R. Farinotti,et al.  Clinical Pharmacokinetics and Metabolism of Chloroquine , 1996, Clinical pharmacokinetics.

[9]  Md Abdul Alim Al-Bari,et al.  Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases , 2015, The Journal of antimicrobial chemotherapy.

[10]  Sharon Einav,et al.  A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19 , 2020, Journal of Critical Care.

[11]  C. Delaugerre,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 , 2020, Médecine et Maladies Infectieuses.

[12]  Jung-Han Kim,et al.  Stereotactic Core-Needle Biopsy of Non-Mass Calcifications: Outcome and Accuracy at Long-Term Follow-Up , 2003, Korean journal of radiology.

[13]  Jieliang Chen,et al.  Pathogenicity and transmissibility of 2019-nCoV—A quick overview and comparison with other emerging viruses , 2020, Microbes and Infection.

[14]  Michael S. Lee.  Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy , 2011 .

[15]  Q. Nguyen,et al.  Faculty Opinions recommendation of Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. , 2011 .

[16]  Ş. Kobak,et al.  Retinopathy due to antimalarial drugs in patients with connective tissue diseases: are they so innocent? A single center retrospective study , 2010, International journal of rheumatic diseases.

[17]  R. Grainger,et al.  A Rush to Judgment? Rapid Reporting and Dissemination of Results and Its Consequences Regarding the Use of Hydroxychloroquine for COVID-19 , 2020, Annals of Internal Medicine.

[18]  N. Abdel-Karim,et al.  Exosomes as a Surrogate Marker for Autophagy in Peripheral Blood, Correlative Data from Phase I Study of Chloroquine in Combination with Carboplatin/Gemcitabine in Advanced Solid Tumors , 2019, Asian Pacific journal of cancer prevention : APJCP.

[19]  E. De Clercq,et al.  Design and synthesis of hydroxyferroquine derivatives with antimalarial and antiviral activities. , 2006, Journal of medicinal chemistry.

[20]  D. Raoult,et al.  Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial , 2020, International Journal of Antimicrobial Agents.

[21]  Jianjun Gao,et al.  Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. , 2020, Bioscience trends.

[22]  E. Chorin,et al.  The QT Interval in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine/Azithromycin , 2020, medRxiv.

[23]  Marc Van Ranst,et al.  In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine , 2004, Biochemical and Biophysical Research Communications.

[24]  M. V. Van Beek,et al.  Antimalarials , 2001, Dermatologic clinics.

[25]  A. Bast,et al.  Ranking Self-reported Gastrointestinal Side Effects of Pharmacotherapy in Sarcoidosis , 2020, Lung.

[26]  C. Gordon,et al.  Increased Incidence of Gastrointestinal Side Effects in Patients Taking Hydroxychloroquine: A Brand-related Issue? , 2017, The Journal of Rheumatology.

[27]  Hyon K. Choi,et al.  Hydroxychloroquine retinopathy — implications of research advances for rheumatology care , 2018, Nature Reviews Rheumatology.

[28]  Kathryn L. Schornberg,et al.  Ebola Virus and Severe Acute Respiratory Syndrome Coronavirus Display Late Cell Entry Kinetics: Evidence that Transport to NPC1+ Endolysosomes Is a Rate-Defining Step , 2014, Journal of Virology.

[29]  M. Marmor,et al.  Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision). , 2016, Ophthalmology.

[30]  A. Savarino,et al.  Chloroquine and beyond: exploring anti-rheumatic drugs to reduce immune hyperactivation in HIV/AIDS , 2015, Retrovirology.

[31]  Alexis Jacquier,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 , 2020, Travel Medicine and Infectious Disease.

[32]  R. Amaravadi,et al.  Emerging strategies to effectively target autophagy in cancer , 2016, Oncogene.

[33]  I. Ben-Zvi,et al.  Hydroxychloroquine: From Malaria to Autoimmunity , 2011, Clinical Reviews in Allergy & Immunology.

[34]  Science multicenter collaboration group of Department of,et al.  [Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia]. , 2020, Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases.

[35]  E. Holmes,et al.  Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding , 2020, The Lancet.

[36]  V. Richard,et al.  Insights into atherosclerosis therapy in antiphospholipid syndrome. , 2007, Autoimmunity reviews.

[37]  Wu Zhong,et al.  Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro , 2020, Cell Research.

[38]  Sheetal Patel,et al.  Suspected hydroxychloroquine-associated QT-interval prolongation in a patient with systemic lupus erythematosus. , 2013, Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases.

[39]  Zhan Zhang,et al.  Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial , 2020, medRxiv.

[40]  C. Dolea,et al.  World Health Organization , 1949, International Organization.

[41]  A. Dreisbach,et al.  Randomized Dose-Ranging Controlled Trial of AQ-13, a Candidate Antimalarial, and Chloroquine in Healthy Volunteers , 2007, PLoS clinical trials.

[42]  M. Weisman,et al.  Dose-loading with hydroxychloroquine improves the rate of response in early, active rheumatoid arthritis: a randomized, double-blind six-week trial with eighteen-week extension. , 1999, Arthritis and rheumatism.

[43]  R. Kandolf,et al.  Chloroquine cardiomyopathy – a review of the literature , 2013, Immunopharmacology and immunotoxicology.

[44]  Dhanunjaya R. Lakkireddy,et al.  Guidance for cardiac electrophysiology during the COVID-19 pandemic from the Heart Rhythm Society COVID-19 Task Force; Electrophysiology Section of the American College of Cardiology; and the Electrocardiography and Arrhythmias Committee of the Council on Clinical Cardiology, American Heart Associat , 2020, Heart Rhythm.

[45]  S. Katz,et al.  Re-evaluation of antimalarials in treating rheumatic diseases: re-appreciation and insights into new mechanisms of action , 2011, Current opinion in rheumatology.

[46]  L. Pelkmans,et al.  Coronavirus Cell Entry Occurs through the Endo-/Lysosomal Pathway in a Proteolysis-Dependent Manner , 2014, PLoS pathogens.

[47]  A. Lanzone,et al.  Is there any role for the hydroxychloroquine (HCQ) in refractory obstetrical antiphospholipid syndrome (APS) treatment? , 2015, Autoimmunity reviews.

[48]  Zhìhóng Hú,et al.  Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro , 2020, Cell Discovery.

[49]  Xu Liu,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) , 2020, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[50]  G. Hripcsak,et al.  Safety of hydroxychloroquine, alone and in combination with azithromycin, in light of rapid wide-spread use for COVID-19: a multinational, network cohort and self-controlled case series study , 2020, medRxiv.