Heterogeneity in susceptibility to hydroxychloroquine of SARS-CoV-2 isolates
Accepted: 26 November 2021 Published: 30 December 2021
Background: Despite the fact that the clinical efficacy of hydroxychloroquine is still controversial, it has been demonstrated in vitro to control SARS-CoV-2 multiplication on Vero E6 cells. In this study, we tested the possibility that some patients with prolonged virus excretion could be infected by less susceptible strains. Method: Using a high-content screening method, we screened 30 different selected isolates of SARS-CoV-2 from different patients who received azithromycin
 Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. New England Journal of Medicine. 2020; 382: 727–733.
 Zhang Y, Holmes EC. A Genomic Perspective on the Origin and Emergence of SARS-CoV-2. Cell. 2020; 181: 223–227.
 Yao H, Song Y, Chen Y, Wu N, Xu J, Sun C, et al. Molecular Architecture of the SARS-CoV-2 Virus. Cell. 2020; 183: 730–738.e13.
 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. Virology Journal. 2005; 2: 69.
 Keyaerts E, Vijgen L, Maes P, Neyts J, Van Ranst M. In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochemical and Biophysical Research Communications. 2004; 323: 264–268.
 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). Clinical Infectious Diseases. 2020; 71: 732–739.
 Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020; 395: 1569–1578.
 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 Discovery. 2020; 6: 16.
 Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020; 583: 459–468.
 Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Research. 2020; 178: 104787.
 Riva L, Yuan S, Yin X, Martin-Sancho L, Matsunaga N, Pache L, et al. Discovery of SARS-CoV-2 antiviral drugs through largescale compound repurposing. Nature. 2020; 586: 113–119.
 Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020; 181: 271–280.e8.
 Touret F, Gilles M, Barral K, Nougairède A, van Helden J, Decroly E, et al. In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication. Scientific Reports. 2020; 10: 13093.
 Gendrot M, Duflot I, Boxberger M, Delandre O, Jardot P, Le Bideau M, et al. Antimalarial artemisinin-based combination therapies (ACT) and COVID-19 in Africa: in vitro inhibition of SARS-CoV-2 replication by mefloquine-artesunate. International Journal of Infectious Diseases. 2020; 99: 437–440.
 Gendrot M, Andreani J, Boxberger M, Jardot P, Fonta I, Le Bideau M, et al. Antimalarial drugs inhibit the replication of SARS-CoV-2: an in vitro evaluation. Travel Medicine and Infectious Disease. 2020; 37: 101873.
 Hoffmann M, Hofmann-Winkler H, Smith JC, Krüger N, Arora P, Sørensen LK, et al. Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity. EBioMedicine. 2021; 65: 103255.
 Tian L, Qiang T, Liang C, Ren X, Jia M, Zhang J, et al. RNAdependent RNA polymerase (RdRp) inhibitors: the current landscape and repurposing for the COVID-19 pandemic. European Journal of Medicinal Chemistry. 2021; 213: 113201.
 Daikopoulou V, Apostolou P, Mourati S, Vlachou I, Gougousi M, Papasotiriou I. Targeting SARS-CoV-2 Polymerase with New Nucleoside Analogues. Molecules. 2021; 26: 3461.
 Andreani J, Le Bideau M, Duflot I, Jardot P, Rolland C, Boxberger M, et al. In vitro testing of combined hydroxychloroquine and azithromycin on SARS-CoV-2 shows synergistic effect. Microbial Pathogenesis. 2020; 145: 104228.
 Saqrane S, El Mhammedi MA. Review on the global epidemiological situation and the efficacy of chloroquine and hydroxychloroquine for the treatment of COVID-19. New Microbes and New Infections. 2020; 35: 100680.
 Belayneh A. Off-Label Use of Chloroquine and Hydroxychloroquine for COVID-19 Treatment in Africa Against WHO Recommendation. Research and Reports in Tropical Medicine. 2020; 11: 61–72.
 Million M, Lagier JC, Tissot-Dupont H, Ravaux I, Dhiver C, Tomei C, et al. Early combination therapy with hydroxychloroquine and azithromycin reduces mortality in 10,429 COVID-19 outpatients. Reviews in Cardiovascular Medicine. 2021; 22: 1063–1072.
 Pavon AG, Meier D, Samim D, Rotzinger DC, Fournier S, Marquis P, et al. First Documentation of Persistent SARS-Cov-2 Infection Presenting with Late Acute Severe Myocarditis. Canadian Journal of Cardiology. 2020; 36: 1326.e5–1326.e7.
 Gajurel K. Persistently positive severe acute respiratory syndrome coronavirus 2 (SARS-COV2) nasopharyngeal PCR in a kidney transplant recipient. Transplant Infectious Disease. 2020; 22: e13408.
 Khaddour K, Sikora A, Tahir N, Nepomuceno D, Huang T. Case Report: the Importance of Novel Coronavirus Disease (COVID-19) and Coinfection with other Respiratory Pathogens in the Current Pandemic. The American Journal of Tropical Medicine and Hygiene. 2020; 102: 1208–1209.
 Xu K, Chen Y, Yuan J, Yi P, Ding C, Wu W, et al. Factors Associated with Prolonged Viral RNA Shedding in Patients with Coronavirus Disease 2019 (COVID-19). Clinical Infectious Diseases. 2020; 71: 799–806.
 Lagier J, Million M, Gautret P, Colson P, Cortaredona S, Giraud-Gatineau A, et al. Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: a retrospective analysis. Travel Medicine and Infectious Disease. 2020; 36: 101791.
 Francis R, Le Bideau M, Jardot P, Grimaldier C, Raoult D, Bou Khalil JY, et al. High-speed large-scale automated isolation of SARS-CoV-2 from clinical samples using miniaturized co-culture coupled to high-content screening. Clinical Microbiology and Infection. 2021; 27: 128.e1–128.e7.
 La Scola B, Le Bideau M, Andreani J, Hoang VT, Grimaldier C, Colson P, et al. Viral RNA load as determined by cell culture as a management tool for discharge of SARS-CoV-2 patients from infectious disease wards. European Journal of Clinical Microbiology & Infectious Diseases. 2020; 39: 1059–1061.
 Amrane S, Tissot-Dupont H, Doudier B, Eldin C, Hocquart M, Mailhe M, et al. Rapid viral diagnosis and ambulatory management of suspected COVID-19 cases presenting at the infectious diseases referral hospital in Marseille, France, - January 31st to March 1st, 2020: A respiratory virus snapshot. Travel Medicine and Infectious Disease. 2020; 36: 101632.
 Livak KJ, Schmittgen TD. Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method. Methods. 2001; 25: 402–408.
 Korber B, Fischer WM, Gnanakaran S, Yoon H, Theiler J, Abfalterer W, et al. Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus. Cell. 2020; 182: 812–827.e19.
 Colson P, Levasseur A, Gautret P, Fenollar F, Thuan Hoang V, Delerce J, et al. Introduction into the Marseille geographical area of a mild SARS-CoV-2 variant originating from sub-Saharan Africa: an investigational study. Travel Medicine and Infectious Disease. 2021; 40: 101980.
 Francis R, Ominami Y, Bou Khalil JY, La Scola B. Highthroughput isolation of giant viruses using high-content screening. Communications Biology. 2019; 2: 216.
 Bestle D, Heindl MR, Limburg H, Van Lam van T, Pilgram O, Moulton H, et al. TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells. Life Science Alliance. 2020; 3: e202000786.
 Matsuyama S, Nao N, Shirato K, Kawase M, Saito S, Takayama I, et al. Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells. Proceedings of the National Academy of Sciences. 2020; 117: 7001–7003.
 Mulay A, Konda B, Garcia G Jr, Yao C, Beil S, Villalba JM, et al. SARS-CoV-2 infection of primary human lung epithelium forCOVID-19 modeling and drug discovery. Cell Reports. 2021; 35: 109055.
 Mellott DM, Tseng CT, Drelich A, Fajtová P, Chenna BC, Kostomiris DH, et al. A Clinical-Stage Cysteine Protease Inhibitor blocks SARS-CoV-2 Infection of Human and Monkey Cells. American Chemical Society. 2021; 16: 642–650.
 Yamamoto M, Kiso M, Sakai-Tagawa Y, Iwatsuki-Horimoto K, Imai M, Takeda M, et al. The Anticoagulant Nafamostat Potently Inhibits SARS-CoV-2 S Protein-Mediated Fusion in a Cell Fusion Assay System and Viral Infection In Vitro in a Cell-Type-Dependent Manner. Viruses. 2020; 12: 629.
 Tseng CK, Tseng J, Perrone L, Worthy M, Popov V, Peters CJ. Apical entry and release of severe acute respiratory syndromeassociated coronavirus in polarized Calu-3 lung epithelial cells. Journal of Virology. 2005; 79: 9470–9479.
 Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science. 2020; 370: eabd4570.
 Elhabyan A, Elyaacoub S, Sanad E, Abukhadra A, Elhabyan A, Dinu V. The role of host genetics in susceptibility to severe viral infections in humans and insights into host genetics of severe COVID-19: a systematic review. Virus Research. 2020; 289: 198163.
 Choi B, Choudhary MC, Regan J, Sparks JA, Padera RF, Qiu X, et al. Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host. New England Journal of Medicine. 2020; 383: 2291–2293.
 Avanzato VA, Matson MJ, Seifert SN, Pryce R, Williamson BN, Anzick SL, et al. Case Study: Prolonged Infectious SARS-CoV-2 Shedding from an Asymptomatic Immunocompromised Individual with Cancer. Cell. 2020; 183: 1901–1912.e9.
 Senegal says hydroxychloroquine virus treatment is promising n.d. Available at: https://medicalxpress.com/news/2020-04-senegal-hydroxychloroquine-virus-treatment.html (Accessed: 26 November 2020).
 Roundup: Senegal to continue to treat COVID-19 patients with anti-malaria drugs: expert - Xinhua | English.news.cn n.d. Available at:http://www.xinhuanet.com/english/2020-06/07/c_139119593.htm (Accessed: 26 November 2020).
 Arachchillage DRJ, Laffan M. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. Journal of Thrombosis and Haemostasis. 2020; 18: 1233–1234.
 Bowles L, Platton S, Yartey N, Dave M, Lee K, Hart DP, et al. Lupus Anticoagulant and Abnormal Coagulation Tests in Patients with Covid-19. New England Journal of Medicine. 2020; 383: 288–290.
 Devaux CA, Camoin-Jau L, Mege JL, Raoult D. Can hydroxychloroquine be protective against COVID-19-associated thrombotic events? Journal of Microbiology, Immunology and Infection. 2021; 54: 37–45. (in press)
 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. 2016; 23: 231–269.
 Chhonker YS, Sleightholm RL, Li J, Oupický D, Murry DJ. Simultaneous quantitation of hydroxychloroquine and its metabolites in mouse blood and tissues using LC-ESI-MS/MS: an application for pharmacokinetic studies. Journal of Chromatography B Analytical Technologies in the Biomedical and Life Sciences. 2018; 1072: 320–327.
 Hoffmann M, Mösbauer K, Hofmann-Winkler H, Kaul A, Kleine-Weber H, Krüger N, et al. Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2. Nature. 2020; 585: 588–590.
 Park SJ, Yu KM, Kim YI, Kim SM, Kim EH, Kim SG, et al. Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets. mBio. 2020; 11: e01114–20.