Open Access

Heterogeneity in susceptibility to hydroxychloroquine of SARS-CoV-2 isolates

Celine Boschi1,2,Marion Le Bideau1,2,Julien Andreani2,Sarah Aherfi1,2,Priscilla Jardot1,2, Jeremy Delerce1,2,Mathieu Gendrot1,3,4,Bruno Pradines1,3,4,5,Philippe Colson1,2, Anthony Levasseur1,2,*,Bernard La Scola1,2,*
Institut Hospitalo-Universitaire Mediterranée Infection, 13005 Marseille, France
Microbe Evolution Phylogeny and Infection (MEPHI), Aix Marseille University, Institut de recherche pour le développement (IRD), Assistance publique hôpitaux de Marseille (AP-HM), 13005 Marseille, France
Parasitology and Entomology Unit, Infectious Diseases and Microbiology Department, Institut de Recherche Biomédicale des Armées (IRBA), 13005 Marseille, France
Vecteurs -Infections Tropicales et Méditerranéennes (VITROME), Aix Marseille University, Institut de recherche pour le développement (IRD), Service de Santé des Armées (SSA), Assistance publique hôpitaux de Marseille (AP-HM), 13005 Marseille, France
National Reference center for Malaria, 13005 Marseille, France
DOI: 10.52586/5043 Volume 26 Issue 12, pp.1493-1502
Submited: 10 September 2021 Revised: 17 November 2021
Accepted: 26 November 2021 Published: 30 December 2021
*Corresponding Author(s):  
Anthony Levasseur
*Corresponding Author(s):  
Bernard La Scola
Copyright: © 2021 The author(s). Published by BRI. This is an open access article under the CC BY 4.0 license (

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 ±± hydroxychloroquine. We focused on patients with viral persistence, i.e., positive virus detection in a nasopharyngeal sample 10 days, and who were tested during two French epidemic waves, late winter-spring of 2020 and the summer of 2020. Dose-response curves in single-molecule assays with hydroxychloroquine were created for isolates with suspected reduced susceptibility. Genome clustering was performed for all isolates. Results: Of 30 tested strains, three were detected as replicating in the presence of azithromycin + hydroxychloroquine, each at 5 μM. The dose-response model showed a decrease in susceptibility of these three strains to hydroxychloroquine. Whole genome sequencing revealed that these three strains are all from the second epidemic wave and two cluster with isolates from Africa. Conclusions: Reduced susceptibility to hydroxychloroquine was not associated with viral persistence in naso-pharyngeal samples. Rather, it was associated with occurring during the second epidemic wave, which began in the summer and with strains clustering with those with a common genotype in Africa, where hydroxychloroquine was the most widely used.

Key words

SARS-CoV-2; Hydroxychloroquine; Azithromycin; In vitro model; Vero E6; WGS; Africa


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Celine Boschi, Marion Le Bideau, Julien Andreani, Sarah Aherfi, Priscilla Jardot, Jeremy Delerce, Mathieu Gendrot, Bruno Pradines, Philippe Colson, Anthony Levasseur, Bernard La Scola. Heterogeneity in susceptibility to hydroxychloroquine of SARS-CoV-2 isolates. Frontiers in Bioscience-Landmark. 2021. 26(12); 1493-1502.