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Questioning COVID-19 and hydroxychloroquine: a new preclinical study

A new preclinical study piloted by IDMIT and employing experimental infection models for SARS-CoV-2 (causative agent of COVID-19) found no therapeutic antiviral efficacy for hydroxychloroquine. The team behind the study tested the compound both alone and in combination with azithromycin, and as a prophylactic and in early and late infection. Their results have been published on Nature. The study, carried out under the aegis of the multidisciplinary consortium REACTing, united researchers from Inserm, the Institut Pasteur, Paris-Saclay University, the Marseille university hospital network, Claude Bernard Lyon 1 University and Aix-Marseille University.

Published on 22 July 2020

A multi-institutional preclinical study was launched in March 20201 under the aegis of the consortium REACTing2 to determine the in vitro and in vivo antiviral potential of hydroxychloroquine (HCQ) against SARS-CoV-2, the causative agent of COVID-19. The research team considered the compound in prophylaxis and during infection.

First, the team determined the in vitro antiviral efficacy of HCQ in a cell model (Vero E6) and in a reconstituted airway epithelium model (MucilAir). Thereafter, they evaluated HCQ either alone or in combination with azithromycin vs placebo in a SARS-CoV-2-infected non-human primate model.

This in vivo testing involved two steps. The first was to verify the pertinence of the employed animal model. This step did indeed show that the disease observed in non-human primates is very similar to that observed in the majority of humans with COVID-19 not requiring hospitalization. The second step was to ascertain the pharmacokinetics of HCQ, that is, how the molecule behaves once administered in an organism. The pharmacokinetics study enabled the determination of correlations between the amount of HCQ administered and its absorption, distribution and metabolism in the organism. Through this analysis, the researchers confirmed that HCQ levels in the animal model were similar to those found in HCQ-treated humans.

Treatment administration was tested:

  • as a prophylaxis (before infection), 

  • immediately after infection, 

  • and late after infection (with the appearance of symptoms; five days after infection). In addition to testing HCQ with or without azithromycin, the team also performed subgroup analyses for several dosing regimens.

The team did observe dose-dependent antiviral efficacy for HCQ in the conventional in vitro tests with Vero E6 cells. However, efficacy was not observed in the more complex airway epithelium model, where the compound did not show a protective effect for the integrity of the infected epithelial tissue.

As for the in vivo results, the team found no preventive effect for HCQ when administered upstream of infection. Furthermore, concerning treatment after infection, the researchers were unable to find any significant differences in the amount of circulating SARS-CoV-2 between the animals treated with HCQ and those given placebos, regardless of treatment timing or doses.

With this study, it appears thus that HCQ does have antiviral properties in some in vitro tests, but not in the in vivo, non-human primate model as used specifically in the work with, in particular, high pulmonary exposure.

It is important to note however that the study does not yield information on any possible immunomodulatory effect of HCQ, as is observed for the compound in lupus or rheumatoid arthritis, for example. The preclinical nature of the study is complementary to its clinical counterparts. The present study contributes to a better understanding of the pathophysiological mechanisms of SARS-CoV-2 and provides precise information on the biodistribution of HCQ in an animal model, while controlling for numerous parameters and respecting scientific methodology.

These results have been shared through a  press release.

1 : IDMIT on point against COVID-19

2 : REACTing is a multidisciplinary consortium that brings together the partners in Aviesan, the French National Alliance for Life Sciences and Health (CEA, CNRS, INRAE, Inria, Inserm, Institut Pasteur, IRD, CPU and the Conference of Chairmen of Regional and University Hospital Centers) and is coordinated by Inserm.

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