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Authors: P. Maisonnasse et al.

Link to paper: https://www.researchsquare.com/article/rs-27223/v1

Journal/ Pre-Print: Research Square.

Tags: Immunology/Immunity, Therapeutics, Drug discovery/ Drug repurposing.

Research Highlights

1. In vitro administration of Hydroxychloroquine (HCQ) has an antiviral effect on Vero E6 cell line but not on reconstituted human airway epithelium model (HAE)

2. In vivo administration of HCQ alone or in combination with azithromycin (AZT) under different doses or timeline does not help to resolve SARS-CoV2 infection in macaques.

3. HCQ treatment alone or in combination with AZT did not prevent lymphopenia nor pulmonary lesions and liver toxicity was observed in macaques exposed to high HCQ doses.

Summary

The evidence for HCQ efficacy in treatment of COVID-19 is still contradictory. This study reveals that while administration of HCQ displayed antiviral acvitity in Vero E6 cell line, as many other studies have suggested, it barely show any efficacy in reconstituted human airway epithelium model (HAE). In addition, the treatment of HCQ alone or in combination with AZT has no antiviral activity nor clinical efficacy in infected non-human primates under different dose regimes or starting times of treatment. The kinetics of viral load, peak values or time to viral clearance and the clinical signs did not differ between infected and control groups, although the drug concentration in the plasma and lung reached the in vitro EC50 dose.

Impact for SARS-CoV2/COVID19 research efforts

Treat of SARS-CoV2/COVID19 positive individuals.

The study used infected macaques to evaluate whether HCQ alone or with AZT can be used to treat COVID-19 with different doses along with different time points prior or post to infection. The study showed no efficacy of HCQ in the treatment of the macaques infected with SARS-CoV2 thereby not supporting its use for the treatment of COVID-19 in humans. Moreover this study showed a liver toxicity in treated macaques which raises the question about the safety of HCQ in the treatment of Covid-19 patients.

Study Type

· In vitro study

· In vivo study ( macaques)

Strengths and limitations of the paper

Novelty: Since definitive evidence for HCQ efficacy is still missing, this research is important as it suggests for the first time that HCQ should not be used as a treatment for prophylaxis of SARS-CoV2 infection in human patients.

Standing in the field: The effectiveness of HCQ in COVID19 treatment has been previously measured in several clinical studies in parallel. While HCQ improved the clinical recovery in a small randomised trial (https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v3), an observational study (DOI: 10.1056/NEJMoa2012410) did not reproduce this result.

Appropriate statistics: Although figures 3e & 3f lack r-value for correlation, the study has appropriate statistics overall.

Viral model used:

· Vero E6 cell line

· Reconstituted human airway epithelium MucilAirTM model

· Cynomolgus macaque (non-human primate)

Translatability: The study questions the the efficacy of HCQ in the treatment of COVID-19, allowing researchers to leave the limited medical resources for other perhaps more promising clinical approaches.

Main limitations: The study uses young healthy animals which does not exclude the possibility that the drug may work in aged animals , in human, or in some severe cases.