Abstract: Favipiravir at high doses has potent antiviral activity
in SARS-CoV-2−infected hamsters, whereas
hydroxychloroquine lacks activity
a
Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research,
Katholieke Universiteit Leuven, B-3000 Leuven, Belgium; bBiomedical MRI and Molecular Small Animal Imaging Centre, Department of Imaging and
Pathology, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium; cDrug Delivery & Disposition, Department of Pharmaceutical and Pharmacological
Sciences, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; dUnité des Virus Emergents, Aix Marseille University, Institut de Recherche pour le
Développement (IRD) 190, Institut National de la Santé et de la Recherche Médicale (INSERM) 1207, 13005 Marseille, France; eUCL Great Ormond Street
Institute of Child Health, University College London, WC1N 1EH London, United Kingdom; f Molecular Small Animal Imaging Centre, Department of
Imaging and Pathology, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium; gDepartment of Laboratory Medicine, Ghent University Hospital, 9000
Ghent, Belgium; hNuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, Katholieke Universiteit Leuven, B-3000 Leuven,
Belgium; iAssistance Publique–Hôpitaux de Marseille, Aix-Marseille University, Unité des Virus Emergents, Institut de Recherche pour le Développement
(IRD) 190, Institut National de la Santé et de la Recherche Médicale (INSERM) 1207, Laboratoire de Pharmacocinétique et Toxicologie, 13005 Marseille,
France; jTranslational Cell and Tissue Research, Department of Imaging and Pathology, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium; kPharmacy
Department, University Hospitals Leuven, 3000 Leuven, Belgium; lDepartment of Pharmaceutical and Pharmacological Sciences, Katholieke Universiteit
Leuven–University of Leuven, 3000 Leuven, Belgium; and mGlobal Virus Network, Baltimore, MD 21201
Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved September 3, 2020 (received for review July 9, 2020)
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
rapidly spread around the globe after its emergence in Wuhan in
December 2019. With no specific therapeutic and prophylactic options available, the virus has infected millions of people of which
more than half a million succumbed to the viral disease, COVID-19.
The urgent need for an effective treatment together with a lack of
small animal infection models has led to clinical trials using repurposed drugs without preclinical evidence of their in vivo efficacy.
We established an infection model in Syrian hamsters to evaluate
the efficacy of small molecules on both infection and transmission.
Treatment of SARS-CoV-2−infected hamsters with a low dose of
favipiravir or hydroxychloroquine with(out) azithromycin resulted
in, respectively, a mild or no reduction in virus levels. However, high
doses of favipiravir significantly reduced infectious virus titers in the
lungs and markedly improved lung histopathology. Moreover, a
high dose of favipiravir decreased virus transmission by direct contact, whereas hydroxychloroquine failed as prophylaxis. Pharmacokinetic modeling of hydroxychloroquine suggested that the total
lung exposure to the drug did not cause the failure. Our data on
hydroxychloroquine (together with previous reports in macaques
and ferrets) thus provide no scientific basis for the..
DOI record:
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"abstract": "<jats:title>Abstract</jats:title><jats:p>SARS-CoV-2 rapidly spread around the globe after its emergence in Wuhan in December 2019. With no specific therapeutic and prophylactic options available, the virus was able to infect millions of people. To date, close to half a million patients succumbed to the viral disease, COVID-19. The high need for treatment options, together with the lack of small animal models of infection has led to clinical trials with repurposed drugs before any preclinical<jats:italic>in vivo</jats:italic>evidence attesting their efficacy was available. We used Syrian hamsters to establish a model to evaluate antiviral activity of small molecules in both an infection and a transmission setting. Upon intranasal infection, the animals developed high titers of SARS-CoV-2 in the lungs and pathology similar to that observed in mild COVID-19 patients. Treatment of SARS-CoV-2-infected hamsters with favipiravir or hydroxychloroquine (with and without azithromycin) resulted in respectively a mild or no reduction in viral RNA and infectious virus. Micro-CT scan analysis of the lungs showed no improvement compared to non-treated animals, which was confirmed by histopathology. In addition, both compounds did not prevent virus transmission through direct contact and thus failed as prophylactic treatments. By modelling the PK profile of hydroxychloroquine based on the trough plasma concentrations, we show that the total lung exposure to the drug was not the limiting factor. In conclusion, we here characterized a hamster infection and transmission model to be a robust model for studying<jats:italic>in vivo</jats:italic>efficacy of antiviral compounds. The information acquired using hydroxychloroquine and favipiravir in this model is of critical value to those designing (current and) future clinical trials. At this point, the data here presented on hydroxychloroquine either alone or combined with azithromycin (together with previously reported<jats:italic>in vivo</jats:italic>data in macaques and ferrets) provide no scientific basis for further use of the drug in humans.</jats:p>",
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