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..