Favipiravir at high doses has potent antiviral activity in SARS-CoV-2–infected hamsters, whereas hydroxychloroquine lacks activity

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 43; pp. 26955 - 26965
• Main Authors: Kaptein, Suzanne J. F., Jacobs, Sofie, Langendries, Lana, Seldeslachts, Laura, ter Horst, Sebastiaan, Liesenborghs, Laurens, Hens, Bart, Vergote, Valentijn, Heylen, Elisabeth, Barthelemy, Karine, Maas, Elke, De Keyzer, Carolien, Bervoets, Lindsey, Rymenants, Jasper, Van Buyten, Tina, Zhang, Xin, Abdelnabi, Rana, Pang, Juanita, Williams, Rachel, Thibaut, Hendrik Jan, Dallmeier, Kai, Boudewijns, Robbert, Wouters, Jens, Augustijns, Patrick, Verougstraete, Nick, Cawthorne, Christopher, Breuer, Judith, Solas, Caroline, Weynand, Birgit, Annaert, Pieter, Spriet, Isabel, Velde, Greetje Vande, Neyts, Johan, Rocha-Pereira, Joana, Delang, Leen
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 27.10.2020
• Subjects: Amides - pharmacokinetics; Amides - therapeutic use; Animal models; Animals; Antiviral activity; Antiviral agents; Antiviral Agents - therapeutic use; Azithromycin; Betacoronavirus - drug effects; Biocompatibility; Biological Sciences; Chlorocebus aethiops; Clinical trials; Coronavirus Infections - drug therapy; Coronavirus Infections - virology; Coronaviruses; COVID-19; COVID-19 Drug Treatment; Cricetinae; Disease Models, Animal; Disease transmission; Disease Transmission, Infectious - prevention & control; Dose-Response Relationship, Drug; Drug dosages; Drug Evaluation, Preclinical; Female; Hamsters; Health services; Histopathology; Hydroxychloroquine; Hydroxychloroquine - pharmacokinetics; Hydroxychloroquine - therapeutic use; Infections; Lung - drug effects; Lung - pathology; Lung - virology; Lungs; Pharmacokinetics; Prophylaxis; Pyrazines - pharmacokinetics; Pyrazines - therapeutic use; Respiratory diseases; SARS-CoV-2; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Toxicity; Treatment Outcome; Vero Cells; Viral diseases; Viral Load - drug effects; Viruses; SARS-CoV-2; preclinical model; hydroxychloroquine; favipiravir; antiviral therapy
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2014441117

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 use of this drug in COVID-19 patients. In contrast, the results with favipiravir demonstrate that an antiviral drug at nontoxic doses exhibits a marked protective effect against SARS-CoV-2 in a small animal model. Clinical studies are required to assess whether a similar antiviral effect is achievable in humans without toxic effects.