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

Suzanne J F Kaptein, Sofie Jacobs, Lana Langendries, Laura Seldeslachts, Sebastiaan Ter Horst, Laurens Liesenborghs, Bart Hens, Valentijn Vergote, Elisabeth Heylen, Karine Barthelemy, Elke Maas, Carolien De Keyzer, Lindsey Bervoets, Jasper Rymenants, Tina Van Buyten, Xin Zhang, Rana Abdelnabi, Juanita Pang, Rachel Williams, Hendrik Jan ThibautKai Dallmeier, Robbert Boudewijns, Jens Wouters, Patrick Augustijns, Nick Verougstraete, Christopher Cawthorne, Judith Breuer, Caroline Solas, Birgit Weynand, Pieter Annaert, Isabel Spriet, Greetje Vande Velde, Johan Neyts, Joana Rocha-Pereira, Leen Delang

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Abstract

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.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number43
Pages (from-to)26955-26965
Number of pages11
ISSN0027-8424
DOIs
Publication statusPublished - 2020

Keywords

  • Amides/pharmacokinetics
  • Animals
  • Antiviral Agents/therapeutic use
  • Betacoronavirus/drug effects
  • COVID-19/drug therapy
  • Chlorocebus aethiops
  • Coronavirus Infections/drug therapy
  • Cricetinae
  • Disease Models, Animal
  • Disease Transmission, Infectious/prevention & control
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Female
  • Hydroxychloroquine/pharmacokinetics
  • Lung/drug effects
  • Pyrazines/pharmacokinetics
  • SARS-CoV-2
  • Treatment Outcome
  • Vero Cells
  • Viral Load/drug effects

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