The combined treatment of Molnupiravir and Favipiravir results in a potentiation of antiviral efficacy in a SARS-CoV-2 hamster infection model.

Amides / pharmacology Animals Antiviral Agents / pharmacology COVID-19 / transmission Cytidine / analogs & derivatives Disease Models, Animal Drug Therapy, Combination Female Hydroxylamines / pharmacology Lung / virology Mesocricetus Pyrazines / pharmacology RNA, Viral Treatment Outcome Viral Load COVID-19 Drug Treatment

Antivirals Favipiravir, hamsters, coronavirus Molnupiravir SARS-CoV-2

Journal

EBioMedicine

ISSN: 2352-3964

Titre abrégé: EBioMedicine

Pays: Netherlands

ID NLM: 101647039

Informations de publication

Date de publication:
Oct 2021

Historique:

received: 15 06 2021

revised: 09 09 2021

accepted: 09 09 2021

pubmed: 28 9 2021

medline: 12 11 2021

entrez: 27 9 2021

Statut: ppublish

Résumé

Favipiravir and Molnupiravir, orally available antivirals, have been reported to exert antiviral activity against SARS-CoV-2. First efficacy data have been recently reported in COVID-19 patients. We here report on the combined antiviral effect of both drugs in a SARS-CoV-2 Syrian hamster infection model. The infected hamsters were treated twice daily with the vehicle (the control group) or a suboptimal dose of each compound or a combination of both compounds. When animals were treated with a combination of suboptimal doses of Molnupiravir and Favipiravir at the time of infection, a marked combined potency at endpoint is observed. Infectious virus titers in the lungs of animals treated with the combination are reduced by ∼5 log10 and infectious virus are no longer detected in the lungs of >60% of treated animals. When start of treatment was delayed with one day a reduction of titers in the lungs of 2.4 log10 was achieved. Moreover, treatment of infected animals nearly completely prevented transmission to co-housed untreated sentinels. Both drugs result in an increased mutation frequency of the remaining viral RNA recovered from the lungs of treated animals. In the combo-treated hamsters, an increased frequency of C-to-T mutations in the viral RNA is observed as compared to the single treatment groups which may explain the pronounced antiviral potency of the combination. Our findings may lay the basis for the design of clinical studies to test the efficacy of the combination of Molnupiravir/Favipiravir in the treatment of COVID-19. stated in the acknowledgment.

Sections du résumé

BACKGROUND BACKGROUND

Favipiravir and Molnupiravir, orally available antivirals, have been reported to exert antiviral activity against SARS-CoV-2. First efficacy data have been recently reported in COVID-19 patients.

METHODS METHODS

We here report on the combined antiviral effect of both drugs in a SARS-CoV-2 Syrian hamster infection model. The infected hamsters were treated twice daily with the vehicle (the control group) or a suboptimal dose of each compound or a combination of both compounds.

FINDINGS RESULTS

When animals were treated with a combination of suboptimal doses of Molnupiravir and Favipiravir at the time of infection, a marked combined potency at endpoint is observed. Infectious virus titers in the lungs of animals treated with the combination are reduced by ∼5 log10 and infectious virus are no longer detected in the lungs of >60% of treated animals. When start of treatment was delayed with one day a reduction of titers in the lungs of 2.4 log10 was achieved. Moreover, treatment of infected animals nearly completely prevented transmission to co-housed untreated sentinels. Both drugs result in an increased mutation frequency of the remaining viral RNA recovered from the lungs of treated animals. In the combo-treated hamsters, an increased frequency of C-to-T mutations in the viral RNA is observed as compared to the single treatment groups which may explain the pronounced antiviral potency of the combination.

INTERPRETATION CONCLUSIONS

Our findings may lay the basis for the design of clinical studies to test the efficacy of the combination of Molnupiravir/Favipiravir in the treatment of COVID-19.

FUNDING BACKGROUND

stated in the acknowledgment.

Identifiants

DOI: 10.1016/j.ebiom.2021.103595 PMID: 34571361 PMC: PMC8461366

pubmed: 34571361

pii: S2352-3964(21)00388-1

doi: 10.1016/j.ebiom.2021.103595

pmc: PMC8461366

pii:

doi:

Substances chimiques

Amides 0

Antiviral Agents 0

Hydroxylamines 0

Pyrazines 0

RNA, Viral 0

Cytidine 5CSZ8459RP

favipiravir EW5GL2X7E0

molnupiravir YA84KI1VEW

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

103595

Informations de copyright

Déclaration de conflit d'intérêts

Declaration of Competing Interest None to declare.