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Open AccessArticle

In Vitro Combinations of Baloxavir Acid and Other Inhibitors against Seasonal Influenza A Viruses

1
Centre Hospitalier Universitaire de Québec—Centre Hospitalier de l’Université Laval (CHUQ-CHUL) and Laval University, Québec City, QC G1V 4G2, Canada
2
CIRI—Centre International de Recherche en Infectiologie, (Team VirPath), University Lyon, Inserm U1111, Université Claude Bernard Lyon 1, CNRS—Centre National de la Recherche Scientifique UMR5308, ENS de Lyon, F-69007 Lyon, France
3
Signia Therapeutics SAS, 69100 Villeurbane, France
4
VirNext, Faculté de Médecine RTH Laennec, Université Claude Bernard Lyon 1, Université de Lyon, 69008 Lyon, France
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Viruses 2020, 12(10), 1139; https://doi.org/10.3390/v12101139
Received: 21 September 2020 / Revised: 30 September 2020 / Accepted: 1 October 2020 / Published: 8 October 2020
(This article belongs to the Special Issue Antiviral Drug Combinations)
Two antiviral classes, the neuraminidase inhibitors (NAIs) and polymerase inhibitors (baloxavir marboxil and favipiravir) can be used to prevent and treat influenza infections during seasonal epidemics and pandemics. However, prolonged treatment may lead to the emergence of drug resistance. Therapeutic combinations constitute an alternative to prevent resistance and reduce antiviral doses. Therefore, we evaluated in vitro combinations of baloxavir acid (BXA) and other approved drugs against influenza A(H1N1)pdm09 and A(H3N2) subtypes. The determination of an effective concentration inhibiting virus cytopathic effects by 50% (EC50) for each drug and combination indexes (CIs) were based on cell viability. CompuSyn software was used to determine synergism, additivity or antagonism between drugs. Combinations of BXA and NAIs or favipiravir had synergistic effects on cell viability against the two influenza A subtypes. Those effects were confirmed using a physiological and predictive ex vivo reconstructed human airway epithelium model. On the other hand, the combination of BXA and ribavirin showed mixed results. Overall, BXA stands as a good candidate for combination with several existing drugs, notably oseltamivir and favipiravir, to improve in vitro antiviral activity. These results should be considered for further animal and clinical evaluations. View Full-Text
Keywords: baloxavir; combination; influenza; A(H1N1) virus; A(H3N2) virus; polymerase inhibitors; neuraminidase inhibitors; human airway epithelium baloxavir; combination; influenza; A(H1N1) virus; A(H3N2) virus; polymerase inhibitors; neuraminidase inhibitors; human airway epithelium
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Checkmahomed, L.; Padey, B.; Pizzorno, A.; Terrier, O.; Rosa-Calatrava, M.; Abed, Y.; Baz, M.; Boivin, G. In Vitro Combinations of Baloxavir Acid and Other Inhibitors against Seasonal Influenza A Viruses. Viruses 2020, 12, 1139.

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