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

Liva Checkmahomed,Mariana Baz,Andrés Pizzorno,Olivier Terrier,Blandine Padey,Yacine Abed,Manuel Rosa-Calatrava,Guy Boivin

doi:10.3390/v12101139

Abstract

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.

Highlights

Since 1977, two subtypes of influenza A viruses, H1N1 and H3N2, along with influenza B viruses, have co-circulated in the human population
Based on the results obtained in ST6-GalI-MDCK cells, we further evaluated the efficacy of the selected two-drug combination ratios determined in Table 2A in the MucilAirTM reconstituted human airway epithelia (HAE)
Antivirals play a crucial role in the treatment and control of influenza epidemics and pandemics [33]

Summary

Introduction

Since 1977, two subtypes of influenza A viruses, H1N1 and H3N2, along with influenza B viruses, have co-circulated in the human population. Neuraminidase inhibitors (NAIs), such as oseltamivir, zanamivir, peramivir and lanamivir, constitute the main recommended drugs for the treatment of influenza viruses in many countries [9,10,11] These drugs inhibit the neuraminidase (a glycoprotein that enables the virus to be released from host cell) which reduces clinical illness [9,12]. In addition to this major class of antivirals, RNA-dependent RNA polymerase (RdRp) inhibitors are approved in a few countries to treat influenza A and B viruses. We assessed the inhibitory effects of BXA with three NAIs (oseltamivir, zanamivir and peramivir) or two other polymerase inhibitors (favipiravir and ribavirin) in cell cultures and in human airway epithelia (HAE) infected with influenza

Methods

Results

Conclusion