Efficacy of favipiravir against influenza virus resistant to both baloxavir and neuraminidase inhibitors.

Objectives: Widespread resistance of influenza viruses to neuraminidase (NA) inhibitor or polymerase inhibitor, baloxavir, is a major public health concern. The amino acid mutations R152K in NA and I38T in polymerase acidic (PA) are responsible for resistance to NA inhibitors and baloxavir, respectively.
Methods: We generated recombinant A(H1N1)pdm09 viruses possessing NA-R152K, PA-I38T or both mutations by using a plasmid-based reverse genetics system, characterized their virological properties in vitro and in vivo, and examined whether oseltamivir, baloxavir and favipiravir are effective against these mutant viruses.
Results: The three mutant viruses showed similar or superior growth kinetics and virulence to those of wild-type virus. Although oseltamivir and baloxavir blocked the replication of the wild-type virus in vitro, oseltamivir and baloxavir failed to suppress the replication of the NA-R152K and PA-I38T viruses in vitro, respectively. Mutant virus possessing both mutations grew in the presence of oseltamivir or baloxavir in vitro. Baloxavir treatment protected mice from lethal infection with wild-type or NA-R152K virus, but failed to protect mice from lethal infection with PA-I38T or PA-I38T/NA-R152K virus. Favipiravir treatment protected mice from lethal infection with all viruses tested, whereas oseltamivir treatment did not protect at all.
Conclusions: Our findings indicate that favipiravir should be used to treat patients with suspected baloxavir-resistant virus infection.
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