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

by Selleckchem | Jul 09 2023

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.

Comments:

Summary: The widespread resistance of influenza viruses to neuraminidase (NA) inhibitors and the polymerase inhibitor baloxavir is a significant public health concern. Two specific amino acid mutations, R152K in NA and I38T in polymerase acidic (PA), are responsible for conferring resistance to NA inhibitors and baloxavir, respectively. In this study, researchers generated recombinant A(H1N1)pdm09 viruses with either NA-R152K, PA-I38T, or both mutations using a plasmid-based reverse genetics system. They then characterized the virological properties of these mutant viruses in vitro and in vivo and tested the effectiveness of oseltamivir, baloxavir, and favipiravir against these mutant viruses.

The results showed that the three mutant viruses exhibited similar or even superior growth kinetics and virulence compared to the wild-type virus. While oseltamivir and baloxavir effectively inhibited the replication of the wild-type virus in vitro, they failed to suppress the replication of the NA-R152K and PA-I38T mutant viruses, respectively. The mutant virus possessing both mutations was able to grow in the presence of oseltamivir or baloxavir in vitro. In animal experiments, baloxavir treatment protected mice from lethal infection caused by the wild-type or NA-R152K virus but failed to protect against the PA-I38T or PA-I38T/NA-R152K virus. On the other hand, favipiravir treatment successfully protected mice from lethal infection caused by all tested viruses, while oseltamivir treatment provided no protection.

Based on these findings, the researchers concluded that favipiravir should be considered as a treatment option for patients suspected of having baloxavir-resistant influenza virus infection. This suggests that favipiravir may be an effective alternative when NA inhibitors and baloxavir are no longer effective due to widespread resistance.