Influenza polymerase inhibitor resistance: Assessment of the current state of the art - A report of the isirv Antiviral group.

It is more than 20 years since the neuraminidase inhibitors, oseltamivir and zanamivir were approved for the treatment and prevention of influenza. Guidelines for global surveillance and methods for evaluating resistance were established initially by the Neuraminidase Inhibitor Susceptibility Network (NISN), which merged 10 years ago with the International Society for influenza and other Respiratory Virus Diseases (isirv) to become the isirv-Antiviral Group (isirv-AVG). With the ongoing development of new influenza polymerase inhibitors and recent approval of baloxavir marboxil, the isirv-AVG held a closed meeting in August 2019 to discuss the impact of resistance to these inhibitors.

Substitutions at H134 and in the 430-loop region in influenza B neuraminidases can confer reduced susceptibility to multiple neuraminidase inhibitors.

With the introduction of the influenza specific neuraminidase inhibitors (NAIs) in 1999, there were concerns about the emergence and spread of resistant viruses in the community setting. Surveillance and testing of community isolates for their susceptibility to the NAIs was initially carried out by the Neuraminidase Inhibitor Susceptibility Network (NISN) and has subsequently been taken on by the global WHO influenza network laboratories. During the NISN surveillance, we identified two Yamagata lineage influenza B viruses with amino acid substitutions of H134Y (B/Auckland/2/2001) or W438R (B/Yokohama/12/2005) which had slightly elevated IC values for zanamivir and/or oseltamivir, but not sufficiently to be characterized as mild outliers at the time.

Passaging of an influenza A(H1N1)pdm09 virus in a difluoro sialic acid inhibitor selects for a novel, but unfit I106M neuraminidase mutant.

An influenza A(H1N1)pdm09 and an influenza B virus were passaged in 3-fluoro(eq)-4-guanidino difluoro sialic acid (3Feq4Gu DFSA), an inhibitor of the influenza neuraminidase (NA) to determine whether resistant variants could be selected. 3Feq4Gu DFSA is a mechanism-based inhibitor, forming a covalent link to Y406 in the NA active site. Given its similarity to the natural substrate, sialic acid, we predicted resistant variants would be difficult to select.