R292K Substitution and Drug Susceptibility of Influenza A(H7N9) Viruses

Katrina Sleeman¹, Zhu Guo¹, John Barnes, Michael Shaw, James Stevens, and Larisa V. Gubareva

Author affiliations: Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Abstract

Neuraminidase inhibitors are the only licensed antiviral medications available to treat avian influenza A(H7N9) virus infections in humans. According to a neuraminidase inhibition assay, an R292K substitution reduced antiviral efficacy of inhibitors, especially oseltamivir, and decreased viral fitness in cell culture. Monitoring emergence of R292K-carrying viruses using a pH-modified neuraminidase inhibition assay should be considered.

The recent emergence of an avian influenza A(H7N9) virus causing human infections in China (1,2) is of global concern. Most patients infected during this outbreak have experienced severe disease and required hospitalization; the mortality rate is 21% (3). Although epidemiologic investigations have revealed no evidence of sustained human-to-human transmission (4), suspected limited human-to-human transmission has been reported (3).
As with any emergent influenza virus, it is critical to assess the susceptibility of the influenza A(H7N9) outbreak virus to antiviral drugs, which are the first line of defense before an effective vaccine becomes available. Two classes of antiviral drugs are approved for management of influenza A infections, neuraminidase (NA) inhibitors (NAIs) and matrix 2 protein (M2) blockers (adamantanes). The outbreak viruses carry the established adamantane resistance marker, an S31N substitution in the M2 protein (2), leaving NAIs as the only licensed treatment option. Among the 4 NAIs, oseltamivir and zanamivir are approved in many countries; peramivir has been approved in Japan, South Korea, and China; and laninamivir is approved only in Japan. In contrast to those for adamantanes, genetic markers of resistance to NAIs are often subtype specific and drug specific (5). Therefore, monitoring drug susceptibility of the influenza A(H7N9) viruses requires testing in phenotypic assays using all available NAIs.