Community- and hospital-acquired infections with oseltamivir- and peramivir-resistant influenza A(H1N1)pdm09 viruses during the 2015-2016 season in Japan

Abstract

We report five cases of community- and hospital-acquired infections with oseltamivir- and peramivir-resistant A(H1N1)pdm09 viruses possessing the neuraminidase (NA) H275Y mutation during January-February 2016 in Japan. One case was hospitalized and was receiving oseltamivir for prophylaxis. The remaining four cases were not taking antiviral drugs at the time of sampling. These cases were geographically distant and epidemiologically unrelated. The five viruses showed ~300-fold rise in IC₅₀ values against oseltamivir and peramivir, defined as highly reduced inhibition according to the WHO definition. Overall, the prevalence of the H275Y A(H1N1)pdm09 viruses was 1.8 % (5/282). The resistant viruses possessed the V241I, N369 K, and N386 K substitutions in the NA that have been previously reported among A(H1N1)pdm09 to alter transmission fitness. Analysis of Michaelis constant (Km) revealed that two of the isolates had reduced NA affinity to MUNANA, while the other three isolates displayed a slightly decreased affinity compared to the sensitive viruses. Further studies are needed to monitor the community spread of resistant viruses and to assess their transmissibility.

Keywords: Antiviral drug susceptibility; Community transmission; Enzymatic property; Influenza virus A(H1N1)pdm09; Neuraminidase; Oseltamivir resistant.

Fig. 1

Phylogenetic analysis of the hemagglutinin (a) and neuraminidase gene (b) of the five H275Y mutant influenza A(H1N1)pdm09 strains isolated in Niigata and Nagasaki, Japan in January to February 2016. Multiple alignment was constructed by the neighbor-joining method with MEGA, version6. Bootstrap value determined for 1000 interactions. Only values of greater than 70 % are shown. The H275Y mutant strains are shown in red, and those detected in the 2015/2016 season are indicated in closed circle. The sensitive strains that were used for enzymatic property measurement (Km and Vmax) are colored blue. Reference sequences of A(H1N1)pdm09 strains downloaded from the GenBank and GISAID EpiFlu Database (www.gisaid.org.). The amino acid substitutions relative to the A/California/07/2009 strain are shown in the phylogenetic tree (Color figure online)