Characterization of influenza A and B viruses recovered from immunocompromised patients treated with antivirals

Abstract

Emergence of resistance to neuraminidase inhibitors (NAI) is an uncommon event in immunocompetent adults. We analyzed the drug sensitivity of influenza viruses recovered from three immunocompromised patients following prolonged treatment with antivirals. The sequential isolates recovered for each patient were tested in the NA inhibition (NAI) assay that revealed an emergence of resistance. Oseltamivir-resistant mutants of influenza A viruses acquired substitutions E119V (H3N2) and H274Y (H1N1) in the NA active site, which have previously been shown to confer resistance in immunocompetent humans. Additionally, we detected a novel substitution, D198N, in the NA of the influenza B virus recovered on day 28 of oseltamivir treatment. In the NAI assay, the D198N mutant exhibited a 10-fold reduction in susceptibility to oseltamivir compared with that of the first isolate (32 vs. 304 nM). The susceptibility of this mutant to A-315675 was unaltered (IC 50 value=1.7 nM), but was reduced 5–8 fold against zanamivir and peramivir. The influenza A isolates contained molecular markers of resistance to the M2 channel blockers. Failure to cease virus replication, despite the prolonged antiviral treatment and emergence of the mutants resistant to available drugs, indicates the need for improved strategies to control influenza infection in immunocompromised hosts.