[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]
Virus susceptibility analyses from a phase IV clinical trial of inhaled zanamivir treatment in children infected with influenza
Phillip J Yates 1,*, Nalini Mehta 1, Joseph Horton 2 and Margaret Tisdale 1
Author Affiliations: 1GlaxoSmithKline R&D, Stevenage, UK 2GlaxoSmithKline R&D, RTP, USA
A zanamivir post-approval efficacy study was conducted in children (n=279) in Japan during 3 influenza seasons. Pharyngeal swabs (n=714) were obtained for detailed resistance analysis.
From 371 cultured viruses, three viruses (A/H1N1) from two subjects showed reduced susceptibility to zanamivir at Day 1(before treatment), one had a N74S amino acid substitution (fold shift of 46), and two ( Day 1 and Day 2) a Q136K amino acid substitution (fold shift of 292 and 301). The Q136K was only detected in cultured virus and not the swab. From the remaining 118 cultured viruses obtained during or after treatment with zanamivir, no shifts in virus susceptibility were detected. NA population sequencing showed that viruses from twelve subjects had emergent amino acid substitutions but three, with susceptibility data, were not zanamivir resistant. The remainder may be natural variants. Further analysis is planned.
HA sequencing, showed viruses from 20 subjects had 9 HA amino acid substitutions implicated previously in resistance to NIs in in vitro assays or were close to the Receptor Binding site. Their role in in vivo resistance appears to be less important, but is not well understood.
NA clonal sequence analysis was undertaken to determine if minority species of resistant viruses were present. A total of 1,682 clones were analysed from 90 subjects. Single clones from 12 subjects contained amino acid substitutions close to the NA active site. It is unclear whether these single amino acid substitutions could have been amplified after drug pressure or just chance mutations.
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