The development of influenza virus variants with reduced susceptibility following peramivir treatment: an analysis of clinical and post-marketing experience
Methods: The peramivir clinical development program included over 2,800 subjects with laboratory-confirmed influenza infection in 10 phase 2 and 3 studies. The activity of single dose peramivir treatment in the outpatient setting and repeat dose treatment in hospital studies was evaluated. Phenotypic analysis of paired baseline/ post-treatment virus isolates was attempted for all subjects with culturable virus and genotypic analysis of the NA gene (and hemaglutinin [HA] gene in a subset) was conducted on viruses from subjects with prolonged virus shedding or with increased 50% inhibitory concentration (IC50) for peramivir. A surveillance study conducted in Japan since 2010 assessed the prevalence of circulating strains with resistance to peramivir.
Results: Baseline 50% inhibitory concentration (IC50) data was available for over 2300 subjects. Over 1200 subjects were selected for sequence analysis, and partial or complete sequence data was available for 1122 subjects. The only treatment-emergent mutation associated with peramivir exposure detected in more than 1 subject was an H275Y mutation in influenza A/H1N1, which was identified in 13 subjects. Data from postmarketing surveillance in Japan following the approval of peramivir (RAPIACTA™) have identified no novel mutations in circulating seasonal influenza strains that are associated with loss of susceptibility to peramivir.
Conclusion: Loss of sensitivity to peramivir in clinical isolates appears to be associated primarily with development of an H275Y mutation in the NA gene. The incidence of development of treatment-emergent H275Y substitutions in response to treatment with peramivir appears to be low.
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