Prospective Surveillance of Antiviral Resistance in Hospitalized Infants Less than 12 Months of Age with A(H3N2) Influenza Infection and Treated with Oseltamivir

Abstract

Background

Infants exhibit elevated influenza virus loads and prolonged viral shedding, which may increase the risk for resistance development, especially in cases of suboptimal exposure to antiviral therapy.

Methods

We performed a prospective surveillance of hospitalized infants undergoing oseltamivir therapy during the 2008–2009 and 2011–2012 influenza seasons at two paediatric hospitals in Germany. A total of 37 infants less than 1 year of age with laboratory confirmed influenza A(H3N2) infection received oseltamivir as per physician's order for 5 days (2008–2009 season: 2 mg/kg twice daily; 2011–2012 season: 2.0 mg/kg; 2.5 mg/kg and 3.0 mg/kg twice daily for infants <1 month; 2–3 months and 4–12 months, respectively). Virus load, the susceptibility to neuraminidase inhibitors (NAIs), and the presence of molecular markers of resistance to NAIs was assessed for influenza viruses recovered from respiratory samples collected at baseline and during follow-up visits.

Results

Overall, 73% of the infants continued to shed viral RNA detectable by reverse transcription (RT)-PCR after dose number 10 of oseltamivir; 12 infants shed viruses, 2 of them (both 9 months of age) shed resistant viruses. Resistance was characterized by ≥1,000-fold increase of 50% inhibitory concentration (IC₅₀) for oseltamivir, up to 50-fold for zanamivir and elevated Km values when compared to susceptible A(H3N2) strains. Sanger sequencing revealed the selection of the NA-R292K substitution in both instances (after dose number 10 on day 6).

Conclusions

Our data suggest that it may be relevant to monitor antiviral resistance systematically in all infants, considering that the European Medicines Agency has recently extended the licensure for oseltamivir to include full-term infants.

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