Prophylactic activity of intramuscular peramivir in mice infected with a recombinant influenza A/WSN/33 (H1N1) virus containing the H274Y neuraminidase mutation

Abstract

Peramivir is a neuraminidase (NA) inhibitor (NAI) under development that must be administered by the systemic route. The prophylactic activity of intramuscular (IM) peramivir was evaluated with mice infected with wild-type (WT) and oseltamivir-resistant (H274Y NA mutant) recombinant influenza A/WSN/33 (H1N1) viruses. Treatment regimens consisted of IM injections starting 1 h before viral challenge that were single (45 mg/kg or 90 mg/kg) or multiple (45 mg/kg daily for 5 days). All peramivir regimens prevented mortality and weight loss while significantly reducing lung viral titers (LVT) in mice infected with the WT virus. For animals infected with the H274Y mutant, the multiple-dose regimen completely prevented mortality and was associated with significant reduction in weight loss and LVT compared to untreated animals. In contrast, both single-treatment regimens reduced mortality and weight loss but did not significantly reduce LVT. Although further experiments using different influenza A/H1N1 virus strains and other animal models are needed, our results suggest that 5-day IM peramivir therapy may be considered a prophylactic alternative to control influenza infections caused by oseltamivir-resistant viruses with the H274Y mutation.

FIG. 1.

Impact of IM peramivir regimens on survival in mice infected with 8 × 10³ PFU of the recombinant WT or H274Y neuraminidase mutant influenza A/H1N1 viruses. Peramivir regimen treatments were single (45 mg/kg or 90 mg/kg) or multiple (45 mg/kg once daily for 5 days). The survival curves for mice infected with the WT (A) and the H274Y mutant (B) are shown.

FIG. 2.

Impact of IM peramivir regimens on body weight loss in mice infected with 8 × 10³ PFU of the recombinant WT (A) or H274Y neuraminidase mutant (B) influenza A/H1N1 viruses. Peramivir regimen treatments were single (45 mg/kg or 90 mg/kg) or multiple (45 mg/kg once daily for 5 days). Uninfected mice that received PBS or multiple doses (45 mg/kg once daily for 5 days) as a peramivir regimen were used as controls.

FIG. 3.

Impact of IM peramivir regimens on lung viral titers in mice infected with 8 × 10³ PFU of the recombinant WT or H274Y neuraminidase mutant influenza A/H1N1 viruses. Peramivir regimen treatments were single (45 mg/kg or 90 mg/kg) or multiple (45 mg/kg once daily for 5 days). Lungs were removed from subgroups of 4 mice that were sacrificed on day 4 postinfection. Viral titers were determined by plaque assays in triplicate experiments. Mean lung viral titers with standard deviations are shown. Asterisks denote significant reduction in viral titers (P < 0.05) compared to the corresponding WT- or H274Y NA mutant-untreated groups.