Therapeutic activity of intramuscular peramivir in mice infected with a recombinant influenza A/WSN/33 (H1N1) virus containing the H275Y neuraminidase mutation

Abstract

The therapeutic activity of intramuscular (IM) peramivir was evaluated in mice infected with a recombinant influenza A/WSN/33 virus containing the H275Y neuraminidase (NA) mutation known to confer oseltamivir resistance. Regimens consisted of single (90 mg/kg of body weight) or multiple (45 mg/kg daily for 5 days) IM peramivir doses that were initiated 24 h or 48 h postinfection (p.i.). An oral oseltamivir regimen (1 or 10 mg/kg daily for 5 days) was used for comparison. Untreated animals had a mortality rate of 75% and showed a mean weight loss of 16.9% on day 5 p.i. When started at 24 h p.i., both peramivir regimens prevented mortality and significantly reduced weight loss (P < 0.001) and lung viral titers (LVT) (P < 0.001). A high dose (10 mg/kg) of oseltamivir initiated at 24 h p.i. also prevented mortality and significantly decreased weight loss (P < 0.05) and LVT (P < 0.001) compared to the untreated group results. In contrast, a low dose (1 mg/kg) of oseltamivir did not show any benefits. When started at 48 h p.i., both peramivir regimens prevented mortality and significantly reduced weight loss (P < 0.01) and LVT (P < 0.001) whereas low-dose or high-dose oseltamivir regimens had no effect on mortality rates, body weight loss, and LVT. Our results show that single-dose and multiple-dose IM peramivir regimens retain clinical and virological activities against the A/H1N1 H275Y variant despite some reduction in susceptibility when assessed in vitro using enzymatic assays. IM peramivir could constitute an alternative for treatment of oseltamivir-resistant A/H1N1 infections, although additional studies are warranted to support such a recommendation.

Fig 1

Impact of NAI regimens, starting at 24 h (A) or 48 h (B) after viral challenge, on body weight loss in mice infected with 6.9 × 10³ PFU (A) or 8 × 10³ PFU (B) of the recombinant A/WSN/33 (H1N1) WT virus. Regimens consisted of a single dose (90 mg/kg) or multiple doses (5 × 45 mg/kg, once daily [q.d.]) of IM peramivir (Per) and low-dose (1 mg/kg, q.d.) or high-dose (10 mg/kg, q.d.) oral oseltamivir (Osel). Each symbol represents the mean weight gain or loss of 12 mice ± standard deviation (SD).

Fig 2

Impact of NAI regimens starting at 24 h (A) or 48 h (B) after viral challenge on body weight loss in mice infected with 5.7 × 10³ PFU of the recombinant A/WSN/33 (H1N1) H275Y NA mutant. Regimens consisted of a single dose (90 mg/kg) or multiple doses (5 × 45 mg/kg, q.d.) of IM peramivir and low-dose (1 mg/kg, q.d.) or high-dose (10 mg/kg, q.d.) oral oseltamivir. Each symbol represents the mean weight gain or loss of 12 mice ± SD.