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.

• Authors: Yacine Abed, Andrés Pizzorno, Guy Boivin
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 56 Issue 8 Pg. 4375-80 (Aug 2012) ISSN: 1098-6596 [Electronic] United States
• PMID: 22664977 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acids, Carbocyclic
• Antiviral Agents
• Cyclopentanes
• Guanidines
• Viral Proteins
• Oseltamivir
• NA protein, influenza A virus
• Neuraminidase
• peramivir

Topics

• Acids, Carbocyclic
• Animals
• Antiviral Agents (administration & dosage, therapeutic use)
• Cyclopentanes (administration & dosage, therapeutic use)
• Drug Resistance, Viral (genetics)
• Female
• Guanidines (administration & dosage, therapeutic use)
• Influenza A Virus, H1N1 Subtype (drug effects, genetics)
• Injections, Intramuscular
• Mice
• Mice, Inbred BALB C
• Mutation
• Neuraminidase (genetics)
• Orthomyxoviridae Infections (drug therapy, virology)
• Oseltamivir (therapeutic use)
• Treatment Outcome
• Viral Proteins (genetics)