Therapeutic activity of intramuscular peramivir in mice infected with a recombinant influenza A/WSN/33 (H1N1) virus containing the H275Y neuraminidase mutation.
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.
Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, Quebec City, Quebec, Canada.
Yacine
Y
Abed
Andrés
A
Pizzorno
Guy
G
Boivin
D000146:Acids, Carbocyclic; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D003517:Cyclopentanes / Q000008:administration & dosage* / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D006146:Guanidines / Q000008:administration & dosage* / Q000627:therapeutic use; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000235:genetics*; D007273:Injections, Intramuscular; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009439:Neuraminidase / Q000235:genetics*; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000821:virology; D053139:Oseltamivir / Q000627:therapeutic use; D016896:Treatment Outcome; D014764:Viral Proteins / Q000235:genetics*
D000146:Acids, Carbocyclic; D000998:Antiviral Agents; D003517:Cyclopentanes; D006146:Guanidines; D014764:Viral Proteins; D053139:Oseltamivir; C487630:NA protein, influenza A virus; D009439:Neuraminidase; C414210:peramivir