Treatment of oseltamivir-resistant influenza A (H1N1) virus infections in mice with antiviral agents.

Influenza A/Mississippi/03/2001 (H1N1) and A/Hong Kong/2369/2009 (H1N1) viruses containing the neuraminidase gene mutation H275Y (conferring resistance to oseltamivir) were adapted to mice and evaluated for suitability as models for lethal infection and antiviral treatment. The viral neuraminidases were resistant to peramivir and oseltamivir carboxylate but sensitive to zanamivir. Similar pattern of antiviral activity were seen in MDCK cell assays. Lethal infections were achieved in mice with the two viruses. Oral oseltamivir at 100 and 300mg/kg/day bid for 5day starting at -2h gave 30% and 60% protection from death, respectively, due to the A/Mississippi/03/2001 infection. Intraperitoneal treatments with zanamivir at 30 and 100mg/kg/day starting at -2h gave 60% and 90% protection, respectively. Neither compound at <300mg/kg/day protected mice when treatments began at +24h. Amantadine was effective at 10, 30, and 100mg/kg/day, rimantadine was protective at 10 and 30mg/kg/day (highest dose tested), and ribavirin was active at 30 and 75mg/kg/day, with survival ranging from 60-100% for oral treatments initiated at -2h. For treatments begun at +24h, amantadine was protective at 30 and 100mg/kg/day, rimantadine showed efficacy at 10 and 30mg/kg/day, and ribavirin was active at 75mg/kg/day, with 60-100% survival per group. In the A/Hong Kong/2369/2009 infection, oral oseltamivir at 100 and 300mg/kg/day starting at -2h gave 50% and 70% protection from death, respectively. These infection models will be useful to study newly discovered anti-influenza virus agents and to evaluate compounds in combination.