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

Abstract

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 300 mg/kg/day bid for 5 d starting at −2 h gave 30 and 60% protection from death, respectively, due to the A/Mississippi/03/2001 infection. Intraperitoneal treatments with zanamivir at 30 and 100 mg/kg/day starting at −2 h gave 60 and 90% protection, respectively. Neither compound at ≤300 mg/kg/day protected mice when treatments began at +24 h. Amantadine was effective at 10, 30, and 100 mg/kg/day, rimantadine was protective at 10 and 30 mg/kg/day (highest dose tested), and ribavirin was active at 30 and 75 mg/kg/day, with survival ranging from 60–100% for oral treatments initiated at −2 h. For treatments begun at +24 h, amantadine was protective at 30 and 100 mg/kg/day, rimantadine showed efficacy at 10 and 30 mg/kg/day, and ribavirin was active at 75 mg/kg/day, with 60–100% survival per group. In the A/Hong Kong/2369/2009 infection, oral oseltamivir at 100 and 300 mg/kg/day starting at −2 h 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.

A molecularly engineered antiviral banana lectin inhibits fusion and is efficacious against influenza virus infection in vivo

“…Because influenza strains resistant to the standard-of-care therapy, oseltamivir, do circulate in certain years (7,14,15), we sought to evaluate whether H84T is effective against oseltamivir-resistant viruses. Indeed, H84T inhibited replication of A/Mississippi/3/2001-H275Y (H1N1), a strain reported to be oseltamivir-resistant (16)(17)(18), in Madin-Darby canine kidney (MDCK) cells, with an EC 90 value of 0.074 μg/mL (2.4 nM), as compared to >100 μg/mL for oseltamivir. H84T treatment also decreased spreading infection of two other oseltamivirresistant viruses in tissue culture, A/Texas/12/2007 (H3N2) and A/Louisiana/08/2013 (H1N1)pdm09 (SI Appendix, Fig.…”

Evaluation of cytotoxic, antiviral effect and mutagenic potential of a micronutrient combination in vitro cell culture

“…Ribavirin is used as standard antiviral drug and an antiviral agent effective against a wide variety of viruses, including Hepatitis C Virus and influenza virus. It is effective in treatment and prevention of oseltamivir resistant influenza at 75mg/kg/day and 30mg/kg doses respectively (Smee et al 2012). Cytotoxicity studies of ribavirin have been controversial in terms of high dose toxicity.…”

Combinations of 1,8‐cineol and oseltamivir for the treatment of influenza virus A (H3N2) infection in mice

“…A novel therapy suggests treating influenza virus infection with the combination of anti‐inflammatory agents based on a finding that hyper‐activated cytokine, chemokine responses and uncontrolled viral replication may be a contributing factor to disease manifestation. This can be regarded as a new treatment design constituting the utilization of inflammation inhibitors . Moreover, the expression levels of many cytokines are regulated by nuclear factor (NF)‐κB activation, through a MyD88‐dependent pathway stimulating pro‐inflammatory cytokines .…”