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Influenza virus susceptibility and resistance to oseltamivir.

Abstract

Oseltamivir phosphate is a prodrug of oseltamivir carboxylate, a highly specific inhibitor of influenza virus neuraminidases. Given that oseltamivir carboxylate binds to highly conserved, essential amino acids in the catalytic site of the enzyme, and that the activity of neuraminidase is critical for virus release from infected cells and subsequent virus spread, the drug was expected to have a low propensity to select for viable resistant mutants. Indeed, viruses with neuraminidase (and haemagglutinin) substitutions conferring reduced susceptibility to oseltamivir have been generated with difficulty in vitro, and these mutants generally have reduced infectivity and transmissibility compared with wild-type virus in animal models. Studies of seasonal influenza isolates collected before the introduction of oseltamivir show an absence of naturally occurring resistance. Few resistant mutants have arisen during clinical trials of oseltamivir in seasonal influenza, with cumulative data from all Roche-sponsored studies indicating an incidence of resistance of 0.32% in adults (0.4%, including low-level mutants detected by genotyping alone in mixed virus populations) and 4.1% (5.4%) in children. Higher incidences of resistance were observed in two small Japanese studies, in which children received a different dosing schedule from their Western counterparts. In summary, the overall incidence of influenza virus resistance associated with the seasonal use of oseltamivir is currently low and resistant viruses might be of little clinical significance, except perhaps in immunocompromised individuals. However, continued vigilance, especially of emerging avian H5N1 strains, combined with careful, systematic laboratory-based monitoring, is essential.

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  • Authors+Show Affiliations

    ,

    Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada.

    ,

    Source

    Antiviral therapy 12:4 Pt B 2007 pg 603-16

    MeSH

    Adolescent
    Adult
    Aged
    Antiviral Agents
    Child
    Child, Preschool
    Drug Resistance, Viral
    Enzyme Inhibitors
    Humans
    Infant
    Influenza A Virus, H1N1 Subtype
    Influenza A Virus, H2N2 Subtype
    Influenza A Virus, H3N2 Subtype
    Influenza A virus
    Influenza B virus
    Influenza, Human
    Microbial Sensitivity Tests
    Middle Aged
    Mutation
    Neuraminidase
    Oseltamivir

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't
    Review

    Language

    eng

    PubMed ID

    17944268

    Citation

    Aoki, Fred Y., et al. "Influenza Virus Susceptibility and Resistance to Oseltamivir." Antiviral Therapy, vol. 12, no. 4 Pt B, 2007, pp. 603-16.
    Aoki FY, Boivin G, Roberts N. Influenza virus susceptibility and resistance to oseltamivir. Antivir Ther (Lond). 2007;12(4 Pt B):603-16.
    Aoki, F. Y., Boivin, G., & Roberts, N. (2007). Influenza virus susceptibility and resistance to oseltamivir. Antiviral Therapy, 12(4 Pt B), pp. 603-16.
    Aoki FY, Boivin G, Roberts N. Influenza Virus Susceptibility and Resistance to Oseltamivir. Antivir Ther (Lond). 2007;12(4 Pt B):603-16. PubMed PMID: 17944268.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Influenza virus susceptibility and resistance to oseltamivir. AU - Aoki,Fred Y, AU - Boivin,Guy, AU - Roberts,Noel, PY - 2007/10/20/pubmed PY - 2007/11/2/medline PY - 2007/10/20/entrez SP - 603 EP - 16 JF - Antiviral therapy JO - Antivir. Ther. (Lond.) VL - 12 IS - 4 Pt B N2 - Oseltamivir phosphate is a prodrug of oseltamivir carboxylate, a highly specific inhibitor of influenza virus neuraminidases. Given that oseltamivir carboxylate binds to highly conserved, essential amino acids in the catalytic site of the enzyme, and that the activity of neuraminidase is critical for virus release from infected cells and subsequent virus spread, the drug was expected to have a low propensity to select for viable resistant mutants. Indeed, viruses with neuraminidase (and haemagglutinin) substitutions conferring reduced susceptibility to oseltamivir have been generated with difficulty in vitro, and these mutants generally have reduced infectivity and transmissibility compared with wild-type virus in animal models. Studies of seasonal influenza isolates collected before the introduction of oseltamivir show an absence of naturally occurring resistance. Few resistant mutants have arisen during clinical trials of oseltamivir in seasonal influenza, with cumulative data from all Roche-sponsored studies indicating an incidence of resistance of 0.32% in adults (0.4%, including low-level mutants detected by genotyping alone in mixed virus populations) and 4.1% (5.4%) in children. Higher incidences of resistance were observed in two small Japanese studies, in which children received a different dosing schedule from their Western counterparts. In summary, the overall incidence of influenza virus resistance associated with the seasonal use of oseltamivir is currently low and resistant viruses might be of little clinical significance, except perhaps in immunocompromised individuals. However, continued vigilance, especially of emerging avian H5N1 strains, combined with careful, systematic laboratory-based monitoring, is essential. SN - 1359-6535 UR - https://www.unboundmedicine.com/medline/citation/17944268/Influenza_virus_susceptibility_and_resistance_to_oseltamivir_ L2 - https://www.lens.org/lens/search?q=citation_id:17944268 DB - PRIME DP - Unbound Medicine ER -