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Influenza virus susceptibility and resistance to oseltamivir.
Antivir Ther 2007; 12(4 Pt B):603-16AT

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.

Authors+Show Affiliations

Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada.No affiliation info availableNo affiliation info available

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 -