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Isolation of H5N1 Influenza Virus Resistant to Oseltamivir

By Luciana L. Borio, M.D. and John G. Bartlett, M.D., October 18, 2005

In an article to be published in the journal Nature on October 20, 2005, Mai Le and colleagues report on the isolation of H5N1 influenza virus (A/VietNam/Hanoi/30408/2005) resistant to oseltamivir from a 14 year old Vietnamese girl. The girl had received a prophylactic dose of 75 mg qd x 3 days, and then was switched to a therapeutic dose of 75 mg bid x 7 days. The authors note that virus was not isolated after the switch to the higher therapeutic dose.

High-level antiviral resistance to oseltamivir results from the substitution of a single amino acid in N1 neuraminidase (His274Tyr, or H274Y). Sequence analysis of the neuraminidase genes and neuraminidase inhibitor susceptibility testing of the isolates from the girl revealed a “mixed” virus population of amino acid residues 274-H (wild-type) and 274-Y (resistant) sequences. The IC50, which is the dose required for 50% inhibition of neuraminidase activity, was shifted upward, indicating that the virus was less susceptible to oseltamivir when compared with other H5N1 isolates and oseltamivir-sensitive viruses. The girl’s brother, from whom she acquired the infection, was treated with oseltamivir 75 mg bid; sequence analysis revealed wild-type virus.

Experiments in ferrets showed that although viral titers were lower in animals infected with oseltamivir-resistant virus when compared with animals infected with oseltamivir-sensitive virus, therapy with oseltamivir did not reduce viral titers in animals infected with resistant virus. Of note, the resistant strains retained sensitivity to zanamivir, and in ferrets, viral titers were reduced in animals infected with oseltamivir-sensitive or resistant strains that were treated with zanamivir.

In a previous study with H1N1 human influenza A, oseltamivir-resistant variants were detected in up to 18% of children treated with oseltamivir. However, in that study, children weighing less than 15 kg received a dose of oseltamivir lower than typically recommended [1]. Although oseltamivir-resistant H1N1 variants are less infectious in cell culture and less virulent in animals as compared with susceptible virus, they are still transmissible in ferrets [2].

Mai Le’s report is worrisome. If more oseltamivir-resistant viruses were to emerge, our ability to treat patients and prevent disease in close contacts would be severely hampered. The use of prophylactic oseltamivir for the control of an eventual pandemic influenza may need to be revisited given both the limited availability of this drug, and the possibility that lower prophylactic doses may create an environment that fosters the development of resistance [3].

References

  1. Kiso M, Mitamura K, Sakai-Tagawa Y, et al. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet 2004;364(9436):759-65.

  2. Herlocher ML, Truscon R, Elias S, et al. Influenza viruses resistant to the antiviral drug oseltamivir: transmission studies in ferrets. J Infect Dis 2004;190(9):1627-30.

  3. Doucette KE, Aoki FY. Oseltamivir: a clinical and pharmacological perspective. Expert Opin Pharmacother 2001;2(10):1671-83.