760. Detection of Oseltamivir Resistance in Influenza Viruses: Insights from a Ferret Model
Session: Poster Abstract Session: Vaccines: Pediatric
Thursday, October 27, 2016
Room: Poster Hall
Background: A high prevalence of resistance to M2 blockers leaves neuraminidase (NA) inhibitors as the only treatment option for seasonal influenza. Natural genetic variance and treatment are associated with emergence of influenza viruses with mutations at the drug binding site in the NA. Effect of NA mutations on the drug’s ability to inhibit viral enzymatic activity is assessed using NA inhibition (NI) assays. However, results from this assay have not been directly correlated to clinical effectiveness of drug in humans.

Methods: We evaluated the effect of oseltamivir treatment in ferrets infected with viruses that had highly reduced inhibition (HRI) by oseltamivir in NI assays. Three NA mutant viruses carrying H275Y (A/H1N1pdm09), E119V (A/H3N2) or D197E (flu B) and their wildtype (WT) counterparts were used to infect animals at dose 104 TCID50. Animals were treated twice daily for 5 days with a) 12.5 mg/kg oseltamivir; b) 2.5 mg/kg oseltamivir or c) placebo. Nasal washes were collected daily for 10 consecutive days, and viral titers, inflammatory cell counts and total protein were measured. In addition, temperature, body weights and clinical symptoms were recorded for 14 days.

Results:In ferrets, infection with the NA mutants was either slightly milder or similar to infection with WT viruses. Oseltamivir treatment reduced the peak viral titers by ~1.5-2.5 log TCID50 in the WT-infected animals, while ≤0.2 log reduction was observed in the animals infected with flu A mutant viruses. Notably, 0.8-1.0 log reduction was observed in the drug-treated ferrets infected with flu B virus mutant. Oseltamivir treatment reduced inflammatory cell counts by 21-78% in the nasal washes of the WT-infected animals. This effect was less pronounced in the NA mutant-infected groups (16-41%). Similarly, reduction of the total protein levels in the drug-treated WT-infected groups was 40-91% and 0-58% in the NA mutant-infected drug-treated groups. Improvement of clinical symptoms was also more evident in the oseltamivir-treated WT-infected animals.

Conclusion:Our study provides experimental evidence in support of the usefulness of the functional NI assay to detect influenza viruses likely to have clinically relevant decreased susceptibility to oseltamivir in humans.

Larisa Gubareva, MD, PhD1, Henju Marjuki, Ph.D.1, Vasiliy Mishin, PhD1, Anton Chesnokov, MS1,2, Juan a. De La Cruz, M.S.1,2 and Alicia M. Fry, MD, MPH1, (1)Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA, (2)Battelle Memorial Institute, Atlanta, GA


L. Gubareva, None

H. Marjuki, None

V. Mishin, None

A. Chesnokov, None

J. A. De La Cruz, None

A. M. Fry, None

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