94. Emergence of Oseltamivir Resistance in Patients with Influenza A Infections in the Influenza Resistance Information Study (IRIS) is Age-Related and has Little Effect on Clinical Outcomes
Session: Oral Abstract Session: Influenza
Thursday, October 18, 2012: 9:00 AM
Room: SDCC 25 ABC
Background: Following naturally-occurring oseltamivir resistance in 2008, a global observational trial, the Influenza Resistance Information Study (IRIS; NCT00884117) was initiated to study neuraminidase inhibitor (NAI) resistance and the clinical course of influenza in treated and untreated patients.

Methods: Patients with influenza-like illness and/or a positive rapid test result for influenza had throat/nose swabs collected on Days 1, 3, 6 and 10 for real-time RT-PCR analyses of influenza type, subtype and NAI resistance. Positive samples were cultured, sequenced (HA, NA and M2) and phenotypically tested for NAI resistance. Scores for seven influenza symptoms (0 [absent], 1 [mild], 2 [moderate], 3 [severe]) were recorded on diary cards by the patient (Days 1–12).

Results: Of 1855 RT-PCR-positive patients with a single influenza strain infection in years 1 to 3 (925 aged 1–12 years), 1310 had influenza A of whom 700 received oseltamivir monotherapy within 2 days of symptom onset (seasonal H1, 9/47 [19%]; H3N2, 222/335 [66%]; H1N1 [2009], 469/928 [51%]). Emergent resistance (post-Day 1) was detected by mutation-specific RT-PCR in 19 oseltamivir-treated influenza A patients (see Table). In 12 of the 19, viral loads in the sample in which resistance first appeared were too low for phenotyping; in 6 of the 7 that were tested, IC50 was > 10-fold Day 1 mean (extreme outliers). Five of 19 patients (26%) were still RT-PCR positive at Day 10 (cf. 152/1022 (15%) for all influenza A), but their symptoms resolved by Day 6 (combined score ≤2). One other patient with emergent resistance (1-year-old; H275Y in Day 6 sample) had moderate or minor symptoms up to Day 14 and persistent poor appetite, although he was RT-PCR negative on Day 10.

Conclusion: In years 1–3 of IRIS, emergent resistance to oseltamivir in influenza A viruses was mostly found in 1–5-year-olds; this had modest effect on viral clearance and no effect on symptom resolution.

Table. Emergent resistance (mutation-specific RT-PCR) by age group

Age group

Resistance mutation

Resistant sample not cultured (low viral load)

Virus-negative by RT-PCR at Day 10

Resistance rate (treated influenza A patients)

H275Y in H1N1 (2009)

R292K in H3N2

1–5 years

13

1

8

10

14/139 (10.1%)

6–12 years

1

0

1

0

1/149 (0.7%)

≥13 years

3

1

3

4

4/375 (1.1%)

Martin Schutten, PhD1, Charles Boucher2, Regina Dutkowski3, Klaus Klumpp3, Bruno Lina4, Arnold Monto, MD5, Ann Nist3, Albert Osterhaus6, Jonathan Nguyen-Van-Tam7, Xiao Tong3 and Richard Whitley, MD, FIDSA8, (1)Virology, Erasmus Medical Center, Rotterdam, Netherlands, (2)Erasmus Medical Centre, Rotterdam, Netherlands, (3)Hoffmann-La Roche, Inc., Nutley, NJ, (4)University of Lyon, Lyon, France, (5)University of Michigan School of Public Health, Ann Arbor, MI, (6)Rotterdam, Netherlands, (7)University of Nottingham, Nottingham, United Kingdom, (8)University of Alabama at Birmingham, Birmingham, AL

Disclosures:

M. Schutten, F. Hoffmann-La Roche, Ltd: Research Contractor and Scientific Advisor, Consulting fee and Research grant

C. Boucher, F. Hoffmann-La Roche, Ltd: Scientific Advisor, Research support

R. Dutkowski, Hoffmann-La Roche, Inc.: Employee, Salary and Stock options

K. Klumpp, Hoffmann-La Roche, Inc.: Employee, Salary

B. Lina, F. Hoffmann-La Roche, Ltd: Consultant and Scientific Advisor, Consulting fee and Speaker honorarium

A. Monto, F. Hoffmann-La Roche, Ltd: Consultant and Scientific Advisor, Consulting fee

A. Nist, Hoffmann-la Roche, Inc.: Employee, Salary

A. Osterhaus, F. Hoffmann-La Roche, Ltd: Scientific Advisor, Research grant

J. Nguyen-Van-Tam, F. Hoffmann-La Roche, Ltd: Grant Investigator and Scientific Advisor, Educational grant and Honoraria for attendance at Scientific Advisory Boards (no such payments since September 2010)

X. Tong, Hoffmann-La Roche, Inc.: Employee, Salary

R. Whitley, F. Hoffmann-La Roche: Scientific Advisor, Consulting fee

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