Five years of monitoring for the emergence of oseltamivir resistance in patients with influenza A infections in the Influenza Resistance Information Study

Abstract

Background and objectives: The Influenza Resistance Information Study (IRIS) was initiated in 2008 to study the emergence of neuraminidase inhibitor (NAI) resistance and the clinical course of influenza in immunocompetent treated and untreated patients.

Methods: Patients had throat/nose swabs collected on days 1, 3, 6 and 10 for analyses of influenza type, subtype and virus susceptibility to NAIs. RT-PCR-positive samples were cultured and tested for NAI resistance by specific RT-PCR and phenotypic testing. Scores for influenza symptoms were recorded on diary cards (Days 1-10). This study focuses on influenza A-infected cases only.

Results: Among 3230 RT-PCR-positive patients, 2316 had influenza A of whom 1216 received oseltamivir monotherapy within 2 days of symptom onset (9 seasonal H1N1; 662 H3N2; 545 H1N1pdm2009). Except for 9 patients with naturally resistant seasonal H1N1 (2008/9), no resistance was detected in Day 1 samples. Emergence of resistance (post-Day 1) was detected in 43/1207 (3.56%) oseltamivir-treated influenza A-infected patients, with a higher frequency in 1- to 5-year-olds (11.8%) vs >5-year-olds (1.4%). All N1- and N2-resistant viruses had H275Y (n = 27) or R292K (n = 16) substitutions, respectively. For 43 patients, virus clearance was significantly delayed vs treated patients with susceptible viruses (8.1 vs 10.9 days; P < .0001), and 11 (23.2%) remained RT-PCR positive for influenza at Day 10. However, their symptoms resolved by Day 6 or earlier.

Conclusions: Oseltamivir resistance was only detected during antiviral treatment, with the highest incidence occurring among 1- to 5-year-olds. Resistance delayed viral clearance, but had no impact on symptom resolution.

Keywords: antiviral; influenza; neuraminidase inhibitor; resistance.

Figure 1

Geographic distribution and patient recruitment during years 1 to 5 of the IRIS study. IRIS, the Influenza Resistance Information Study

Figure 2

Flow chart of recruitment of patients included in the study. No trt, no treatment; H1N1s, Seasonal H1N1 circulating before the H1N1pdm09 2009 pandemic

Figure 3

Time (days) from symptom onset to first laboratory record with influenza A RNA not detected. Pairwise comparisons between patients with no treatment vs patients treated with oseltamivir (within 48 hours of symptom onset) and vs treated patient with a resistant virus. Both treated and untreated populations included patients infected by influenza A viruses, with no detection of resistant viruses. *The 49 resistant patients comprise 40 patients infected with H3N2 or H1N1pdm09 who developed resistance during the study plus 9 patients infected with seasonal H1N1. All 49 patients were in the treated group. Three patients (2 with H1N1pdm09 and one with H3N2) developed oseltamivir resistance during the study but were not treated until Day 3. These patients are not included in this comparison as they do not meet the definition

Figure 4

Time (days) from symptom onset to all diary cards symptoms becoming mild or absent. Pairwise comparisons between patients with no treatment vs patients treated with oseltamivir (within 48 hours of symptom onset) or treated patient with a resistant virus. The study populations for this comparison are the same as those for the time to RNA not being detected, above. The smaller numbers are due to some patients not supplying a diary card or having no symptoms greater than mild at baseline. *There are only 47 resistant patients, 2 fewer than in the previous comparison (Fig 3) because one had only mild symptoms at baseline and one did not return a diary card. ^$Confidence limits could not be calculated for the untreated group due to the number of patients who were censored close to the final visit