Susceptibility of influenza B viruses to neuraminidase inhibitors: findings from the first 4 years (2008–2012) of the global Influenza Resistance Information Study (IRIS)

Abstract

Background: Type B influenza virus infections continue to account for a substantial proportion of clinical illness. Little is known about comparative disease profiles by virus lineage. A global observational trial (the Influenza Resistance Information Study or IRIS; NCT00884117) was initiated to study neuraminidase inhibitor (NAI) susceptibility and the clinical and virological course of influenza in treated and untreated patients. Materials and Methods: Patients in the northern and southern hemispheres (USA, France, Germany, Poland, Norway, Hong Kong, Australia) with influenza-like illness and/or a positive rapid influenza test result were enrolled. Throat/nasal swabs were performed on Days 1, 3 (self-swab), 6 and 10 and tested for influenza A and B viruses by RT-PCR. Influenzapositive samples collected on Days 1, 6 or 10 were cultured and subsequently sequenced (HA and NA) and phenotypically tested for NAI susceptibility. The lineage of B viruses was determined from sequencing. Clinical information, including the scoring of seven influenza symptoms (scale: 0 [absent], 1 [mild], 2 [moderate], 3 [severe]), was recorded on diary cards by the patient or the patient’s legal guardian (Days 1–12). Symptoms were also assessed by the investigator at each visit. The decision to prescribe an NAI was left to the physician’s discretion. Results: In the first 4 years of IRIS (December 2008 to March 2012), 2262 influenza-positive (RT-PCR) patients were enrolled, of whom 697 presented with a type B influenza virus infection (564 Victoria, 98 Yamagata, 35 undetermined lineage). Most type B patients (402; 58%) were children aged < 13 years. A total of 330 (47%) type B patients were treated with oseltamivir (as monotherapy) within 2 days of symptom onset; a further 26 started oseltamivir 2 days after symptom onset. Eleven patients received zanamivir, one received amantadine and another received rimantidine. A total of 328 (47%) did not receive any influenza antiviral. Symptoms were mild to moderate on Day 1 (mean total score: 12.8, treated; 12.9, untreated), and the mean temperature on Day 1 was 38.2°C. All viruses obtained at baseline or postbaseline were susceptible to NAIs: mean (SD) IC50 values for oseltamivir were 4.8 nM (2.5 nM) and 5.5 nM (2.3 nM) for the Victoria and Yamagata viruses, respectively; the corresponding values for zanamivir were 2.0 nM (1.4 nM) and 2.9 nM (1.6 nM), respectively. No known NAI resistance mutations were detected by NA or HA population sequencing. The proportion of RT-PCR–positive patients on Day 6 was 130/309 (42.1%) for patients treated with oseltamivir and 152/312 (48.7%) for untreated patients. In Kaplan–Meier analyses, no significant differences in median time to influenza RNA clearance were found between oseltamivir-treated and -untreated patients, either in adults or children. The time to symptom resolution (all symptom scores ≤ 1) was 5 days (95% CI, 4–5 days) in oseltamivir-treated children and 6 days (95% CI, 5–6 days) in untreated children (P = .026), but no significant difference in symptom resolution time was found in adults (Kaplan–Meier analysis). Conclusions: Analysis of type B influenza viruses obtained globally between 2008 and 2012 showed that all pre-treatment B/Victoria and B/Yamagata viruses were susceptible to oseltamivir and zanamivir. Moreover, no resistant viruses were detected during treatment. Given the non-randomised design of this study, no definitive conclusions can be drawn with regard to the clinical benefit of oseltamivir in patients infected with type B influenza viruses.