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 objectivesThe 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.MethodsPatients 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.ResultsAmong 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.ConclusionsOseltamivir 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.

Favipiravir, an anti-influenza drug against life-threatening RNA virus infections

“…Oseltamivir, an NAI, has been the treatment of choice for influenza infection. The emergence of a resistant virus (after day 1) was detected in 43/1,207 (3.56%) oseltamivir-treated influenza A-infected patients, with a higher frequency observed in 1-to 5-year-olds (11.8%) than in children aged > 5 years (1.4%), and viral clearance occurred in 8-10 days (Lina, et al, 2018). The overall incidence of an oseltamivir-resistant virus was 10 of 182 (5.5%) (Whitley, et al, 2001) and 9 of 50 (18%) (Kiso, et al, 2004) oseltamivir-treated children.…”

“…The dose of favipiravir used in the study mentioned above was 1,600 mg twice a day on day 1 followed by 600 mg twice a day for 9 days, and the approved favipiravir dose in Japan is 1,600 mg twice a day on day 1 followed by 600 mg twice a day for 4 days. The viral replication period is 6 days or longer for seasonal influenza (Lina, et al, 2018;Memoli, et al, 2014). When drug administration is stopped during the virus replication period or when resistant strains appear, virus replication and fever relapse.…”

Antiviral activity of iridoid glycosides extracted from Fructus Gardeniae against influenza A virus by PACT-dependent suppression of viral RNA replication

“…Although of viral neuraminidase (NA) inhibitors and M2 ion channel blockers are widely used for treatment 12 , some serious side effects and low efficacy have been reported, and the emergence of drug resistant strains is increasing 13,14 . Influenza RNA-dependent RNA polymerase (RdRP) which is composed of three subunits, PA, PB1 and PB2, is a very promising alternative target for novel anti-influenza drug discovery research because it is essential for the transcription and replication of virus genes and is conserved among different types of influenza viruses 15,16 .…”

A Quinolinone Compound Inhibiting the Oligomerization of Nucleoprotein of Influenza A Virus Prevents the Selection of Escape Mutants

“…In clinical studies, resistance to oseltamivir [51] and reduced susceptibility to baloxavir [9] have been reported to occur during treatment. Hence, new antiviral targets for influenza treatments are highly needed to enable the discovery of drugs with reduced potential to induce resistance.…”