Cluster of Oseltamivir-Resistant and Hemagglutinin Antigenically Drifted Influenza A(H1N1)pdm09 Viruses, Texas, USA, January 2020

Abstract

R esistance to antiviral drugs for infl uenza is an ongoing public health concern. The neuraminidase (NA) inhibitor oseltamivir is the most prescribed antiviral drug for controlling infl uenza. However, during 2007-2009, oseltamivir-resistant infl uenza A(H1N1) viruses rapidly spread worldwide (1). Molecular mechanisms implicated in this event were acquisition of NA-permissive mutations that alleviated deleterious fi tness effects of the resistance-conferring mutation NA-H275Y (N1 numbering) (2); changes that improved balance of hemagglutinin (HA) and NA activities (3); and a "hitchhiking" mechanism, in which HA antigenic drift promoted the spread of oseltamivir-resistant viruses (4). Oseltamivir-resistant H1N1 viruses were later displaced by the 2009 pandemic virus, infl uenza A(H1N1)pdm09 (pH1N1), which was antigenically distinct and oseltamivir sensitive (5). The emergence and transmission of oseltamivir-resistant pH1N1 carrying a NA-H275Y mutation was fi rst reported early in the 2009 pandemic (6). In the following years, transmission of oseltamivir-resistant viruses within healthcare settings and communities, or between close contacts, was occasionally observed (1); clusters were reported in Australia in 2011 ( 7) and Japan in 2013 (8). Despite these incidents, widespread circulation of oseltamivir-resistant viruses has yet to occur. The StudyThe Centers for Disease Control and Prevention (CDC) receives infl uenza-positive specimens collected globally for virological surveillance. Viral genomes are analyzed using next-generation sequencing (NGS) to identify strains of epidemiologic, virologic, and clinical importance (9). To supplement US national antiviral surveillance, pyrosequencing is used by public health laboratories to screen additional viruses either in-house or by the National Infl uenza Reference Center (10).During the 2019-20 infl uenza season, the pH1N1 subtype predominated in the United States. Later in the season, fewer infl uenza samples were identifi ed, likely because of COVID-19 pandemic mitigation strategies. Of 951 pH1N1 isolates collected nationwide during October 2019-September 2020, 4 (0.4%) had the NA-H275Y marker. Supplemental surveillance, conducted on 282 viruses from 18 states collected November 2019-March 2020, detected another 6 (2.1%) NA-H275Y viruses, bringing the total detected nationwide to 10 (10/1,233;

Global update on the susceptibilities of human influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2018–2020

“…The detection of A(H1N1)pdm09 viruses in untreated patients is an indicator of community transmission of resistant NA-H275Y viruses ( Hurt et al, 2012 ; Takashita et al, 2015b ), and this needs to be closely monitored. Notably, a small cluster of NA-H275Y viruses was detected in the United States in 2020 ( Mohan et al, 2021 ) and the antigenically drifted hemagglutinin of these viruses may facilitate their spread.…”

“…Notably, an increased frequency of A(H1N1)pdm09 viruses with potential RI/HRI in 2019–2020 (1.2%, 52/4195) was observed, compared to 2018–2019 (0.8%, 54/6765), based on analysis of sequences available in GISAID which matches frequencies of A(H1N1)pdm09 viruses analyzed by WHO CCs displaying RI/HRI (1.3% for 2019–2020 vs 0.7% for 2018–2019) ( section 2.2 .). Among these, three NA-H275Y viruses belonged to a cluster of oseltamivir-resistant viruses detected in the United States ( Mohan et al, 2021 ). Eight NA sequences had substitutions at residue 223 (NA-I223M/K/R/T), and three had NA-S247G substitutions.…”

Assessing the fitness of a dual-antiviral drug resistant human influenza virus in the ferret model

“…Previous studies have also shown that both A(H1N1)pdm09 and A(H3N2) viruses with PA-I38T had good stability in ferret transmission studies 43,44 , but have shown limited person-to-person transmission 23,45 . Additionally, NA-H275Y stability has been demonstrated by widespread community transmission of the previous seasonal A(H1N1) virus in 2008-2009 8,9 and localised transmission in A(H1N1)pdm09 viruses [46][47][48] .…”

Assessment of influenza A (H1N1, H3N2) oseltamivir resistance during 2017-2019 in Iran

“…Mutations in influenza viruses, like the most of RNA viruses, occur frequently due to the lack of viral RNA polymerase proofreading. These variations create mutants that are no longer preventive by vaccine ( 32 ). Therefore, antiviral medications can be of great importance in prophylaxis until new vaccine is available.…”