EID Journal: Cluster of Oseltamivir-Resistant & Antigenically Drifted Influenza A(H1N1)pdm09 Viruses, Texas, USA, January 2020

#16,027

In the months prior to the emergence of the 2009 H1N1 `swine flu' pandemic virus, public health agencies around the globe were scrambling because the old H1N1 virus had - in the space of roughly a year - gone from showing about 1% resistance to oseltamivir (aka `Tamiflu') to being nearly 100% resistant.

The CDC was forced to issue major new guidance for the use of antivirals (see CIDRAP article With H1N1 resistance, CDC changes advice on flu drugs).

This resistance was due to the acquisition of an H275Y mutation - where a single amino acid substitution (histidine (H) to tyrosine (Y)) occured at the neuraminidase position 275 (Note: some scientists use 'N2 numbering' (H274Y)). 

While 4 months later the world would find itself facing its first influenza pandemic in more than 5 decades, the one saving grace of the 2009 H1N1pdm09 virus is that it supplanted the old H1N1 virus with one that was still susceptible to oseltamivir.  

How the following 2009-2010 influenza season would have turned out had fate not intervened is unknowable, but going forward without our primary pharmaceutical weapon against influenza would have been a challenge. 

We've been watching ever since then for any signs that the new pH1N1 virus has been gaining resistance, but for the most part, the news has been pretty good. That said, we have seen a few worrisome instances of H1N1pdm viruses showing resistant to NAI antiviral drugs around the globe, including:

• In December of 2011, in NEJM: Oseltamivir Resistant H1N1 in Australia, we looked at a cluster of oseltamivir (Tamiflu ®) resistant H1N1 viruses in and around the Newcastle area of New South Wales.
• In 2014's Eurosurveillance: Community Cluster Of Antiviral Resistant pH1N1 in Japan, we looked at a cluster of six genetically similar resistant viruses in Sapporo, Japan  - but without epidemiological links. 
• Also in 2014, in PLoS Pathogens: Fitness Advantage From Permissive NA Mutations In Oseltamivir Resistant pH1N1, we saw a study that explored the potential of pH1N1 eventually following the same course as its predecessor.
• In 2016, in Eurosurveilance: A(H1N1)pdm09 Virus With Cross-Resistance To Oseltamivir & Peramivir - Japan, March 2016 we looked at an elevated number of NAI resistant viruses with `permissive mutations' circulating in Japan.
And in the spring of 2018, in Russia's Late Season Flu Surge Continues - More Resistant H1N1pdm In Moscow, we saw handful of Oseltamivir-resistant viruses reported from Russia. 

For all of these reasons, we keep a sharp eye out for any signs of growing antiviral resistance in influenza around the world. Somewhat reassuringly, as the reports above show, previous clusters of NAI resistance in H1N1pdm have failed to take hold.

All of which brings us to an EID Journal Dispatch, published late last week, which describes a cluster of H275Y, and antigenically drifted, H1N1 viruses detected in Texas just before the 2019-2020 flu season collapsed in the face of the COVID-19 pandemic.

I've posted some excerpts from the report below, but you'll want to follow the link to read it in its entirety. I'll have a brief postscript when you return. 

Volume 27, Number 7—July 2021
Dispatch
Cluster of Oseltamivir-Resistant and Hemagglutinin Antigenically Drifted Influenza A(H1N1)pdm09 Viruses, Texas, USA, January 2020
 
Teena Mohan1, Ha T. Nguyen1, Krista Kniss, Vasiliy P. Mishin, Angiezel A. Merced-Morales, Jennifer Laplante, Kirsten St. George, Patricia Blevins, Anton Chesnokov, Juan A. De La Cruz, Rebecca Kondor, David E. Wentworth, and Larisa V. Gubareva

Abstract

Four cases of oseltamivir-resistant influenza A(H1N1)pdm09 virus infection were detected among inhabitants of a border detention center in Texas, USA. Hemagglutinin of these viruses belongs to 6B.1A5A-156K subclade, which may enable viral escape from preexisting immunity. Our finding highlights the necessity to monitor both drug resistance and antigenic drift of circulating viruses.

Resistance to antiviral drugs for influenza is an ongoing public health concern. The neuraminidase (NA) inhibitor oseltamivir is the most prescribed antiviral drug for controlling influenza. However, during 2007–2009, oseltamivir-resistant influenza A(H1N1) viruses rapidly spread worldwide (1). Molecular mechanisms implicated in this event were acquisition of NA-permissive mutations that alleviated deleterious fitness 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, influenza 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 first 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.

         (SNIP)

Conclusions

Although no evidence of oseltamivir-resistant virus transmission outside the detention center was found, the properties of the cluster viruses are concerning. They belong to an HA antigenically drifted group, and escape from preexisting immunity may contribute to the spread of oseltamivir-resistant viruses in coming seasons.

Dr. Mohan is a member of the Molecular Epidemiology Team in the Virology, Surveillance, and Diagnosis Branch of the Influenza Division, National Center for Immunization and Respiratory Diseases, CDC. Her research interests include the molecular mechanisms of influenza virus resistance to antiviral medications and the effect of resistance mutations on viral fitness in vitro and in vivo.

(Continue . . . )

While we have more influenza antiviral options today than we had in 2009 -  (see FDA Approval Of Xofluza : A New Class Of Influenza Antiviral) - an antigenically drifted, and oseltamivir-resistant, H1N1 virus could still prove daunting should it become dominant. 

And as we saw in 2019, the effectiveness of newer antiviral drugs remain susceptible to erosion from mutated flu viruses (see Nature MicroB.: Influenza A Variants with Reduced Susceptibility to Baloxavir Are Fit & Transmit Easily).

Although our current viral enemy is SARS-COV-2, influenza A has plagued humans for hundreds - perhaps thousands - of years, sparking yearly epidemics and occasional pandemics, and exacting a heavy toll. 

Credit Pandemic Influenza's 500th Anniversary

Influenza A - which has ample non-human reservoirs in which to ride out the COVID pandemic - will eventually return.  And after a prolonged hiatus, we shouldn't be terribly surprised if it has picked up some new tricks in its absence.