Credit NIAID
#18,135
Last week, in EID Journal: Multicountry Spread of Influenza A(H1N1)pdm09 Viruses with Reduced Oseltamivir Inhibition, May 2023–February 2024, we looked at an early report on what may be the biggest threat to our armamentarium of influenza antivirals since 2008.
Although the numbers remain small, the trends are worrisome, as described by the authors:
Since May 2023, a novel combination of neuraminidase mutations, I223V + S247N, has been detected in influenza A(H1N1)pdm09 viruses collected in countries spanning 5 continents, mostly in Europe (67/101). The viruses belong to 2 phylogenetically distinct groups and display ≈13-fold reduced inhibition by oseltamivir while retaining normal susceptibility to other antiviral drugs.
Admittedly oseltamivir (aka Tamiflu) isn't our only antiviral option (see FDA Approved Xofluza : A New Class Of Influenza Antiviral), but it is the most popular antiviral, and has been stockpiled by countries the most.
While rare, spontaneous mutations (primarily H275Y) have long been observed in a small percentage (1%-2%) of people receiving oseltamivir. These mutations exacted a `fitness price', causing these viruses to transmit poorly, making them essentially dead-end infections.But in 2008 the H1N1 virus developed `permissive secondary mutations' that allowed the H1N1 virus to spread efficiently even with the H275Y mutation. Within a year, the H1N1 virus had gone from being nearly 100% susceptible to oseltamivir to 100% resistant (see CIDRAP article With H1N1 resistance, CDC changes advice on flu drugs).
The future of oseltamivir appeared bleak going into 2009, when in a Deus Ex Machina moment a new swine-origin H1N1 virus - one that happened retain its sensitivity to Tamiflu - swooped in as a pandemic strain in the spring of 2009, supplanting the older resistant H1N1 virus.
Since then we've been looking for any signs of growing resistance to NAI inhibitors. For the most part, we've seen the same 1% incidence of spontaneous mutations in people receiving the antiviral, although we've seen a few `clusters' of cases.
- Four years ago, in EID Journal: Cluster of Oseltamivir-Resistant & Antigenically Drifted Influenza A(H1N1)pdm09 Viruses, Texas, USA, January 2020, we looked at a cluster of resistant seasonal flu viruses which emerged just before COVID shut down influenza around the globe.
- 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.
- 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.
While the incidence of resistance in seasonal H1N1 still appears to be very low - and with luck, it may never take off - in 2008 we saw it go from near zero to nearly 100% in a matter of months.
So we are watching these changes with considerable interest.
