Thursday, June 16, 2016

Eurosurveilance: A(H1N1)pdm09 Virus With Cross-Resistance To Oseltamivir & Peramivir - Japan, March 2016

Credit NIAID


While it's difficult to think of anything good to say about an emerging pandemic virus - unlike the seasonal H1N1 circulating before it  - 2009's pH1N1 virus had one big up side.

The (now-seasonal, formerly pandemic) pH1N1 virus has remained conveniently susceptible to NAI (Neuraminidase Inhibiting) antiviral drugs like Oseltamivir (Tamiflu (c)) and zanamivir (Relenza (c)).

Although occasional instances of Oseltamivir resistance in the old H1N1 virus were reported prior to 2007, in nearly every case, it developed after a person was placed on the drug (due to so-called `spontaneous mutations’).

While of concern to the patient being treated, that happened in only about 1% of treated cases, and studies suggested that these resistant strains were `less biologically fit’, and were therefore thought unlikely to spread.

Which of course, is exactly what they ended up doing

Between 2007 and 2008, the virus picked up `permissive mutations' that enabled resistant seasonal H1N1 viruses to literally explode around the globe (see PLoS Pathogens Role of Permissive Neuraminidase Mutations in Influenza A/Brisbane/59/2007-like (H1N1) Viruses).

By the end of 2008, nearly all of the H1N1 samples tested in the United States were resistant to oseltamivir and 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 primarily to the acquisition of an H275Y mutation - where a single amino acid substitution (histidine (H) to tyrosine (Y)) occurs at the neuraminidase position 275 (Note: some scientists use 'N2 numbering' (H274Y)). 

Had it not been replaced in the spring of 2009 with a new, NAI susceptible virus, treatment options for severe H1N1 influenza over the past seven years would have been substantially reduced.

We've been watching ever since 2009 for any signs that the new pH1N1 virus has been gaining resistance, but for the most part, the news has been pretty good.

Rates of resistant pH1N1 viruses have been low - around 1% - and like we saw prior to 2007, have generally been seen in (often immunocompromised) patients after they were placed on antivirals - again via `spontaneous mutations’.

And as before, these pH1N1 viruses carrying the H275Y mutation have been seen as taking a `fitness' hit, being less likely to transmit efficiently and spread widely. 

But the news hasn't all been positive.

We have seen a few worrisome clusters of NAI resistant flu (see Eurosurveillance: Community Cluster Of Antiviral Resistant pH1N1 in Japan & NEJM: Oseltamivir Resistant H1N1 in Australia), which have raised concerns that we could one day see a repeat of the 2007-2008 rise in antiviral resistance in our current H1N1 strain.

And 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.

Their assessment was not particularly rosy.

All of which brings us to a new report, published today in the ECDC journal Eurosurveillance, which finds an elevated number of NAI resistant viruses with `permissive mutations' circulating in Japan, and describes the discovery of resistant pH1N1 carrying a G147R substitution that conferred resistance to both Oseltamivir and Peramivir.

Eurosurveillance, Volume 21, Issue 24, 16 June 2016

Rapid communication 

Received:20 May 2016; Accepted:16 June 2016