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

Credit NIAID

#11,465


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 

Influenza A(H1N1)pdm09 virus exhibiting enhanced cross-resistance to oseltamivir and peramivir due to a dual H275Y/G147R substitution, Japan, March 2016

E Takashita ¹ , S Fujisaki ¹ , M Shirakura ¹ , K Nakamura ¹ , N Kishida ¹ , T Kuwahara ¹ , Y Shimazu ² , T Shimomura ³ , S Watanabe ¹ , T Odagiri ¹ , The Influenza Virus Surveillance Group of Japan ⁴

Received:20 May 2016; Accepted:16 June 2016

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An influenza A(H1N1)pdm09 virus carrying a G147R substitution in combination with an H275Y substitution in the neuraminidase protein, which confers cross-resistance to oseltamivir and peramivir, was detected from an immunocompromised inpatient in Japan, March 2016.

This dual H275Y/G147R mutant virus exhibited enhanced cross-resistance to both drugs compared with the single H275Y mutant virus and reduced susceptibility to zanamivir, although it showed normal inhibition by laninamivir.

While the bulk of this report centers around the discovery of a dual H275Y/G146R substitution in an immunocompromised patient while receiving peramivir treatment, the reports of   clusters of regular H275Y (with permissive mutations) pH1N1 viruses circulating in Japan over the past couple of years are worth our attention as well.

A couple of excerpts from the Discussion follow (bolding mine), but you'll want to read the report in its entirety.

Discussion

The first widespread community cluster of the H275Y mutant A(H1N1)pdm09 virus was detected in Newcastle, Australia in 2011 [7]. The H275Y substitution in the NA protein would destabilise the mutant virus. However, two additional V241I and N369K substitutions in the NA of H275Y mutant viruses were reported to increase their replication and transmission fitness, contributing to efficient transmission [8,9]. 

Almost all recently circulating A(H1N1)pdm09 viruses possess these permissive substitutions, suggesting an increased risk for H275Y mutant viruses to emerge and spread globally [10]. 

Indeed, during the 2013/14 influenza season, the H275Y mutant viruses from a large community cluster in Hokkaido, Japan carried these permissive substitutions. Following this finding, we subsequently increased nationwide monitoring for the H275Y mutant viruses in the 2015/16 season and detected an H275Y mutant with V241I and N369K and an additional G147R substitution in the NA protein from an immunocompromised inpatient. The IC₅₀ fold changes of a number of NA inhibitors for the dual H275Y/G147R mutant virus compared with those for the single H275Y viruses showed clearly the synergistic effect of this dual substitution (Figure 2).

(SNIP)

Immunocompromised patients are at great risk for emergence of the antiviral resistant virus because of the selective pressure from prolonged exposure to antiviral drugs [16]. A high rate and prolonged shedding of the H275Y mutant A(H1N1)pdm09 virus in immunocompromised patients treated with oseltamivir and/or peramivir were reported previously [17]. As a specimen from the husband of the patient was unavailable, we cannot rule out that the patient was infected with a virus readily carrying the G147R substitution. Results of this study nevertheless suggest that this substitution likely occurred in the patient during peramivir treatment. On the other hand, whether the H275Y mutation had already occurred or not before infection remains unclear. Other additional substitutions, I223R and S247N, in the NA protein of H275Y mutant A(H1N1)pdm09 viruses have been reported and showed a synergistic effect with the H275Y substitution on the reduction of NA inhibitor susceptibility [18,19]. 

 Although the frequencies of these dual substitutions were low, the surveillance of antiviral-resistant viruses should be continued to protect public health and support clinical management, particularly for high risk populations.