MIT: Genetic Changes In A 2014 Indian H1N1pdm09 Virus

Flu Virus binding to Receptor Cells – Credit CDC

 

# 9810

 

A little over a week ago, in EID Journal: Emergence of D225G Variant A/H1N1, 2013–14 Flu Season, Florida, we re-visited one of the mutations linked to greater virulence in the (formerly pandemic, now seasonal) A/H1N1pdm09 virus.

 

This relatively rare amino acid substitution at position 225 (222 using H1 Numbering) from aspartic acid (D) to glycine (G) allows the virus to bind to receptors found deeper in the lungs, and is linked to the development of more severe pneumonia.

.

A 2013 study in Influenza Other Respir Viruses called A(H1N1)pdm09 hemagglutinin D222G and D222N variants are frequently harbored by patients requiring extracorporeal membrane oxygenation and advanced respiratory assistance for severe A(H1N1)pdm09 infection linked this, and the D225N mutation to more severe respiratory symptoms.

While probably the best known, and most studied, of the virulence enhancing mutations in the pH1N1 virus, D225G/N is certainly not the only one.  And in truth, there are likely other  mutations – or combinations of amino acid substitutions – that would increase the virus’s transmissibility, replication, antiviral resistance, or pathogenicity that we don’t even know about.

 

With the D225G/N mutation, it is believed that while it increases virulence, it reduces transmissibility.   But that may simply mean that the right combination of concurrent changes hasn’t emerged to increase both . . . yet.

 

Last November, in When Influenza Goes Rogue, we looked at the long history of extreme variability between flu seasons, and the emergence of mutated, or `drifted’ viruses.  And by now everyone knows that this year we are experiencing exactly that scenario with an antigenically drifted H3N2 virus.

 

The point being that flu viruses – even seasonal flu viruses that have been around for a long time – can occasionally throw us a curve. 

 

This winter we’ve seen India reporting a large number of pH1N1 cases – which they call `swine flu’ – supposedly with an unusually high mortality rate.    We’ve seen these sorts of reports from India in the past, and so it has been difficult to determine if anything is really different about this year’s flu strain (see India swine flu toll inches towards 1500).

 

Although the numbers seem high (and likely represent only the smallest tip of much larger iceberg), in a nation of over a billion people –  millions would be expected to contract the flu in an average year - and of those, thousands would likely die. 

A couple of weeks ago, in India’s H1N1 Outbreak, we looked at some of these reports along the Indian Government’s denials that anything untoward was occurring . India’s National Institute of Virology (NIV) and their National Centre for Disease Control (NCDC) both reported No mutation of H1N1.

 

Today, however, we’ve a report that suggests (based on very limited data) that perhaps something has changed with the H1N1 virus, and that it may be affecting its transmissibility, and severity, in India.

 

First, this press release, and then a link to the study.

 

Analysis suggests a more virulent swine flu virus in the Indian subcontinent

Cell Press

A flu outbreak in India that has claimed over 1200 lives may not be identical to the 2009 North American strain, as recently reported in India. A comparative analysis conducted by scientists at the Massachusetts Institute of Technology (MIT) shows that the flu virus in India seems to have acquired mutations that could spread more readily and therefore requires deeper studies. As flu season in India winds down, the researchers call on officials to increase surveillance of this and future flu outbreaks and rethink vaccination strategies to account for potential new viruses.

The MIT analysis, which compared viral proteins important for virulence and transmissibility in the 2009 and 2014 flu epidemics, was conducted by professor Ram Sasisekharan, PhD, at the Koch Institute for Integrative Cancer Research, and his research scientist colleague Kannan Tharakaraman, PhD. It appears in the March 11 issue of the journal Cell Host & Microbe.

"It has been extensively reported in India that a virus similar to A/California/07/2009 is responsible for the current outbreak," Sasisekharan says. "Examination of the Indian H1N1 flu viruses that circulated in 2014 shows amino acid mutations that make them distinct (in terms of receptor binding, virulence, and antigenic drift) from the A/California/07/2009 virus."

"It is widely believed that the current H1N1 flu vaccine is still effective for the most part," he adds.  "Effectiveness of the current H1N1 flu vaccine is debatable, and there have been calls for updating the vaccine. The Indian H1N1 viruses that circulated in 2014 are different compared to the 2009 vaccine strain A/California/07/2009."

(Continue . . .. )

 

This commentary (see below), which calls for greater testing and genetic sequencing on the Indian Subcontinent, notes that - despite the vastness of the Indian subcontinent, only two sequences have been deposited during 2014–2015 from India, suggesting poor surveillance and potentially limiting the response to a deadly outbreak.

Based on an analysis of Indian-origin strain A/India/6427/2014, they reported finding:

 

Although there are limited Indian-origin influenza sequences available in the public database to make any causal inference on the perceived increased fatalities in India, examination of the 2014 Indian H1N1 HA sequences shows traits with potential cause for concern. Amino acid changes in specific positions in the receptor binding site (RBS) of 2009pdmH1N1 have been shown to impact glycan RBS specificity and have been linked to increased virulence and disease severity.

Among these changes, the Indian-origin strain A/India/6427/2014 contains amino acid changes T200A and D225N compared to the 2009pdmH1N1 pandemic strain. The T200A amino acid change has been shown to improve human glycan receptor-binding of 2009pdmH1N1 HA (Xu et al., 2012b). The D225N mutation has been linked to increased virulence and disease severity in patients infected by the 2009 pdm virus (Ruggiero et al., 2013).

 

A third mutation,  K166Q, was also detected and has been linked to increased severity of pH1N1 in middle-aged adults during the 2013-14 flu season (see CIDRAP Study: Middle-aged adults susceptible to recent flu virus mutation).

The lack of any recent sequencing of H1N1 viruses from India is particularly frustrating in light of recent news reports. The authors write:  It is unknown if the strain A/India/6427/2014 is still in circulation; however, the apparent severity of the current outbreak seems to suggest that it could be.

 

The entire report/commentary – which emphasizes the need for more robust and timely influenza surveillanece and sequencing data -  may be accessed at:

 

Influenza Surveillance: 2014–2015 H1N1 “Swine”-Derived Influenza Viruses from India

Kannan Tharakaraman , Ram Sasisekharan

DOI: http://dx.doi.org/10.1016/j.chom.2015.02.019

Summary

The 2014-15 H1N1 outbreak in India has reportedly led to 800 fatalities. The reported influenza hemagglutinin sequences from India indicate that these viruses contain amino acid changes linked to enhanced virulence and are potentially antigenically distinct from the current vaccine containing 2009 (Cal0709) H1N1 viral hemagglutinin.

J. Virol: Continued Reassortment Of Swine Flu Viruses With Genes From pH1N1 In China

 

# 8820

 

Big changes in influenza viruses – the kind that can create a novel, and potentially pandemic producing strain – come about through antigenic shift, also known as reassortment.  For shift to occur, two different flu strains must infect the same host simultaneously, and swap one or more gene segments.

 

Most reassortant viruses are evolutionary failures, but every once in awhile a more `fit’ virus emerges.

 

While seemingly an unlikely confluence of events – for pigs - who number in the millions, live in close quarters, have frequent contact with other pigs, birds, and humans, and who are notoriously susceptible to flu – shift happens with surprising frequency.

 

Since pigs can be infected by more than one flu virus at the same time, it is possible for two viruses to swap genetic material (reassort), resulting in a new hybrid strain.

 

Here in North America we’ve been watching the evolution of several swine variant viruses (H1N1v, H1N2v, H3N2v) over the past few years, all of which have reassorted with - and picked up the M gene segment from – the 2009 H1N1 virus (see Keeping Our Eyes On The Prize Pig).

 

Although reassortant flu viruses can emerge anywhere in the world (2009 H1N1 first emerged in North America), nowhere are pigs watched with more interest than in China, where huge populations of pigs are raised with frequent contact with other species, including humans.

 

Last year, in  EID Journal: Predicting Hotspots for Influenza Virus Reassortment, we saw China ranked as one of the globe’s top breeding grounds for new flu strains. 

 

Today we’ve a new paper, appearing in the Journal of Virology, that looks at the expanding diversity of reassorted swine flu viruses carrying genes from the 2009 H1N1 pandemic virus in Chinese pigs.  While the fully `humanized’ 2009 H1N1 virus doesn’t circulate in swine, researchers have isolated at least 17 reassortants  containing pH1N1-origin genes.

 

First the link and abstract, then I’ll have a bit more.

 

 

Expansion of genotypic diversity and establishment of 2009 H1N1 pandemic-origin internal genes in pigs in China

Huyi Lianga,b,c, Tommy Tsan-Yuk Lama,b,c, Xiaohui Fand, Xinchun Chena, Yu Zenga,c, Ji Zhoua,b,c, Lian Duana,b,c, Maying Tseb, Chung-Hei Chanb, Lifeng Lib,c, Tak-Ying Leungb, Chun-Hung Yipb, Chung-Lam Cheungb, Boping Zhoua, David K. Smithb,c, Leo Lit-Man Poona,b, Malik Peirisa,b, Yi Guana,b,c⇑ and Huachen Zhua,b,c⇑

ABSTRACT

‘Two-way' transmission of influenza viruses between humans and swine has been frequently observed and the occurrence of the 2009 H1N1 pandemic influenza (pdm/09) demonstrated that swine-origin viruses could facilitate the genesis of a pandemic strain. Although multiple introductions to and reassortment in swine of the pdm/09 virus have been repeatedly reported in both Eurasia and the Americas, its long-term impact on the development of swine influenza viruses (SIVs) has not been systematically explored. Our comprehensive evolutionary studies on the complete genomes of 387 SIVs obtained from 2009 to 2012 in influenza surveillance in China revealed 17 reassortant genotypes with pdm/09-origin genes.

Even though the entire 2009 pandemic virus and its surface genes cannot persist, its internal genes have becoming established and are now the predominant lineages in pigs in the region. The main persistent pdm/09-origin reassortant forms had at least 5 pdm/09-origin internal genes and their surface genes primarily of European avian-like (EA) or human H3N2-like SIV origin. These findings represent a marked change to the evolutionary patterns and ecosystem of SIVs in China. It is possible that the pdm/09-origin internal genes may be in the process of replacing EA- or triple reassortant-like internal genes. These alterations to the SIV gene pool need to be continually monitored to assess changes in the potential for SIVs to transmit to humans.

 

 

Remarkably, in less than five years, the swine influenza virus (SIV) gene pool in China has been dramatically re-invented with the internal genes derived from the pH1N1 virus now dominant, and continuing to expand. 

 

While their surface genes (HA & NA) remain more or less stable, the acquisition of as many as 5 internal genes from an already `humanized’  flu virus is of concern.

 

The authors write:

 

Over the survey period, these internal genes became predominant, potentially replacing those of the enzootic SIV lineages. The altered diversity of the SIV gene pool needs to be closely monitored for changes in the potential of SIVs to transmit to humans.

 

Although with the emergence of H7N9, H10N8, and H5N8 our attentions have been focused more on avian influenzas these past couple of years, in truth, a reassortant virus could emerge from practically any species susceptible to multiple flu strains (see Study: Dogs As Potential `Mixing Vessels’ For Influenza, mBio: A Mammalian Adapted H3N8 In Seals ).

 

Historically, avian and swine influenzas have a track record of producing pandemic strains, and so we tend to watch both arenas with particularly interest. 

 

For more on influenza reassortment, you may wish to revisit:

 

Viral Reassortants: Rocking The Cradle Of Influenza

Study: Novel & Variant Swine Influenzas In Korean Pigs

Seroprevalence Study: Avian Flu In Chinese Pigs

PLoS Pathogens: Fitness Advantage From Permissive NA Mutations In Oseltamivir Resistant pH1N1

 

 

# 8429

 

Hopefully today’s blog won’t be as tedious as the title might first suggest.

 

Oseltamivir (aka Tamiflu ®) – an NAI (Neuraminidase Inhibiting) antiviral drug – is our primary pharmaceutical weapon against influenza.   While it doesn’t `cure’  the flu - when started early enough (preferentially within 48 hrs of onset of symptoms) - it can reduce both the severity and duration of infection (see Effectiveness Of NAI Antivirals In Reducing Mortality In Hospitalized H1N1pdm09 Cases).

Up until the middle of the last decade, we had another class of antiviral drugs - M2 ion channel blockers (e.g. Amantadine, Rimantadine) –  which were first developed in the late 1950s. But excessive use over the years (including in agricultural settings) eventually led to widespread resistance.

 

The replacement antivirals introduced during the last decade include Oseltamivir (Tamiflu), Zanamivir (Relenza), and Peramivir. Of these, Oseltamivir is by far the most widely used, and has been stockpiled by many governments for use in the event of a pandemic.

 

While occasional instances of Oseltamivir resistance was recorded prior to 2007, in nearly every case, it developed after a person was placed on the drug (`spontaneous mutations’).  While of concern to the patient being treated, it occurred in only about 1% of treated cases, and studies suggested that these resistant strains were `less biologically fit’, and were therefore believed to be unlikely to spread.

 

Which of course, is exactly what they did do.  Between 2007 and 2008, the incidence of resistant seasonal H1N1 viruses literally exploded around the globe. 

 

So much so, that 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 primarily due to 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)). 

 

While this mutation had been seen before, obviously something had changed between 2006 and 2008 to allow the resistant form of the virus to spread so quickly.

 

In 2010  Bloom, Gong & Baltimore discussed these `enabling’ changes in the Journal Science in  a report called Permissive Secondary Mutations Enable the Evolution of Influenza Oseltamivir Resistance.

ABSTACT

The His²⁷⁴→Tyr²⁷⁴ (H274Y) mutation confers oseltamivir resistance on N1 influenza neuraminidase but had long been thought to compromise viral fitness. However, beginning in 2007–2008, viruses containing H274Y rapidly became predominant among human seasonal H1N1 isolates. We show that H274Y decreases the amount of neuraminidase that reaches the cell surface and that this defect can be counteracted by secondary mutations that also restore viral fitness.

Two such mutations occurred in seasonal H1N1 shortly before the widespread appearance of H274Y. The evolution of oseltamivir resistance was therefore enabled by “permissive” mutations that allowed the virus to tolerate subsequent occurrences of H274Y. An understanding of this process may provide a basis for predicting the evolution of oseltamivir resistance in other influenza strains.

 

In 2011 Abed,  Pizzorno,  Bouhy &  Boivin identified several `permissive’ neuraminidase mutations that occurred just prior to the spread of resistant H1N1 - that when combined with H275Y -  `enabled’ its efficient transmission (see PLoS Pathogens Role of Permissive Neuraminidase Mutations in Influenza A/Brisbane/59/2007-like (H1N1) Viruses).

 

This pervasive spread of resistant H1N1 would have been a much bigger deal had it not been for the arrival of the 2009 H1N1 pandemic virus, which effectively supplanted the old (resistant) H1N1, and replaced it with a new – but fortunately, still susceptible to NAIs – H1N1 virus.

 

Fast forward five years, and the (now seasonal, formerly pandemic) pH1N1 virus remains overwhelmingly susceptible to Oseltamivir and other NAI antiviral drugs, although we have seen a few signs of `creeping resistance’. 

 

Reassuringly, the latest FluView report (week 12) indicated that of 4524 viruses tested this flu season in the United States, only 54 (1.2%) showed signs of NA Inhibitor resistance.

 

But 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 has raised concerns that we could see a repeat of the 2007-2008 rise in antiviral resistance in our current H1N1 strain.

 

All of which serves as prelude to a new study that appears in PloS Pathogens, that looks at the potential of pH1N1 following the same course as its predecessor.  Their assessment is not particularly rosy.

 

Estimating the Fitness Advantage Conferred by Permissive Neuraminidase Mutations in Recent Oseltamivir-Resistant A(H1N1)pdm09 Influenza Viruses

Jeff Butler, Kathryn A. Hooper, Stephen Petrie, Raphael Lee, Sebastian Maurer-Stroh, Lucia Reh, Teagan Guarnaccia, Chantal Baas, Lumin Xue, Sophie Vitesnik, Sook-Kwan Leang, Jodie McVernon, Anne Kelso, Ian G. Barr, James M. McCaw, Jesse D. Bloom, Aeron C. Hurt mail

Published: April 03, 2014  DOI: 10.1371/journal.ppat.1004065

Abstract

Oseltamivir is relied upon worldwide as the drug of choice for the treatment of human influenza infection. Surveillance for oseltamivir resistance is routinely performed to ensure the ongoing efficacy of oseltamivir against circulating viruses.

Since the emergence of the pandemic 2009 A(H1N1) influenza virus (A(H1N1)pdm09), the proportion of A(H1N1)pdm09 viruses that are oseltamivir resistant (OR) has generally been low. However, a cluster of OR A(H1N1)pdm09 viruses, encoding the neuraminidase (NA) H275Y oseltamivir resistance mutation, was detected in Australia in 2011 amongst community patients that had not been treated with oseltamivir. Here we combine a competitive mixtures ferret model of influenza infection with a mathematical model to assess the fitness, both within and between hosts, of recent OR A(H1N1)pdm09 viruses.

In conjunction with data from in vitro analyses of NA expression and activity we demonstrate that contemporary A(H1N1)pdm09 viruses are now more capable of acquiring H275Y without compromising their fitness, than earlier A(H1N1)pdm09 viruses circulating in 2009. Furthermore, using reverse engineered viruses we demonstrate that a pair of permissive secondary NA mutations, V241I and N369K, confers robust fitness on recent H275Y A(H1N1)pdm09 viruses, which correlated with enhanced surface expression and enzymatic activity of the A(H1N1)pdm09 NA protein.

These permissive mutations first emerged in 2010 and are now present in almost all circulating A(H1N1)pdm09 viruses. Our findings suggest that recent A(H1N1)pdm09 viruses are now more permissive to the acquisition of H275Y than earlier A(H1N1)pdm09 viruses, increasing the risk that OR A(H1N1)pdm09 will emerge and spread worldwide.

 

Fair warning: the methods and materials section is lengthy, complex, and pretty tough sledding for those without a solid background in virology.  Those interested in the details (or with a masochistic bent) will want to read this report in its entirety.

 

The bottom line, however, is that since the 2009 H1N1 virus emerged five years ago, it has managed to pick up a series of `permissive’ mutations that are believed to increase its ability to replicate when it carries the H275Y resistance mutation.

 

Which in theory, should promote its spread.

 

Given that these mutations are already entrenched, it is a bit surprising we haven’t already seen an expansion in resistant pH1N1, beyond a couple of documented clusters in Australia and Japan.  The authors write:

One explanation is that a high level of circulating A(H1N1)pdm09 viruses may be required for a A(H1N1)pdm09 OR virus to become established and spread. The Australian HNE2011 virus cluster emerged [25], [26] during a season when A(H1N1)pdm09 viruses accounted for almost 40% of all influenza A and B viruses detected globally but, in 2012 and 2013, the proportion of A(H1N1)pdm09 viruses circulating has been considerably lower (9% and 25% respectively) [52].

In the most recent 2013/14 Northern Hemisphere influenza season, a cluster of A(H1N1)pdm09 H275Y OR viruses that contained both the V241I and N369K PPMs plus an additional N386K NA mutation, was detected in Sapporo, Japan [53], during a period of the season where A(H1N1)pdm09 viruses contributed approximately 50% of the circulating influenza strains [54].

We’ve just come through an H1N1 dominated flu season in North America, and the incidence of H274Y has remained low, so other factors may be involved. The authors suggest:

Apart from NA PPMs, it may be that other properties, such as antigenic novelty, are also necessary for an OR virus to spread widely. In 2007–2008, the H275Y NA mutation became fixed in a new seasonal A(H1N1) antigenic variant (A/Brisbane/59/2007-like), suggesting that the antigenic novelty of the OR virus assisted its prolific spread.

In this vein, the authors warn:

A(H1N1)pdm09 viruses have now been circulating in humans for over four years, but are yet to undergo a significant antigenic change (as evidenced by the continued inclusion of A/California/7/2009 in the human seasonal influenza vaccine since 2009).

As the H1 component of the vaccine has been updated, on average, every 2.8 years (range 1 to 8 years), and the H3 component every 1.8 years (range 1 to 4 years) since 1980, it is reasonable to anticipate that A(H1N1)pdm09 viruses will undergo antigenic change in the near future.

The significance being that an antigenic change in the virus might be the spark needed to spread the resistant mutation, and at the same time would reduce the effectiveness of the current vaccine (and evade herd immunity), and therefore increase our need for effective antiviral medications.

 

Viruses and bacteria evolve and adapt very quickly. The sobering truth is pharmacological victories over them tend to be fleeting. New classes of drugs are going to be needed, along with prudent stewardship of the drugs currently in our arsenal.

 

The authors of this study wrap up by saying:

 

Here we demonstrate that contemporary A(H1N1)pdm09 viruses have acquired NA mutations which permit the acquisition of NA H275Y without compromising viral fitness. These mutations, which are now present in virtually all circulating A(H1N1)pdm09 viruses, enhance the surface expression and enzymatic activity of the A(H1N1)pdm09 H275Y NA protein in vitro and result in enhanced viral fitness in vivo.

Hence, the risk that H275Y A(H1N1)pdm09 viruses will spread globally, in a similar manner to OR seasonal A(H1N1) viruses in 2007–2008, now appears greater than at any time since the A(H1N1)pdm09 lineage emerged in 2009.

Eurosurveillance: Community Cluster Of Antiviral Resistant pH1N1 in Japan

Photo Credit – Wikipedia

 

 

# 8150

 

While it’s not easy to find anything good to say about a pandemic influenza virus, the 2009 pH1N1 strain had at least one saving grace; unlike the old seasonal H1N1 strain it replaced, it was overwhelming sensitive to Neuraminidase Inhibitor (NAI) antiviral drugs like oseltamivir (Tamiflu ®) and zanamivir (Relenza ®).

In 2006 we only saw a smattering of oseltamivir resistant seasonal H1N1 cases, almost always attributed to `spontaneous mutations’  within a patient receiving the drug.  While of concern to the patient being treated, it appeared to be poorly transmissible.

 

In the 2006-2007 flu season, laboratories found no resistant strains in Europe or Japan, and in less than 1% of samples from the United States.

 

Resistance in this viral strain was mostly caused by a mutation called H275Y, where a single amino acid substitution (histidine (H) to tyrosine (Y)) occurs at the neuraminidase position 275.

 

(Note: some scientists use 'N2 numbering' (H274Y) and some use 'N1 numbering' (H275Y))

 

The following year, during the 2007-2008 flu season, oseltamivir resistant viruses suddenly took flight, and by the spring of 2008 roughly 25% of European samples tested showed the H275Y mutation (see Increased Tamiflu Resistance In Seasonal Influenza).

 

By December of 2008 nearly all of the 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).

 

The arrival of a the pandemic H1N1 in the spring of 2009 effectively removed this resistant strain from circulation, and in the five ensuing years, nearly 99% of the  pH1N1 viruses tested have remained sensitive to NA inhibiting drugs.  The latest FluView report (week 52) indicated that of 910 viruses tested, only 10 showed signs of NA Inhibitor resistance.

 

While 99% sensitivity is an excellent batting average in any league, 5 of the 10 resistant viruses were detected in Louisiana and Mississippi, suggesting a geographic clustering of cases.

 

Although we have seen some signs the pH1N1 might be figuring its way around our arsenal of antivirals, most often this occurs after a patient is placed on antivirals, occasionally resulting in a spontaneous mutation within the host. 

But we have seen some signs of community spread of resistant pH1N1 as well.

 

Readers with good memories will recall that 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.

 

The lead author of that NEJM correspondence was Aeron C. Hurt, Ph.D. from the World Health Organization (WHO) Collaborating Centre for Reference and Research on Influenza, North Melbourne, VIC, Australia.  

 

What Hurt and his colleagues found was evidence for the sustained community transmission of a resistant strain of the H1N1pdm09 virus.

After analyzing viral samples pulled from 182 patients seen in emergency departments, intensive care units, and doctor’s offices in New South Wales between May and August of 2011, they found 29 (16%) carried the H275Y resistance mutation.

 

In 2011, we also saw reports of a `mildly resistant’ version of pH1N1 – with a different mutation S247N (serine (S) to asparagine (N)) mutation at the neuraminidase position 247) – showing up with some frequency in  Australia, Brunei and Singapore (see Eurosurveillance: A `Mildly’ Resistant Strain of H1N1 Emerges).

 

But neither of these strains has gained much traction globally, and the World Health Organization still reports only about 2% of samples tested are resistant to our frontline antiviral drugs.

 

Today, we’ve a Rapid Communications  in the journal Eurosurveillance that details a recent community cluster of resistant pH1N1 (with the H275Y mutation) in Sapporo, Japan.  Six genetically similar viruses were detected, although none of the patients had known contact with each other, which suggests a resistant strain may be starting to spread in that region.

 

Rapid communications

A community cluster of influenza A(H1N1)pdm09 virus exhibiting cross-resistance to oseltamivir and peramivir in Japan, November to December 2013

E Takashita¹, K Ejima¹, R Itoh¹, M Miura¹, A Ohnishi², H Nishimura³, T Odagiri¹, M Tashiro ()¹

1. Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo, Japan
2. Sapporo City Institute of Public Health, Hokkaido, Japan
3. Virus Research Center, Sendai Medical Center, Miyagi, Japan

---

Citation style for this article: Takashita E, Ejima K, Itoh R, Miura M, Ohnishi A, Nishimura H, Odagiri T, Tashiro M. A community cluster of influenza A(H1N1)pdm09 virus exhibiting cross-resistance to oseltamivir and peramivir in Japan, November to December 2013. Euro Surveill. 2014;19(1):pii=20666. Available online: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20666
Date of submission: 30 December 2013

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Six influenza A(H1N1)pdm09 viruses were detected in Sapporo, Japan, between November and December 2013. All six viruses possessed an H275Y substitution in the neuraminidase protein, which confers cross-resistance to oseltamivir and peramivir. No epidemiological link among the six cases could be identified; none of them had received neuraminidase inhibitors before specimen collection. The haemagglutinin and neuraminidase genes of the six viruses were closely related to one another, suggesting clonal spread of a single resistant virus.

(Continue . . .)

In their discussion, the authors write:

It has been shown that oseltamivir-resistant influenza A(H1N1) virus infection reduced the effectiveness of oseltamivir and this tendency was more apparent in children 0 to 6 years old [14-16]. Among patients from whom oseltamivir- and peramivir-resistant A(H1N1)pdm09 viruses have been detected in Japan, the percentage with no known exposure to NA inhibitors has increased significantly, from 16% during the pandemic period to 44% during the post-pandemic period [2]. These observations may suggest that human-to-human transmission with H275Y mutant viruses has increased gradually in the post-pandemic period. Consequently, surveillance of antiviral-resistant influenza viruses should be continued and strengthened, particularly for the choice of antiviral drugs.

 

 

Since 2009 we’ve seen sporadic cases of antiviral resistance show up in the new H1N1 virus, but only rarely have we seen clusters that suggest limited community spread.  So we are nowhere near the level of concern over antiviral resistance that we experienced in 2008.

 

That said,  we know that pharmacological victories over viruses and bacteria have always been fleeting at best. Pathogens – given enough time – have demonstrated a keen ability to evade each new generation of drugs we throw at them.

 

A reminder that in our ongoing battle against infectious diseases, that nature always bats last.

Spot Shortages Of Tamiflu Reported In Some Regions

Photo Credit – Wikipedia

 

# 8109

 

With the 2013-14 influenza season now well underway, and concerns over the severity of the H1N1 virus – particularly in younger patients and those with co-morbidities – the CDC is urging doctors to consider the early use of antivirals in high risk patients with suspected or confirmed influenza (see CDC HAN Advisory On Early pH1N1 Influenza Activity).

 

While there does not seem to be a national shortage of oseltamivir (Tamiflu ®) – the most commonly prescribed antiviral for influenza – in a few regions (mainly in the South) that have already been hit hard by the flu, some pharmacies are reporting trouble keeping the drug in stock.

 

A couple of  reports on these shortages, after which I’ll be back with a little more on Tamiflu, and this year’s H1N1 flu.

 

Shortage in flu medication worries pharmacists

LITTLE ROCK, Ark. (KTHV) - "We can't find the regular adult dose anywhere right now," Dr. Ray Turnage explained.

Turnage is one of many pharmacists dealing with a shortage of Tamiflu. He said, "There's only one manufacturer for that drug and nationwide all the wholesalers are saying it's a manufacture delay."

Tamiflu is the only medication on the market used to treat the flu and with a shortage in the drug, it could create problems for patients needing it. "Probably the demand is exceeding their supply. So that's the problem is we can't even get adult doses right now," Turnage continued.

Although there have been very minimal cases of the flu this year in Little Rock, with 3 to 4 months left in the flu season, that could change pretty quickly. If it does, Tamiflu in stock could disappear. Turnage said, "That's part of the situation is a few families can, if they can find it, can take all that the pharmacy may have."

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Shortage reports on Tamiflu in Atlanta, local pharmacies stocked – WSOC-TV

 

The bottom line is, that if you are prescribed Tamiflu, you may have to call around to more than one pharmacy to locate the drug.

While Tamiflu continues to get a strong recommendation from the CDC (see CDC Research On Benefits Of Antivirals For Uncomplicated Influenza), you’ll find no shortage of critics of the drug.  Due in large part to a prolonged reluctance on the part of Roche laboratories to release all of their clinical trial data, and a not totally undeserved reputation of `Big Pharma’ to massage test results. 

 

This has resulted in a vociferous backlash against the government stockpiling of Tamiflu in some quarters (see Dr. Ben Goldacre Opinion Piece). 

 

While academics and activists tend to have a dim view of Roche and their antiviral drug, clinicians obviously see value in oseltamivir,  and continue to prescribe it.  The CDC continues to recommend its use – particularly for high-risk influenza patients - or for the treatment of novel flu (see 2012 blog The CDC Responds To The Cochrane Group’s Tamiflu Study).

 

Although this year’s flu season is being billed in the media as `The Return of Swine Flu’, in truth, the H1N1 virus never departed.  But it has been dominated in North America by the H3N2 virus for the past couple of years.   The following snapshot of last year’s moderately severe flu season comes from last summer’s  MMWR Influenza Activity — United States, 2012–13 Season and Composition of the 2013–14 Influenza Vaccine.

 

Among the seasonal influenza A viruses, 34,922 (68%) were subtyped; 33,423 (96%) were influenza A (H3N2) viruses, and 1,497 (4%) were pH1N1 viruses. In addition, two variant influenza A (H3N2v) viruses were identified.

 

The season before that (2011-12) was the mildest flu season in decades (see 2011-2012 Flu Season Draws to a Close), that while H3N2 dominated, neither strain had a huge impact.

 

The truth is, flu seasons can vary greatly in impact from year-to-year,and with two influenza A strains in global circulation, we usually see one strain or the other dominate (although what strain is dominant in North America my differ from what is dominant in Europe, or Asia the same year).  Often we see 2 or 3 years with one strain in control, and then – as community immunity levels wane – the other takes hold.

 

The CDC’s most recent attempt to estimate the number of deaths associated with flu in the United States finds:

 

An August 27, 2010 MMWR report entitled “Thompson MG et al. Updated Estimates of Mortality Associated with Seasonal Influenza through the 2006-2007 Influenza Season. MMWR 2010; 59(33): 1057-1062.," provides updated estimates of the range of flu-associated deaths that occurred in the United States during the three decades prior to 2007. CDC estimates that from the 1976-1977 season to the 2006-2007 flu season, flu-associated deaths ranged from a low of about 3,000 to a high of about 49,000 people.

 

As much as a 16-fold difference in the number of estimated deaths between a mild flu season, and a heavy one. 

 

Thus far, its been H1N1’s year to roar, and since that strain often impacts those under the age of 65, it tends to get more publicity. The flu death of a young adult from influenza is more unexpected, and has more societal impact, than that of an octagenarian.  And this year, sadly, we are seeing a fair number of such reports (see Texas DSHS Statement On Recent Spike In Flu Activity).

 

Regardless of the strain of flu in circulation, you are much better off avoiding infection rather than treating it. So while it may only provide moderate protection, getting the flu shot each year is cheap insurance. 

That, and following good flu hygiene practices (covering coughs, washing hands frequently, staying home when sick, avoiding close contact with those who are sick),  are your best defense against our yearly flu epidemic.

CDC HAN Advisory On Early pH1N1 Influenza Activity

 

 

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After a couple of lackluster influenza seasons immediately following the 2009 pandemic, last year saw a particularly nasty H3N2 season, with some of the highest hospitalization and P&I mortality rates (particularly among the elderly) that we’d seen in a decade. 

 

This year, it is the 2009 H1N1 virus (aka pH1N1) that is dominant, and it has already made a serious impact, particularly in the Southern tier of states (see Texas DSHS Statement On Recent Spike In Flu Activity). Unlike H3N2, which generally impacts the elderly hardest, H1N1 has a history of skewing towards younger patients.

 

Late yesterday the CDC released a HAN ADVISORY to clinicians advising them of this early spike in flu activity, and the dominance of the pH1N1 strain. They continue to recommend vaccination, and the early administration of antivirals for anyone with confirmed or suspected influenza who is hospitalized; has severe, complicated, or progressive illness; or is at higher risk for influenza complications.

You’ll find excerpts from this HAN advisory below.  Follow the link to read it in its entirety.

 

Distributed via the CDC Health Alert Network
December 24, 2013, 14:30 ET (2:30 PM ET)
CDCHAN-00359

Notice to Clinicians: Early Reports of pH1N1-Associated Illnesses for the 2013-14 Influenza Season

Summary

From November through December 2013, CDC has received a number of reports of severe respiratory illness among young and middle-aged adults, many of whom were infected with influenza A (H1N1) pdm09 (pH1N1) virus. Multiple pH1N1-associated hospitalizations, including many requiring intensive care unit (ICU) admission, and some fatalities have been reported. The pH1N1 virus that emerged in 2009 caused more illness in children and young adults, compared to older adults, although severe illness was seen in all age groups. While it is not possible to predict which influenza viruses will predominate during the entire 2013-14 influenza season, pH1N1 has been the predominant circulating virus so far. For the 2013-14 season, if pH1N1 virus continues to circulate widely, illness that disproportionately affects young and middle-aged adults may occur.

 

Seasonal influenza contributes to substantial morbidity and mortality each year in the United States. In the 2012-13 influenza season, CDC estimates that there were approximately 380,000 influenza-associated hospitalizations [1]. Although influenza activity nationally is currently at low levels, some areas of the United States are already experiencing high activity, and influenza activity is expected to increase during the next few weeks.

 

The spectrum of illness observed thus far in the 2013-14 season has ranged from mild to severe and is consistent with that of other influenza seasons. While CDC has not detected any significant changes in pH1N1 viruses that would suggest increased virulence or transmissibility, the agency is continuing to monitor for antigenic and genetic changes in circulating viruses, as well as watching morbidity and mortality surveillance systems that might indicate increased severity from pH1N1 virus infection. In addition, CDC is actively collaborating with state and local health departments in investigation and control efforts.

 

CDC recommends annual influenza vaccination for everyone 6 months and older. Anyone who has not yet been vaccinated this season should get an influenza vaccine now. While annual vaccination is the best tool for prevention of influenza and its complications, treatment with antiviral drugs (oral oseltamivir and inhaled zanamivir) is an important second line of defense for those who become ill to reduce morbidity and mortality. Antiviral treatment is recommended as early as possible for any patient with confirmed or suspected influenza who is hospitalized; has severe, complicated, or progressive illness; or is at higher risk for influenza complications.

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A personal note: I know several people who have already been hit very hard by this year’s `flu’, and they have described it as being particularly `nasty’.  If you haven’t taken this year’s flu shot, it isn’t too late to do so.  It isn’t perfect protection, but can probably cut your odds of contracting the flu in half.

And it is particularly important to maintain good flu hygiene right now.   The CDC recommends:

• Wash your hands often with soap and water or an alcohol-based hand rub.
• Avoid touching your eyes, nose, or mouth. Germs spread this way.
• Try to avoid close contact with sick people.
• Practice good health habits. Get plenty of sleep and exercise, manage your stress, drink plenty of fluids, and eat healthy food.
• Cover your nose and mouth with a tissue when you cough or sneeze. Throw the tissue in the trash after you use it.
• If you are sick with flu-like illness, stay home for at least 24 hours after your fever is gone without the use of fever-reducing medicine.