Emergence of seasonal influenza viruses type A/H1N1 with oseltamivir resistance in some European Countries at the start of the 2007-8 influenza

[HenryN]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::

INFLUENZA VIRUS, OSELTAMIVIR RESISTANCE (06): JAPAN
************************************************** *
A ProMED-mail post
<http://www.promedmail.org>
ProMED-mail is a program of the
International Society for Infectious Diseases
<http://www.isid.org>

Date: Thu 26 Feb 2008
Source: YomiuriShimbun Newspaper [trans. & summ. by a Japanese Corr., edited]
<http://www.yomiuri.co.jp/national/news/20080228-OYT1T00267.htm>


The Institute of Public Health of the City of Yokohama (see
<http://www.city.yokohama.jp/me/kenkou/eiken/infection_inf/2008nen/rinji0805.pdf>)
reported the 1st Japanese cases of Tamiflu-resistant influenza virus
in the 5th week [28 Jan to 3 Feb 2008?] to the World Health
Organization. [Tamiflu is the trade name of the neuraminidase
inhibiter oseltamivir].

Five patients between 8 and 13 years of age all resided in the same
ward. A cluster of 3 children attended the same elementary school,
and 2 were treated in the same hospital. They had received no Tamiflu
treatment prior to testing. All showed positive results for Relenza
sensitivity. [Relenza is the trade name for the neuraminidase
inhibiter zanamivir].

[Our correspondent has provided the following background information
as a footnote]:
1) Yokohama is the 2nd largest city in Japan, a city of 3 630 000
inhabitants living in 19 wards.
2) In Japan, elementary school children are from 6 to 12 years of age.
3) The meaning of "the same hospital" is not clear from the text of
the newspaper article [same hospital as the 3 from the school, or same
hospital as each other?] But an official report stated that 2 cases
were reported from a designated hospital for periodic reporting.

--
Communicated by:
A Japanese correspondent known to ProMED who wishes to remain anonymous.

[This is the 1st report of Tamiflu-resistant/Relenza-sensitive
influenza virus from Japan. Such viruses have been reported widely
throughout Europe and North America (see (ProMED-mail references
below) during the current influenza season. It is presumed that the
resistant virus isolated in Japan is the A/H1N1 serotype, as observed
elsewhere in the current influenza season. So far, there has been no
obvious explanation for the simultaneous appearance of
Tamiflu-resistant influenza virus across the Northern Hemisphere.

Tamiflu and Relenza are neuraminidase inhibitors. Tamiflu (oseltamivir
phosphate) is an oral anti-viral drug suitable for the prevention and
treatment of uncomplicated influenza in patients one year and older
whose flu symptoms have not lasted more than 2 days. This drug is
approved to treat Type A and B influenza virus infections. Efficacy of
Tamiflu in the treatment of influenza in subjects with chronic cardiac
disease and/or [other] respiratory disease has not been established.

Relenza (zanamivir) is another anti-viral drug suitable for persons
aged 7 years and older for the treatment of uncomplicated influenza
illness. This drug is approved to treat type A and B influenza. For
the drug to be effective, patients needed to start treatment within 2
days of the onset of symptoms. Relenza is approved for preventive use
to decrease the risk of developing influenza illness for persons aged
5 and older. Relenza is a powder that is inhaled twice a day for 5
days from a breath-activated plastic device called a Diskhaler for
treatment of influenza.

Information confirming the A/H1N1 serotype identity (or not) of the
Tamiflu-resistant virus isolated in Japan would be welcomed.

[see also:
Influenza A (H1N1) virus, oseltamivir resistance (05): China (HK)
20080203.0438
Influenza A (H1N1) virus, oseltamivir resistance (03): corr. 20080203.0430
Influenza A (H1N1) virus, oseltamivir resistance (04): CA, USA 20080202.0428
Influenza A (H1N1) virus, oseltamivir resistance (03): Europe 20080201.0399
Influenza A (H1N1) virus, oseltamivir resistance (02): Europe 20080129.0371
Influenza A (H1N1) virus, oseltamivir resistance - Norway 20080128.0361
2006
----
Avian influenza, human (162): oseltamivir resistance 20061010.2907
Avian influenza, human (155): Thailand, Indonesia 20060927.2757
2005
----
Avian influenza, human - East Asia (203): Tamiflu resistance 20051222.3659
Influenza viruses, drug resistance (06) 20051016.3021
Influenza viruses, drug resistance (02): RFI 20051001.2878]
.................................................. ......cp/msp/jw

[HenryN]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::

INFLUENZA VIRUS, OSELTAMIVIR RESISTANCE (06): JAPAN
************************************************** *

Information confirming the A/H1N1 serotype identity (or not) of the
Tamiflu-resistant virus isolated in Japan would be welcomed.
- Mod.CP]


For the pattern recognition challenged, the resistant strains will be H1N1 and the polymorphism will be H274Y (and the sub-type will not be the Brisbane strain).

The sudden appearance of H274Y on different genetic backgrounds is not easily explained by adaptive mutations.

[gsgs]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::

> adamantane resistance is more likely attributable to its interaction with fitness-enhancing
> mutations at other genomic sites rather than to direct drug selection pressure

oseltamivir resistance could be similar ?
so the resistance and the increase in drug use is coincicidence ??

http://mbe.oxfordjournals.org/cgi/content/abstract/24/8/1811

A dramatic rise in the frequency of resistance to adamantane drugs by influenza A (H3N2) viruses has occurred in recent years?from 2% to 90% in multiple countries worldwide?and associated with a single S31N amino acid replacement in the viral matrix M2 protein. To explore the emergence and spread of these adamantane resistant viruses we performed a phylogenetic analysis of recently sampled complete A/H3N2 genome sequences. Strikingly, all adamantane resistant viruses belonged to a single lineage (the "N-lineage") characterized by 17 amino acid replacements across the viral genome. Further, our analysis revealed that the genesis of the N-lineage was due to a 4+4 segment reassortment event involving 2 distinct lineages of influenza A/H3N2 virus. A subsequent study of hemagglutinin HA1 sequences suggested that the N-lineage was circulating widely in Asia during 2005, and then dominated the Northern hemisphere 2005-2006 season in Japan and the USA. Given the infrequent use of adamantane drugs in many countries, as well as the decades of use in the US associated with little drug resistance, we propose that the globally increasing frequency of adamantane resistance is more likely attributable to its interaction with fitness-enhancing mutations at other genomic sites rather than to direct drug selection pressure. This implies that adamantanes may not be useful for treatment and prophylaxis against influenza viruses in the long term. More generally, these findings illustrate that drug selection pressure is not the sole factor determining the evolution and maintenance of drug resistance in human pathogens.

[HenryN]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::

> adamantane resistance is more likely attributable to its interaction with fitness-enhancing
> mutations at other genomic sites rather than to direct drug selection pressure

oseltamivir resistance could be similar ?
so the resistance and the increase in drug use is coincicidence ??

http://mbe.oxfordjournals.org/cgi/content/abstract/24/8/1811

A dramatic rise in the frequency of resistance to adamantane drugs by influenza A (H3N2) viruses has occurred in recent years?from 2% to 90% in multiple countries worldwide?and associated with a single S31N amino acid replacement in the viral matrix M2 protein. To explore the emergence and spread of these adamantane resistant viruses we performed a phylogenetic analysis of recently sampled complete A/H3N2 genome sequences. Strikingly, all adamantane resistant viruses belonged to a single lineage (the "N-lineage") characterized by 17 amino acid replacements across the viral genome. Further, our analysis revealed that the genesis of the N-lineage was due to a 4+4 segment reassortment event involving 2 distinct lineages of influenza A/H3N2 virus. A subsequent study of hemagglutinin HA1 sequences suggested that the N-lineage was circulating widely in Asia during 2005, and then dominated the Northern hemisphere 2005-2006 season in Japan and the USA. Given the infrequent use of adamantane drugs in many countries, as well as the decades of use in the US associated with little drug resistance, we propose that the globally increasing frequency of adamantane resistance is more likely attributable to its interaction with fitness-enhancing mutations at other genomic sites rather than to direct drug selection pressure. This implies that adamantanes may not be useful for treatment and prophylaxis against influenza viruses in the long term. More generally, these findings illustrate that drug selection pressure is not the sole factor determining the evolution and maintenance of drug resistance in human pathogens.

H274Y is on at least two H1 genetic backgrounds.

[gsgs]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::

let's wait for the sequences.
Lots of HAs some days ago from airforce, but no NA for H1N1 yet

[Giuseppe]

::ECDC WEEKLY UPDATE::

FROM EUROPEAN CENTRE OF DISEASES PREVENTION AND CONTROL WEBSITE:

Resistance to oseltamivir (Tamiflu) found in some European influenza virus
samples

Updated 6th March 2008

In late January 2008 preliminary results from surveillance of antiviral drug susceptibility among seasonal influenza viruses circulating in Europe (the EU-EEA-EFTA countries) revealed that some of the A (H1N1) viruses in circulation this season (winter 2007-8) were resistant to the antiviral drug, oseltamivir (also know by the brand name Tamiflu).

According to data uploaded onto the EISS-Virgil database as of March 5th so far, 1756 samples of influenza A(H1N1) viruses isolated between November 2007 and early March in 24 European countries have been tested by the EU-funded VIRGIL network and National Influenza Centres.

Surveillance in previous years by the same Virgil Project found minimal numbers of resistant findings so this is a new finding this season.

Of the 1756 samples, 346 from 15 countries showed evidence of resistance to oseltamivir, another 9 countries have had specimens tested and not yet shown any sign of resistance. The data are shown as a figure with a linked table.

It should be noted that for a number of countries the numbers tested are low and therefore these proportions are likely to changes as more testing is undertaken.

This year the predominant type of influenza A viruses in Europe are of the A/H1N1 type and these conform well to the types of influenza viruses used for this seasons influenza vaccine in the Northern Hemisphere.

Hence that vaccine is expected to give good protection against the resistant and non-resistant viruses.

There are also increasing numbers of B viruses as the season progresses but few other A viruses circulating in Europe.

Further details on the virus distribution this season (which varies from country to country) are available on the European Influenza Surveillance Scheme (EISS) weekly update which is also summarised in ECDC?s Influenza News

The proportion of A/H1N1 viruses that are resistant varies significantly across Europe.

The highest proportion of resistant viruses to date have been in Norway where 111 (67%) of the 167 samples tested positive for resistance to oseltamivir.

Given the initial indication of a high level of resistance to oseltamivir in the A H1N1 viruses circulating in Norway, once the information came to their attention, the Norwegian authorities notified their EU partners and the World Health Organization (WHO) of this situation when the information cam to light at the end of January.

The Norwegian Public Health Institute also published an advisory to doctors and the public on its website that evening.

The country with the second highest proportion is France with 80 (39%) of 207 specimens showing the mark for oseltamivir resistance.

Experts from the European Centre for Disease Prevention and Control (ECDC), the European Commission, the European Influenza Surveillance Scheme and the World Health Organization (WHO) are currently assessing the significance of the data from the EISS VIRGIL network.

An interim European risk assessment has been published by ECDC and comments on this are welcomed to influenza@ecdc.europa.eu. Global surveillance has started coordinated by WHO and has this has found evidence of similarly resistant viruses in North America and the Far East. All data including that on the WHO web-site are updated every Thursday at present.

These are the first human influenza viruses resistant to oseltamivir found transmitting in the community anywhere in the world.

Similar viruses have been seen before but usually following treatment and those viruses have not been able to transmit and infect and have rapidly disappeared.

From the experience in Norway it seems that people who become ill with the oseltamivir resistant strain of A(H1N1) do not appear to become any more or less sick than people infected with ?normal? seasonal influenza.

That said, it should be remembered that any influenza A can cause severe disease or death in vulnerable people (older people, those with debilitating illnesses and the very young).

There is no evidence that the appearance of these new viruses are related to use of oseltamivir which is currently thought not to be widely prescribed in most European countries. ECDC is now working to gather more information on routine oseltamivir use in Europe.

At this stage it is difficult to comment fully on the significance of these finding and difficult to predict whether these viruses will become more or less common as the season progresses though analyses on trends has begun. ECDC, WHO, EISS, VIRGIL and authorities in the member states are investigating the new findings intensely and progress will be reported through this and other relevant web-pages. A summary of the arrangements for the EU EEA & EFTA Countries is available.

For information on seasonal influenza and how to protect yourself against it.

Data were provided by the European Influenza Surveillance Scheme http://www.eiss.org/index.cgi and the VIRGIL Project http://www.virgil-net.org/ ECDC would like to thank all countries, virologists, clinicians and others for contributing data. Funding for the VIRGIL project comes from the European Union FP6 Research Programme http://ec.europa.eu/research/health/...proj13_en.html and EISS is supported by ECDC. Laboratories in EISS contribute to the Global Influenza Surveillance Network managed by WHO.

1) Virgil Project http://www.virgil-net.org/
2) EISS Weekly Bulletin http://www.eiss.org/index.cgi
3) ECDC Influenza News http://ecdc.europa.eu/Health_topics/influenza/news.html
4) ECDC, Graph, http://ecdc.europa.eu/Health_topics/...als_graph.html
5) ECDC, Risk Assessment, http://ecdc.europa.eu/pdf/080127_os.pdf
6) WHO, http://www.who.int/csr/disease/influ.../en/index.html
7) EU EEA AND EFTA, http://ecdc.europa.eu/Health_topics/..._seasonal.html
8) How to Protect, http://ecdc.europa.eu/Health_topics/...nza/facts.html


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http://www.ecdc.europa.eu/Health_topics/influenza/antivirals.html

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[Giuseppe]

::WHO UPDATE, 7 MARCH 2008::

Influenza A(H1N1) virus resistance to oseltamivir - Last quarter 2007 to 06 March 2008

The detection of an increased number of A(H1N1) viruses with resistance to oseltamivir was initially reported
to WHO from Norway on 25th January (see WHO website: http://www.who.int/csr/disease/influ.../en/index.html ).

Before recent detection of a high prevalence of oseltamivir resistance in influenza A (H1N1) viruses with a specific neuraminidase mutation
(H274Y) in Norway, such resistance was rarely observed in community isolates.

During the previous northern hemisphere winter season (2006/07), surveillance through GISN laboratories found no oseltamivir - resistant
H1N1 viruses in isolates from Japan and Europe, and less than 1&#37; prevalence in H1N1 isolates from the USA.

In addition to Norway, several other countries in Europe and North America have found an elevated prevalence of oseltamivir-resistant viruses this season (Table). However, insufficient data are available at present to determine the full geographic scope, origins, or patterns of transmission of these oseltamivir resistant H1N1 viruses.

WHO is collecting global data about this phenomenon from multiple laboratories participating in GISN. Data for European countries participating in EISS were provided by the EISS and VirGil project.
WHO would like to thank all countries, virologists, clinicians and others for contributing data.
This summary table will be updated regularly as new data and reports become available.

Oseltamivir resistance results were obtained with using phenotypic and/or genotypic analysis.

-

http://www.who.int/csr/disease/influenza/Resistance%20Web%2020080305.pdf

------

[Giuseppe]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::

[SEASONAL INFLUENZA, ANTIVIRALS, ECDC, UPDATE] Antivirals and Antiviral Resistance - Influenza

Updated 13th March 2008

In late January 2008 antiviral drug susceptibility surveillance of seasonal influenza viruses in Europe (the EU-EEA-EFTA countries) by the EU-funded VIRGIL network and National Influenza Centres revealed that some of the A (H1N1) viruses circulating this season (winter 2007-8) were resistant to the antiviral drug, oseltamivir through mutation at position 274 in the viral neuraminidase gene.

Analysis of 1900 A(H1N1) viruses from 24 European countries isolated between November 2007 and early March (data archived on March 12th) showed that 398 were resistant to oseltamivir, but retained sensitivity to zanamivir and amantadine. The data are shown as a figure with a linked table(1).

The proportion of A/H1N1 viruses that are oseltamivir resistant varies significantly across Europe(2).

The highest proportion of resistant viruses to date have been in Norway where 127 (69%) of the 184 samples are resistant to oseltamivir, whereas no resistant viruses have been detected in nine of the 24 countries.

It should be noted that for some countries the numbers of viruses tested are low and therefore these proportions may change as more data accumulate.

Surveillance in previous years by the Virgil Project(3) found <1% of circulating viruses to be resistant.

The predominant influenza A viruses in Europe in winter 07/08 are A/H1N1 viruses, antigenically similar to the A/Solomon Islands/3/2006 virus included in the 2007/08 N Hemisphere vaccine.

As the season progresses influenza B has started to circulate, but there is only limited circulation of other influenza A in Europe.

Further details on country to country virus distribution this season are available on the European Influenza Surveillance Scheme (EISS) weekly update(4) which is also summarised in ECDC?s Influenza News(5).

Following the observation of a high level of resistance to oseltamivir in the A H1N1 viruses circulating in Norway, the Norwegian authorities notified their EU partners and the World Health Organization (WHO) of this situation at the end of January.

The Norwegian Public Health Institute also published an advisory to doctors and the public(6).

The country with the second highest proportion is France with 106 (38%) of 279 specimens showing the marker for oseltamivir resistance.

There is no evidence that the appearance of these new viruses are related to use of oseltamivir which is currently seemingly not widely prescribed in most European countries.

ECDC is now working with the manufacturer and national authorities to gather more information on routine oseltamivir use in Europe.

Experts from the European Centre for Disease Prevention and Control (ECDC), the European Commission, the European Influenza Surveillance Scheme and the World Health Organization (WHO) are currently assessing the significance of the data from the EISS VIRGIL network.

An interim European risk assessment has been published by ECDC(7) and comments on this are welcomed to influenza@ecdc.europa.eu.

Global surveillance has started coordinated by WHO and has this has found evidence of similarly resistant viruses in North America and the Far East.

All data including that on the WHO web-site(8) are updated every Thursday at present.

Although sporadic low level transmission of drug resistant viruses may have taken place since 1999 when the Neuraminidase Inhibitor drugs first were licensed, the 07/08 winter season is the first time there has been widespread and sustained transmission of such viruses in the community.

Similar viruses have been seen before, but usually following treatment .

Such viruses previously have not been able to readily transmit and have rapidly disappeared.

Clinical experience in Norway suggests that people who become ill with an oseltamivir resistant strain of A(H1N1) have a similar spectrum of illness to those infected with ?normal? seasonal influenza A which can cause severe disease or death in vulnerable people (older people, those with debilitating illnesses and the very young).

This is now being investigated in national and international studies coordinated by ECDC.

At this stage the significance of these findings remains uncertain.

The emergence of drug resistance in the context of limited drug use is unexpected, and the extent of future circulation is difficult to predict.

ECDC, WHO, EISS, VIRGIL and authorities in the member states are undertaking intensive surveillance and progress will be reported through this and other relevant web-pages.

A summary of the arrangements for the EU EEA & EFTA Countries(9) is available.

Briefing for policy makers in the EU and EEA/EFTA Member States(10)

For information on seasonal influenza and how to protect yourself against it(11).
-
Links:
(1) Table with recent isolates resistant to oseltamivir: http://ecdc.europa.eu/Health_topics/...als_graph.html
(2) Table with isolated resistant, from EU countries: http://ecdc.europa.eu/Health_topics/...als_graph.html
(3) Virgil Project Website: http://www.virgil-net.org/
(4) European Influenza Surveillance Scheme Website: http://www.eiss.org/index.cgi
(5) European Centre of Diseases Prevention and Control, Influenza Update: http://ecdc.europa.eu/Health_topics/influenza/news.html
(6) Norwegian statement: http://www.fhi.no/eway/default.aspx?...1:5569:1:::0:0
(7) ECDC Risk Assessment: http://ecdc.europa.eu/pdf/080127_os.pdf
(8) World Health Organization, http://www.who.int/csr/disease/influ.../en/index.html
(9) Summary of the arrangements in EU / EEA / EFTA: http://ecdc.europa.eu/Health_topics/..._seasonal.html
(10) Briefing for policy makers: http://www.ecdc.europa.eu/Health_top..._EU_%20EEA.pdf
(11) Information for the public: http://ecdc.europa.eu/Health_topics/...nza/facts.html

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http://www.ecdc.europa.eu/Health_topics/influenza/antivirals.html

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[Giuseppe]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::

[SEASONAL INFLUENZA, ANTIVIRALS, WHO, UPDATES] Influenza A(H1N1) virus resistance to oseltamivir - Last quarter 2007 to 13 March 2008

The detection of an increased number of A(H1N1) viruses with resistance to oseltamivir was initially reported to WHO from Norway on 25th January (see WHO website).

Before recent detection of a high prevalence of oseltamivir resistance in influenza A (H1N1) viruses with a specific neuraminidase mutation (H274Y) in Norway, such resistance was rarely observed in community isolates.

During the previous northern hemisphere winter season (2006/07), surveillance through GISN laboratories found no oseltamivir - resistant H1N1 viruses in isolates from Japan and Europe, and less than 1% prevalence in H1N1 isolates from the USA.

In addition to Norway, several other countries in Europe and North America have found an elevated prevalence of oseltamivir-resistant viruses this season (Table).

However, insufficient data are available at present to determine the full geographic scope, origins, or patterns of transmission of these oseltamivir resistant H1N1 viruses.

WHO is collecting global data about this phenomenon from multiple laboratories participating in GISN.

Data for European countries participating in EISS were provided by the EISS and VirGil project.

WHO would like to thank all countries, virologists, clinicians and others for contributing data.

This summary table will be updated regularly as new data and reports become available.

Oseltamivir resistance results were obtained with using phenotypic and/or genotypic analysis.

-

http://www.who.int/csr/disease/influenza/H1N1ResistanceWeb20080313.pdf

-----


------

[gsgs]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::

47 H1N1-HA sequences from Austria 2008 are available at genbank.
Only HA, not NA which would determine the resistance.

44 of the 47 are the new Brisbane strain, while 3 are different -
Solomon-like , similar to viruses from Texas and Korea from 2008.

5 from 68 Austrian H1N1 viruses 2008 were reported Tamiflu resistant above



145 H1N1 - HA sequences from 2008 at genbank
76 of these are "AF" (=airforce?) , from Korea,Japan,USA
from the 69 remaining viruses, 47 are from Austria

124 of the 145 are Brisbane, 21 are Solomon

while CDC reports:
Solomon:261 , Brisbane:100 , other:20


-----edit--------

I just noticed the genbank update:
ftp://ftp.ncbi.nih.gov/genomes/INFLU...fluenza_na.dat


30 H1N1-NA from 2008 available now.
9 of these have H274Y, all 9 are Brisbane-like and look similar

[HenryN]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::

Updated list of sequences with H274Y

gb|EU681266.1| Influenza A virus (A/Bursa-TR/1231/2007(H1N1))... 28.2 149
gb|EU681265.1| Influenza A virus (A/Istanbul-TR/1219/2007(H1N... 28.2 149
gb|EU681264.1| Influenza A virus (A/Istanbul-TR/1198/2007(H1N... 28.2 149
gb|EU681263.1| Influenza A virus (A/Ankara-TR/170/2008(H1N1))... 28.2 149
gb|EU681262.1| Influenza A virus (A/Istanbul-TR/111/2008(H1N1... 28.2 149
gb|EU702755.1| Influenza A virus (A/Hong Kong/17/2008(H1N1)) ... 28.2 149
gb|EU716587.1| Influenza A virus (A/Washington/01/2008(H1N1))... 28.2 149
gb|EU716580.1| Influenza A virus (A/Florida/02/2008(H1N1)) se... 28.2 149
gb|EU624316.1| Influenza A virus (A/England/557/2007(H1N1)) s... 28.2 149
gb|EU570806.1| Influenza A virus (A/Bursa-TR/28/2008(H1N1)) n... 28.2 149
gb|EU567014.1| Influenza A virus (A/New Jersey/06/2008(H1N1))... 28.2 149
gb|EU567009.1| Influenza A virus (A/Arizona/13/2007(H1N1)) se... 28.2 149
gb|EU567006.1| Influenza A virus (A/Arizona/14/2007(H1N1)) se... 28.2 149
gb|EU566999.1| Influenza A virus (A/Wisconsin/01/2008(H1N1)) ... 28.2 149
gb|EU566998.1| Influenza A virus (A/Maryland/04/2007(H1N1)) s... 28.2 149
gb|EU566987.1| Influenza A virus (A/New Jersey/20/2007(H1N1))... 28.2 149
gb|EU566983.1| Influenza A virus (A/New Jersey/05/2008(H1N1))... 28.2 149
gb|EU566977.1| Influenza A virus (A/Pennsylvania/02/2008(H1N1... 28.2 149
gb|EU566968.1| Influenza A virus (A/Arizona/15/2007(H1N1)) se... 28.2 149
gb|EU516201.1| Influenza A virus (A/New Jersey/16/2007(H1N1))... 28.2 149
gb|EU516200.1| Influenza A virus (A/Illinois/10/2007(H1N1)) s... 28.2 149
gb|EU516199.1| Influenza A virus (A/Georgia/20/2006(H1N1)) se... 28.2 149
gb|EU516198.1| Influenza A virus (A/Georgia/20/2006(H1N1)) se... 28.2 149
gb|EU516197.1| Influenza A virus (A/Georgia/20/2006(H1N1)) se... 28.2 149
gb|EU516196.1| Influenza A virus (A/Arizona/03/2007(H1N1)) se... 28.2 149
gb|EU516148.1| Influenza A virus (A/New Jersey/15/2007(H1N1))... 28.2 149
gb|EU516141.1| Influenza A virus (A/Minnesota/23/2007(H1N1)) ... 28.2 149
gb|EU516125.1| Influenza A virus (A/Hawaii/28/2007(H1N1)) seg... 28.2 149
gb|EU516123.1| Influenza A virus (A/Hawaii/28/2007(H1N1)) seg... 28.2 149
gb|EU516112.1| Influenza A virus (A/Hawaii/21/2007(H1N1)) seg... 28.2 149
gb|EU516028.1| Influenza A virus (A/Massachusetts/05/2007(H1N... 28.2 149
gb|EU516027.1| Influenza A virus (A/Texas/31/2007(H1N1)) segm... 28.2 149
gb|EU567011.1| Influenza A virus (A/Indiana/01/2008(H1N1)) se... 26.3 590

[Giuseppe]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::

[ANTIVIRALS, SEASONAL INFLUENZA, ECDC, UPDATES] Resistance to oseltamivir (Tamiflu) in some European influenza virus samples

As the influenza season is over, all data on the WHO, ECDC and EISS web-sites will now be updated only monthly with the next update at the end of June. Data can be expected to change because of testing of specimens taken earlier in the season

Updated 28th May 2008
In late January 2008, antiviral drug susceptibility surveillance of seasonal influenza viruses in Europe (the EU-EEA-EFTA countries) by the EU-funded VIRGIL network and National Influenza Centres revealed that some of the A (H1N1) viruses circulating this season (winter 2007-8) were resistant to the antiviral drug, oseltamivir through mutation at position 274 in the viral neuraminidase gene.

Analysis of 2748 A(H1N1) viruses from 24 European (European Union, EEA/EFTA) countries isolated between November 2007 and late May (data archived on May 28th) showed that 680 were resistant to oseltamivir, but retained sensitivity to zanamivir and amantadine.

The data are shown as a figure with a linked table.

It should be noted that the influenza season has now finished in Europe so that new detections like this and other changes in the totals are the result of testing of specimens from during the season and checking of data for example to eliminate duplicates.

The proportion of A(H1N1) viruses that are oseltamivir resistant varied significantly across Europe.

The highest proportion of resistant viruses to date have been in Norway where 182 (67%) of the 270 samples are resistant to oseltamivir, whereas no resistant viruses have been detected in five of the 24 countries.

Surveillance in previous years by the Virgil Project found <1% of circulating viruses to be resistant The predominant influenza A viruses in Europe in winter 07/08 were A(H1N1) viruses, antigenically similar to the A/Solomon Islands/3/2006 virus included in the 2007/08 N Hemisphere vaccine.

As the season progressed influenza B viruses started to circulate and then predominated.

There were only limited circulation of other influenza A in Europe.

Further details on country to country virus distribution this season are available on the European Influenza Surveillance Scheme (EISS) weekly update which were also summarised in ECDC?s Influenza News.

Following the observation of a high level of resistance to oseltamivir in the A(H1N1) viruses circulating in Norway, the Norwegian authorities notified their EU partners and the World Health Organization (WHO) of this situation at the end of January.

The Norwegian Public Health Institute also published an advisory to doctors and the public.

The country with the second highest proportion has been France with 231 (47%) of 496 specimens showing the marker for oseltamivir resistance.

This was followed by the Netherlands and Luxembourg with proportions of 30% and 26% respectively. There is no evidence that the appearance of these new viruses are related to use of oseltamivir which is currently seemingly not widely prescribed in most European countries. ECDC is now working with the manufacturer and national authorities to gather more information on routine oseltamivir use in Europe.

Experts from the European Centre for Disease Prevention and Control (ECDC), the European Commission, the European Influenza Surveillance Scheme and the World Health Organization (WHO) are currently assessing the significance of the data from the EISS VIRGIL network.

An interim European risk assessment has been published by ECDC and comments on this are welcomed to influenza@ecdc.europa.eu.
Global surveillance has started coordinated by WHO and has this has found evidence of similarly resistant viruses in North America and the Far East. All data including that on the WHO web-site are updated every Thursday at present.

Although sporadic low level transmission of drug resistant viruses may have taken place since 1999 when the Neuraminidase Inhibitor drugs first were licensed, the 07/08 winter season is the first time there has been widespread and sustained transmission of such viruses in the community.

Similar viruses have been seen before, but usually following treatment.

Such viruses previously have not been able to readily transmit and have rapidly disappeared.

Clinical experience in Norway suggests that people who become ill with an oseltamivir resistant strain of A(H1N1) have a similar spectrum of illness to those infected with ?normal? seasonal influenza A which can cause severe disease or death in vulnerable people (older people, those with debilitating illnesses and the very young). This is now being investigated in national and international studies coordinated by ECDC.

At this stage the significance of these findings remains uncertain.

The emergence of drug resistance in the context of limited drug use is unexpected, and the extent of future circulation is difficult to predict.

ECDC, WHO, EISS, VIRGIL and authorities in the member states are undertaking intensive surveillance and progress will be reported through this and other relevant web-pages.

A summary of the arrangements for the EU EEA & EFTA Countries is on the ECDC web-site this is also available in a pdf version as a briefing for policy makers in the EU and EEA/EFTA Member States

For information on seasonal influenza and how to protect yourself against it.

Data were provided by the European Influenza Surveillance Scheme and the VIRGIL Project

ECDC would like to thank all countries, virologists, clinicians and others for contributing data. Funding for the VIRGIL project comes from the
European Union FP6 Research Programme

Information on Antivirals and Antiviral Resistance
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From the latest two ECDC reports there are:

- 7th May: 2680 H1N1 isolates and 660 total resistant to oseltamivir (24%)

- 28th May: 2748 H1N1 isolates and 680 total resistant to oseltamvir (24%)

- New isolates: 68 H1N1, 20 resistant to oseltamivir (29%). IOH
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[HenryN]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with oseltamivir resistance in some European Countries at the start of the 2007-8 influenza

More Tamiflu resistant isolates at Genabnk

gb|EU779650.1| Influenza A virus (A/North Carolina/02/2008(H1... 26.3 593
gb|EU779643.1| Influenza A virus (A/New Jersey/10/2008(H1N1))... 26.3 593
gb|EU779641.1| Influenza A virus (A/Memphis/03/2008(H1N1)) ne... 26.3 593

[gsgs]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with oseltamivir resistance in some European Countries at the start of the 2007-8 influenza

new 2008-sequences were uploaded to genbank.
But most were from USA, little from Europe.
There was an unclear statement frm ECDC that Tamiflu-resistence
might have happened in 2 genetically different backgrounds of H1N1,
which would be strong evidence for resistance development
because of drug use.
But all published sequences from this year are so far from the same
background and almost all are very similar.

mutation table:

http://www.setbb.com/fluwiki2/viewtopic.php?p=913

(list only complete for 2008)

the critical mutation is C0823T (H274Y in protein),
the critical group of resistant sequences is 47-71

strains:
Brisbane:1-122
Solomon:161-163
Hawaii:164-179
Caledonia:123-160

so, considering NA only, I'd say that 42 uploaded US-H1N1 viruses
from 2008 are Brisbane (11 of these have H274Y) and 2 Hawaii.


CDC gives: (for HA)

267 (68&#37 of the 395 H1N1 viruses were characterized as A/Solomon Islands/3/2006-like
108 (27%) of the 395 viruses were characterized as A/Brisbane/59/2007-like.
20 (5%) of the 395 viruses were different


for HA I get: (USA,H1N1,2008)
Brisbane:~100
Hawaii:~12

I don't have any 2008 US-H1N1-HA which I would classify
as Solomon rather than Brisbane, so this is mysterious to me

[Giuseppe]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with oseltamivir resistance in some European Countries at the start of the 2007-8 influenza :::

Resistance to oseltamivir (Tamiflu) in some European influenza virus samples

As the influenza season is over, all data on the WHO, ECDC and EISS web-sites will now only be updated monthly with the next update at the end of August.

Data can be expected to change because of testing of specimens taken earlier in the season.

Updated 7th August 2008 ? next update at the end of August

In late January 2008, antiviral drug susceptibility surveillance of seasonal influenza viruses wascarried out in Europe (the EU-EEA-EFTA countries) by the EU-funded VIRGIL network.

The National Influenza Centres revealed that some of the A (H1N1) viruses circulating this season (winter 2007-8) are resistant to the antiviral drug oseltamivir through mutation at position 274 in the viral neuraminidase gene.

Analysis of 2898 A(H1N1) viruses from 25 European (European Union, EEA/EFTA) countries isolated between November 2007 and late July 2008 (data archived on August 6th) showed that 704 were resistant to oseltamivir, but retained sensitivity to zanamivir and amantadine.

The data are shown as a figure with a linked table. http://ecdc.europa.eu/Health_topics/...als_graph.html

It should be noted that the influenza season has now finished in Europe so changes in the totals are the result of testing of specimens taken during the influenza season and checking of data for example to eliminate duplicates.

The proportion of A(H1N1) viruses that are oseltamivir resistant varied significantly across Europe http://ecdc.europa.eu/Health_topics/...als_graph.html.

The highest proportion of resistant viruses to date have been in Norway where 184 (67%) of the 273 samples are resistant to oseltamivir, whereas no resistant viruses have been detected in five of the 25 countries.

Due to back testing of specimens previously collected some results are now available.

What is new this month from EU countries are the first data for Estonia, where 3 of 7 A(H1N1) specimens show the marker for resistance.

Surveillance in previous years by the Virgil Project http://www.virgil-net.org/ found <1% of circulating viruses to be resistant

The predominant influenza A viruses in Europe in winter 07/08 were A(H1N1) viruses, antigenically similar to the A/Solomon Islands/3/2006 virus included in the 2007/08 N Hemisphere vaccine.

As the season progressed influenza B viruses started to circulate and then predominated.

There were only limited circulation of other influenza A in Europe.

Further details on country to country virus distribution this season are available on the European Influenza Surveillance Scheme (EISS) http://www.eiss.org/index.cgi weekly update as well as in Influenza News http://ecdc.europa.eu/Health_topics/influenza/news.html.

Following the observation of a high level of resistance to oseltamivir in the A(H1N1) viruses circulating in Norway, the Norwegian authorities notified their EU partners and the World Health Organization (WHO) of this situation at the end of January.

The Norwegian Public Health Institute also published an advisory to doctors and the public.

The country with the second highest proportion is now Belgium (53%) followed by France with 231 (47%) of 496 specimens showing the marker for oseltamivir resistance.

This is then followed by the Netherlands and Luxembourg with proportions of 27% and 26% respectively.

There is no evidence that the appearance of these new viruses are related to use of oseltamivir which is currently seemingly not widely prescribed in most European countries.

ECDC is now working with the manufacturer and national authorities to gather more information on routine oseltamivir use in Europe.

Experts from the European Centre for Disease Prevention and Control (ECDC), the European Commission, the European Influenza Surveillance Scheme and the World Health Organization (WHO) http://www.who.int/csr/disease/influ.../en/index.html are currently assessing the significance of the data from the EISS VIRGIL network.

An interim European risk assessment has been published by ECDC http://ecdc.europa.eu/pdf/080127_os.pdf and comments on this are welcomed to influenza@ecdc.europa.eu.

Global surveillance has started and is being coordinated by WHO, and evidence has been found of similarly resistant viruses in North America and the Far East. All data including that on the WHO web-site are updated at monthly intervals at present.

At the global level the most recent notable finding was from South Africa where all 23 influenza A/H1N1 specimens gathered since the last quarter of 2007 and now that have been tested showed the marker of resistance.

Their findings have been confirmed by WHO Collaborating Centres.

To date there have only been 111 specimens influenza A/H1N1 specimens tested from WHO?s Africa Region and none of these have shown the markers of resistance apart from those from South Africa.

Other significant national proportions of A/H1N1 specimens showing resistance for which there are data on more than 50 specimens are from the Russian Federation 45%, 58 of 128), Canada 26% (127 of 486), United States 12% (126 of 1026), Japan 3% (44 of 1652), Hong Kong 12% (98 of 797), Australia 4% (3 of 83), Madagascar (none of 59), Korea (none of 99%) and New Zealand (none of 88).

At present there are no data on the new Southern Hemisphere influenza season which has recently started.

As well as the WHO monthly table http://www.who.int/csr/disease/influ...te18072008.pdf . WHO is publishing less frequent analytic summaries on the WHO web-site http://www.who.int/csr/disease/influ.../en/index.html . WHO also published regular summaries on influenza in the world.

The last of these was published in late July http://www.who.int/csr/disease/influ.../en/index.html .

Although sporadic low level transmission of drug resistant viruses may have taken place since 1999 when the Neuraminidase Inhibitor drugs first were licensed, the 07/08 winter season is the first time there has been widespread and sustained transmission of such viruses in the community.

Similar viruses have been seen before, but usually following treatment. Such viruses previously have not been able to readily transmit and have rapidly disappeared.

Clinical experience in Norway and elsewhere suggests that people who become ill with an oseltamivir resistant strain of A(H1N1) have a similar spectrum of illness to those infected with ?normal? seasonal influenza A which can cause severe disease or death in vulnerable people (older people, those with debilitating illnesses and the very young).

This is now being investigated in national studies and international studies coordinated by ECDC.

At this stage the significance of these findings remains uncertain. The emergence of drug resistance in the context of limited drug use is unexpected, and the extent of future circulation is difficult to predict.

ECDC, WHO, EISS, VIRGIL and authorities in the member states are undertaking intensive surveillance and progress will be reported through this and other relevant web-pages. A summary of the arrangements for the EU EEA & EFTA Countries is on the ECDC web-site http://ecdc.europa.eu/Health_topics/..._seasonal.html this is also available in a pdf version as a briefing for policy makers in the EU and EEA/EFTA Member States http://ecdc.europa.eu/Health_topics/..._EU_%20EEA.pdf

For information on seasonal influenza and how to protect yourself against it http://ecdc.europa.eu/Health_topics/...nza/facts.html.

Data were provided by the European Influenza Surveillance Scheme http://www.eiss.org/index.cgi and the VIRGIL Project http://www.virgil-net.org/ ECDC would like to thank all countries, virologists, clinicians and others for contributing data. Funding for the VIRGIL project comes from the European Union FP6 Research Programme.
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http://www.ecdc.europa.eu

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