Flu Found Resistant to Main Antiviral Drug

[HenryN]

Re: Flu Found Resistant to Main Antiviral Drug

only HA,NA

are they maybe hiding a possible reassortment, the main cause
why one strain suddenly becomes dominant ?

Please stop posting nonsense about reassortment as the "main cause".

Most of the isolates that involve only HA and or NA sequences were submitted by the CDC, who has acknowledge recombination in genetic drift, the main driver of infleunza evolution.

When p values get into the 10 billion range, hand waving about the whole sequence database being wrong really are not very convincing (especially when the data base proves that such statements are utter nonsense).

Remember the three stages of denial:

1. It can't be true.

2. Even if it was true, it can't be important.

3. We knew it all along.

CDC is moving into phase 3 with regard to homolgous recombination in influenza. Too many sequences to contine the fairy tale about reassortment as the driver.

CDC has moved on, while you are still clinging to the reassortment fairy tale.

[gsgs]

Re: Flu Found Resistant to Main Antiviral Drug

looks like a prepared, standardized reply.

Please stop posting nonsense about recombination, which is not supported elsewhere.

Ask CDC whether they "acknowledge recombination in genetic drift, the main driver of infleunza evolution."
(and whether they consider reassortment a "fairy tale")

[HenryN]

Re: Flu Found Resistant to Main Antiviral Drug

looks like a prepared, standardized reply.

Please stop posting nonsense about recombination, which is not supported elsewhere.

Ask CDC whether they "acknowledge recombination in genetic drift, the main driver of infleunza evolution."
(and whether they consider reassortment a "fairy tale")

The CDC power point and transcript of last week's presentation on H274Y are public.

Reassortment "driver" is history.

[HenryN]

Re: Flu Found Resistant to Main Antiviral Drug

<early> in the 2008/09 influenza season, influenza (A/H1N1) shares oseltamivir resistance (H275Y *) occur in situations [first report]</early>

要約
昨シーズン初め以来、オセルタミビル（商品名タミフル）に対して耐性を示すA/H1N1亜型（ソ連型）インフルエンザウイルスが世界各国で高頻度に分離されている。

Summary
since early last season, oseltamivir (Tamiflu name) to be resistant A/H1N1 subtype (Soviet-type) are separated by a high frequency of flu around the world.

わが国でも2008/09シーズンに入ってから、A/H1N1分離株の98％がオセルタミビル耐性となっている。

In Japan since the 2008/09 season, A/H1N1 in 98&#37; of isolates resistant to oseltamivir.

これらの耐性株は別の抗インフルエンザ薬であるザナミビル（商品名リレンザ）には感受性である 。

Zanamivir resistance of these shares is another anti-flu drug (product name Relenza) are sensitive.

病原性も通常のA/H1N1流行株とほとんど変わらず、特に重症例との関連は報告されていない。

Some of the most pathogenic A/H1N1 unchanged and the epidemic strain, particularly associated with severe case has not been reported.

タミフル耐性ウイルスの抗原性は、今シーズンのA/H1N1ワクチン株A/ブリスベン/59/2007に類似しているので、ワクチンが有効であると予想される。

Tamiflu-resistant virus antigenicity, season A/H1N1 vaccine strain A / Brisbane / 59/2007, so it is similar to, which is expected to be effective vaccines.

昨シーズンに引き続き、今シーズンも抗インフルエンザ薬耐性株の流行動向調査が全国規模で実施中であるが、 本稿は2009年1月現在のまとめである。

After the last season, is a nationwide survey conducted in the fashion of the season and shares the anti-flu drug resistance, this paper is a summary of the current 2009.

はじめに
昨シーズン初旬（2007年11月頃）から、ノイラミニダーゼ（NA）蛋白質の275番目のアミノ酸がヒス チジンからチロシン(H275Y*)に置換して、抗インフルエンザ薬オセルタミビルに対して耐 性となったA/H1N1亜型インフルエンザウイルスが、北欧諸国を中心に高頻度に報告された。

Introduction
beginning of last season (11, around 2007), neuraminidase (NA) protein of 275 amino acid tyrosine from the second histidine (H275Y *) to replace, were resistant to anti-flu drug oseltamivir A / H1N1 subtype influenza virus has been reported frequently in the Nordic countries.

その後、この耐性ウイルスは北半球諸国へと拡大し、昨年の南半球の流行シーズンでは、この耐性 ウイルスがA/H1N1ウイルスのほとんどを占めていた。

Since then, the virus resistant to this expansion of northern hemisphere countries, the epidemic in the Southern Hemisphere season last year, this A/H1N1 virus was resistant to occupy most of the virus.

現時点では、北半球の2008/09流行シーズンは始まったばかりなので分離株数はまだ少ないが、米国ではA/H1N1分離株の97％、EU諸国では95％、また豪州、中米、アフリカ諸国では80～100％がオセルタ ミビル耐性となっている。

Currently, the number of shares of the Northern Hemisphere 2008/09 fashion season just started so separation is still low in the United States of A/H1N1 isolate 97%, EU countries 95%, Australia, Central America, with African countries is 80 to 100 percent are resistant to oseltamivir.

日本周辺では、韓国でのA/H1N1分離株の94％が、台湾での100％が耐性である。

In Japan, the A/H1N1 isolates in South Korea 94 percent, 100 percent of the resistance in Taiwan.

これらの耐性ウイルスは、ザナミビルとアマンタジンには感受性を示し、抗原性は現在のワクチン 株A/ブリスベン/59/2007と近縁である。

These viruses resistant to amantadine and Zanamivir shows the sensitivity, the antigenicity of the current vaccine strain A / Brisbane / 59/2007 and is closely related.

一方、中国では欧米諸国の流行株とは遺伝的に異なる系統のA/H1N1株が流行しており、これらの大半は、オセルタミビル感受性だがアマンタジン耐性である。

Meanwhile, in China and Western countries the epidemic strain of genetically different strains are prevalent A/H1N1 shares, most of these, it is resistant to amantadine sensitivity oseltamivir.

耐性株の大半はオセルタミビルが使用されていない地域で発生しており、またオセルタミビルを服用していない 患者から分離されているので、タミフルの使用によって耐性ウイルスが選択されて流行しているわ けではない。

Most of the shares has caused resistance in the region are not used oseltamivir, have been isolated from patients not taking oseltamivir, but the epidemic is selected by the use of Tamiflu-resistant virus is not .

病原性も通常のA/H1N1流行株とは変わらず、臨床的にはノルウェーから肺炎や副鼻腔炎の合併が多い傾向が示唆されているが 、特に重篤な症状を引き起こすとの報告はない 1, 2)。

Of normal and pathogenic A/H1N1 epidemic strain is unchanged, clinically suggests that the tendency of the merger of sinusitis and pneumonia, from Norway, reported to cause severe symptoms is not particularly 1, 2).

わが国でも昨シーズンに、国立感染症研究所（感染研）が全国の地方衛生研究所（地研）と共同でオセルタミビ ル耐性A/H1N1株の流行状況を緊急調査したが、1,734株中45株のみが耐性であり、出現頻度は2.6％と、諸 外国に比べて極めて低い状況であった 3)。

The last season in Japan, National Institute of Infectious Diseases (call infection) National Institute of Health of the region (call destination) oseltamivir resistance investigation in conjunction with the emergency situation A/H1N1 epidemic of shares, shares only 45 stocks in 1734 and resistance, frequency, and 2.6 percent, conditions were very low compared to other countries 3).

一方、今シーズン（2008/09）についてはまだ流行初期なのでインフルエンザウイルス株の分離数は少ないが、仙台市や滋賀県などから オセルタミビル耐性A/H1N1株の分離報告が相次いでいる 4), 5)。

Meanwhile, this season (2008/09) for the separation of several early pandemic strain of influenza virus is still so small, and resistant to oseltamivir, Shiga and Sendai A/H1N1 have been reported four separate stocks), 5) .

そのため、わが国でも昨シーズンとは異なり、耐性株の大規模な流行が懸念されている。

Therefore, unlike last season in Japan is concerned about the prevalence of resistant stocks.

本稿は、2009年1月16日現在で、地研から感染研へ送られ、解析が完了した52株についての中間報告で ある。

However, in January 2009 at 16, was sent to the call of infection from the call destination, a complete analysis of the interim report of 52 shares.

＊各種論文ではH274Yの表記をしているが、これは、H3N2亜型ウイルスのNA蛋白質のアミノ酸番号を もとにした表記法（N2表記法）であり、H1N1のNA蛋白質の場合は、耐性マーカーのアミノ酸番号はメチ オニンから数えて275番目となる。

* H274Y various papers have representation, which, H3N2 subtype of the virus NA notation on a number of amino acids of the protein (N2 notation) and, H1N1 in the NA if the protein is resistant number of markers is counted from the amino acid methionine and the second 275.

よって、本文では耐性マーカーのアミノ酸番号をH275Yで統一する。

Thus, the number of amino acid in the body of a unified resistance marker H275Y.

１. 日本国内の耐性株発生状況
インフルエンザ発生動向調査事業によって、今シーズンに各地研で分離されたA/H1N1株についてNA遺伝子の塩基配列を決定し、H275Yの耐性マーカーの有無を指標とした遺伝子解析 を中心に検討した。

1. Situation occurred in Japan shares
Some business resistance survey flu, separated by A/H1N1 call throughout the season to determine the shares NA gene sequences, H275Y indicator of whether a marker of resistance Analysis of the studied genes.

その結果、A/H1N1の総解析数52株中51株にH275Y耐性マーカーが同定され、耐性株の発生頻度は98%であ った[ 図１ (pdf)]。

As a result, A/H1N1 total number of analysis of the 52 stocks 51 stocks have been identified H275Y resistance marker, the frequency tolerance of 98% share [Figure 1 (pdf)].

現時点での解析数は限られているが、地域的には本州を中心に18の道府県で耐性ウイルスが検出されており、 各地におけるA/H1N1分離株のほぼ100％がオセルタミビル耐性であった。

Based on current analysis is limited, the number is 18 in the mainland have been found in the prefectures of resistant virus, A/H1N1 in various parts of nearly 100 percent of the isolates were resistant to oseltamivir.

これに加えて、各地研および関連施設からも同様の解析により耐性株の分離報告を受けている。

In addition, the separation of the shares of the same resistance from the analysis of related facilities and call around.

これによると、青森県で12/12株（耐性株数/解析株数）、新潟県で2/2株、仙台医療センターで9/9株、仙台市で10/10株、東京都で13/13株、堺市で7/7株、和歌山県で1/1株、兵庫県で2/2株、福岡県で3/3株、宮崎県で10/10株と、各地で高頻度に耐性株が検出されている。

According to this, in Aomori Prefecture 12/12 shares (shares resistant / stock analysis), in Niigata 2 / 2 share, in the Sendai Medical Center, 9 / 9 share, in the city of Sendai shares 10/10, 13/13, Tokyo Shares in Sakai 7 / 7 share, in Wakayama 1 / per share, in Hyogo Prefecture / 2 share, in Fukuoka 3 / 3 share, and shares in Miyazaki 10/10, share a high frequency of resistance in many parts have been detected.

一方、全体におけるインフルエンザウイルス分離株の中でA/H1N1が約1/3を占めているので、オセルタミビル耐性のA/H1N1株は全国的に広く蔓延していることが示唆されている。

Meanwhile, shares in the total isolation of influenza A/H1N1 virus is about 1 / 3 because of the total, A/H1N1 share of oseltamivir resistance is suggested that widespread throughout the country.

２. NAI薬剤感受性試験
次に、現時点までに感染研が入手した耐性株遺伝子マーカーをもつ国内分離株について、オセルタミビルおよび ザナミビルに対する薬剤感受性試験を、合成基質を用いた化学発光法によって解析した。

2. NAI
then drug susceptibility testing, isolate domestic stocks with a genetic marker of resistance to currently available to call infection, drug susceptibility testing for Zanamivir and oseltamivir, and analyzed by chemiluminescent substrate using a synthetic did.

その結果、解析した13株のA/H1N1オセルタミビル耐性ウイルスは、すべて感受性株に比べて、400倍以上も高いIC50値を示し、オ セルタミビルに強い耐性であることが確認された。

The analysis of the 13 stocks that oseltamivir resistance A/H1N1 virus, compared to the all-sensitive shares, more than 400 times higher indicates IC50 value was found to be resistant to oseltamivir resistance.

一方、これらのオセルタミビル耐性株は、すべてザナミビルに対しては感受性を保持していた。

Meanwhile, shares of these oseltamivir resistance against all Zanamivir was holding sensitive.

３. 抗原性解析
国内の耐性株13株について、新旧ワクチン株およびその類似株に対するフェレット参照抗血清を用いた赤血球 凝集抑制（HI）試験により、抗原性を解析した。

3. Antigenic analysis of the national resistance
shares of 13 stocks, using a serum hemagglutination inhibition antibody ferrets see similar to stocks and shares its old and new vaccines (HI) test by the analysis of the antigen.

その結果、解析したすべての耐性株の抗原性は、今シーズンのA/H1N1ワクチン株A/ブリスベン/59/2007とほとんど同じか4倍以内の抗原変異に収まり、抗原性はワクチン株に類似していることが示され た[ 表1 (pdf) ]。

The antigenic analysis of all the shares of tolerance, this season A/H1N1 vaccine strain A / Brisbane / 59/2007 settlement or the same as four times less antigen mutation, is antigenically similar to vaccine strain indicated that [Table 1 (pdf)].

このことから、これらのオセルタミビル耐性A/H1N1ウイルスに対しても、今シーズンのワクチンは有効であることが示唆されている。

Thus, these oseltamivir resistance against A/H1N1 virus vaccine for the season is suggested to be valid.

４. NA遺伝子系統樹解析
ここ数年のA/H1N1流行株は、NA遺伝子の系統樹上では、クレード2B（アミノ酸マーカー：H45N、G249K、T 287I、K329E、G354D）およびクレード2C（アミノ酸マーカー：S82P、M188I、I26 7M、L367I、V393I、T453I）に大きく分けられる。

4. NA phylogenetic analysis of gene
A/H1N1 epidemic strain in recent years, NA in the genetic family tree, clade 2B (amino acid markers: H45N, G249K, T287I, K329E, G354D) and clade 2C (amino acids Marker: S82P, M188I, I267M, L367I, V393I, T453I) greatly divided.

中国での流行株の大半はクレード2Cに含まれるもので、オセルタミビル感受性、アマンタジン耐 性である。

Most of the epidemic strain in China is not included in the clade 2C, sensitivity to oseltamivir, amantadine resistance.

これに対して、わが国での流行株を含めた世界中の主なA/H1N1流行株は、今シーズンのワクチン株A/ブリスベン/59/2007を代表株とするクレード2Bに属する[ 図２ (pdf) ]）。

The major share of the world, including the epidemic strain A/H1N1 epidemic in our country, this season's vaccine strain A / Brisbane / 59/2007 clade 2B representing the shares belonging to the [Figure 2 ( pdf)]).

さらにクレード2Bは、D354Gという特徴的なアミノ酸置換のマーカー配列を持つ群（北欧系統）と持たな い群（ハワイ系統）に細分される。

2B is more clades, D354G group with an array of markers that are characteristic of amino acid substitution (Nordic strain) and has no group (HI system) to be subdivided.

今シーズンに流行しているオセルタミビル耐性株のほとんどは国内外ともに北欧系統に属しており、昨シーズン に米国や日本でわずかに検出されたハワイ系統の耐性株は、今シーズンでは見つかっていない。

Most of the shares that oseltamivir resistance in vogue this season belongs to the Nordic system in both domestic and overseas stock HI-resistant strains were detected only in the United States and Japan last season, this season has not been found.

５. A/H3N2亜型およびＢ型インフルエンザウイルスに対するNAI耐性株サーベイランス
今シーズンに国内各地で分離されて感染研に送付されたA/H3N2（香港型）26株およびＢ型（6株）についても、オセルタミビルおよびザナミビルに対する薬剤感受 性試験を行った。

5. A/H3N2 subtype B and to share surveillance NAI-resistant influenza virus was sent to call infection
been separated in different parts of the country this season A/H3N2 (Hong Kong) shares and 26 B-(6 shares ), the drug susceptibility testing for Zanamivir and oseltamivir.

その結果、これらの分離株は全て両薬剤に対して感受性であり、今のところ、これらに対する耐性株は見つかっ ていない。

As a result, these isolates are all sensitive to both drugs, so far, resistance to these shares is not found.

同様に、海外諸国で分離されたA/H3N2亜型、B型ウイルスについても耐性株は報告されていない。

Similarly, separated by overseas countries subtype A/H3N2, B shares also resistant virus has not been reported.

おわりに
昨シーズンに国内で分離されたオセルタミビル耐性A/H1N1株の発生頻度は2.6％と、諸外国に比べて極めて低かった。

Conclusion
oseltamivir resistance in an isolated frequency A/H1N1 in last season's 2.6 percent share, and extremely low compared to other countries.

しかし、今シーズンに入り、オセルタミビル耐性A/H1N1株が相次いで分離されている。

However, entering the season, A/H1N1 oseltamivir resistance has been a series of separate stocks.

現時点での報告は18道府県からで、頻度は解析が終わった52株のA/H1N1株のうち51株（98%）が耐性であった。

The current report from 18 prefectures, frequency analysis of 52 stocks ended A/H1N1 share of 51 stocks (98%) were resistant.

わが国でも諸外国と同様に、流行中のA/H1N1ウイルスのほとんどすべてがオセルタミビル耐性であり、これが全国的に蔓延していることが推測され る。

Like other countries in Japan, oseltamivir resistance is A/H1N1 epidemic in almost all of the virus, estimated to have spread nationwide.

現時点（1月15日現在）でのインフルエンザウイルスの分離・検出状況は、A/H3N2が45％、A/H1N1が36％、B型が19％と、3種類のウイルスの混合流行であるが、A型ウイルスでは2つの亜型がほ ぼ同じ規模で流行している。

At this time (January 15) status of the flu virus detected in isolation, A/H3N2 by 45%, A/H1N1 by 36%, B-19 percent and the three types of virus is a mixture of fashion , A virus that is prevalent in almost the same size single subtype.

まだ流行の初期段階で分離ウイルス数が少ないので、全国レベルで予測は困難であるが、オセルタ ミビル耐性A/H1N1株が全国的規模に分散していること、全体のインフルエンザ分離ウイルス数の約1/3を占めていることから、今後本格的な流行を迎えると、全国各地でもオセルタミビル耐性A/H1N1ウイルスが高頻度に検出されると予想される。

Virus isolation because there are few still in the early stages of the epidemic, predicted at the national level is difficult, A/H1N1 oseltamivir resistance that the shares distributed to a nationwide basis, the overall number of influenza virus isolation 1 / 3 to account for that, and face a future outbreak, oseltamivir resistance in A/H1N1 nationwide are expected to be a high frequency of virus detection.

臨床現場では、インフルエンザの診断に迅速診断キットが頻用されており、その結果にもとづいて抗インフルエ ンザウイルス薬の処方がされている。

The clinical sites are頻用a rapid diagnostic kit to diagnose influenza, is the prescription of anti-flu drug on the basis of the results.

迅速診断キットでは、A型かB型かの鑑別は可能であるが、A/H1かA/H3かの亜型の識別は不可能である。

The rapid diagnostic kit, A or type B or type of differentiation is possible, A/H1 or famous A/H3 subtype identification is impossible.

今シーズンに流行しているA/H3N2およびB型ウイルスはオセルタミビルとザナミビルの両薬剤に対して感受性であるが、A/H1N1ウイルスはほぼ100％がオセルタミビル耐性となっている。

For the season to season A/H3N2 and B virus is sensitive to both the drug Oseltamivir and Zanamivir, A/H1N1 virus was almost 100 percent are resistant to oseltamivir.

すなわち、Ａ型インフルエンザとの型診断ができても、このＡ型ウイルスがオセルタミビルに感受性なのか耐性 なのかを判別できない。

In other words, A diagnosis can be the type of flu type A can not determine whether this is a resistance or susceptibility to oseltamivir of the virus.

Ａ型ウイルスの約半数をA/H1N1が占めつつある現状では、今後、臨床現場では抗インフルエンザウイルス薬の選択などの治療戦略に大 きな混乱が起こることが心配される。

A A/H1N1 virus about half are occupied at present, the future is concerned at the site of treatment may cause a major disruption in the selection and treatment strategy of anti-flu drugs.

このような状況を踏まえて、米疾病対策センター（CDC）が、暫定的ながら、今冬における抗インフルエンザ 薬の選択方針についての勧告を医師向けに出している。

Based on these circumstances, the U.S. Centers for Disease Control (CDC), while preliminary, they are an advisory to doctors about the selection policy of anti-influenza drug in the winter.

抗インフルエンザウイルス薬の選択には、地域でのインフルエンザ流行ウイルスの流行状況を十分に考慮するこ とが強調されている6)。

The selection of anti-flu drug, has stressed that due consideration to the situation of pandemic flu virus in the region).

A/H3N2やＢ型が流行の主流なのか、A/H1N1が多数を占めるのかの流行状況によって、オセルタミビルかザナミビルかの選択をするとの実践的な治 療戦略である。

A/H3N2 and B is the type of mainstream fashion, A/H1N1 the epidemic situation of the majority of treatment strategies and practical selection of Oseltamivir or Zanamivir.

わが国では、900万人分のオセルタミビルと300万人分のザナミビルが今シーズンに向けて準備されており 、今後の流行動向の推移や臨床所見などを見ながら逐次適切な指針が出される予定である。

In Japan, oseltamivir and 900 of the 300 million people are preparing for the season Zanamivir million, will be given the proper guidance and with a sequential clinical fashion trends and future trends .

従って、今シーズンのインフルエンザサーベイランスは、わが国のインフルエンザ対策にとって極めて重要な役 割をもつことになる。

Therefore, surveillance of influenza this season, will have a vital role for the nation's flu prevention.

A/H1N1に対する耐性株サーベイランスを全国レベルで実施するだけでなく、A/H3N2およびＢ型株を含めた通常のウイルス株サーベイランスを強化・継続していく必要がある。

A/H1N1 implementation at the national level as well as the resistance to share surveillance, A/H3N2 and B need to continue to strengthen surveillance of the virus strain, including the normal strain.

さらに、これらのサーベイランスから得られる情報は、随時更新されるとともに、速やかに臨床現場に還元され て治療方針の選択に役立てることが望まれる。

In addition, information from the surveillance will be updated from time to time, are expected to help choose the line of treatment is to quickly return to the site of treatment.

一方、今シーズンのワクチンに含まれるA/H1N1抗原（A/ブリスベン/59/2007）は耐性株に対しても有効に働くことが期待できるので、インフルエンザ罹患時に重症化や入院などの リスクが予想される場合には、今からでもワクチン接種が推奨される。

The season included the A/H1N1 vaccine antigen (A / Brisbane / 59/2007) can be expected to work well for resistant stocks, and predicted the risk of hospitalization when serious and has the flu When the vaccination is now recommended.

文　献

献statement
[LEFT]1) [COL (H275Y shares on resistance FAQ)

2) Hauge SH et al ., Oseltamivir-Resistant Influenza Viruses A (H1N1), Norway, 2007-08. Emerg Infect Dis. 2009

2) Hauge SH et al., Oseltamivir-Resistant Influenza Viruses A (H1N1), Norway, 2007-08. Emerg Infect Dis. 2009

3) http://idsc.nih.go.jp/iasr/29/346/pr3462.html (インフルエンザ（A/H1N1）オセルタミビル耐性株（H275Y*）の国内発生状況　[第２報])

3) http://idsc.nih.go.jp/iasr/29/346/pr3462.html (influenza (A/H1N1) shares oseltamivir resistance (H275Y *) occur in situations [II])

4) http://idsc.nih.go.jp/iasr/rapid/pr3481.html (集団発生事例から分離されたA/H1N1亜型インフルエンザウイルスについて―仙台市)

4) http://idsc.nih.go.jp/iasr/rapid/pr3481.html (isolated from cases of epidemic influenza virus subtype A/H1N1 - Sendai)

5) http://idsc.nih.go.jp/iasr/rapid/pr3482.html (2008/09シーズン初集団かぜからのAH1亜型インフルエンザウイルスの分離―滋賀県)

5) http://idsc.nih.go.jp/iasr/rapid/pr3482.html (2008/09 season from the cold mass separation of influenza virus subtype AH1 - SHIGA)

6) [URL="http://66.102.1.101/translate_c?hl=en&sl=ja&u=http://www2a.cdc.gov/HAN/ArchiveSys/ViewMsgV.asp%3FAlertNum%3D00279&prev=/search%3Fq%3Dh274y%26hl%3Den%26lr%3D%26rlz%3D1T4TS HA_enUS307%26as_qdr%3Dd&us (米CDCによる今冬における暫定的な薬剤の治療方針のガイドライン)[/LEFT]
6) [URL="http://66.102.1.101/translate_c?hl=en&sl=ja&u=http://www2a.cdc.gov/HAN/ArchiveSys/ViewMsgV.asp%3FAlertNum%3D00279&prev=/search%3Fq%3Dh274y%26hl%3Den%26lr%3D%26rlz%3D1T4TS HA_enUS307%26as_qdr%3Dd&usg=A (CDC guidelines for the U.S. policy of drug treatment in the interim by this winter) [LEFT]国立感染症研究所ウイルス第三部第一室インフルエンザ薬剤耐性株サーベイランスチーム製品評価技術基盤機構 バイオテクノロジー本部ゲノム解析部門インフルエンザウイルス遺伝子解析チーム全国地方衛生研 究所

National Institutes of Health team regional influenza virus gene biotechnology sector Genome Organization of Technology and Evaluation Division Surveillance teams share drug-resistant flu viruses third room of the Ministry of National Institute of Infectious Diseases

http://translate.google.com/translate?hl=en&sl=ja&u=http://idsc.nih.go.jp/iasr/rapid/pr3483.html&sa=X&oi=translate&resnum=6&ct=result&prev=/search%3Fq%3Dh274y%26hl%3Den%26lr%3D%26rlz%3D1T4TSHA_enUS307%26as_qdr%3Dd

[HenryN]

Re: Flu Found Resistant to Main Antiviral Drug

NA tree

http://idsc.nih.go.jp/iasr/rapid/graph/pf34832.pdf

[gsgs]

Re: Flu Found Resistant to Main Antiviral Drug

hmm, presenting them as phylotrees is not so good, IMO.
You could easily transmit with just a few bytes per strain
the whole genetic information (of NA).
Just list all the names and for each strain list all the differences to the preceding one.

This would be computer-readable and less space-consuming than
the phylo-tree.
A simple software could read the data and from it contruct
the very phylo-tree, if wanted, or print mutation tables
as I often used them here, or easily merge and resort the data
with other lists. It would be clearly superior to these trees.

Why isn't it being done ? I speculate it's some "copyright" .
They want us to see their analsis but don't want us to be able
to redo the analysis, to merge the data with other sets, to standardize
it for computer usage and use it to understand the global picture.

It's so strange. Theoreticians won't do it. I think it's just the economical
world, they create methods of presentation (.pdf) which are not
computer-readable to prevent others from redoing their work.
But they hate to admit it, so they are trying to hide it and provide
excuses (other reasons why .pdf is used) but a statistical
analysis of all these similar events clearly provides the
global picture with high significance.

[HenryN]

Re: Flu Found Resistant to Main Antiviral Drug

hmm, presenting them as phylotrees is not so good, IMO.
You could easily transmit with just a few bytes per strain
the whole genetic information (of NA).
Just list all the names and for each strain list all the differences to the preceding one.

This would be computer-readable and less space-consuming than
the phylo-tree.
A simple software could read the data and from it contruct
the very phylo-tree, if wanted, or print mutation tables
as I often used them here, or easily merge and resort the data
with other lists. It would be clearly superior to these trees.

Why isn't it being done ? I speculate it's some "copyright" .
They want us to see their analsis but don't want us to be able
to redo the analysis, to merge the data with other sets, to standardize
it for computer usage and use it to understand the global picture.

It's so strange. Theoreticians won't do it. I think it's just the economical
world, they create methods of presentation (.pdf) which are not
computer-readable to prevent others from redoing their work.
But they hate to admit it, so they are trying to hide it and provide
excuses (other reasons why .pdf is used) but a statistical
analysis of all these similar events clearly provides the
global picture with high significance.

Please. H274Y is at 100%. No statistics required. Those who know how to read phylogenetic trees use them all the time. It is state of the art and used in almost all publications.

[HenryN]

Re: Flu Found Resistant to Main Antiviral Drug

The Japanese tree indiactes that all isolates this season are on the same branch that produced H5N1 in Europe. including D354G. Many are also on the same branch as US isolates from this season. Earlier isolates with H274Y are in green. Reading the tree is straight forward (it includes many public sequences, including those from the US this season and last season).

[Giuseppe]

Re: Flu Found Resistant to Main Antiviral Drug

[Half-empty / half-full glass media wire - IOH]

Tamiflu Remains Fully Effective Against 94 Percent Of Circulating Influenza Viruses In Europe

Tamiflu Remains Fully Effective Against 94 Percent Of Circulating Influenza Viruses In Europe

Article Date: 20 Jan 2009 - 3:00 PST

Latest surveillance data coming through the European Centre for Disease Prevention and Control (ECDC) from virologists and clinicians indicates that the influenza A(H3N2) virus is the predominant strain in Europe so far this season.


Based on the data published by ECDC Roche confirms that the oral antiviral Tamiflu (oseltamivir) is fully active against influenza A(H3N2) and influenza B, which currently comprise 94 percent of circulating viruses in Europe this year.1

Tamiflu resistance reported in the 2008-2009 influenza seasons is confined to H1N1. No resistance has been seen with other circulating seasonal viruses - H3N2 and influenza B.

"Recent media reporting has elevated awareness of the H1N1 seasonal resistance seen this year in the United States and the Far East. However, in Europe the picture is different with H3N2 being the dominant strain so far. The circulating H3N2 viruses, which often cause a more severe illness than H1N1, are sensitive to oseltamivir, which means that oseltamivir will be active against the vast majority of influenza infections in Europe this season, if current trends continue," comments Prof Albert Osterhaus, Head of Virology, Erasmus Medical Centre, Rotterdam. "It is important that doctors understand that oseltamivir remains an effective treatment for patients across Europe."

Vaccines are considered first line in the management of seasonal influenza, however, people who show symptoms or have been in close contact with an infected person may require more immediate intervention, such as Tamiflu, which can rapidly treat and prevent influenza.

European surveillance data
The ECDC reports that in the 2008-2009 season, influenza activity is increasing rapidly across Europe. The first countries to report high intensity of influenza activity were Portugal and Ireland. To date, medium or high intensity activity has been reported in nineteen countries.1 Of 2488 viruses which have been typed and sub-typed in Europe so far this influenza season, the majority, 2128, were H3N2, with a smaller proportion,141, subtype H1N1 and 219 were type B. The data to date indicate that influenza A (H3N2) and B viruses which Tamiflu is active against make up over 90 percent of the viruses circulating in Europe based on the latest information.1

US surveillance data
While influenza A(H1N1) has been the most common strain circulating in the US so far this season, the Centers for Disease Control and Prevention (CDC) has noted that it is early in the flu season and it is difficult to predict this season's dominant strain. Last season in the US, the dominant influenza strain changed from H1N1 to H3N2 in late January.

In December 2008, the CDC issued interim guidance for the 2008-2009 influenza season which recommends treatment with either zanamavir or Tamiflu in combination with rimantadine when influenza A(H1N1) virus infection or exposure is suspected.2 The CDC has reminded clinicians to remain alert for additional changes in recommendations as the influenza season progresses.

At the same time ECDC noted that the epidemiological situation was different in Europe and that therefore the same considerations might not apply in Europe. Infections with influenza A(H3N2), the predominant strain in Europe this season, or B viruses can be treated with either Tamiflu or zanamavir.

In addition to monitoring by government agencies, WHO collaborating laboratories and other public health institutions, Roche recently initiated the global Influenza Resistance Information Study (IRIS), which will include 1,200 patients per influenza season from 2008-2011. Roche also continues to support the activities of the Neuraminidase Inhibitor Susceptibility Network (NISN).

Sensitivity of H5N1 (bird flu) to Tamiflu
Recently published data confirms that the H5N1 avian influenza (bird flu) strain remains sensitive to Tamiflu. Greater than ninety nine percent of H5N1 samples studied did not exhibit mutations that confer oseltamivir resistance.3

According to Benjamin Schwartz, MD, CDC National Vaccine Program Office, "the mutations that have made the H1N1 virus resistant are unlikely to occur in a pandemic virus, so therefore we have not changed our recommendations for planning and stockpiling".4 Tamiflu remains the World Health Organization's "primary recommended antiviral agent of choice for the treatment of A(H5N1) virus infections".5

H1N1 Tamiflu resistant virus
The currently circulating Tamiflu resistant H1N1 virus was first identified in Norway in January 2008 and, subsequently, in other European countries where the use of Tamiflu is low, indicating that the resistance was likely to be naturally acquired and not due to Tamiflu use. This is further supported by data showing that patients with resistant virus had not taken Tamiflu or been in recent contact with anyone taking the drug.6 Clinical symptoms associated with the resistant H1N1 strain do not appear to be significantly worse than those with Tamiflu-sensitive virus.6

Difference between a pandemic strain of influenza and seasonal influenza
A pandemic strain of influenza is always of the A variety and is a completely new strain to which there will be no immunity whereas a seasonal strain of influenza is one that has previously been circulating, which may have changed slightly (antigenic drift) and to which a level of immunity exists.

Differences between seasonal strains
Human influenza viruses are usually classified into three broad types A, B and C according to differences in the antigenic properties of their external coat. Influenza A viruses are clinically the most important. Type C viruses do not cause significant human disease, so, only type A and B viruses are of concern. The A(H1) influenza virus is usually associated with mild epidemics, while the A(H3) virus is known to cause more severe illness. Currently circulating A virus subtypes are A(H3N2) and A(H1N1).

About Tamiflu
Tamiflu is designed to be active against all clinically relevant influenza viruses and works by blocking the action of the neuraminidase (NA) enzyme on the surface of the virus. When neuraminidase is inhibited, the spread of the virus to other cells in the body is inhibited. It is licensed for the treatment and prophylaxis of influenza in children aged one year and above and in adults. The most frequently reported adverse events in clinical studies were nausea, vomiting, and diarrhea. Tamiflu is available for the treatment of influenza in more than 80 countries worldwide. Tamiflu was approved based on studies in seasonal influenza. The magnitude of effect of Tamiflu in treating and preventing novel strains of influenza (such as those that may be involved in a pandemic or associated with avian flu) cannot be predicted. The WHO has recommended that higher doses and longer duration may be required

Roche and Gilead
Tamiflu was invented by Gilead Sciences and licensed to Roche in 1996. Roche and Gilead partnered on clinical development, with Roche leading efforts to produce, register and bring the product to the markets. Under the terms of the companies' agreement, amended in November 2005, Gilead participates with Roche in the consideration of sub-licenses for the pandemic supply of Tamiflu in resource-limited countries. To ensure broader access to Tamiflu for all patients in need, Gilead has agreed to waive its right to full royalty payments for product sold under these sub-licenses.

About Roche
Headquartered in Basel, Switzerland, Roche is one of the world's leading research-focused healthcare groups in the fields of pharmaceuticals and diagnostics. As the world's biggest biotech company and an innovator of products and services for the early detection, prevention, diagnosis and treatment of diseases, the Group contributes on a broad range of fronts to improving people's health and quality of life. Roche is the world leader in in-vitro diagnostics and drugs for cancer and transplantation, and is a market leader in virology. It is also active in other major therapeutic areas such as autoimmune diseases, inflammatory and metabolic disorders and diseases of the central nervous system. In 2007 sales by the Pharmaceuticals Division totalled 36.8 billion Swiss francs, and the Diagnostics Division posted sales of 9.3 billion francs. Roche has R&D agreements and strategic alliances with numerous partners, including majority ownership interests in Genentech and Chugai, and invested over 8 billion Swiss francs in R&D in 2007. Worldwide, the Group employs about 80,000 people. Additional information is available on the Internet at http://www.roche.com.

1. EISS - Weekly Electronic Bulletin Week 2 :05/01/2009-11/01/2009 16 January 2009, Issue N? 287
2. The Centres for Disease Control and Prevention (CDC). Interim Antiviral Guidance for 2008-09 http://www2a.cdc.gov/HAN/ArchiveSys/...AlertNum=00279 Accessed 6 January 2009
3. Hill AW et al. Evolution of drug resistance in multiple distinct lineages of H5N1 avian influenza. Infections, Genetics and Evolution. 2008
4. 'Cost, resistance aired in HHS webcast on antivirals'. CIDRAP News. December 17 2008 http://www.cidrap.umn.edu/cidrap/con...08webinar.html Accessed 16 January 2009
5. Clinical management of human infection with avian influenza A(H5N1) virus. World Health Organization. 15 August 2007 http://www.who.int/csr/disease/avian...nagement07.pdf Accessed 16 January 2009
6. Hauge et al. Oseltamivir-Resistant Influenza Viruses A (H1N1), Norway, 2007-08. Emerg Infect Dis. 2009
-

<cite cite="http://www.medicalnewstoday.com/articles/136036.php">Tamiflu Remains Fully Effective Against 94 Percent Of Circulating Influenza Viruses In Europe</cite>

[HenryN]

Re: Flu Found Resistant to Main Antiviral Drug

Commentary

http://www.recombinomics.com/News/01210901/H274Y_China.html

[AlaskaDenise]

Re: Flu Found Resistant to Main Antiviral Drug

[quote=niman;203490]Commentary

http://www.recombinomics.com/News/01...na.html[/quote]
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H1N1 Tamiflu Resistance In China Raises Concerns
Recombinomics Commentary 01:19
January 21, 2009


The Japan NIH has issued a report on H1N1 that included phylogenetic analysis of 33 of the 50 H274Y isolates reported to date in Japan. All 33 mapped into the sub-clade with D354G, which was in the dominant sub-clade with H274Y last season. However, this season the isolates in the United States emerged from a sub-clade within this dominant sub-clade, and all isolates had A193T on HA.

An earlier phylogenetic analysis from Japan had three isolates from a major outbreak in Sendai. Those sequences matched the dominant sub-clade from the United States, which had three receptor binding domain changes (G189V, A193T, H196R). The NA from those sequences had N28S which was seen in isolates from Yokohama and Sendai (see list below). Another grouping had two other NA polymorphisms, A86T and T339A (from Miyagi and Yamaguchi). Those changes matched A/Hawai/19/2008, which also had A193T.

The largest branch from Japan had isolates that did not have synonymous changes, but mapped on a branch with the above isolates, suggesting this branch (with isolates from Sapporo, Mie, Osaka, Sakai, Sopporo, Shiuoka, Kobe, and Hiroshima) also identified islates with A193T on HA.

In addition one isolate had N73K, which was in the major sub-clade from South Africa, which also had A193T. Thus, it appears that 31/33 of the isolates from Japan have HA A193T. The two exceptions were from Shiga.

Moreover, an isolate from China, A/Jilin-Chaoyang/1191/08, maps with the US isolates, suggesting this same sub-clade has spread to China. Another isolate from China, A/Beijing-Huairou/15/08, is closely related, raising concerns that H274Y levels in H1N1 in China are also near 100%.

The spread of resistant H1N1 to China raises concerns with regard to co-circulating H5N1. China has just reported four confirmed cases of H5N1 and four additional contacts are suspect cases. These patients, as well as contacts, are treated with oseltamivir, raising concerns that patients or contacts infected with H5N1 could also be infected with H1N1 with H274Y, which could lead to the emergence of H5N1 with H274Y.

Japan isolates (31/33)

N28S
Yokahama/95/08
Yokohama/96/08
Sendai/103/08
Sendai/104/08
Sendai/105/08
Sendai-H/2103/08
Texas/15/2008
Texas/16/2008
Texas/17/2008
Texas/18/2008
Pennsylvania/08/08
Pennsylvania/09/08
Hawaii/21/08

A86T T339A
Miyagi/35/08
Yamaguchi/26/08
Yamaguchi/27/08
Yamagichi/28/08
Hawaii/19/08

Related to above
Hiroshima/44/08
Hiroshima/45/08
Hiroshima/46/08
Hiroshima/48/08
Kobe/49/08
Mie/32/08
Osaka-C/39/08
Sakai/30/08
Sakai/47/08
Sapporo/63/08
Sapporo/64/08
Sapporo/66/08
Sapporo/68/08
Sapporo/70/08
Sapporo/72/08
Sapporo/80/08
Sapporo/83/08
Shizouka-C/51/08
Shizouka-C/54/08

N73K
Chiba/86/08
Johannesburg/12/2008
Johannesburg/14/2008
Johannesburg/33/2008
Johannesburg/35/2008

.

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[gsgs]

Re: Flu Found Resistant to Main Antiviral Drug

they may know, where/when/why the resistance emerged
but don't want to tell us (yet)

[HenryN]

Re: Flu Found Resistant to Main Antiviral Drug

they may know, where/when/why the resistance emerged
but don't want to tell us (yet)

Please. The resistance emerged in 2006 as is clear from PUBLIC sequences.

[HenryN]

Re: Flu Found Resistant to Main Antiviral Drug

they may know, where/when/why the resistance emerged
but don't want to tell us (yet)

Who is "they"?
Who is "us"?
What's with the "yet" nonsense.

This thread was started for real media and science reports related to H274Y Tamiflu resistance, not handwaving conspiracy musings, which would be more appropriate elsewhere.

[HenryN]

Re: Flu Found Resistant to Main Antiviral Drug

http://precedings.nature.com/documen...ion/1#comments

New comments posted.