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Influenza Virus A/h1n1 Resistant To Oseltamivir: W.h.o. Preliminary Summary

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Apparently we have humor-challenged members. Message removed.


I do seem to remember reading reports that Norwegian nursing homes had been hit hard by seasonal influenza and that Tamiflu was being doled out like candy in an attempt to stop institutional epidemics.

Maybe in the elderly, it's very easy to select for drug resistance when tamiflu is used and drug resistant recombination quasi-strains are in circulation within the susceptible (in this case, geriatric) cases. They have been identified as high risk patient group for spreading influenza in the community (as have infants/toddlers).

However, tamiflu use in the latter age cohort was constrained by questions of correct dosing and toxicity (EU approved changes in dosing for young children, late 07).
 
Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

gsgs said:
submitted H1N1 sequences increased a lot in 2007.


---edit1----
of course, drug usage having created the resistance is also a possibility,
we haven't ruled this out yet. But not much evidence for this, except
timing with increased Tamiflu-usage.
Click to expand...

From the Netherlands

Oseltamivir use:
For the sentinel patients data on oseltamivir use was available for all 41 patients sampled. None of the sentinel patients (41) or their household contacts (40) reported the use of oseltamivir in the two weeks prior to the date of specimen collection.
For the non-sentinel patients, data on oseltamivir use was available for 15 patients (further data are currently being collected). None of the non-sentinel patients reported the use of oseltamivir in the two weeks prior to the date of specimen collection. Household contacts of one patient with an oseltamivir sensitive A(H1N1) virus had used oseltamivir in the two weeks prior to the date of specimen collection.​

http://www.who.int/csr/disease/influenza/Netherlands_2008_06_25.pdf
 
Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Asking questions is one thing. Badgering is another.

I am asking that members do not antagonize each other either in tone, repeated questions, or actual words.


Thanks.
 
Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

here the tables in text-format for computer-analysis
and better reading:




sequences from the japan.pdf NA-phylo-tree


Code: 
resistant
  non-resistant
---------------------
Norway/1745/07
Norway/1747/07
Norway/1701/07
Norway/1731/07
Norway/1743/07
Norway/1736/07
Norway/1687/07
Arizona/03/07
New Jersey/16/07
England/557/07
New Jersey/15/07
Yokohama/77/08
Paris/0577/07
Yokohama/79/08
Yokohama/78/08
Paris/0644/07
Illinois/10/07
  Ishikawa/419/08
  South Dakota/06/07E
  Hawaii/19/07E
Toshigi/39/08
Toshigi/34/08
Yamagata/68/08
  Yamagata/35/08
Shimane/59/08
  Shizuoka-C/9/08
  Akita/8/08
  Fukui/21/08
  Kanagawa/17/08
  Nepal/4715/07E
  Washington/28/07
Tottori/29/08
Tottori/28/08
  Yamagata/31/08
  Hiroshima/22/08
  Kawasaki/27/08
  Johannesburg/67/07
  Hawaii/20/07
  Chiba/92/07
  Brisbane/59/07E
Kobe/27/08
Aichi/76/08
  Miyagi/23/08
  Hawaii/31/07E
Hawaii/28/07
Hawaii/21/07
Gifu-C/17/08
Tottori/23/08
Tottori/21/08
  Shimane/7/08
  Yamaguchi/14/08
Gifu-C/38/08
  Kyoto-C/1/08
  Yamagata/144/08
Yokohama/30/08
Yokohama/34/08
Yokohama/31/08
Yokohama/35/08
Yokohama/22/08
  Nagano/1041/08
Tochigi/8/08
  Shimane/32/08
  Niigata/66/08
  Nagano/1074/08
  Aomori/3/08
  Kobe/6/08
  Nagano/1089/08
  Okinawa/6/08
  Shizuoka/12/08
  Hyogo/31/07
  Texas/05/07
  St.Petersburg/96/07E


looks as if the H274Y mutation happened and was spread and isolated multiple times



Table2 Oseltamivir-resistant viruses, Japan season 2007/8
-------------------------------------------------------

Code: 
A/Yokohama/91,2007/11/30, Y,O5,05,M,Kindergarten,u
A/Tochigi/8  ,2008/01/15,HY,O5,04,M,Nursery,v
A/Gifu-C/17  ,2008/01/25, Y,00,04,F,Outpatient,-
A/Tottori/29 ,2008/01/25, Y,uu,05,F,Outpatient,u
A/Tottori/28 ,2008/01/26, Y,uu,05,M,Outpatient,u
A/Yokohama/22,2008/01/28, Y,Z?,10,M,school,-
A/Yokohama/30,2008/01/28, Y,00,12,M,Outpatient,u
A/Yokohama/31,2008/01/28, Y,00,13,M,Outpatient,u
A/Yokohama/34,2008/01/28, Y,Z?,08,F,school,v
A/Yokohama/35,2008/01/28, Y,Z?,09,M,school,v
A/Tottori/23 ,2008/01/29, Y,??,04,M,Outpatient,u
A/Tottori,21 ,2008/01/30, Y,??,06,M,Outpatient,u
A/Tochigi/34 ,2008/02/18, Y,00,01,F,Outpatient,u
A/Tochigi/39 ,2008/02/18, Y,00,04,F,Outpatient,u
A/Aichi/76   ,2008/02/19, Y,Z5,08,F,Outpatient,u
A/Shimane/59 ,2008/02/26, Y,00,14,F,Outpatient,v
A/Yokohama/77,2008/02/26, Y,00,23,M,Outpatient,u
A/Yokohama/78,2008/02/28, Y,00,50,F,Outpatient,u
A/Yokohama/79,2008/02/28, Y,00,52,M,Outpatient,u
A/Gifu-C/38  ,2008/03/07, Y,00,04,F,Outpatient,v
A/Kobe/27    ,2008/03/11, Y,00,03,F,Outpatient,u
A/Yamagata/68,2008/03/11, Y,00,08,M,Outpatient,u
 
Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

gsgs said:
here the tables in text-format for computer-analysis
and better reading:




sequences from the japan.pdf NA-phylo-tree


Code: 
resistant
  non-resistant
---------------------
Norway/1745Y/07/NIMR
Norway/1747Y/07
Norway/1701Y/07
Norway/1731Y/07
Norway/1743Y/07
Norway/1736Y/07
Norway/1687Y/07
Arizona/03Y/07
New Jersey/16/07
England/557/07
New Jersey/15/07
Yokohama/77/08
Paris/0577/07
Yokohama/79/08
Yokohama/78/08
Paris/0644/07
Illinois/10/07
  Ishikawa/419/08
  South Dakota/06/07E
  Hawaii/19/07E
Toshigi/39/08
Toshigi/34/08
Yamagata/68/08
  Yamagata/35/08
Shimane/59/08
  Shizuoka-C/9/08
  Akita/8/08
  Fukui/21/08
  Kanagawa/17/08
  Nepal/4715/07E
  Washington/28/07
Tottori/29/08
Tottori/28/08
  Yamagata/31/08
  Hiroshima/22/08
  Kawasaki/27/08
  Johannesburg/67/07
  Hawaii/20/07
  Chiba/92/07
  Brisbane/59/07E
Kobe/27/08
Aichi/76/08
  Miyagi/23/08
  Hawaii/31/07E
Hawaii/28/07
Hawaii/21/07
Gifu-C/17/08
Tottori/23/08
Tottori/21/08
  Shimane/7/08
  Yamaguchi/14/08
Gifu-C/38/08
  Kyoto-C/1/08
  Yamagata/144/08
Yokohama/30/08
Yokohama/34/08
Yokohama/31/08
Yokohama/35/08
Yokohama/22/08
  Nagano/1041/08
Tochigi/8/08
  Shimane/32/08
  Niigata/66/08
  Nagano/1074/08
  Aomori/3/08
  Kobe/6/08
  Nagano/1089/08
  Okinawa/6/08
  Shizuoka/12/08
  Hyogo/31/07
  Texas/05/07
  St.Petersburg/96/07E




Table2 Oseltamivir-resistant viruses, Japan season 2007/8
-------------------------------------------------------

Code: 
A/Yokohama/91,2007/11/30, Y,O5,05,M,Kindergarten,u
A/Tochigi/8  ,2008/01/15,HY,O5,04,M,Nursery,v
A/Gifu-C/17  ,2008/01/25, Y,00,04,F,Outpatient,-
A/Tottori/29 ,2008/01/25, Y,uu,05,F,Outpatient,u
A/Tottori/28 ,2008/01/26, Y,uu,05,M,Outpatient,u
A/Yokohama/22,2008/01/28, Y,Z?,10,M,school,-
A/Yokohama/30,2008/01/28, Y,00,12,M,Outpatient,u
A/Yokohama/31,2008/01/28, Y,00,13,M,Outpatient,u
A/Yokohama/34,2008/01/28, Y,Z?,08,F,school,v
A/Yokohama/35,2008/01/28, Y,Z?,09,M,school,v
A/Tottori/23 ,2008/01/29, Y,??,04,M,Outpatient,u
A/Tottori,21 ,2008/01/30, Y,??,06,M,Outpatient,u
A/Tochigi/34 ,2008/02/18, Y,00,01,F,Outpatient,u
A/Tochigi/39 ,2008/02/18, Y,00,04,F,Outpatient,u
A/Aichi/76   ,2008/02/19, Y,Z5,08,F,Outpatient,u
A/Shimane/59 ,2008/02/26, Y,00,14,F,Outpatient,v
A/Yokohama/77,2008/02/26, Y,00,23,M,Outpatient,u
A/Yokohama/78,2008/02/28, Y,00,50,F,Outpatient,u
A/Yokohama/79,2008/02/28, Y,00,52,M,Outpatient,u
A/Gifu-C/38  ,2008/03/07, Y,00,04,F,Outpatient,v
A/Kobe/27    ,2008/03/11, Y,00,03,F,Outpatient,u
A/Yamagata/68,2008/03/11, Y,00,08,M,Outpatient,u
Click to expand...
Why is the a Y in the sample number for the patients from Norway?
 
Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Public full sequences or phylograms showing North-EU subclade of 2B

Arizona/3/07
Arizona/13/07
Arizona/14/07
Arizona/15/07
England/557/07
Illinois/10/07
Lyon/1337/07
Maryland/04/07
New Jersey/5/07
New Jersey/10/07
New Jersey/15/07
New Jersey/16/07
New Jersey/20/07
Norway/1630/07
Norway/1651/07
Norway/1687/07
Norway/1701/07
Norway/1731/07
Norway/1736/07
Norway/1743/07
Norway/1745/07
Norway/1747/07
Paris/0577/07
Paris/0644/07
Sydney/142/07
Sydney/143/07
Sydney/144/07
Hawaii/1/08
Hawaii/2/08
Indiana/1/08
Memphis/3/08
Minnesota/1/08
New Jersey/06/08
North Carolina/2/08
Pennsylvania/2/08
Washington/1/08
Wisconsin/01/08
Yokohama/77/08
Yokohama/78/08
Yokohama/79/08
 
Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Y removed. That was my first idea to mark H274Y, but indentation
seems better. It shows how resistant and non-resistant isolates alternate.

In my mutation tables this would look like vertically sprenkled
dots or multiple short lines or dots in the same column,
which is rare
 
Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

gsgs said:
Y removed. That was my first idea to mark H274Y, but indentation
seems better. It shows how resistant and non-resistant isolates alternate.

In my mutation tables this would look like vertically sprenkled
dots or multiple short lines or dots in the same column,
which is rare
Click to expand...
Recent H5N1 would look the same for G743A
 
Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

not quite. 4 distant spots not this sprenkling (English?). -edit--(scattered)

my current theory is, that it's due to drug use.
Not (necessarily) in the sampled patients but
earlier, undetected.
The prevalent strain this year may have some other mutations
not seen before which counterbalances the earlier found
worse spreading of strains with H274Y.
I hope this will be determined.

But the reason for the establishing of Amantadine-resistance
some years ago was never found, AFAIK.
 
Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

I don't really know, how these phylo-trees are generated.
The rules, the source-code.
Maybe we could generate the sequences from the tree,
modulo the exact positions of the mutations, which is not
so important.

The most natural ordering of sequences would be to
always add as next one the closest sequence to the last selected one
out of the remaining ones.
 
Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

gsgs said:
not quite. 4 distant spots not this sprenkling (English?).

my current theory is, that it's due to drug use.
Not (necessarily) in the sampled patients but
earlier, undetected.
The prevalent strain this year may have some other mutations
not seen before which counterbalances the earlier found
worse spreading of strains with H274Y.
I hope this will be determined.

But the reason for the establishing of Amantadine-resistance
some years ago was never found, AFAIK.
Click to expand...
The problem is that you don't know how to generate or read the trees, which clearly show the H274Y was acquired AFTER the branches were formed.
Same story for G743A.
The data and sequences are CLEAR.
Case is closed.
 
Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

cause I consider the trees less informative and inferior to
computer-available direct data.
Presumably that's why they give trees in non-computer-readable .pdf
but withhold sequences
 
Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

gsgs said:
cause I consider the trees less informative and inferior to
computer-available direct data.
Presumably that's why they give trees in non-computer-readable .pdf
but withhold sequences
Click to expand...
The trees can be generated with free public software, as long as you have the sequences.
The tree from Japan, as well as the others I linked had public sequences, so it was easy to map the public and non-public sequences and see the H274Y was appended onto MULTIPLE branches AFTER the branches were formed.
The data have been made public and are easily interpreted.
 
Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

"cause I consider the trees less informative and inferior to
computer-available direct data.
Presumably that's why they give trees in non-computer-readable .pdf
but withhold sequences"

Wrong. Phylogenetic relationships have been mapped as 'trees' for decades by Systematics and Cladistics Biologists. The input data can be physical (morphological or anatomical features), biochemical (enzyme assay, protein structure), or genetic, or a combination thereof (treated as 'layers' within a cladistics analysis model). The goal is to map the characteristics of individuals to the best fit evolutionary relationships when comparing members of a group.

As Niman *patiently* points out, the software is within the public domain, as are websites that explain their use. The sequence data is also published within the public domain - as you well know.

The output file forms vary according to use. Pdf format has nothing to do with tree making.
 
Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Oracle said:
"cause I consider the trees less informative and inferior to
computer-available direct data.
Presumably that's why they give trees in non-computer-readable .pdf
but withhold sequences"

Wrong. Phylogenetic relationships have been mapped as 'trees' for decades by Systematics and Cladistics Biologists. The input data can be physical (morphological or anatomical features), biochemical (enzyme assay, protein structure), or genetic, or a combination thereof (treated as 'layers' within a cladistics analysis model). The goal is to map the characteristics of individuals to the best fit evolutionary relationships when comparing members of a group.

As Niman *patiently* points out, the software is within the public domain, as are websites that explain their use. The sequence data is also published within the public domain - as you well know.

The output file forms vary according to use. Pdf format has nothing to do with tree making.
Click to expand...
Yes, the phylogenetic trees are the "industry standard" and although they have shortcomings (they can't handle recombination very well), they do provide a basis for analysis.

The trees from Japan included several public sequences (from the US), so it was fairly easy to take a tree of the public data, see where the public sequences on the Japan tree mapped, and figure out where the unpublished sequences would map. The same is true for the other trees that I linked.

As a result, I listed the isolates that would be on the branch labled "Northern EU-like"

http://www.who.int/csr/disease/influenza/japan_2008_06_25.pdf

on the tree from Japan.

http://www.flutrackers.com/forum/showpost.php?p=168413&postcount=29

Since all isolates on this branch have H274Y, they all could have originated from a single sequence with H274Y. As can be seen by the length of the list and the locations, this is the major version of Bisbane/59 with H274Y.

However, it is the isolates with H274Y that are NOT on this branch that represent independent acquistion of H274Y and these other isolates are on branches that have isolates with and without the change. Since some of the branch members do NOT have H274Y, those branches were formed BEFORE H274Y was acquired (because if H274Y came first, all branch members would have H274 - except for rare revertants).

As was described in earlier commentaries, in the US there are two such branches. One has isolates from Hawaii and California, but only two of the Hawaii isolates have the change (one of the Hawaii isolates with the chnage is listed on the tree from Japan, as well as the other trees I linked).

Another branch is formed by isoates from Florida. Two of the Florida isolates are from 2007 and they don't have the change, while the isolate from 2008 does, indicating the 2008 acquistion was in Florida (or on a Florida-like sequence).

The tree from Japan has several additional branches which have some isolates from Japan without the change, and others from Japan with the change, indicating these were also acquisitions AFTER these other branches were formed, and were independent of the acquisitions on the other branches.

Most of the isolates in Japan were from patients who either definitely did not have Tamiflu prior to collection, or probably did not have Tamiflu prior to collection. Only 2 of 22 isolates definitely had Tamiflu prior to collection and one of the two is in group 2A, which isn't included in the above analysis.

The story is in the sequence, and the sequence is an EASY read.
 
Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Phylogenetic relationships are on the edge of applicability for microbial (bacterial, viral, plasmid) isolate comparisons because of that issue of host-environment interaction causing active 'editing' of genes, even within just a few generations.

Which brings us to an interesting conundrum when comparing a small number of outbreak samples and making assumptions on their geographic representativeness, given the exceptional plasticity of these viruses in susceptible hosts (human, mammal, avian).

Also of comparing sequences for all three pandemics of the last century, given that paucity of samples for all three (6, 3, and I believe 3-4 for the last one, 1968). Furthermore, the last two pandemics have isolates have been 'passed' repeatedly while maintained in culture. Taubenberger mentions this in a 2003 paper analyzing the two 1918 variants.

It's not surprising, for instance, to read that the Marburg virus isolate from the Dutch patient (deceased) is 'different' than the type isolate from the outbreak in Uganda in 2007. Despite being from very nearly the same locale.

They are different for a reason other temporal, locale or arising from different patients groups.
 
Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

Re: _|INFLUENZAVIRUS A/H1N1 RESISTANT TO OSELTAMIVIR: W.H.O. PRELIMINARY SUMMARY|_

so, why do they give trees but withhold sequences ?

is there software to construct the sequences from the trees, modulo locations ?

is there OCR software to read trees into the computer ?



Obviously the trees are less informative than my mutation tables wrt.
some (most) aspects. Are such tables and pictures used elsewhere ?
You can't track single polymorphisms with the trees.
 
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