Influenza viruses resistant to oseltamivir, news and updates

[HenryN]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

first resistant strains were in

England 15.Nov
NJ, 24.Nov

and the slightly different lineage in Hawaii 22.Oct
with other identical (except at 274) strains in Hawaii 2007

dates of
Hawaii 18,31,35 or Calif.28 ?

<TABLE style="WIDTH: 218pt; BORDER-COLLAPSE: collapse" cellSpacing=0 cellPadding=0 width=291 border=0 x:str><COLGROUP><COL style="WIDTH: 170pt; mso-width-source: userset; mso-width-alt: 8301" width=227><COL style="WIDTH: 48pt" width=64><TBODY><TR style="HEIGHT: 12.75pt" height=17><TD style="BORDER-RIGHT: #e0dfe3; BORDER-TOP: #e0dfe3; BORDER-LEFT: #e0dfe3; WIDTH: 170pt; BORDER-BOTTOM: #e0dfe3; HEIGHT: 12.75pt; BACKGROUND-COLOR: transparent" width=227 height=17>Hawaii/18/2007</TD><TD class=xl22 style="BORDER-RIGHT: #e0dfe3; BORDER-TOP: #e0dfe3; BORDER-LEFT: #e0dfe3; WIDTH: 48pt; BORDER-BOTTOM: #e0dfe3; BACKGROUND-COLOR: transparent" align=right width=64 x:num="39740">19-Oct</TD></TR><TR style="HEIGHT: 12.75pt" height=17><TD style="BORDER-RIGHT: #e0dfe3; BORDER-TOP: #e0dfe3; BORDER-LEFT: #e0dfe3; BORDER-BOTTOM: #e0dfe3; HEIGHT: 12.75pt; BACKGROUND-COLOR: transparent" height=17>Hawaii/31/2007</TD><TD class=xl22 style="BORDER-RIGHT: #e0dfe3; BORDER-TOP: #e0dfe3; BORDER-LEFT: #e0dfe3; BORDER-BOTTOM: #e0dfe3; BACKGROUND-COLOR: transparent" align=right x:num="39722">1-Oct</TD></TR><TR style="HEIGHT: 12.75pt" height=17><TD style="BORDER-RIGHT: #e0dfe3; BORDER-TOP: #e0dfe3; BORDER-LEFT: #e0dfe3; BORDER-BOTTOM: #e0dfe3; HEIGHT: 12.75pt; BACKGROUND-COLOR: transparent" height=17>Hawaii/35/2007</TD><TD class=xl22 style="BORDER-RIGHT: #e0dfe3; BORDER-TOP: #e0dfe3; BORDER-LEFT: #e0dfe3; BORDER-BOTTOM: #e0dfe3; BACKGROUND-COLOR: transparent" align=right x:num="39731">10-Oct</TD></TR><TR style="HEIGHT: 12.75pt" height=17><TD style="BORDER-RIGHT: #e0dfe3; BORDER-TOP: #e0dfe3; BORDER-LEFT: #e0dfe3; BORDER-BOTTOM: #e0dfe3; HEIGHT: 12.75pt; BACKGROUND-COLOR: transparent" height=17>California/28/2007</TD><TD class=xl22 style="BORDER-RIGHT: #e0dfe3; BORDER-TOP: #e0dfe3; BORDER-LEFT: #e0dfe3; BORDER-BOTTOM: #e0dfe3; BACKGROUND-COLOR: transparent" align=right x:num="39723">2-Oct</TD></TR></TBODY></TABLE>

[HenryN]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

you can always have clumbs of different viruses attached
together in a small dust-corn or such and then you get
an infection with resistant and non-resistant virus
simultaneously.

These long, filamentous viruses, could they contain multiple NA-ribonucleins ?
Some years ago there was a paper that 11 segments were in average in a virus,
but they corrected it to 8 later in another paper (packaging signals), however occasionally there
could be an additional copy or mutant of NA in a virus

It would make sense for the virus to remember critical,successful
mutations and then preferrably try them, but this was never reported.

Please (viruses are plaque purified for a reason).

[HenryN]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

you can always have clumbs of different viruses attached
together in a small dust-corn or such and then you get
an infection with resistant and non-resistant virus
simultaneously.

These long, filamentous viruses, could they contain multiple NA-ribonucleins ?
Some years ago there was a paper that 11 segments were in average in a virus,
but they corrected it to 8 later in another paper (packaging signals), however occasionally there
could be an additional copy or mutant of NA in a virus

It would make sense for the virus to remember critical,successful
mutations and then preferrably try them, but this was never reported.

Viruses recombine (and reassort) in cells (no dust required)

[gsgs]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

these 6 NAs are closely related:

@Hawaii/21/2007 22-Oct
@Hawaii/28/2007
Hawaii/18/2007 19-Oct
Hawaii/31/2007 1-Oct
Hawaii/35/2007 10-Oct
California/28/2007 2-Oct


looks as if H274Y had happened in mid Oct. 2007 in Hawaii
and then maybe spread to Japan ?
The sequences should show it. (C348A,A1200G)
If this were true, then they presumably would have mentioned it already,
so probably H274Y had emerged in Japan independently

[HenryN]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

these 6 NAs are closely related:

@Hawaii/21/2007 22-Oct
@Hawaii/28/2007
Hawaii/18/2007 19-Oct
Hawaii/31/2007 1-Oct
Hawaii/35/2007 10-Oct
California/28/2007 2-Oct


looks as if H274Y had happened in mid Oct. 2007 in Hawaii
and then maybe spread to Japan ?
The sequences should show it.
If this were true, then they presumably would have mentioned it already,
so probably H274Y had emerged in Japan independently

Please. The written analysis is not that specific or speculative.

The phylogenetic tree from Japan includes BOTH of the isolates (21 and 28) from Hawaii (along with Hawaii/31/07 which did not have H274Y), and shows which isolates are on the lower portion of the same branch (Gifu-C/17/08, Gifu-C/38/08, Tottori/21/08, Tottori/23/08) along with three isolates that did not have H274Y (Shimane/7/08, Yamaguchi/14/08, Kyoto-C/1/08).

The data is there (on the phylogentic tree) for the reading (including the label "Hawaii-like") and it is a VERY easy read (and branches with isolates with and without H274Y were formed BEFORE H274Y was acquired - otherwise ALL isolates on the branch would have H274Y).

[kent nickell]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

This lack of transparency that we all realize is really pretty profound and affects currently infected patients as well as national strategic plans...

Taking Indonesia as an example (they have at least acknowleged H5N1 infected patients and certainly many other countries have worse transparency problems) basic medical practice for an H5N1 infected patient would be to isolate the virus and test it genetically (sequencing to determine any known genetic markers for resistance) and phenotypically (test the live virus in a test tube to see how well it replicates in the presence of various antivirals as more of an empirical test) and then compare this to what the patient is actually being treated with and how they respond clinically.

This information should then be immediately posted on the internet so that other clinicians would know what is working if they are confronted with a similar patient. This may also encourage other countries to report on their patients. This would also give the public more of a realistic understanding of the magnitude of human disease (probably not large but also not insignificant) and would give national planners better advice for their strategic plans.

Some of this information is probably being shared behind the scenes but the sparsity of this type of information makes it difficult for the public to act as responsible stakeholders for such decisions as spending millions of taxpayer dollars on antiviral stockpiles or analyzing their risk to evaluate the usefulness of prepandemic vaccines or planning for nonpharmaceutical types of interventions.

Withholding of sequences for publication and various economic and political ploys of various governments, universities and corporations are both adversely affecting current patients with H5N1 as well as strategic planning for the potential benefit of millions of people...

If planners came to the conclusion that a prepandemic priming type vaccine would be useful in curbing the spread of this disease for say Indonesia or Egypt this could certainly have benefits well beyond these 2 countries....

[HenryN]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

these 6 NAs are closely related:

@Hawaii/21/2007 22-Oct
@Hawaii/28/2007
Hawaii/18/2007 19-Oct
Hawaii/31/2007 1-Oct
Hawaii/35/2007 10-Oct
California/28/2007 2-Oct


looks as if H274Y had happened in mid Oct. 2007 in Hawaii
and then maybe spread to Japan ?
The sequences should show it. (C348A,A1200G)
If this were true, then they presumably would have mentioned it already,
so probably H274Y had emerged in Japan independently

I don't think you are reading the trees properly. They paint a fairly clear picture of multiple introductions of H274Y, which is why "random mutations" is heading for the trash bin.

H274Y is just like G743A on N1 in H5N1. The same change appears on multiple backgrounds in diverse areas at the same time. Trying to explain that pattern with random mutations is not easy, especially when there isn't a clear advantage. G743A is silent - it doesn't change the protein, but it appeared suddenly on multiple clade 2.2 backgrounds at the beginning of 2007 (in Egypt, Kuwait, Russia, Ghana, Nigeria).

The same is true for H274Y. It is appearing simultaneously on multiple clade 2B (Brisbane/59) backgrounds on N1 in H1N1. In the US, as well as countries with a high incidence, H274Y is on the "northern EU" branch in the tree from Japan. Since all isolate on that branch have H274Y, only one introdution was required (followed by expansion and additional changes lead to multiple subsequent branches).

However, it is the appearance of H274Y on other branches, which have isolates lacking H274Y, that signals new introductions.

In the US, one introduction was on the Hawaiian branch. This branch was formed by a number of isolates in Hawaii and California that were closely related and had changes not found on other clade 2B isolates (which is why they formed a branch). The isolates without the change were collected in early October, 2007, while the two with H274Y were collected on October 22. However, even without the dates, the presence of isolates with and without H274Y means that the branch was formed BEFORE H274Y was acquired, which is why it is only in a subset of leaves on that branch.

The same was true for a Florida branch, which was composed of three isolates from Florida. The two isolates collected in 2007 didn't have H274Y, while the 2008 isolate did have H274Y. Once again the H274Y would have been an independent event, so the isolates in the US required at least three independent acquisitions of H274Y to account for the published US isolates with H274Y.

In Japan, in addition to the three isolates on the "northern EU" branch, there are many isolates on other branches and those other branches include isolates without H274Y, so each again requires separate introductions (and the high percentage of isolates with H274Y means there are MANY such branches that just haven't been reported).

The liklihood that this explosion of independent introductions is being driven by selction of the change due to Tamiflu usage is remote. In the past, H274Y was rare, especially in countries other than Japan. It is likely that the additional isolates that are not "northern EU-like" will also represent more independent introductions that are not likely linked to Tamiflu.

Thus, it is the sudden appearance of H274Y due to multiple independent introductions that makes a random mutation argument EXTREMELY unlikely, which is why the influenza "experts" were "startled" and "baffled" (and will remain so if rely on "random mutations" to explain the data).

[gsgs]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

I updated my table, now many with exact dates

http://www.setbb.com/fluwiki2/viewtopic.php?p=936

(scroll down to 2nd table)

numbers 13,17,19,20,26,53,58,60,63,70,81,107
also appear on the Japanese tree

[gsgs]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

kent nickell, we are not so much concerned about quick and appropriate
treatment of actual patients.
That's individually important too, of course, even in "normal" times.

But why we are here that's the potential of the forming of a
devastating pandemic.
Not so likely, but possible (~3&#37; per year,IMO)
enough to be concerned.
That multiplies the possible damage from withholding of sequences.
Same for non-cooperation of scientists.

[HenryN]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

kent nickell, we are not so much concerned about quick and appropriate
treatment of actual patients.
That's individually important too, of course, even in "normal" times.

But why we are here that's the potential of the forming of a
devastating pandemic.
Not so likely, but possible (~3% per year,IMO)
enough to be concerned.
That multiplies the possible damage from withholding of sequences.
Same for non-cooperation of scientists.

What is the basis of the 3% per year estimate for the probablility of a pandemic?

[gsgs]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

niman, yes, probably multiple times that H274Y had formed.

Let's concentrate on the one strain in Hawaii/21/2007.
It's very specific in the 6 isolates with two polymorphisms
which don't appear elsewhere.
And it was 3 months earlier than the GifuC-KyotoC
resistances. It would be interesting to see, whether
those have the 2 Hawaii/21 markers.
Also Miyagi/23, but not resistant.

Then we have the Yokohama viruses which are more different and probably
got 274Y from elsewhere.

In Norway, do we think there was just one introduction
of 274Y (together with 274H) or did 274Y also form inside
Norway ? How often, how likely is H274Y happening ?
Do we also see Y274H ?

[gsgs]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

3% for a devastating pandemic, 7% for any pandemic.
Just my feeling, my interpretation of the expert statements
which I see. Plus some individual sorting, which experts
I consider more reliable.
Plus some private thoughts and arguments about
influenza-history and H5N1 evolution from examining
sequences and distances and MRCADs and

[gsgs]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

> A seond version emerged later, labeled "Hawiian".
> It had to recombine with the northern version to acquire
> H274Y and it look awhile for the two to meet.


if it had recombined with the Northern EU - strain,
then why did it acquire the 274Y but no other polymorphisms
from the Northern EU-strain were acquired ?

[HenryN]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

3&#37; for a devastating pandemic, 7% for any pandemic.
Just my feeling, my interpretation of the expert statements
which I see. Plus some individual sorting, which experts
I consider more reliable.
Plus some private thoughts and arguments about
influenza-history and H5N1 evolution from examining
sequences and distances and MRCADs and

Hopes and dreams (with a pseudo-math overlay)?

[HenryN]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

> A seond version emerged later, labeled "Hawiian".
> It had to recombine with the northern version to acquire
> H274Y and it look awhile for the two to meet.


if it had recombined with the Northern EU - strain,
then why did it acquire the 274Y but no other polymorphisms
from the Northern EU-strain were acquired ?

The sequences are VERY closley related and acquistions appear as SNPs (most of the acquired region is identical in both parents. Same pattern was seen for G743A and MANY other examples as noted many times here and in papers at Nature Precedings).

http://precedings.nature.com/tags/Recombination

As noted in the J Virol paper on human influenza, such acquistions tend to be less than 100 BPs (but odds are a billion to one that the acquistions aren't random).