Influenza viruses resistant to oseltamivir, news and updates

[Oracle]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Influenza Activity in Europe

During week 10 2008, the majority of European countries reported decreasing activity. Widespread influenza activity was reported in eight countries, regional activity in one country (Germany), local activity in six countries,
sporadic activity in 13 countries and no activity was reported in Wales. Influenza virus type B accounted for 63% of the total positive specimens collected during week 10 2008; however the majority of virus detections since the start of the season were influenza A (H1N1) viruses. Based on (sub)typing data of all influenza virus detections this season (N=13278; sentinel and non-sentinel data), 4871 (37%) were influenza A (unsubtyped), 4305 (32%) were A (H1), 121 (1%) were A (H3) and 3981 (30%) were B.

Based on the antigenic and/or genetic characterisation of 2913 influenza viruses, 60 were A/New Caledonia/20/99 (H1N1)-like, 1993 were A/Solomon Island/3/2006 (H1N1)-like, 17 were A/Wisconsin/67/2005 (H3N2)-like, 55 were A/Brisbane/10/2007 (H3N2)-like, 774 were B/Florida/4/2006-like (B/Yamagata/16/88 lineage) and 14 were B/Malaysia/2506/2004-like (B/Victoria/2/87 lineage).

Despite the mismatch of the circulating influenza B viruses with the vaccine strain, it is expected that the 2007/2008 vaccine still provides valuable protection due to cross reactive antibodies induced by the vaccine. A
number of recent A (H1N1) viruses are distinguishable from the vaccine virus in antigenic analyses. <b>As these viruses show better antigenic match to A/Brisbane/59/2007, the WHO has recommended that an A/Brisbane/59/2007-like virus is included in the vaccine for the 2008/2009 season. As there is still significant antigenic similarity, the present vaccine is expected to provide protection against the current H1N1 viruses.</b>

Influenza Weekly Surveillance Report
Week 11 2008 (10th? 16th March 2008)
A REPORT BY THE HEALTH PROTECTION SURVEILLANCE CENTRE
THE NATIONAL VIRUS REFERENCE LABORATORY &
THE DEPARTMENTS OF PUBLIC HEALTH

==============
Caught this on an internet search, posted 2002 meeting presentation slides.

http://images.medscape.com/pi/editorial/cmecircle/2002/1840/zangwill/slide11.gif

Influenza Viruses Resistant to Oseltamivir and Representing Three Distinct NA Genotypes Isolated by Hoffmann LaRoche from Clinical Studies Employing Oseltamivir as Treatment

Yes+, especially at lower infectious doses

H274Y ? interact with functional (histidine to tyrosine)
Only oseltamivir
A/New Caledonia/99
(H1N1)
[A/Texas/36/91-like]

Yes+, instability of NA but not enzyme activities
^E119V ? framework
(glutamic acid to valine)

Only oseltamivir
A/Wuhan/359/95-like
(H3N2)

Yes+ , serious effect on NA activity
*R292K ? functional
(arginine to lysine)

Both oseltamivir and zanamivir

A/Sydney/5/97-like
(H3N2)


Neuraminidase Inhibitor-Resistant Influenza Viruses May Differ Substantially in Fitness and Transmissibility. Webster et al. Antimicrob Agents Chemother. 2005 49(10):4075?4084.

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1251536

Several studies in animal models have examined the infectivity of NAI-resistant viruses with mutations at the conserved NA residues. These viruses exhibited reduced virulence in mice and ferrets (3, 14, 19, 33). However, A/Wuhan/359/95-like (H3N2) virus with the E119V NA mutation was recently reported to be transmitted as efficiently as the wild-type virus in ferrets (15). This finding contrasted with previous observations that A/Sydney/5/97-like (H3N2) influenza virus with the R292K NA mutation was not transmissible under conditions in which the wild-type virus was efficiently transmitted (14) and that A/New Caledonia/20/99-like (H1N1) virus with the H274Y NA mutation required a challenge dose 100 times higher and was less transmissible than the wild-type virus (14).

~

Webster/Hoffman LaRoche appear to have forecast the result obtained in the 2007-08 influenza season, although transmission efficiency results were not quite in line with reality.

I think the Tamiflu makers were well aware that these strains would give rise to drug resistant mutants. Nobody said peep-one that they were integral to years of commercial influenza vaccines, however, since it would result in a hard hit to drug sales (which had been flagging anyway, due to cautionary reports of child/adolescent drug neurological side effects, 2006-07 out of Japan and hit-ir-miss protection against seasonal influenza).

Far as I can tell, the influenza vaccine and antiviral drug industry set up conditions ripe for widespread resistance.

[gsgs]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Seems that the Europeans just don't distinguish Solomon and Brisbane H1N1,
both are subsumed under Solomon.

> Yes+, especially at lower infectious doses

Are you saying H274Y preferrably occurs at lower infectious doses ? Why is it ?

> Far as I can tell, the influenza vaccine and antiviral drug industry set up conditions ripe for
> widespread resistance.

deliberately ? ["scientists are buffled..."]
I can't see how vaccine should contribute to drug resistance.
And whether drug use contributed is still being debated.

[Oracle]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Antiviral mutation occurs when drug dosage is ineffective, when the drug is given too late to be effective, or when other factors interfere with drug efficacy. OR when environmental conditions provide selective pressure for naturally occurring polymorphisms (either single or multiple acquisitions).

" According to a study from the United States, "Antigenic variation is a viral strategy exploited to promote survival in the face of the host immune response and represents a major challenge for efficient vaccine development. Influenza viruses are pathogens with high transmissibility and mutation rates, enabling viral escape from immunity induced by prior infection or vaccination. Intense selection from neutralizing antibody drives antigenic changes in the viruses."

Perforin and Fas pathways affect influenza CD8+ escape variants. (2005)
Journal of Virology, July 2005, p. 8545-8559, Vol. 79, No. 13

http://jvi.asm.org/cgi/content/abstract/79/13/8545

The issue of widespread tamiflu resistance has nothing to do with drug use per se. It has everything to do with selection of naturally occurring but formerly low-abundance viral phenotypes. That is why pre drug use isolates demonstrating various polymorphic variations known to confer antiviral drug resistance were identified and reported quite some time ago (before significant antiviral resistance arose).

Why the heck do you think adamantane-derivative resistance came on like a sledgehammer? (essentially, one season).

Homo fecae, hetero deus.

If drug and vaccine companies knew of this polymorphic adaptation potential, and they continued to peddle product despite this knowledge, just what do suppose the sudden global acquisition of tamiflu-resistance is due to, gs?

[gsgs]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

> pre drug use isolates demonstrating various polymorphic variations
> known to confer antiviral drug resistance were identified and
> reported quite some time ago (before significant antiviral resistance arose).

those polymorphisms were rare and the 31-mutation wasn't dominating


> adamantane-derivative resistance came on like a
> sledgehammer? (essentially, one season).

adamantane resistance grew from a few% to >90% in a few years (two?).
AFAIK it's still disputed whether drug use contributed

> Homo fecae, hetero deus

not found (typo?)

> If drug and vaccine companies knew of this polymorphic
> adaptation potential, and they continued to peddle product
> despite this knowledge, just what do suppose the sudden
> global acquisition of tamiflu-resistance is due to, gs?

they knew about the potential, but not that the danger was so big.
(see the headline of this thread)

I'm uncertain whether tamiflu-resistance is caused by drug use (50%)

[Giuseppe]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_



Isolate tested for H1N1 were 106. Remaining samples may contain further resistant isolates. But since last update no data is available

SOURCE (http://www.ministerosalute.it/influe...ir30-04-08.pdf) Italian Ministry of Health

[Giuseppe]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

(1.1): Antiviral Res. 2008 Jul 5. [Epub ahead of print]

Adamantane resistance in influenza A(H1) viruses increased in 2007 in South East Asia but decreased in Australia and some other countries.

Barr IG, Deng YM, Iannello P, Hurt AC, Komadina N. - WHO Collaborating Centre for Reference and Research on Influenza, 45 Poplar Road, Parkville, Melbourne, Victoria 3052, Australia; Monash University Gippsland, Churchill, Victoria 3842, Australia.

The adamantanes (amantadine and rimantadine) were the initial antivirals licensed for use against influenza A viruses and have been used in some countries to control seasonal influenza and have also been stockpiled for potential pandemic use.

While high rates of resistance have been observed in recent years with A(H3) viruses, the rates of resistance with A(H1) viruses has varied widely.

In this study we analysed 281 human influenza A viruses isolated in 2007 that were referred to the WHO Collaborating Centre for Reference and Research in Melbourne, mainly from Australia and the surrounding regions, for evidence of resistance to adamantanes and a subset of these was examined for resistance to the neuraminidase inhibitors (NIs).

We found that the rates of adamantane resistance in A(H3) viruses continued to increase in most countries in 2007 but a distinct variation was seen with A(H1) resistance levels.

A(H1) viruses from Australia, New Zealand and Europe had low rates of resistance (2-9&#37 whereas viruses from a number of South East (SE) Asian countries had high rates of resistance (33-100%).

This difference can be attributed to the spread of A/Brisbane/59/2007-like viruses to many parts of the world with the exception of SE Asia where A/Hong Kong/2652/2006-like viruses continue to predominate.

When these two A(H1) subgroups were compared for their in vitro sensitivity to the other class of influenza antiviral drugs, the neuraminidase inhibitors, no difference was seen between the groups with both showing normal levels of sensitivity to these drugs,
The finding of reducing A(H1) resistance rates in Australia and rising levels in SE Asia in 2007, reverses the trend seen in 2006 when A(H1) resistance levels were rising in Australia and elsewhere but remained low in most of SE Asia.

PMID: 18611414 [PubMed - as supplied by publisher]
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http://www.flutrackers.com/forum/showpost.php?p=168806&postcount=1

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[HenryN]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

(1.1): Antiviral Res. 2008 Jul 5. [Epub ahead of print]


A(H1) viruses from Australia, New Zealand and Europe had low rates of resistance (2-9%) whereas viruses from a number of South East (SE) Asian countries had high rates of resistance (33-100%).

This difference can be attributed to the spread of A/Brisbane/59/2007-like viruses to many parts of the world with the exception of SE Asia where A/Hong Kong/2652/2006-like viruses continue to predominate.

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http://www.flutrackers.com/forum/showpost.php?p=168806&postcount=1

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In the other phylograms, Brisbane/59 is 2B, while HK/2652 is 2C (Solomon Island is 2A).

In the US, 2C is also present this past season, but Hawaii has a newer version.

[gsgs]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

> the spread of A/Brisbane/59/2007-like viruses to many parts of the world
> with the exception of SE Asia where A/Hong Kong/2652/2006-like viruses
> continue to predominate.

that puts the published resistance rates in another light.
We should consider resistance-rates (H274Y) in Brisbane/59 alone
in order to track where / how it occurred / amplified !





---------edit1-------------

region
H1N1-samples
with H274Y

Africa       88   0 (00%)
NAmerica   1489 236 (16%)
LAmerica     20   3 (15%)
Europe     2896 724 (25%) 
Ozeania     186   3 (02%)
Hong Kong   581  68 (12%) 
Japan      1544  42 (03%) 
restEAsia   174   1 (01%)

[HenryN]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

> the spread of A/Brisbane/59/2007-like viruses to many parts of the world
> with the exception of SE Asia where A/Hong Kong/2652/2006-like viruses
> continue to predominate.

that puts the published resistance rates in another light.
We should consider resistance-rates (H274Y) in Brisbane/59 alone
in order to track where / how it occurred / amplified !

The japan phylogram had all three subclades labeled (2a, 2b, 2c).

[Oracle]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

INFORMATION FOR THE VACCINE AND RELATED BIOLOGICAL PRODUCTS ADVISORY COMMITTEE
CBER, FDA FEBRUARY 21, 2008

The CDC's notes from this meeting, available on the web in pdf format, clearly shows a tree rooted in New Caledonia 99. See page 8 for the phylogram.

This is prototypical H1N1 strain used for 5 flu seasons for vaccines, chosen because it was a 'fast grower' and seasonal vaccine efficacy study had shown it to be semi-effective, 2003-2006.

"Fast growers' are
Good for pumping out many doses of vaccines.
Bad for fostering immune escapees in:

- infants/toddlers
- the elderly
- the immunocompromised

All three are veritable 'pathogen incubators' due to less than robust immune response, plus they silently excrete active virus for a LONG TIME after symptoms have ceased. All three are LIKELY to be hospitalized and therefore present strong potential for local spread of strains carrying antiviral resistance mutations. This propensity continues as they are also likely to be seen in clinics for followup, where they have plenty of opportunity to spread infection because they also have a tendency to express disease symptoms for an extended period of time due to secondary infections.

Note to Experts who are BAFFLED but also sit on key international public health recommendation committees (and hence, unwilling to point fingers):

Do NOT employ the same strain of 'fast grower' in large-scale public vaccine mixes for many years running, especially if the strain prototype has been aptly demonstrated to mutate for drug avoidance.

<b>Be VERY AWARE that your choice patient type for vaccination is the EPITOME of host type for viral escape for vaccines and antiviral drugs.</b>

[HenryN]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

INFORMATION FOR THE VACCINE AND RELATED BIOLOGICAL PRODUCTS ADVISORY COMMITTEE
CBER, FDA FEBRUARY 21, 2008

The CDC's notes from this meeting, available on the web in pdf format, clearly shows a tree rooted in New Caledonia 99. See page 8 for the phylogram.

This is prototypical H1N1 strain used for 5 flu seasons for vaccines, chosen because it was a 'fast grower' and seasonal vaccine efficacy study had shown it to be semi-effective, 2003-2006.

"Fast growers' are
Good for pumping out many doses of vaccines.
Bad for fostering immune escapees in:

- infants/toddlers
- the elderly
- the immunocompromised

All three are veritable 'pathogen incubators' due to less than robust immune response, plus they silently excrete active virus for a LONG TIME after symptoms have ceased. All three are LIKELY to be hospitalized and therefore present strong potential for local spread of strains carrying antiviral resistance mutations. This propensity continues as they are also likely to be seen in clinics for followup, where they have plenty of opportunity to spread infection because they also have a tendency to express disease symptoms for an extended period of time due to secondary infections.

Note to Experts who are BAFFLED but also sit on key international public health recommendation committees (and hence, unwilling to point fingers):

Do NOT employ the same strain of 'fast grower' in large-scale public vaccine mixes for many years running, especially if the strain prototype has been aptly demonstrated to mutate for drug avoidance.

Be VERY AWARE that your choice patient type for vaccination is the EPITOME of host type for viral escape for vaccines and antiviral drugs.

Yes, the relationship between selection of the target and the technical nicities is not a good one. In 2002 it was clead that the Fujian strain should replace Panama. However, there were technical issues for getting Fujian to grow in eggs. It would grow after one passage in a mammalian cell, but grow in a mammalian cell was in the protocal and the FDA objected, so Panama was used again and many children needlessly died.

The choice of Solomon Island for the last season was a likely factor in the emergence of Brisbane in the past season, leading to an explosion of H274Y.

[miso]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Thanks for the warm welcome.

Referring back to the topic of this thread and the article that spawned it.
I'm a scientist (of the lowest order, a mere BSc.) and I think I see where the problem is. Firstly , let's call a spade a spade. The topic should have been TAMIFLU resistance baffles scientists. Secondly, I'm baffled that scientists are baffled; didn't they read the published studies that showed how Tamiflu worked and the simple mutations that would make it ineffective? That stuff wasn't hidden.

[Oracle]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Oh, I'm much more interested in the match of Spanish 'Flu herald wave outbreaks (pre-1918) and significant H1N1 tamiflu resistance late 2007-early 2008. Same countries. France, Norway, Germany, the UK and US.

Coincidence, right?

The supposedly mild first wave, Spring 1918, it was reported in the US (NYC, then elsewhere by early February). It wasn't mild everywhere.

What was it doing in Peking (Bejing) in March and Shanghai in April/May 1918?

1. I don't think we have the full picture of the 1918 pandemic yet.
2. It has strong bearing on the only strain to attain many of the same lethal phenotype (H5N1) characteristics, and the sudden acquisition of multiple key polymorphisms in a related, commonly circulating strain of human influenza.

Nothing to do with Tamiflu; everything to do with a change in cellular targets.

[HenryN]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Thanks for the warm welcome.

Referring back to the topic of this thread and the article that spawned it.
I'm a scientist (of the lowest order, a mere BSc.) and I think I see where the problem is. Firstly , let's call a spade a spade. The topic should have been TAMIFLU resistance baffles scientists. Secondly, I'm baffled that scientists are baffled; didn't they read the published studies that showed how Tamiflu worked and the simple mutations that would make it ineffective? That stuff wasn't hidden.

The baffled part relats to the sudden appearance and spread in countries not using Tamiflu, as well as the absence of at fitness penalty, which was widely touted when H274Y was first reported for H5N1. In addition the resistance is only in H1N1 - and virtually exclusively in the Brisbane (clade 2B) strain.

[Oracle]

Re: _|ANTIVIRAL RESISTANCE BAFFLES SCIENTISTS|_

Yeah, Brisbane is a VERY interesting place.