Denmark - Dane with novel H1N1 found resistant to Tamiflu

[theforeigner]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

Wild type is the scientific term for the "normal" gene. In this case, it would be an NA gene that is not Tamiflu resistant.
As far as information is concerned, most countries have been VERY withholding of specifics, citing privacy laws. However, countries in Europe, including Denmark, have done a very minimal level of testing. They have focused on imported cases and contacts, as described in this case/cluster, but little real data has been released.

Although sequences have been released promptly, the number from Denmark remains at ONE. It was collected in late April and released promptly in early May, but of course it is almost July, so there is no public data on sequences from Denmark for almost the past 2 months.

Thus, the recent spread of Tamiflu resistance in Denmark would not be seen in public sequences, and many other European countries also have limited positives and even fewer sequences.

In all liklihood, there is no sequence from the contact, which is why statements include "probably" and "appears". There is no data showing that the H1N1 in the contact who traveled overseas was infected with tamiflu sensitive (wild type) H1N1, and the only reason the H1N1 was collected from the female patient was becasue she developed flu-like symptoms while taking tamiflu.

Thanks for explaining Niman .

 

[HenryN]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

I´m not sure if this has any significance, but on the danish Statens Serum Institut report about the Tamiflu resistent patient "A", they also added this statement:



En tilsvarende udvikling af resistens over for oseltamivir (Tamiflu®) er også set hos det vinter-influenzavirus A H1N1, der har cirkuleret de seneste to vintersæsoner

My translation:
A corresponding development of resisitant twards oseltamivir (Tamiflu®) has been observed in the winter-influenzavirus A H1N1, which has circulated the last to vinter seasons


http://www.ssi.dk/sw174.asp?PAGE=1&ArtNo=3651423



(SSI)

Yes, that is how they say H274Y without saying H274Y. This change was predicted, based on the high level in seasonal flu, and the ability of the change to jump from one genetic background to another via recombination. Those in denial about recombination think it will jump via reassortment in which the entire human NA gene from H1N1 replaces the swine NA gene. However, in this case there was no reassortment.

Roche maintains that the H274Y was a "random mutation" selected by the Tamiflu treatment (and wasn't in the contact or the patient intially - this is well into the "hopes and dream" category).

If the resistance is due to H274Y, their argument is diminished, because H274Y jumped from one H1N1 seasonal flu genetic background to another in patients NOT taking Tamiflu, because the seasonal H1N1 with H274Y was evolutionarily fit. All of the Tamiflu resistance in seasonal flu was in H1N1 and all involved H274Y.

A re-run in swine H1N1 is Roche's worst nightmare (and that development is pretty high on the nightmare list for most others).

I suspect more countries will start looking harder and H274Y will be found in many isolates from patients not taking Tamiflu in the VERY near future.

 

[HenryN]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

Thanks for explaining Niman .

Here are the predictions in May (both have been recently reported)

<a rel="nofollow" href="http://www.recombinomics.com/News/05100901/Swine_H1N1_WA_Fatality.html">Commentary</a>

The rapid spread in the human population increases the likelihood of co-infection with H1N1 seasonal flu and the acquisition of key polymorphisms linked to adaptation in human hosts. Two likely acquisitions are NA H274Y and PB2 E627K, which are fixed in human H1N1.

 

[HenryN]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

Here are the predictions in May (both have been recently reported)

<a rel="nofollow" href="http://www.recombinomics.com/News/05100901/Swine_H1N1_WA_Fatality.html">Commentary</a>

The rapid spread in the human population increases the likelihood of co-infection with H1N1 seasonal flu and the acquisition of key polymorphisms linked to adaptation in human hosts. Two likely acquisitions are NA H274Y and PB2 E627K, which are fixed in human H1N1.

<a rel="nofollow" href="http://www.recombinomics.com/News/05080901/Swine_H1N1_Mexico_Fatalities.html">Commentary</a>

Concerns that the virus will recombine with seasonal flu and acquire key changes such as oseltamivir resistance (H274Y), as well as PB2 E627K highlight the importance of sequence surveillance.

 

[Commonground]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

and then....what? We are left with Relenza.

 

[theforeigner]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

Yes, that is how they say H274Y without saying H274Y. This change was predicted, based on the high level in seasonal flu, and the ability of the change to jump from one genetic background to another via recombination. Those in denial about recombination think it will jump via reassortment in which the entire human NA gene from H1N1 replaces the swine NA gene. However, in this case there was no reassortment.

Roche maintains that the H274Y was a "random mutation" selected by the Tamiflu treatment (and wasn't in the contact or the patient intially - this is well into the "hopes and dream" category).

If the resistance is due to H274Y, their argument is deminished, because H274Y jumped from one H1N1 seasonal flu genetic background to another in patients NOT taking Tamiflu, becasue the seasonal H1N1 with H274Y was evolutionarily fit. All of the Tamiflu resistance in seasonal flu was in H1N1 and all involved H274Y.

A re-run in swine H1N1 is Roche's worst nightmare (and that development is pretty high on the nightmare list for most others).

I suspect more countries will start looking harder and H274Y will be found in many isolates from patients NOT taking Tamiflu in the VERY near future.

OK let me ask you if I´v got this right? (I don´t have knowhow concerning the technical part of the virus )

The Tamiflu resistant patient "A" possibly/proably got/developed a virus where Swine flu virus and preexisting Tamiflu resistant sesonal flu virus H274Y had mixed into a new Tamiflu-resistant Swine flu variation ?

Is that close? or am I totaly off ?

 

[HenryN]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

OK let me ask you if I´v got this right? (I don´t have knowhow concerning the technical part of the virus )

The Tamiflu resistant patient "A" possibly/proably got/developed a virus where Swine flu virus and preexisting Tamiflu resistant sesonal flu virus H274Y had mixed into a new Tamiflu-resistant Swine flu variation ?

Is that close? or am I totaly off ?

You are close. You have described how the resistance formed, but it was probably not in patient A or B. It has been circulating undetected. The overseas traveler was infected, but recovered even though the Tamiflu played no role (many recover without Tamiflu treatment). He infected the Denmark contact and the Tamiflu also didn't help her, but she needed antiviral help, so when she developed symptoms while taking Tamiflu, the Drs knew there was a good chance that the H1N1 was resistant, so they isolated it. They also switched treatment to Relenza, which worked.

The bottom line is the resistant strain is circulating, but surveillence is poor and the only reason it was detected was because the contact develped symptoms while taking Tamiflu and she responded to Relenza.

However, now countries will look harder and find H274Y in patients not taking tamiflu and realize it has been silently spreading (as happened with seasonal flu in 2007/2008. It had been circulating for MONTHS prior to detection in Norway (and for YEARS at low levels prior to that - in patients that were NOT taking Tamiflu).

 

[theforeigner]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

You are close. You have described how the resistance formed, but it was probably not in patient A or B. It has been circulating undetected. The oversease traveler was infected, but recovered even though the Tamiflu played no role (many recover without Tamiflu treatment). He infected the Denmark contact and the Tamiflu also didn't help her, but she needed antiviral help, so when she developed symptoms while taking Tamiflu, the Drs knew there was a good chance that the H1N1 was resistant, so they isolated it. They also switched treatment to Relenza, which worked.

The bottom line is the resistant strain is circulating, but surveillence is poor and the only reason it was detected was because the contact develped symptoms while taking Tamiflu and she responded to Relenza.

However, now countries will look harder and find H274Y in patients not taking tamiflu and realize it ahs been silently spreading (as happened with seasonal flu in 2007/2008. It had been circulating for MONTHS prior to detection in Norway (and for YEARS at low levels prior to that - patients that were NOT taking Tamiflu).

Thanks again Niman for taking time to explain to us who lack this kind of knowledge

 

[Commonground]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

He infected the Denmark contact and the Tamiflu also didn't help her, but she needed antiviral help, so when she developed symptoms while taking Tamiflu, the Drs knew there was a good chance that the H1N1 was resistant, so they isolated it. They also switched treatment to Relenza, which worked.

I don't know how severe her symptoms were - but there are many who are going without Tamiflu now, eligible only when their symptoms are severe and they have an underlying condition.

Or is it, "eligible only when their symptoms are severe OR they have an underlying condition? I'm not sure.

 

[HenryN]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

<a rel="nofollow" href="http://www.recombinomics.com/News/06300901/H274Y_Swine_Silent.html">Commentary</a>

 

[HenryN]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

I don't know how severe her symptoms were - but there are many who are going without Tamiflu now, eligible only when their symptoms are severe and they have an underlying condition.

Or is it, "eligible only when their symptoms are severe OR they have an underlying condition? I'm not sure.

She had no symptoms. She was treated prophylatically because of contact with a confirmed case.

 

[HenryN]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

Thanks again Niman for taking time to explain to us who lack this kind of knowledge

So have any of the Danish sites actiually come out and said the resistance was due to H274Y (or said the resistance was the same as seasonal flu).

 

[HenryN]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

Meanwhile, lab workers in Denmark are reporting the first known case of swine flu that is resistant to Tamiflu, the main anti-viral drug that governments have been stockpiling in case this strain of H1N1 turns nasty this summer. The single case of drug resistance is worth noting but not yet cause for alarm, according to the CDC. NPR's Richard Knox sent this background note to explain why:
"It's not good. But experts say it doesn't necessarily mean all or even most swine flu viruses will soon become resistant to the mainstay antiviral.
The Danish patient reportedly has recovered from the flu. And as far as anyone knows, he or she did not pass the resistant virus on to anyone else.
Experts have been worried swine flu might become Tamiflu-resistant because many of the ordinary seasonal flu viruses that circulated in North America this past season were unfazed by the drug. One of these unfazed seasonal strains is also from the H1N1 family.
Roche, which makes Tamiflu, says the Danish patient's virus had only one genetic mutation, called H-274-Y. That mutation has long been known to arise in the viruses infecting a small percentage of people on Tamiflu, in response to treatment. But here's the difference: The Tamiflu-resistant seasonal flu virus has a half-dozen mutations, including H-274-Y. Scientists don't know if the swine flu virus can or will acquire this suite of resistance mutations.
Actually, it's pretty surprising that the pandemic virus hasn't acquired the H-274-Y mutation more often, given the thousands of people treated with Tamiflu lately.
"It's certainly likely that we will see this in the United States," says Dr. Carolyn Bridges of the Centers for Disease Control. But so far the CDC has tested almost 200 swine flu viruses for Tamiflu resistance and hasn't found any.
One reason, Bridges says, is that the new H1N1 virus has an "N1" gene that's very different from the corresponding gene of the seasonal H1N1. That's significant, because Tamiflu works by blocking neuraminidase --- that's what the "N" stands for. So maybe the pandemic virus's N-gene isn't as susceptible to the Tamiflu resistance mutation as the analogous gene in its very distant cousin, the seasonal H1N1 virus.
But the Danish case shows that it can happen.

http://www.npr.org/blogs/health/2009/06/morning_rounds_updates_on_swin.html?ft=1&f=103537970

 

[HenryN]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

The first lots of swine flu vaccine are based on the virus without H274Y. Would that vaccine provide protection against the virus with H274Y?

H274Y is on the N and one of many changes trageted by the vaccine. H274Y alone would probably not significantly impact the vaccine, but it would impact Tamiflu as well as the Biocryst antiviral, which is also affected by H274Y.

 

[HenryN]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

Please. Drug resistance is a phenotype. This is high school definition time.

Phenotype = the observable characteristics and traits of an organism. In this case, we observe drug resistance.

Genotype = the genetic makeup of an organism. H274Y is one of several genotypes that can confer the phenotype of drug resistance.

Until and unless the sequences from the Danish patient are published, we do not know the genotype of the flu strain she had, but we do know that the phenotype was a drug resistant one. There are no grounds for the assertion that the resistance is due to H274Y. However, if the patient she caught it from had a non-resistant strain, then that would constitute very good evidence that the resistance is due to a de novo mutation in this individual patient, and not indicative of wider circulation of a resistant strain.

Dick Knox at NPR has a piece this morning
http://www.npr.org/blogs/health/2009/06/morning_rounds_updates_on_swin.html?ft=1&f=103537970

indicating the "mutation" is H274Y, support the prediction that swine H1N1 would acquire H274Y from seasonal H1N1 via recombination.

 

[theforeigner]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

So have any of the Danish sites actiually come out and said the resistance was due to H274Y (or said the resistance was the same as seasonal flu).

I havent seen any so far.
Only the SSI note, which I posted a link and translation to, but that didn?t directly link H274Y to the H1N1 mutated virus.

 

[HenryN]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

I havent seen any so far.
Only the SSI note, which I posted a link and translation to, but that didn´t directly link H274Y to the H1N1 mutated virus.

The Dick Knox piece at NPR is what I was looking for. H274Y was predicted and is not a coincidence or a new "mutation".

 

[Giuseppe]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

UK. HPA - Swine Flu Sample Resistant to Antiviral Oseltamivir (June 30, 2009, edited)

Swine Flu Sample Resistant to Antiviral Oseltamivir - 30 June 2009


​

The National Influenza Centre of Denmark at Statens Serum Institut has reported to the World Health Organisation (WHO) the identification of an isolate of swine flu (H1N1v) resistant to the antiviral oseltamivir.

Following testing in Denmark, resistance was also confirmed by the WHO Collaborating Centre at the Medical Research Council (MRC) National Institute for Medical Research (NIMR) in the UK.

The virus remained susceptible to the antiviral zanamivir.


Professor Maria Zambon, Director of the Health Protection Agency's Centre for Infections and Head of the UK WHO National Influenza Centre, said:

"We have been monitoring antiviral drug resistance since the beginning of this outbreak. Routine sampling in the UK has shown that there is currently no resistance to either oseltamivir or zanamivir."

''HPA continues to watch for antiviral resistance and will be carrying out regular sample testing throughout this outbreak."

To help the Health Protection Agency identify cases of swine flu in the community, regular flu surveillance work is continuing throughout the summer, at the same pace that is applied during the normal "flu season" (October to May). This includes the routine sampling of swine flu samples for antiviral resistance.

General infection control practices and good respiratory hand hygiene can help to reduce transmission of all viruses, including swine flu. This includes:

• Maintaining good basic hygiene, for example washing hands frequently with soap and water to reduce the spread of virus from your hands to face or to other people.
• Cleaning hard surfaces (e.g. door handles) frequently using a normal cleaning product.
• Covering your nose and mouth when coughing or sneezing, using a tissue when possible.
• Disposing of dirty tissues promptly and carefully.
• Making sure your children follow this advice.

Ends


For further information on swine flu visit the Health Protection Agency's website at www.hpa.org.uk/swineflu

For media enquiries only please contact the Health Protection Agency's Centre for Infections press office on
020 8327 7080
020 8327 6647
020 8327 7098
020 8327 7097
020 8327 6690

Last reviewed: 30 June 2009
-
​

<cite cite="http://www.hpa.org.uk/webw/HPAweb&HPAwebStandard/HPAweb_C/1246345135429?p=1231252394302">HPA - Swine Flu Sample Resistant to Antiviral Oseltamivir</cite>

 

[kent nickell]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

If H274Y takes hold and takes out both tamiflu and peramivir it does seem that for all practical purposes we would be left with inhaled Relenza (and its inherent problems of being able to be inhaled deep enough in young children and in people with lung problems)... 2 other drugs in the pipeline A-315675 (a possible oral alternative to tamiflu) and long acting zanamivir dimers also both look like they have their problems in development .. A-315675 though may be worth some clinical trials as it appears to have some effectiveness against H274Y although it appears difficult to sort out its in vitro and in vivo effectiveness (in mice)...


http://www.sciencedirect.com/scienc...serid=10&md5=30c45280c3e0da047dde530560201c11

""These results confirm the potent inhibitory effect of A-315675 against oseltamivir-resistant influenza viruses of the N1 and N2 subtypes and support the clinical development of its bioavailable prodrug A-322278.""


http://aac.asm.org/cgi/content/full/53/2/791

"""Finally, we confirmed that the A/H1N1 H274Y mutant virus is as virulent as the WT virus, at least in this mouse model and in the A/WSN/33 background (2), which correlates with its natural occurrence and high transmissibility in humans during the 2007 to 2008 influenza season. Of note, A-322278 appears to be somewhat less effective in protecting mice challenged with the NA H274Y mutant virus than those infected with the WT virus. As we have previously reported similar 50% lethal dose values for the two viruses in mice (i.e., 103 PFU) (2), it is possible that such differences in activity could be attributable to low-level cross-resistance between the two drugs that is not measurable in in vitro assays. Clinical trials of A-322278 are warranted in the context of an eventual pandemic and in consideration of the limited alternatives to oseltamivir. """

 

[Giuseppe]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

WHO says Tamiflu-resistant H1N1 "an isolated case" (AlertNet, edited)

WHO says Tamiflu-resistant H1N1 "an isolated case"

30 Jun 2009 16:41:54 GMT
Source: Reuters
GENEVA, June 30 (Reuters)


The first H1N1 infection found to be resistant to the antiviral Tamiflu represents an "isolated case" with "no public health implication" at this time, the World Health Organisation (WHO) said on Tuesday.


The United Nations agency has declared a global pandemic is underway from the virus known as swine flu which has so far been treatable with Roche's <rog.vx> Tamiflu.

WHO spokesman Dick Thompson said that the discovery of a patient in Denmark whose infection did not respond to the drug, revealed by the Swiss drug company and Danish officials on Monday, did not amplify the severity of the virus.

"This is an isolated case. At this time, there is no public health implication. But we must remain alert as the virus can change at any time and we must not be complacent," he told Reuters. Officials say the patient is now well and no further contagion with the resistant virus was detected.

(Reporting by Stephanie Nebehay and Laura MacInnis)
-
</rog.vx>​

<cite cite="http://www.alertnet.org/thenews/newsdesk/LU175902.htm">Reuters AlertNet - WHO says Tamiflu-resistant H1N1 "an isolated case"</cite>