Denmark - Dane with novel H1N1 found resistant to Tamiflu

[HenryN]

Originally Posted by theforeigner

My translation of the black highlighted part of the newsreport:

The person was originally not ill at all. The person was in precaution treatment with Tamiflu, because the person had been in close contact with a person who was infected with Swine Flu abroad (OR the person had been abroad and been in close contact with a H1N1 infected person, can´t be sure which it is). After 5 days treatment with Tamiflu, the person suddenly got sick with H1N1, but it didn´t seem like the treatment had any effect. It turned out via tests her in Denmark and in UK, that the person had developed resistance twards Tamiflu, explains Nils Strandberg ( President & CEO of -Statens Serum Institut )
Insted the person was treated with Relenza. - We can be glad that the person today is well and have not infected others said Nils Strandberg.

The Journalist ask Nils Strandberg:
But isen´t it a worrying perspectives that Tamiflu now no longer can be concidered a safe tratment against Swine Flu?

-Yes it is worrying if Tamiflu does not work on the most vulnerable groups. But there are still things that work if a vulnerable patient get infected with H1n1. There is another treatment Relenza.




http://ekstrabladet.dk/kup/sundhed/article1188161.ece

Dansker er resistent overfor Tamiflu



En dansker er som den første i verden blevet resistent overfor medicin mod svineinfluenza H1N1. Dystre perspektiver for risiko-patienter

16:40 - 29. jun. 2009 | Frederik Bjerre Andersen, Gitte Hejberg


Statens Serum Institut har fundet den første person i verden, der er resistent overfor medicinen oseltamivir, der sælges under navnet Tamiflu og blandt andet har vist sig virksom mod svineinfluenzaen H1N1.

Det er det første tilfælde af resistens overfor medicinen på verdensplan. Det er forventeligt, at influenzavirus kan mutere spontant. Resistensen har ikke ændret H1N1-virus’ evne til at smitte eller fremkalde sygdom, meddeler instuttet.

- Både bakterier og vira kan mutere og blive resistente. Og det er altså det, der er sket her, bekræfter administrerende direktør på Statens Serums Institut Nils Strandberg.

- Vedkommende var til at begynde med slet ikke syg. Den pågældende var i forebyggende behandling med Tamiflu, fordi vedkommende havde været i tæt kontakt med en svineinfluenza-ramt i udlandet. Da der var gået fem dage med Tamiflu, blev personen så pludselig syg med H1N1, men det så ikke ud til, at medicinen virkede. Det viste sig så via prøver her og i England, at personen var blevet resistens, fortæller Nils Strandberg.

Uheldigt for alvorligt syge
I stedet blev patienten behandlet med medicinen Relenza.

- Vi kan glæde os over, at personen i dag er helt rask og ikke har smittet andre, siger Nils Standberg.

- Men der er vel dystre perspektiver i, at Tamiflu nu ikke længere kan betragtes som et sikkert middel mod svineinfluenza?

- Ja, det er bekymrende, hvis Tamiflu ikke virker på de mest udsatte grupper. Men der er stadig noget at gøre, hvis en svagelig patient bliver smittet med H1N1. Der er jo et andet stof, som man kan bruge.
Skruer ned for forebyggende brug
Ifølge Nils Strandberg vil fundet af den resistente dansker betyde, at lægerne fremover vil blive mere tilbageholdende med at bruge Tamiflu forebyggende - med mindre der altså ligefrem er tale om meget syge og skrøbelige patienter.

- Hvorfor er det netop en dansker, der bliver den første resistente influenza-patient?

- Det beror nok mest på et tilfælde. Vi har et godt system, hvor vi er gode til at overvåge situationen.

Episoden slår fast, at influenza-virus kan mutere, og at Tamiflu på ingen måde kan betragtes som mirakelmedicin. Tamiflu kan i forvejen ikke kurere influenza, men medicinen kan nedsætte symptomerne og forkorte forløbet.

Epidemi til efteråret
Selv om sommeren, udendørslivet og de lukkede skoler er ensbetydende med mindre influenzasmitte i Danmark, vil danskernes rejseaktivitet sommeren over betyde, at der bliver slæbt mere smitte til landet.

- Vi skal formodentlig frem til det sene efterår eller vinter, før vi kan risikere en H1N1-epidemi herhjemme. Men det behøver ikke at give problemer, da det stadig er en ret mild influenzatype, siger Nils Standberg.

Google translation

Swine Influenza: Danish is resistant to Tamiflu
..
Statens Serum Institut have found the first person in the world who are resistant to the medication oseltamivir, sold under the name Tamiflu, and among others have proven company against swine flu H1N1.

It is the first case of resistance to the drug worldwide. It is expected that influenza virus can mutate spontaneously. Resistance has not changed the H1N1 virus' ability to infect or cause disease, shall instuttet.

- Both bacteria and viruses can mutate and become resistant. And that is what has happened here, confirms CEO at Statens Serum Institut Nils Strandberg.

- He had to start with no ill. That was in the preventive treatment with Tamiflu, because he had been in close contact with a swine influenza hit abroad. Since there had been five days of Tamiflu, the person suddenly ill with H1N1, but it not appear that the medicine worked. It appeared as through the samples here and in England that the person had been resistance, "says Nils Strandberg.

Disadvantageous for the seriously ill
Instead, the patient was treated with medication Relenza.

- We can rejoice that the person is today is quite healthy and has not infected others, says Nils Stand Berg.

- But there is surely bleak prospects that Tamiflu will no longer be regarded as a safe weapon against swine flu?

- Yes, it is worrying if Tamiflu does not work on the most vulnerable groups. But there is still something to do if a sickly patient become infected with H1N1. There is another substance that can be used.

Turn down the preventive use
According to Nils Strandberg would find the resistant Dane mean that doctors will be more reluctant to use preventive Tamiflu - unless there actually are very sick and frail patients.

- Why is it just a Dane who is the first resistant influenza patient?

- It probably depends most on a case. We have a good system where we are good to monitor the situation.

The incident confirms that influenza virus can mutate and that Tamiflu can not be regarded as miracle drugs. Tamiflu is already not cure flu, but the medication can reduce symptoms and shorten the process.

Epidemic in the autumn
Even in summer, outdoor life and the closed schools will mean less flu infection in Denmark, the Danes will travel over the summer mean that there will be dragged more infections in the country.

- We should probably until the late autumn or winter before we can risk a H1N1 epidemic at home. But it need not cause problems, since it is still a relatively mild influenza, "says Nils Stand Berg.

[HenryN]

Originally Posted by niman

Google translation

- He had to start with no ill. That was in the preventive treatment with Tamiflu, because he had been in close contact with a swine influenza hit abroad. Since there had been five days of Tamiflu, the person suddenly ill with H1N1, but it not appear that the medicine worked. It appeared as through the samples here and in England that the person had been resistance, "says Nils Strandberg.

The above translation confirms that the patient had been in contact with an infected person abroad, but had been asymptomatic in Denmark for five before becoming ill. A sample was collected and sequenced in Denmark and England (Weybridge or Mill Hill) and both labs identified a resistance marker (almost certainly H274Y).

The long incubation time of 5 days leaves open the source of the infection. Since the patient was asymptomatic upon arrival, it is unlikley that there are samples collected prior to the start of prophylactic treatment and even if a sample existed, it is unlikely that virus could be isolated.

In fact the 5 day delay in disease onset leave open the strong possibility that the patient was NOT infected by the known foreign contact, and was in fact infected while traveling to Denmark or after arriving in Denmark.

The resistance was identified because the patient developed symptoms (five DAYS after arriving, suggesting the infecting dose was low if it originated outside of Denmark) while being treated, but there is NO evidence even remotely suggesting that the patient was infected by wild type H1N1, unless virus was isolated from the foreign contact, or that the two isolates matched (other than the acquired resistance markers). The article makes no mention of an isolate or sequence from the known contact, and without such a match, there is nothing to suggest that the resistance developed while under prophylactic treatment.

[theforeigner]

Originally Posted by niman

The above translation confirms that the patient had been in contact with an infected person abroad, but had been asymptomatic in Denmark for five before becoming ill. A sample was collected and sequenced in Denmark and England (Weybridge or Mill Hill) and both labs identified a resistance marker (almost certainly H274Y).

The long incubation time of 5 days leaves open the source of the infection. Since the patient was asymptomatic upon arrival, it is unlikley that there are samples collected prior to the start of prophylactic treatment and even if a sample existed, it is unlikely that virus could be isolated.

In fact the 5 day delay in disease onset leave open the strong possibility that the patient was NOT infected by the known foreign contact, and was in fact infected while traveling to Denmark or after arriving in Denmark.

The resistance was identified because the patient developed symptoms (five DAYS after arriving, suggesting the infecting dose was low if it originated outside of Denmark) while being treated, but there is NO evidence even remotely suggesting that the patient was infected by wild type H1N1, unless virus was isolated from the foreign contact, or that the two isolates matched (other than the acquired resistance markers). The article makes no mention of an isolate or sequence from the known contact, and without such a match, there is nothing to suggest that the resistance developed while under prophylactic treatment.

Hi Niman

I´m danish, and I have now read several of the Tamiflu resistant patient reports in danish, and I belive fully that this is the correct info due to what has been reported on Statens Serum Institut website and elsewere.
http://www.ssi.dk/sw174.asp?PAGE=1&ArtNo=3651423

It was only the report from "Ekstrabladet" which was written in a way that could be misunderstod in regards to were "A" had been infected, but it turn out that it was aimed to the location were "B" was infected; abroad.

So, here is the correct info:

The tamiflu resistent person "A" (a woman, according to newsreport) had NOT been abroad.
"A" had been in contact with a person, we name him/her "B"
"B" had recently been abroad and had gotten infected with H1N1
Therefore "A " was given Tamiflu as a precausionn treatment
After "A" had been taking Tamiflu for 5 days she devloped flu symptoms
A test showed that "A" was infected with H1N1
Additional tests at Statens Serum Institut showed that the virus in question, H1N1, had mutated. It (the H1N1) is resistent to tamiflu but is still sensetive to Relenza.

If I find additional info I´ll post it in this thread.


By the way the machin translation is VERY bad, belive me

[HenryN]

Originally Posted by theforeigner

Hi Niman

I´m danish, and I have now read several of the Tamiflu resistant patient reports in danish, and I belive fully that this is the correct info due to what has been reported on Statens Serum Institut website and elsewere.
http://www.ssi.dk/sw174.asp?PAGE=1&ArtNo=3651423

It was only the report from "Ekstrabladet" which was written in a way that could be misunderstod in regards to were "A" had been infected, but it turn out that it was aimed to the location were "B" was infected; abroad.

So, here is the correct info:

The tamiflu resistent person "A" (a woman, according to newsreport) had NOT been abroad.
"A" had been in contact with a person, we name him/her "B"
"B" had recently been abroad and had gotten infected with H1N1
Therefore "A " was given Tamiflu as a precausionn treatment
After "A" had been taking Tamiflu for 5 days she devloped flu symptoms
A test showed that "A" was infected with H1N1
Additional tests at Statens Serum Institut showed that the virus in question, H1N1, had mutated. It (the H1N1) is resistent to tamiflu but is still sensetive to Relenza.

If I find additional info I´ll post it in this thread.


By the way the machin translation is VERY bad, belive me

Thanks for the clarification. That would narrow down the source of the woman's infection, and the 5 day delay included the time to get infected by the traveler contact, who was in Denmark (the classic 5 day gap in disease onset). However, even though the source was in Denmark, it still sounds like there was no data for the H1N1 from the source to show that the source was wild type. This is infered because the source recovered and was probably treated with Tamiflu, but many recover without Tamiflu treatment, so the recovery of the source does not signal wild type. However, the failure of the contact to recover in spite of treatment does signal resistance, so that sample was sequenced and was resistant (almost certainly H274Y). Thus, without the sequence from the traveler, there is still no evidence that the traveler didn't also have resistant H1N1 (or that the travel was the actual source of H1N1, since the only sequence described was from the patient who failed to respond to tamiflu).

[HenryN]

Originally Posted by theforeigner

Hi Niman

I´m danish, and I have now read several of the Tamiflu resistant patient reports in danish, and I belive fully that this is the correct info due to what has been reported on Statens Serum Institut website and elsewere.
http://www.ssi.dk/sw174.asp?PAGE=1&ArtNo=3651423

It was only the report from "Ekstrabladet" which was written in a way that could be misunderstod in regards to were "A" had been infected, but it turn out that it was aimed to the location were "B" was infected; abroad.

So, here is the correct info:

The tamiflu resistent person "A" (a woman, according to newsreport) had NOT been abroad.
"A" had been in contact with a person, we name him/her "B"
"B" had recently been abroad and had gotten infected with H1N1
Therefore "A " was given Tamiflu as a precausionn treatment
After "A" had been taking Tamiflu for 5 days she devloped flu symptoms
A test showed that "A" was infected with H1N1
Additional tests at Statens Serum Institut showed that the virus in question, H1N1, had mutated. It (the H1N1) is resistent to tamiflu but is still sensetive to Relenza.

If I find additional info I´ll post it in this thread.


By the way the machin translation is VERY bad, belive me

Do the reports indicate that she "suddenly" developed symptoms (at day 5)? The sudden development would also suggest that she was infected with H1N1 that was already resistant. The prophylatic tamiflu did nothing. She was exposed for 5 days and the sudden onset suggests that she had a significant exposure, leading to sudden disease onset, instead of a milder infection that became more severe as the Tamiflu sensitive H1N1 declined due to tamiflu treatment and was replaced by resistant H1N1.

[HenryN]

First Tamiflu-resistant case in Denmark

www.chinaview.cn 2009-06-30 16:36:37

Print

BEIJING, June 30 (Xinhuanet) -- The first case of swine flu resistant to Tamiflu--the anti-viral drug to combat the pandemic, has been found in Denmark, the National Board of Health confirmed Monday. The Danish patient was given the drug after exposure to the swine flu. Despite the medication, she became ill with the disease and has now recovered. "It appears the strain developed in a patient who was taking the drug to prevent illness, and it has not spread to others. That's a much better scenario than if the patient had not been taking Tamiflu and picked up a drug-resistant strain already spreading through the public," said Bridges, associate director for science in the U.S. Centers for Disease control and Prevention'sinfluenza division. Tamiflu, if taken early, eases the symptoms of swine flu, making it less likely to spread. Scientists have been worried about the new swine flu swapping genes with seasonal or other types of flu and mutating into a more dangerous or more infectious form. So far this does not appear to be the case. Until an effective vaccine is developed, the drugs Tamiflu and Relenza have been considered the best available defense against the swine flu virus.

http://news.xinhuanet.com/english/20...t_11627434.htm

[theforeigner]

Originally Posted by niman

Thanks for the clarification. That would narrow down the source of the woman's infection, and the 5 day delay included the time to get infected by the traveler contact, who was in Denmark (the classic 5 day gap in disease onset). However, even though the source was in Denmark, it still sounds like there was no data for the H1N1 from the source to show that the source was wild type. This is infered because the source recovered and was probably treated with Tamiflu, but many recover without Tamiflu treatment, so the recovery of the source does not signal wild type. However, the failure of the contact to recover in spite of treatment does signal resistance, so that sample was sequenced and was resistant (almost certainly H274Y). Thus, without the sequence from the traveler, there is still no evidence that the traveler didn't also have resistant H1N1 (or that the travel was the actual source of H1N1, since the only sequence described was from the patient who failed to respond to tamiflu).

Your welcom .
And yes you are right there is no info on the "traveler" whom I name "B".
Why the danish HA doesen´t release any info on "B" and also more detalied info on "A" is a mystery to me, we can only hope that WHO release detailes on both "B" and the tamiflu resisten patient whom I name "A"

Could you please explain "wild type" ?

[theforeigner]

Originally Posted by niman

Do the reports indicate that she "suddenly" developed symptoms (at day 5)? The sudden development would also suggest that she was infected with H1N1 that was already resistant. The prophylatic tamiflu did nothing. She was exposed for 5 days and the sudden onset suggests that she had a significant exposure, leading to sudden disease onset, instead of a milder infection that became more severe as the Tamiflu sensitive H1N1 declined due to tamiflu treatment and was replaced by resistant H1N1.

Yes that first scenario is correct; she "suddenly" developed symptoms at day 5 (after 5 days on prophylatic Tamiflu) and she had been in close contact with "B" who had been infected abroad.

[HenryN]

Originally Posted by theforeigner

Your welcom .
And yes you are right there is no info on the "traveler" whom I name "B".
Why the danish HA doesen´t release any info on "B" and also more detalied info on "A" is a mystery to me, we can only hope that WHO release detailes on both "B" and the tamiflu resisten patient whom I name "A"

Could you please explain "wild type" ?

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.

[theforeigner]

Originally Posted by niman

http://news.xinhuanet.com/english/20...t_11627434.htm

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


29. juni 2009 - Resistens hos pandemisk influenza A H1N1v påvist i Danmark

Det første tilfælde af resistens over for oseltamivir (Tamiflu®) hos det pandemiske influenzavirus A H1N1v er fundet i Danmark. Dette er det første påviste tilfælde på verdensplan.

Det er velkendt og forventeligt, at influenzavirus kan mutere spontant. Resistensen har ikke ændret virus’ evne til at smitte eller fremkalde sygdom, og vurderingen er, at der fortsat er tale om en relativ mild influenza.

Personen er nu rask, og der er ikke påvist yderligere smitte med det resistente virus. Den smittede var i forebyggende behandling med oseltamivir (Tamiflu®) på grund af tæt kontakt med et tilfælde, der var smittet i udlandet. Alligevel fik vedkommende influenzasymptomer. En prøve viste, at personen var inficeret med influenzavirus A H1N1v. Yderligere undersøgelser på Statens Serum Institut har nu vist, at det pågældende virus er muteret. Det er modstandsdygtigt over for det antivirale middel oseltamivir (Tamiflu®), mens zanamivir (Relenza®) fortsat kan anvendes til behandling.

Verdenssundhedsorganisationen WHO opfordrer på baggrund af det danske tilfælde til en øget opmærksomhed på muligheden for udvikling af resistens hos det pandemiske influenzavirus A H1N1v.

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.

Det enkelte fund i Danmark er som nævnt ikke uventet. Det udgør ikke en risiko for folkesundheden og giver heller ikke anledning til at ændre anbefalingerne for brugen af oseltamivir (Tamiflu®).

I Danmark følges situationen fortsat tæt med overvågning af sygdomsforekomst og undersøgelse af alle isolerede influenzavirus A H1N1v.

(SSI)

[theforeigner]

Originally Posted by niman

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]

Originally Posted by theforeigner

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]

Originally Posted by theforeigner

Thanks for explaining Niman .

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

Commentary

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]

Originally Posted by niman

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

Commentary

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.

Commentary

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]

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

[theforeigner]

Originally Posted by niman

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]

Originally Posted by theforeigner

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]

Originally Posted by niman

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]

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]

Commentary

[HenryN]

Originally Posted by Commonground

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]

Originally Posted by theforeigner

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]

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...=1&f=103537970

[HenryN]

Originally Posted by Zac

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]

Originally Posted by pjie2

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...=1&f=103537970

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

[theforeigner]

Originally Posted by niman

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]

Originally Posted by theforeigner

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 Michieli]

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
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HPA - Swine Flu Sample Resistant to Antiviral Oseltamivir

[kent nickell]

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/science...de530560201c11

""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 Michieli]

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 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)
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Reuters AlertNet - WHO says Tamiflu-resistant H1N1 "an isolated case"