Emergence of seasonal influenza viruses type A/H1N1 with oseltamivir resistance in some European Countries at the start of the 2007-8 influenza

[HenryN]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::

Drug-Resistant Flu Virus on the Rise

Thursday, Jan. 31, 2008 By LAURA BLUE
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<!--sridhar@MT added the following code -->An elderly patient receives a flu shot, courtesy of the city of Chicago.
Tim Boyle / Getty

This winter's most common flu strain is showing resistance to the frontline anti-flu treatment, new data shows. More than 10% of virus samples taken in Western Europe this winter were resistant to oseltamivir, better known as Tamiflu, according to figures from the European Centre for Disease Prevention and Control (ECDC). Nearly 10% of the samples in Canada were resistant too, according to national authorities there, and the U.S. found nearly 7% resistance. The number of resistant strains are still small overall, but the superbugs aren't evenly distributed around the world: In Norway, a staggering 75% of the 16 samples taken this winter were drug-resistant — enough to pull up Western Europe's average by about 8 percentage points.
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<!-- End Article Side Bar -->All the samples are from a strain of flu virus known as H1N1, a subtype of the influenza A virus: the regular run-of-the-mill seasonal flu, not the dreaded H5N1 avian flu that's prompted countries around the world to stockpile tens of millions of doses of Tamiflu. So how worried should people be about the prospect of drug-resistant strains of influenza A? Only modestly, says World Health Organization spokeswoman Sari Setiogi in Geneva. "Influenza A has been circulating for many years. It's not likely to cause a pandemic," she says. The patients who gave samples for the European study all showed only mild symptoms. What's more, just because a flu bug has adapted to survive drug treatment, it doesn't mean the bug is necessarily more dangerous to humans. In fact, lab studies suggest that Tamiflu-resistant flu viruses may be less infectious.
In the end, the most troubling thing about the ECDC study was the 75% resistance rate found in Norway. Like doctors elsewhere in Western Europe — and in the U.S. and Canada — Norwegians don't routinely prescribe Tamiflu to their patients. (Tamiflu is not a flu vaccine, but a post-exposure treatment that helps prevent the virus from spreading within the body, and reduces symptoms.) They just tell them to get some rest and drink plenty of fluids. It's a bit of a mystery, then, why so many of Norway's samples are drug-resistant. In theory, viruses should develop resistance to drugs the same way bacteria do: through evolution. Since organisms with drug-resistant traits are better able to withstand contact with the drugs, they survive long enough to replicate and pass their traits to the next generation. With repeated exposure, a population will become increasingly resistant, with a larger and larger proportion of the organisms showing the protective attributes. Already, U.S. health authorities recommend against using two other flu antivirals, amantadine and rimantadine (sold as Symmetrel and Flumadine, respectively), due to concerns that influenza A has become resistant. But, so far, Tamiflu resistance doesn't seem to be following the logical path. In Japan, Tamiflu prescriptions are commonplace, but researchers there continue to report low levels of drug-resistance: less than 3% this season and last.
One thing is certain. The news won't help Roche Holding AG, the Swiss holding company for Tamiflu manufacturer Hoffman-La Roche. Tamiflu sales dropped off sharply in the second half of 2007, Roche announced this week. But the main reason wasn't drug-resistance; it was simply a saturated market. As countries meet their targets for an anti-flu-pandemic Tamiflu stockpile, global demand for the drug is tapering off. For now, at least, those national stockpiles still offer an advantage: To date, the H5N1 bird flu shows only limited resistance to the drug.

http://www.time.com/time/health/article/0,8599,1708867,00.html

[Gert van der Hoek]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::

Tamiflu-Resistant Flu Found in Nine European Nations (Update1)

By Jason Gale

Feb. 1 (Bloomberg) -- Influenza strains resistant to Roche Holding AG's Tamiflu were found in a samples from five more countries, indicating the mutant bug is more widespread than health officials reported earlier this week.

Tests on 437 virus specimens from patients with the H1N1 flu strain in 18 countries found 59 that harbored resistance to the pill, the European Centre for Disease Prevention and Control said in a statement yesterday. Resistant viruses were found in nine European countries, with Norway accounting for almost half.

Emerging resistance to Tamiflu, also known as oseltamivir, has led doctors to consider GlaxoSmithKline Plc's Relenza and other treatments for a disease the World Health Organization estimates causes 250,000 to 500,000 deaths globally each year. Experts are assessing the significance of the data and will release an interim assessment in the coming days, ECDC said.

``At this stage, it is impossible to say what the level of resistance is in influenza across Europe,'' the Stockholm-based health agency said. ``However from the limited data, the proportion of influenza viruses exhibiting resistance to oseltamivir must be significant, but not as high as in Norway.''

The H1N1 viruses identified in Europe that aren't susceptible to Tamiflu carry a so-called H274Y gene mutation that confers ``high-level resistance,'' Frederick Hayden, a researcher with the WHO's Global Influenza Program in Geneva, said in a Jan. 28 interview.

U.S. Strains

Of 109 H1N1 viral samples tested in the U.S. during the 2007-2008 flu season, 5.5 showed the same resistance-inducing mutation, according to the Centers for Disease Control and Prevention in Atlanta.

Recent tests on samples from Europe found viruses with the H274Y mutation in Germany, Netherlands, Portugal, Sweden and Finland, scientists from the U.K.'s Health Protection Agency said in a report published yesterday in Eurosurveillance, a newsletter on communicable diseases.

Earlier sampling found the mutant strain in France, the U.K., Denmark, France and Norway, the ECDC said in a Jan. 27 risk assessment report. Of 37 samples from Norway tested, 26 harbor resistance, the agency said yesterday.

``The oseltamivir resistance investigation is still in its early stages,'' researchers from the ECDC's Influenza Project Team wrote in a separate report in yesterday's Eurosurveillance. ``A more accurate picture will only emerge when many more specimens have been tested and more epidemiological information is available.''

Tests so far show that the mutated viruses are susceptible to Relenza and an older class of antiviral drugs known as adamantanes, the researchers said. There's insufficient evidence for authorities to consider changes to clinical guidelines, the researchers said.

No More Virulent

People who become ill with the Tamiflu-resistant H1N1 strain don't appear to become any more sick than people infected with ``normal'' seasonal flu, ECDC said.

Tamiflu, which generated 2.09 billion francs ($1.9 billion) in sales for Basel, Switzerland-based Roche in 2007, is the company's fifth-best-selling drug. Relenza, an inhaled medicine, had sales of 91 million pounds ($181 million) in 2006 for London-based Glaxo.

The medicines are being stockpiled by the Geneva-based WHO and governments around the world for use in the event of a pandemic, and to treat the H5N1 avian flu strain that's spread to more than 60 countries, infecting people in 14 of them.

The H5N1 bird flu strain could trigger a global outbreak if it adopts some of the characteristics of seasonal flu that enable it to be spread easily through coughing and sneezing.

To contact the reporter on this story: Jason Gale in Singapore at j.gale@bloomberg.net

Last Updated: February 1, 2008 00:53 EST

http://www.bloomberg.com/apps/news?pid=20601102&sid=augKlqXymSj8

[gsgs]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::

I assume that travelors are more likely to treat their flu with Tamiflu,
thus contributing to resistance-selection.

Can we test the blood for Tamiflu on airports ?
Or make Tamiflu reportable and do occasional tests with penalty on non-reporting.
Reported people with Tamiflu are being controlled for virus-shedding
with household-quarantine or such in case of resistant viruses.

[HenryN]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::

I assume that travelors are more likely to treat their flu with Tamiflu,
thus contributing to resistance-selection.

Can we test the blood for Tamiflu on airports ?
Or make Tamiflu reportable and do occasional tests with penalty on non-reporting.
Reported people with Tamiflu are being controlled for virus-shedding
with household-quarantine or such in case of resistant viruses.

Please.

It has been noted multiple times now that the patients with H274Y in H1N1 were NOT treated with Tamiflu.

If you have data to support Tamiflu treatment, post it.

[Giuseppe]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::

See post #43, 1b), paragraph 10.

[gsgs]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::

not the patients where the mutation was found,
but maybe those where that mutation first appeared
and who then did spread it to others.

Do we (or the experts) believe, that Tamiflu usage didn't contribute
to this ? That is not yet clear to me.

The airport question is also (hypothetically) interesting/important in a pandemic.


"Determining the origins and genesis of these drug-resistant strains, which appear to have emerged in regions of the world where there is little drug pressure, will be important in understanding the emergence and persistence of oseltamivir resistance in relation to the evolution of influenza viruses and drug use. "

so there could be a relation between drug use and emergence and resistence of H274Y,
they are not sure about it ?!

[gsgs]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::

we observe H1N1-evolution since 90 years and this is the first time
that we have a significant portion of H274Y.
Tamiflu had been in widespread use since only some years.
Coincidence ?

I think this is the first time with 2-3 consecutive H1N1-seasons (?)
(I will have to check..)

[gsgs]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::

how was it with Amantadine ?
I remember that widespread resistance had been commonly attributed to
drug usage. Although I couldn't quickly find this now in papers
or articles (?!)


OK, here some excerts of what I found about Amantane-resistance:
(note that resistance in H1N1 is not so high )

http://www.ncbi.nlm.nih.gov/pubmed/11225319?ordinalpos=17&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Amantadine has been found to have an efficacy of 50 to 90% prevention of illness. However amantadine-resistant viruses have been recovered approximately 30% patients treated with amantadine, as early as 2-3 days into treatment.

http://www.ncbi.nlm.nih.gov/pubmed/12825171?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Clinical samples from 15 amantadine-treated children were collected serially-before, during, and/or after treatment-and were studied to determine the actual prevalence, timing, and clinical implications of M2 mutational events.
5 Amantadine-resistance mutations were found in 12 of 15 children,
and 9 patients had >1 (2-4) mutant virus.
6 patients with at least 4 serial samples.


A systematic review of 20 comparative randomised trials involving about 2500 healthy people showed that amantadine reduced the frequency of flu-like syndromes by about 7% in absolute terms (26.3% versus 33.1% with placebo). Zanamivir and oseltamivir have only been shown to reduce the frequency of serologically confirmed episodes of influenza (0.4% to 2.5%, compared to 4.4% to 14.9% with placebo).

http://content.nejm.org/cgi/content/abstract/307/10/580

450 volunteers participated in a placebo-controlled, double-blind, randomized trial of the prophylactic effects of rimantadine and amantadine during an outbreak of influenza A. The subjects received drugs orally at a dose of 100 mg twice a day for six weeks. Influenza-like illness occurred in 41 per cent of the subjects receiving placebo but in only 14 per cent of those receiving rimantadine and 9 per cent of these receiving amantadine (P less than 0.001 for either drug vs. placebo). Laboratory-documented influenza occurred in 21 per cent of placebo recipients, 3 per cent of rimantadine recipients, and 2 per cent of amantadine recipients (P less than 0.001). These findings represent efficacy rates of 85 per cent for rimantadine and 91 per cent for amantadine, as compared with placebo. More recipients of amantadine (13 per cent) than recipients of rimantadine (6 per cent; P less than 0.05) or placebo (4 per cent; P less than 0.01) withdrew from the study because of central-nervous-system side effects. On the basis of this study, rimantadine appears to be the drug of choice for the prophylaxis of influenza A.



A comprehensive analysis of influenza strains indicated that 96 percent
of the H3N2 strains as well as 15 percent of the H1N1 viruses currently
circulating worldwide are amantadine resistant.

http://jama.ama-assn.org/cgi/content/full/295/8/891

A total of 209 influenza A(H3N2) viruses isolated in 2006/6 from patients in 26 states were screened, of which 193 (92.3%) contained a change at amino acid 31 (serine to asparagine [S31N]) in the M2 gene known to be correlated with adamantane resistance. Two of 8 influenza A(H1N1) viruses contained the same mutation. Drug-resistant viruses were distributed across the United States.

increase in resistance from below 2% in 1995-2002 to 12.3% in 2004.15 In the United States, the frequency of resistance increased significantly from 1.9% in 2004 to 14.5% during the first 6 months of the 2004-2005 influenza season (October 2004 through March 2005).15 The rate of resistance in the United States for the entire 2004-2005 season was 11% (R.A.B., CDC, unpublished data, 2006).

Canada recently reported that among H3N2 isolates tested for the 2005-2006 influenza season, 43 of 47 (91%) contained this same mutation, showing that adamantane-resistant influenza viruses are circulating in other regions of North America.16 In addition, preliminary and limited data indicate that the rate of resistance for the 2004-2005 influenza season continued to increase over the previous report for some counties in Asia (China, 96%; Hong Kong, 72%; South Korea, 36%; Singapore, 42%) (R.A.B., CDC, unpublished data, 2006)

[Anty]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::

New update from The Norwegian Institute of Public Health today
The % with the mutation has fallen to 66%.
38 out of 58 norwegian virus samples have the mutation.
It is still striking high.

link (in norwegian)

http://fhi.no/eway/default.aspx?pid=233&trg=MainLeft_5565&MainArea_5661=5565:0:15,1214:1:0:0:::0:0&MainLeft_5565=5544:67376::1:5569:1:::0:0

[tropical]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::

From previous posts:
"... Dr. Frank Plummer, said, noting the resistance mutation spotted in the Winnipeg testing is the same one that has been reported over the past few days from Norway, several other European countries and the United States. <!-- CPPara3End-->
Eight of 81 H1N1 viruses tested carry the H274Y mutation - one each from British Columbia and Newfoundland and Labrador, and six from Ontario. Plummer said that total includes one virus (from British Columbia) recovered from a child who is believed to have been infected in Sudan.
His surprise is shared by experts with the World Health Organization's Global Influenza Program, which convened a teleconference of about 50 scientists from leading influenza laboratories around the world Tuesday to try to get a handle on how far this virus has spread, how common it is in places where it is being found and what is driving the spread. ..."

I shall suggest that any of FT's try to drag here some results of the (terminated) 50 world top scientists teleconference meeting about this matter.

[gsgs]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::

seems that peramivir won't work for H274Y either,
hattip to miso:

http://aac.asm.org/cgi/content/full/48/12/4542

The peramivir-selected variant had a H274Y mutation in the neuraminidase (NA) gene conferring resistance
to peramivir and oseltamivir but susceptibility to zanamivir.

[HenryN]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::

WHO reports Tamiflu-resistant flu in U.S., Canada

Fri 1 Feb 2008, 13:58 GMT
<INPUT id=CurrentSize type=hidden value=13 name=CurrentSize>
[-] Text [+]

(Adds details on Canada in first and fifth paragraphs)
By Stephanie Nebehay
GENEVA, Feb 1 (Reuters) - The main flu virus circulating in the United States and Canada has shown "elevated resistance" to the antiviral drug Tamiflu, in line with findings in parts of Europe, the World Health Organisation (WHO) said on Friday.
The United Nations agency said it was too early to know what potential there may be for increased Tamiflu resistance in H5N1 avian influenza. It did not change its recommendation that Tamiflu be used to treat human cases of bird flu.
A number of governments have been stockpiling Tamiflu, made by Switzerland's Roche Holding Ag and Gilead Sciences Inc of the United States, for use as a first line of defence in case bird flu sparks a human influenza pandemic.
The WHO said it was investigating the extent of resistance worldwide to Tamiflu, known generically as oseltamivir, in some seasonal H1N1 flu viruses that have a mutation making them "highly resistant."
The U.S. Centers for Disease Control and Prevention has reported a five percent prevalence of resistance to Tamiflu in samples of H1N1 virus tested to date. In Canada, 8 out of 81 samples showed resistance -- more than a 10 percent resistance rate, WHO spokeswoman Sari Setiogi said.
"These preliminary data indicate that oseltamivir resistance in H1N1 viruses is geographically variable but not limited to Europe," the WHO said in a statement.
A preliminary survey issued by the European Centre for Disease Control (ECDC) this week said that of 148 samples of influenza A virus isolated from 10 European countries during November and December, 19 showed signs of resistance to Tamiflu.
Of 16 samples from Norway, 12 tested positive for resistance against Tamiflu, according to the ECDC study.
The new "elevated resistance to oseltamivir" appears limited to seasonal H1N1 viruses, and does not involve H3N2 or influenza B viruses which are also circulating, the WHO said.
"This means that oseltamivir would most likely be ineffective for treating or preventing infections caused by these resistant H1N1 strains, although the drug will be effective against other influenza virus infections," it added.
The WHO said it was contacting national health authorities to determine the extent of resistance to the drug. Neither Japan -- where Tamiflu is widely prescribed for seasonal flu -- nor Hong Kong had seen increased resistance to date, it said.
Past studies had found Tamiflu resistance rates ranging from zero to 0.5 percent, according to the U.N. agency.
"The frequency of oseltamivir resistance in H1N1 viruses in the current influenza season is unexpected and the reason why a higher percentage of these viruses are resistant is currently unknown," the WHO said.
Tamiflu has been proposed for treating H5N1 bird flu in humans. Health experts fear that virus, which now mainly affects poultry, could mutate into a form that spreads easily among people and trigger a deadly pandemic. (Reporting by Stephanie Nebehay, editing by Keith Weir)

http://africa.reuters.com/commodities/news/usnL0133927.html

[HenryN]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::

how do you know ? They were uploaded 09.Jan.2008

A/Hawaii/21/2007 , submitted Jan.09,2008 (HA -Jan.06,2008)
A/Hawaii/28/2007 , submitted Jan.09,2008 (HA : Jan.06,2008)
A/Hawaii/28/2007 (same ?)
A/Massachusetts/05/2007 , only HA available, "Oseltamivir resistant" , HA submitted Aug.08,2008
A/Minnesota/23/2007 , submitted Jan.09,2008
A/Texas/31/2007 , submitted Oct.30,2007 (HA : Oct.30,2007)
A/Kansas/UR06-0104/2007 , submitted 18.Oct.2007 , collected 30.Jan.2007


BTW A/Texas/12/2007(H3N2) was also Oseltamivir resistant

hmm, Hawaii is 20? N, same as Hongkong,Taiwan,Okinawa
and has maybe not much seasonality.

A/Texas/12/2007(H3N2) is Adamantane resistant

ANTIGEN_CHARACTER: A/WISCONSIN/67/2005-LIKE
PASSAGE_DETAILS: X/C2
COMMENTS: Adamantane Resistant

http://flu.lanl.gov/search/view_record.html?accession=ISDN257663&database=fluA

It does not have H274Y.

Why do you think it is Oseltamivir resistant?

[Malcolm]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::

seems that peramivir won't work for H274Y either,
hattip to miso:

http://aac.asm.org/cgi/content/full/48/12/4542

The peramivir-selected variant had a H274Y mutation in the neuraminidase (NA) gene conferring resistance
to peramivir and oseltamivir but susceptibility to zanamivir.

The article link you provide does not even mention peramivir or oseltamivir.

Your conclusion that peramivir and zanamivir won't work fo r H274Y is based on what?????

[gsgs]

Re: :::Emergence of seasonal influenza viruses type A/H1N1 with:::

A/Texas/12/2007(H3N2) is Adamantane resistant

ANTIGEN_CHARACTER: A/WISCONSIN/67/2005-LIKE
PASSAGE_DETAILS: X/C2
COMMENTS: Adamantane Resistant

http://flu.lanl.gov/search/view_record.html?accession=ISDN257663&database=fluA

It does not have H274Y.

Why do you think it is Oseltamivir resistant?

they say so here:

http://flu.lanl.gov/search/view_record.html?accession=ISDN256028&database=fluA