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

[gsgs]

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

I think evidence grows that Tamiflu-resistance was not driven
by drug usage.

---------------------------------------------

I think, we should expand the examination and sequencing of
viruses from India, i.e. Kolkata/West Bengalen in summer.
They are still rare as compared to flu-viruses from other regions
like USA,Europe,Singapore,Japan,HongKong,Australia,New Zealand,
South Korea,
Maybe USA,Europe,WHO,Gates Foundation,... can pay for it ?

If it turns out to be true and maybe monsoon plays a role,
then we could be able to "plant" new strains and mutations,
to "breed" viruses that are less virulent, better managable,
not resistant to drugs.

We could find out in summer, what strains will be circulating in
winter in USA,Europe and improve the vaccine.
Thi vaccine is usually decided in ~April, but maybe we could
improve it, speed up production, and wait until June

[gsgs]

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

today at genbank :


these 2 viruses from July 2007
A/Kolkata/975/2007/07(H1N1)
A/Kolkata/985/2007/07(H1N1)
have C439T(8)
(only segments 2(partial) and 8 are given)
this mutation appears together with H274Y(6),
the tamiflu resistance that appeared in H1N1 in Europe in 2008.
This strain is now almost distinct due to the new pandemic.

Another example that new successful strains often
are first seen (emerge ?) in summer in Kolkata/India

and then maybe spread during the monsoon season

[HenryN]

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

Sequences with H274Y
emb|FM174468.1| Influenza A virus (A/Luxembourg/456/2008(H1N1... 26.3 619
emb|FM174467.1| Influenza A virus (A/Luxembourg/421/2008(H1N1... 26.3 619
emb|FM174466.1| Influenza A virus (A/Luxembourg/402/2008(H1N1... 26.3 619
emb|FM174465.1| Influenza A virus (A/Luxembourg/382/2008(H1N1... 26.3 619
emb|FM174464.1| Influenza A virus (A/Luxembourg/373/2008(H1N1... 26.3 619
emb|FM174463.1| Influenza A virus (A/Luxembourg/285/2008(H1N1... 26.3 619
emb|FM174462.1| Influenza A virus (A/Luxembourg/278/2008(H1N1... 26.3 619
emb|FM174461.1| Influenza A virus (A/Luxembourg/273/2008(H1N1... 26.3 619
emb|FM174460.1| Influenza A virus (A/Luxembourg/265/2008(H1N1... 26.3 619
emb|FM174458.1| Influenza A virus (A/Luxembourg/215/2008(H1N1... 26.3 619
emb|FM174457.1| Influenza A virus (A/Luxembourg/187/2008(H1N1... 26.3 619
emb|FM174456.1| Influenza A virus (A/Luxembourg/182/2008(H1N1... 26.3 619
emb|FM174455.1| Influenza A virus (A/Luxembourg/132/2008(H1N1... 26.3 619
emb|FM174453.1| Influenza A virus (A/Luxembourg/164/2008(H1N1... 26.3 619
emb|FM174430.1| Influenza A virus (A/Luxembourg/022/2008(H1N1... 26.3 619
emb|FM174428.1| Influenza A virus (A/Luxembourg/019/2008(H1N1... 26.3 619
emb|FM174427.1| Influenza A virus (A/Luxembourg/016/2008(H1N1... 26.3 619
emb|FM174426.1| Influenza A virus (A/Luxembourg/006/2008(H1N1... 26.3 619
emb|FM174425.1| Influenza A virus (A/Luxembourg/098/2008(H1N1... 26.3 619
emb|FM174424.1| Influenza A virus (A/Luxembourg/090/2008(H1N1... 26.3 619
emb|FM174423.1| Influenza A virus (A/Luxembourg/086/2008(H1N1... 26.3 619
emb|FM174420.1| Influenza A virus (A/Luxembourg/286/2008(H1N1... 26.3 619
emb|FM174419.1| Influenza A virus (A/Luxembourg/279/2008(H1N1... 26.3 619
emb|FM174418.1| Influenza A virus (A/Luxembourg/261/2008(H1N1... 26.3 619
emb|FM174416.1| Influenza A virus (A/Luxembourg/249/2008(H1N1... 26.3 619
emb|FM174415.1| Influenza A virus (A/Luxembourg/234/2008(H1N1... 26.3 619
emb|FM174414.1| Influenza A virus (A/Luxembourg/222/2008(H1N1... 26.3 619
emb|FM174411.1| Influenza A virus (A/Luxembourg/176/2008(H1N1... 26.3 619
emb|FM174407.1| Influenza A virus (A/Luxembourg/116/2008(H1N1... 26.3 619
emb|FM174406.1| Influenza A virus (A/Luxembourg/115/2008(H1N1... 26.3 619

[Giuseppe]

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

September 29 World Health Organization update at: http://www.flutrackers.com/forum/showthread.php?t=81154

[HenryN]

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

Roche Announces Tamiflu<SUP>?</SUP> Antiviral Flu Medication in Ample Supply for 2008-2009 Flu Season

• - Rapid Response Program Provides Pharmacies Quick Access During Winter Months -

Nutley, NJ, September 23, 2008 ? Roche announced today that ample supplies of its prescription antiviral medication Tamiflu<SUP>?</SUP> (oseltamivir phosphate) will be widely available throughout the U.S. this flu season. Tamiflu, cited by the Centers for Disease Control and Prevention (CDC) as an important second line of defense against flu, is indicated for the treatment and prevention of influenza in adults and children one year and older.
To help ensure the medication gets to the pharmacies and people who need it, Roche coordinates a rapid response system with distributors nationwide. Through the program, pharmacists can order additional Tamiflu through a toll-free number (1-800-526-0625) and have it delivered within 24 hours by a local distributor.
?We understand that pharmacists do their best to stock appropriate amounts of antiviral medications, such as Tamiflu, for use during flu season,? said Dominick Iacuzio, Ph.D, medical
director at Roche. ?However, the incidence and severity of seasonal flu remains unpredictable from year to year, and some pharmacies still may be faced with greater-than-expected demand during the season.?
Roche also created an early signaling system called FluSTAR? and advises pharmacies when flu may be spreading in their local area.
Antiviral medications, such as Tamiflu, are one of three steps (along with vaccination and good hygiene) outlined in the CDC?s ?Take 3? influenza initiative. Available in a capsule and liquid suspension form, Tamiflu is the only oral antiviral medication recommended by the CDC for influenza treatment and prevention during the 2008-2009 flu season. Unlike the vaccine, which is reformulated each year to work against three specific strains of the virus, Tamiflu is designed to be active against all clinically relevant influenza virus strains.
?Because Tamiflu prevents the influenza virus from spreading inside the body, it has to be given within the first 48 hours of flu symptoms in order to be effective,? said Iacuzio. ?People need to be aware of typical flu symptoms, and call the doctor quickly as soon as symptoms arise, for proper diagnosis.?
While not a substitute for vaccination, prescription antiviral drugs are an important adjunct, offering a second line of defense in preventing and treating seasonal influenza.
Flu Treatment
If a person does contract the virus, antiviral medications are available by prescription to treat the flu. According to the CDC, ?for treatment, influenza antiviral drugs should be started within two days after becoming sick and taken for five days.? Tamiflu can reduce flu symptoms and shorten the time of sickness.
Flu Prevention
Antiviral medications such as Tamiflu can also be given prophylactically to people who have been exposed to influenza to help contain the spread in certain settings, such as family members passing the virus to one another in a household.
Preventive doses of Tamiflu following exposure to the flu can also be considered for controlling outbreaks in closed or semi-closed settings, such as nursing homes or dormitories. Clinical trials indicate that Tamiflu is up to 92 percent effective in preventing flu in adults ? and 82 percent effective in preventing flu in children ? when taken within 48 hours of exposure.
About Tamiflu Tamiflu, co-developed by Gilead Sciences, Inc., based in Foster City, CA, is indicated for the treatment of uncomplicated influenza caused by viruses types A and B in patients one year and older who have had flu symptoms for no more than two days. Tamiflu is also indicated for the prevention of influenza in patients one year and older. Tamiflu is not a substitute for annual early vaccination as recommended by the CDC. Prescribers should consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use Tamiflu.
In post-marketing experience, rare cases of anaphylaxis and serious skin reactions have been reported. There have been post-marketing reports (mostly from Japan) of self-injury and delirium with the use of Tamiflu in patients with influenza. The reports were primarily among children. The relative contribution of the drug to these events is not known. Patients with influenza should be closely monitored for signs of abnormal behavior throughout the treatment period.
The most frequently reported adverse events in clinical studies were nausea, vomiting, and diarrhea. Tamiflu is available for the treatment of influenza in more than 80 countries worldwide. Prescribing information for Tamiflu is available at www.rocheusa.com/products/tamiflu.
About Roche
Hoffmann-La Roche Inc. (Roche), in Nutley, N.J., is the U.S. pharmaceuticals headquarters of the Roche Group, a leading, global healthcare company. For more than 100 years, Roche has been developing innovative products and services that address prevention, diagnosis and treatment of disease.
For more information, visit http://www.rocheusa.com. Product and treatment information for U.S. healthcare professionals is available at www.RocheExchange.com. Prescribing information for Tamiflu is available at www.rocheusa.com/products/tamiflu.

[HenryN]

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

Updated list of isolates with H274Y

gb|FJ179363.1| Influenza A virus (A/Illinois/15/2007(H1N1)) s... 34.2 2.5
gb|FJ179362.1| Influenza A virus (A/Illinois/16/2007(H1N1)) s... 34.2 2.5
gb|FJ179361.1| Influenza A virus (A/Pennsylvania/13/2007(H1N1... 34.2 2.5
gb|EU914908.1| Influenza A virus (A/Johannesburg/45/2008(H1N1... 34.2 2.5
gb|EU914907.1| Influenza A virus (A/Johannesburg/36/2008(H1N1... 34.2 2.5
gb|EU914906.1| Influenza A virus (A/Johannesburg/35/2008(H1N1... 34.2 2.5
gb|EU914905.1| Influenza A virus (A/Johannesburg/33/2008(H1N1... 34.2 2.5
gb|EU914904.1| Influenza A virus (A/Johannesburg/14/2008(H1N1... 34.2 2.5
gb|EU914903.1| Influenza A virus (A/Johannesburg/21/2008(H1N1... 34.2 2.5
gb|EU914902.1| Influenza A virus (A/CapeTown/26/2008(H1N1)) n... 34.2 2.5
gb|EU914901.1| Influenza A virus (A/Johannesburg/12/2008(H1N1... 34.2 2.5
gb|EU685788.1| Influenza A virus (A/Paris/1170/2008(H1N1)) ne... 34.2 2.5
gb|EU551826.1| Influenza A virus (A/Paris/749/2007(H1N1)) neu... 34.2 2.5
gb|EU551824.1| Influenza A virus (A/Paris/847/2007(H1N1)) neu... 34.2 2.5
gb|EU551821.1| Influenza A virus (A/Paris/963/2008(H1N1)) neu... 34.2 2.5
gb|EU551815.1| Influenza A virus (A/Paris/577/2007(H1N1)) neu... 34.2 2.5
gb|EU551814.1| Influenza A virus (A/Paris/1157/2008(H1N1)) ne... 34.2 2.5
gb|EU551813.1| Influenza A virus (A/Paris/1208/2008(H1N1)) ne... 34.2 2.5
gb|EU551812.1| Influenza A virus (A/Paris/1154/2008(H1N1)) ne... 34.2 2.5
gb|EU551811.1| Influenza A virus (A/Paris/341/2007(H1N1)) neu... 34.2 2.5
gb|EU551810.1| Influenza A virus (A/Paris/910/2007(H1N1)) neu... 34.2 2.5
gb|EU551809.1| Influenza A virus (A/Paris/644/2007(H1N1)) neu... 34.2 2.5
gb|EU887035.1| Influenza A virus (A/South Carolina/01/2008(H1... 34.2 2.5
gb|EU879082.1| Influenza A virus (A/Zhejiang/Xiangshan522/200... 34.2 2.5
gb|EU879064.1| Influenza A virus (A/Gansu/Chenguan/1129/2007(... 34.2 2.5
gb|EU851986.1| Influenza A virus (A/Minnesota/01/2008(H1N1)) ... 34.2 2.5
gb|EU851982.1| Influenza A virus (A/Hawaii/02/2008(H1N1)) seg... 34.2 2.5
gb|EU851980.1| Influenza A virus (A/Hawaii/01/2008(H1N1)) seg... 34.2 2.5
gb|EU779650.1| Influenza A virus (A/North Carolina/02/2008(H1... 34.2 2.5
gb|EU779643.1| Influenza A virus (A/New Jersey/10/2008(H1N1))... 34.2 2.5
gb|EU779641.1| Influenza A virus (A/Memphis/03/2008(H1N1)) ne... 34.2 2.5
gb|EU681266.1| Influenza A virus (A/Bursa-TR/1231/2007(H1N1))... 34.2 2.5
gb|EU681265.1| Influenza A virus (A/Istanbul-TR/1219/2007(H1N... 34.2 2.5
gb|EU681264.1| Influenza A virus (A/Istanbul-TR/1198/2007(H1N... 34.2 2.5
gb|EU681263.1| Influenza A virus (A/Ankara-TR/170/2008(H1N1))... 34.2 2.5
gb|EU681262.1| Influenza A virus (A/Istanbul-TR/111/2008(H1N1... 34.2 2.5
gb|EU702755.1| Influenza A virus (A/Hong Kong/17/2008(H1N1)) ... 34.2 2.5
gb|EU716587.1| Influenza A virus (A/Washington/01/2008(H1N1))... 34.2 2.5
gb|EU716580.1| Influenza A virus (A/Florida/02/2008(H1N1)) se... 34.2 2.5
gb|EU624316.1| Influenza A virus (A/England/557/2007(H1N1)) s... 34.2 2.5
gb|EU570806.1| Influenza A virus (A/Bursa-TR/28/2008(H1N1)) n... 34.2 2.5
gb|EU567014.1| Influenza A virus (A/New Jersey/06/2008(H1N1))... 34.2 2.5
gb|EU567011.1| Influenza A virus (A/Indiana/01/2008(H1N1)) se... 34.2 2.5
gb|EU567009.1| Influenza A virus (A/Arizona/13/2007(H1N1)) se... 34.2 2.5
gb|EU567006.1| Influenza A virus (A/Arizona/14/2007(H1N1)) se... 34.2 2.5
gb|EU566999.1| Influenza A virus (A/Wisconsin/01/2008(H1N1)) ... 34.2 2.5
gb|EU566998.1| Influenza A virus (A/Maryland/04/2007(H1N1)) s... 34.2 2.5
gb|EU566987.1| Influenza A virus (A/New Jersey/20/2007(H1N1))... 34.2 2.5
gb|EU566983.1| Influenza A virus (A/New Jersey/05/2008(H1N1))... 34.2 2.5
gb|EU566977.1| Influenza A virus (A/Pennsylvania/02/2008(H1N1... 34.2 2.5
gb|EU566968.1| Influenza A virus (A/Arizona/15/2007(H1N1)) se... 34.2 2.5
gb|EU516201.1| Influenza A virus (A/New Jersey/16/2007(H1N1))... 34.2 2.5
gb|EU516200.1| Influenza A virus (A/Illinois/10/2007(H1N1)) s... 34.2 2.5
gb|EU516196.1| Influenza A virus (A/Arizona/03/2007(H1N1)) se... 34.2 2.5
gb|EU516148.1| Influenza A virus (A/New Jersey/15/2007(H1N1))... 34.2 2.5
gb|EU516125.1| Influenza A virus (A/Hawaii/28/2007(H1N1)) seg... 34.2 2.5
gb|EU516123.1| Influenza A virus (A/Hawaii/28/2007(H1N1)) seg... 34.2 2.5
gb|EU516112.1| Influenza A virus (A/Hawaii/21/2007(H1N1)) seg... 34.2 2.5

[HenryN]

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

This demostrantes the fitness of oseltamivir-resistant H1N1 viruses but it shouldn't be drawn further conclusions that these viruses are more virulent than oseltamivir-susceptible ones.

The patient was very ill with a severe blood disease and infected by other pathogens thus a poor outcome may be due to this complex situation rather than the presence of a H1N1-resistant virus.

Noteworthy, the concurrent emersion of a sub-population of H1N1-oseltamivir and amantadine resistant viruses.

However, it should be noted that the viral load remained high for three weeks due to Tamiflu resistance prior to treatment and amantadine resistance which developed during treatment. Viral load fell to baseline 8 days after Relenza treatment, which began on day 20.

[Giuseppe]

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

This demostrantes the fitness of oseltamivir-resistant H1N1 viruses but it shouldn't be drawn further conclusions that these viruses are more virulent than oseltamivir-susceptible ones.

The patient was very ill with a severe blood disease and infected by other pathogens thus a poor outcome may be due to this complex situation rather than the presence of a H1N1-resistant virus.

Noteworthy, the concurrent emersion of a sub-population of H1N1-oseltamivir and amantadine resistant viruses.

[Sally Furniss]

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

Fatal Oseltamivir-Resistant Influenza Virus Infection

<table align="right" border="0" cellpadding="0" cellspacing="0" width="200"> <tbody><tr> <td width="20"> </td> <td bgcolor="#336699"> <table border="0" cellpadding="0" cellspacing="1"> <tbody><tr valign="top"> <td align="center" bgcolor="#e8e8d1" width="200">

</td> </tr><tr> <td> <table bgcolor="#ffffff" border="0" cellpadding="2" cellspacing="0" width="100%"> <tbody><tr valign="top"><td colspan="2"></td></tr> <tr valign="top"><td align="center" valign="top" width="15"></td><td valign="middle"> PDF</td></tr> <tr valign="top"><td align="center" valign="top" width="15"></td><td valign="middle">PDA Full Text</td></tr> <tr valign="top"><td colspan="2"></td></tr> </tbody></table> </td> </tr> <tr> <td align="center" bgcolor="#e8e8d1" width="200">

</td> </tr> <tr> <td> <table bgcolor="#ffffff" border="0" cellpadding="2" cellspacing="0" width="100%"> <tbody><tr valign="top"><td colspan="2"></td></tr> <tr valign="top"><td align="center" valign="top" width="15"></td><td valign="middle">Add to Personal Archive</td></tr> <tr valign="top"><td align="center" valign="top" width="15"></td><td valign="middle">Add to Citation Manager</td></tr> <tr valign="top"><td align="center" valign="top" width="15"></td><td valign="middle">Notify a Friend</td></tr> <tr valign="top"><td align="center" valign="top" width="15"></td><td valign="middle">E-mail When Cited</td></tr> <tr valign="top"><td align="center" valign="top" width="15"></td><td valign="middle">E-mail When Letters Appear</td></tr> <tr valign="top"><td colspan="2"></td></tr> </tbody></table> </td> </tr> <tr> <td align="center" bgcolor="#e8e8d1" width="200">

</td> </tr> <tr> <td> <table bgcolor="#ffffff" border="0" cellpadding="2" cellspacing="0" width="100%"> <tbody><tr valign="top"><td colspan="2"></td></tr> <tr valign="top"><td colspan="2"></td></tr> </tbody></table> </td> </tr> </tbody></table> </td></tr></tbody></table> <!-- end of outer content box1 --> <!-- end of outer content box2 --> <!-- TEXT --> <!-- <CENTER> Fatal Oseltamivir-Resistant Influenza Virus Infection

</CENTER> --> To the Editor: The incidence of influenza A (H1N1) viruses thatcarry the neuraminidase H274Y mutation has increased by 30%this year in the Netherlands.¹ Influenza A (H1N1) viruses thatcarry this mutation are resistant to oseltamivir but remainsensitive to zanamivir.² However, these mutant viruses are consideredto have attenuated pathogenicity.³^,⁴
A 67-year-old man who had received a diagnosis of chronic lymphocyticleukemia 3 years earlier was admitted to the hospital becauseof dyspnea, dry cough, and fever. One week before admission,he had received a course of cyclophosphamide, vincristine, andprednisolone chemotherapy. At admission, his white-cell countwas 137,000 per cubic millimeter, with 99% lymphocytes and noneutrophils. Because of acute respiratory failure, empiricalantibacterial therapy was initiated, and mechanical ventilationwas required by the second hospital day (Figure 1). Computedtomography (CT) revealed patchy infiltrates in both lungs, andinfluenza A (H1N1) virus was detected in respiratory secretions.During the entire hospital course, no other respiratory pathogenswere detected in bronchoalveolar-lavage specimens. The onlyother pathogens identified in blood cultures were Candida albicansand Enterococcus faecium, for which fluconazole and vancomycinwere given.
<!-- null --> <table cellpadding="0" cellspacing="0"><tbody><tr bgcolor="#e8e8d1"><td><table cellpadding="2" cellspacing="2"><tbody><tr bgcolor="#e8e8d1"><td align="center" bgcolor="#ffffff" valign="top">
View larger version (29K):
<nobr>[in this window]
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</nobr> </td><td align="left" valign="top"> Figure 1. Leukocyte Counts, Viral Loads, and Treatment during the Hospital Course in a Patient Infected with Influenza A (H1N1) Virus with the H274Y Mutation. Panel A shows the patient's granulocyte and monocyte counts. The gradual increase in the granulocyte count was consistent with bone marrow recovery. Panel B shows the viral load in the respiratory specimens. The dashed red line indicates the lower limit of detection. Various therapeutic and empirical antiviral therapies, shown in Panel C, and antibacterial and antifungal therapies, shown in Panel D, were given to the patient at different intervals (shaded bars). The red portions of the bars in Panel C indicate detection of resistance mutations for either oseltamivir (neuraminidase H274Y) or amantidine (M2-channel L26F), and the blue boxes indicate detection of the wild-type genotype. The L26F resistance mutation in the M2 protein was detected only on day 20, whereas the H274Y mutation was present before and after oseltamivir was administered.

</td></tr></tbody></table></td></tr></tbody></table>
Oseltamivir was administered for the influenza virus infection,beginning on the sixth hospital day, but it was discontinuedon day 13 because sequence analysis revealed the H274Y mutation,and no decrease in the viral load was observed. In retrospect,the H274Y mutation was present in the specimen obtained beforeoseltamivir therapy was initiated. The patient's hospital recordand his family indicated that he had had no contact with patientswho had received oseltamivir. On day 15, amantadine was addedto the patient's treatment regimen. Four days later, the neutrophilcount increased, indicating bone marrow recovery. Mechanicalventilation was discontinued on day 20, and zanamivir by inhalationwas initiated. However, respiratory failure occurred on day22, mechanical ventilation was reinstituted, and therapy withzanamivir was discontinued. On day 26, the influenza virus wasno longer detectable. Because sequence analyses showed an amantadine-resistancemutation in the viral M2 protein (L26F) and zanamivir therapyhad been limited to three doses, clearance of the virus wasprobably due to recovery of the immune system. A second CT scan,obtained on day 28, revealed progression of the pulmonary infiltrates.Because of the poor prognosis, mechanical ventilation was discontinuedon day 34. The patient died 3 days later.
It has been suggested that the H274Y mutation, which confersresistance to oseltamivir, leaves the influenza A (H1N1) virusseverely compromised.³^,⁴ However, the case we describe suggeststhat this oseltamivir-resistant virus can be pathogenic, atleast in an immunocompromised patient.


Erhard van der Vries, M.Sc.
Bart van den Berg, M.D., Ph.D.
Martin Schutten, Ph.D.
Erasmus University Medical Center
3015CE Rotterdam, the Netherlands


http://content.nejm.org/cgi/content/full/359/10/1074

[sharon sanders]

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

Link to above chart:

http://www.who.int/csr/disease/influenza/H1N1webupdate20082008_kf.pdf

[Giuseppe]

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

[NEW UPDATE]

Influenza A(H1N1) virus resistance to oseltamivir - 2008 influenza season, southern hemisphere - 20 August 2008

During weeks 28-32 (6 July -9 August), influenza activity is increased in the southern hemisphere.

Widespread influenza activity was reported by New Zealand with influenza A(H3) and B viruses circulating.

Sporadic influenza activity has been detected in Argentina A(H1), Brazil (A, B) and Chile (A, B), (see Seasonal influenza activity in the world, 2008
http://www.who.int/csr/disease/influ.../en/index.html ).

WHO has received several reports from National Influenza Centres in the southern hemisphere regarding influenza A(H1N1) virus resistance to oseltamivir.

In South Africa, a total of 139 A(H1N1) viruses have been isolated during the 2008 influenza season to date.

Of those, 107 isolates have been tested for oseltamivir resistance by the National Institute of Communicable Diseases (NICD) and 100&#37; were found to be resistant to oseltamivir by genotypic analysis.

Only one of these 107 patients was receiving oseltamivir at the time of sampling, and no unusual clinical features or underlying conditions were found.

From Australia, 10 of 10 A(H1N1) viruses tested, and from Chile, 4 of 32 A (H1N1) viruses tested showed the specific neuraminidase mutation (H274Y) associated with oseltamivir resistance.

WHO is collecting global data about this phenomenon from multiple laboratories participating in Global Influenza Surveillance Network. Data from European countries participating in EISS were provided by the EISS and VirGil project.

This summary table will be updated regularly (every four weeks).

Oseltamivir resistance results were based on phenotypic and/or genotypic analyses.

For background and summary until week 24, 2008, see Influenza A(H1N1) virus resistance to oseltamivir, Last quarter 2007 to first quarter 2008, Preliminary summary and future plans
-

http://www.who.int/csr/disease/influenza/oseltamivir_summary/en/index.html

------

[HenryN]

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

Smoking gun travel log on H274Y emergence

gb|EU551821.1| Influenza A virus (A/Paris/963/2008(H1N1)) neu... 34.2 0.016
gb|EU879082.1| Influenza A virus (A/Zhejiang/Xiangshan522/200... 34.2 0.016
gb|EU879064.1| Influenza A virus (A/Gansu/Chenguan/1129/2007(... 34.2 0.016
gb|EU716580.1| Influenza A virus (A/Florida/02/2008(H1N1)) se... 34.2 0.016
gb|EU516199.1| Influenza A virus (A/Georgia/20/2006(H1N1)) se... 34.2 0.016
gb|EU516198.1| Influenza A virus (A/Georgia/20/2006(H1N1)) se... 34.2 0.016
gb|EU516197.1| Influenza A virus (A/Georgia/20/2006(H1N1)) se... 34.2 0.016
gb|EU516141.1| Influenza A virus (A/Minnesota/23/2007(H1N1)) ... 34.2 0.016
gb|EU516125.1| Influenza A virus (A/Hawaii/28/2007(H1N1)) seg... 34.2 0.016
gb|EU516123.1| Influenza A virus (A/Hawaii/28/2007(H1N1)) seg... 34.2 0.016
gb|EU516112.1| Influenza A virus (A/Hawaii/21/2007(H1N1)) seg... 34.2 0.016
gb|EU516028.1| Influenza A virus (A/Massachusetts/05/2007(H1N... 34.2 0.016
gb|EU516027.1| Influenza A virus (A/Texas/31/2007(H1N1)) segm... 34.2 0.016
gb|CY027037.1| Influenza A virus (A/Kansas/UR06-0104/2007(H1N... 34.2 0.016

[Giuseppe]

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

Resistance to oseltamivir (Tamiflu) in some European influenza virus samples

As the influenza season is over, all data on the WHO, ECDC and EISS web-sites will now only be updated monthly with the next update at the end of August.

Data can be expected to change because of testing of specimens taken earlier in the season.

Updated 7th August 2008 ? next update at the end of August

In late January 2008, antiviral drug susceptibility surveillance of seasonal influenza viruses wascarried out in Europe (the EU-EEA-EFTA countries) by the EU-funded VIRGIL network.

The National Influenza Centres revealed that some of the A (H1N1) viruses circulating this season (winter 2007-8) are resistant to the antiviral drug oseltamivir through mutation at position 274 in the viral neuraminidase gene.

Analysis of 2898 A(H1N1) viruses from 25 European (European Union, EEA/EFTA) countries isolated between November 2007 and late July 2008 (data archived on August 6th) showed that 704 were resistant to oseltamivir, but retained sensitivity to zanamivir and amantadine.

The data are shown as a figure with a linked table. http://ecdc.europa.eu/Health_topics/...als_graph.html

It should be noted that the influenza season has now finished in Europe so changes in the totals are the result of testing of specimens taken during the influenza season and checking of data for example to eliminate duplicates.

The proportion of A(H1N1) viruses that are oseltamivir resistant varied significantly across Europe http://ecdc.europa.eu/Health_topics/...als_graph.html.

The highest proportion of resistant viruses to date have been in Norway where 184 (67%) of the 273 samples are resistant to oseltamivir, whereas no resistant viruses have been detected in five of the 25 countries.

Due to back testing of specimens previously collected some results are now available.

What is new this month from EU countries are the first data for Estonia, where 3 of 7 A(H1N1) specimens show the marker for resistance.

Surveillance in previous years by the Virgil Project http://www.virgil-net.org/ found <1% of circulating viruses to be resistant

The predominant influenza A viruses in Europe in winter 07/08 were A(H1N1) viruses, antigenically similar to the A/Solomon Islands/3/2006 virus included in the 2007/08 N Hemisphere vaccine.

As the season progressed influenza B viruses started to circulate and then predominated.

There were only limited circulation of other influenza A in Europe.

Further details on country to country virus distribution this season are available on the European Influenza Surveillance Scheme (EISS) http://www.eiss.org/index.cgi weekly update as well as in Influenza News http://ecdc.europa.eu/Health_topics/influenza/news.html.

Following the observation of a high level of resistance to oseltamivir in the A(H1N1) viruses circulating in Norway, the Norwegian authorities notified their EU partners and the World Health Organization (WHO) of this situation at the end of January.

The Norwegian Public Health Institute also published an advisory to doctors and the public.

The country with the second highest proportion is now Belgium (53%) followed by France with 231 (47%) of 496 specimens showing the marker for oseltamivir resistance.

This is then followed by the Netherlands and Luxembourg with proportions of 27% and 26% respectively.

There is no evidence that the appearance of these new viruses are related to use of oseltamivir which is currently seemingly not widely prescribed in most European countries.

ECDC is now working with the manufacturer and national authorities to gather more information on routine oseltamivir use in Europe.

Experts from the European Centre for Disease Prevention and Control (ECDC), the European Commission, the European Influenza Surveillance Scheme and the World Health Organization (WHO) http://www.who.int/csr/disease/influ.../en/index.html are currently assessing the significance of the data from the EISS VIRGIL network.

An interim European risk assessment has been published by ECDC http://ecdc.europa.eu/pdf/080127_os.pdf and comments on this are welcomed to influenza@ecdc.europa.eu.

Global surveillance has started and is being coordinated by WHO, and evidence has been found of similarly resistant viruses in North America and the Far East. All data including that on the WHO web-site are updated at monthly intervals at present.

At the global level the most recent notable finding was from South Africa where all 23 influenza A/H1N1 specimens gathered since the last quarter of 2007 and now that have been tested showed the marker of resistance.

Their findings have been confirmed by WHO Collaborating Centres.

To date there have only been 111 specimens influenza A/H1N1 specimens tested from WHO?s Africa Region and none of these have shown the markers of resistance apart from those from South Africa.

Other significant national proportions of A/H1N1 specimens showing resistance for which there are data on more than 50 specimens are from the Russian Federation 45%, 58 of 128), Canada 26% (127 of 486), United States 12% (126 of 1026), Japan 3% (44 of 1652), Hong Kong 12% (98 of 797), Australia 4% (3 of 83), Madagascar (none of 59), Korea (none of 99%) and New Zealand (none of 88).

At present there are no data on the new Southern Hemisphere influenza season which has recently started.

As well as the WHO monthly table http://www.who.int/csr/disease/influ...te18072008.pdf . WHO is publishing less frequent analytic summaries on the WHO web-site http://www.who.int/csr/disease/influ.../en/index.html . WHO also published regular summaries on influenza in the world.

The last of these was published in late July http://www.who.int/csr/disease/influ.../en/index.html .

Although sporadic low level transmission of drug resistant viruses may have taken place since 1999 when the Neuraminidase Inhibitor drugs first were licensed, the 07/08 winter season is the first time there has been widespread and sustained transmission of such viruses in the community.

Similar viruses have been seen before, but usually following treatment. Such viruses previously have not been able to readily transmit and have rapidly disappeared.

Clinical experience in Norway and elsewhere suggests that people who become ill with an oseltamivir resistant strain of A(H1N1) have a similar spectrum of illness to those infected with ?normal? seasonal influenza A which can cause severe disease or death in vulnerable people (older people, those with debilitating illnesses and the very young).

This is now being investigated in national studies and international studies coordinated by ECDC.

At this stage the significance of these findings remains uncertain. The emergence of drug resistance in the context of limited drug use is unexpected, and the extent of future circulation is difficult to predict.

ECDC, WHO, EISS, VIRGIL and authorities in the member states are undertaking intensive surveillance and progress will be reported through this and other relevant web-pages. A summary of the arrangements for the EU EEA & EFTA Countries is on the ECDC web-site http://ecdc.europa.eu/Health_topics/..._seasonal.html this is also available in a pdf version as a briefing for policy makers in the EU and EEA/EFTA Member States http://ecdc.europa.eu/Health_topics/..._EU_%20EEA.pdf

For information on seasonal influenza and how to protect yourself against it http://ecdc.europa.eu/Health_topics/...nza/facts.html.

Data were provided by the European Influenza Surveillance Scheme http://www.eiss.org/index.cgi and the VIRGIL Project http://www.virgil-net.org/ ECDC would like to thank all countries, virologists, clinicians and others for contributing data. Funding for the VIRGIL project comes from the European Union FP6 Research Programme.
-

http://www.ecdc.europa.eu

----------

[gsgs]

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

new 2008-sequences were uploaded to genbank.
But most were from USA, little from Europe.
There was an unclear statement frm ECDC that Tamiflu-resistence
might have happened in 2 genetically different backgrounds of H1N1,
which would be strong evidence for resistance development
because of drug use.
But all published sequences from this year are so far from the same
background and almost all are very similar.

mutation table:

http://www.setbb.com/fluwiki2/viewtopic.php?p=913

(list only complete for 2008)

the critical mutation is C0823T (H274Y in protein),
the critical group of resistant sequences is 47-71

strains:
Brisbane:1-122
Solomon:161-163
Hawaii:164-179
Caledonia:123-160

so, considering NA only, I'd say that 42 uploaded US-H1N1 viruses
from 2008 are Brisbane (11 of these have H274Y) and 2 Hawaii.


CDC gives: (for HA)

267 (68&#37 of the 395 H1N1 viruses were characterized as A/Solomon Islands/3/2006-like
108 (27%) of the 395 viruses were characterized as A/Brisbane/59/2007-like.
20 (5%) of the 395 viruses were different


for HA I get: (USA,H1N1,2008)
Brisbane:~100
Hawaii:~12

I don't have any 2008 US-H1N1-HA which I would classify
as Solomon rather than Brisbane, so this is mysterious to me

[HenryN]

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

More Tamiflu resistant isolates at Genabnk

gb|EU779650.1| Influenza A virus (A/North Carolina/02/2008(H1... 26.3 593
gb|EU779643.1| Influenza A virus (A/New Jersey/10/2008(H1N1))... 26.3 593
gb|EU779641.1| Influenza A virus (A/Memphis/03/2008(H1N1)) ne... 26.3 593