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100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
Excerpt from WHO update:
(...)
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% 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.
(...)
For full text and tables see at the link listed in the above post.
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
Zimbabwe flu outbreak information here
FT Seasonal Flu 2008 - 2009 thread here
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
Tamiflu-Resistant Flu Is `Widespread' in South Africa (Update1)
By Jason Gale
Aug. 22 (Bloomberg) --
Roche Holding AG's Tamiflu may be ineffective in fighting the dominant flu strain in South Africa this winter, with studies showing the highest level of resistance to the drug globally, World Health Organization data show.
Tests on 107 people with the H1N1 strain -- one of the three most common flu viruses in humans -- found all had a mutant bug that's likely to render Roche's medicine ineffective, the Geneva- based WHO said in an Aug. 20 statement.
Only one person was taking Tamiflu at the time of sampling, the WHO said.
``The patients are from across the country, so the resistant strain is widespread,'' Terry Besselaar, director of South Africa's National Influenza Centre in Johannesburg, said in an e- mail today.
Tamiflu-evading flu has been reported in 40 countries in Europe, North and South America, Africa, Asia and Australia since widespread resistance to the pill was first reported to the WHO by Norway in January.
Its emergence has prompted doctors to consider other medicines, such as GlaxoSmithKline Plc's Relenza, to fight a disease that the WHO estimates causes 250,000 to 500,000 deaths annually.
Doctors ``and public health officials would be advised to know that one of their drugs might not be effective or is less effective in treating influenza,'' said Ian Barr, deputy director of the WHO Collaborating Centre for Influenza in Melbourne. Barr's lab tested some of the South African samples.
Roche's medicine, also known by the chemical name oseltamivir, is effective against type B influenza and the H3N2 strain that also commonly causes seasonal flu in humans, according to the WHO.
Bird Flu
Tamiflu is being stockpiled by the 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 15 of them.
During the 2006-07 northern hemisphere winter, less than 1 percent of H1N1 virus samples in the U.S. showed Tamiflu resistance, and no resistant variants were detected in Japan or Europe, according to the WHO. Past studies had also found little evidence of spread of resistant H1N1 virus within the community.
``Laboratory experiments had previously demonstrated that flu viruses that have this mutation are not as fit,'' said Jennifer McKimm-Breschkin, a virologist at the Commonwealth Science and Industrial Research Organization in Melbourne.
``This is why it's a surprise. It's certainly looking like it's a robust enough virus to persist even between flu seasons in the northern and southern hemispheres.''
Tests on 788 samples taken from H1N1 flu patients in 12 countries, mostly in the southern hemisphere, from April 1 to Aug. 20 found that 242, or 31 percent, had the so-called H274Y mutation associated with Tamiflu resistance, the WHO said.
Southern Hemisphere
In the southern hemisphere, incidence of the mutation in tests on the H1N1 virus ranged from 100 percent in South Africa to 13 percent in Chile, according to the WHO.
That compares with a resistance rate of 16 percent found in 7,528 samples tested from the last quarter of 2007 to March 31 in 34 countries, mostly in the northern hemisphere.
``What we're seeing is the evolution of the resistance gene and the distribution of it throughout the world,'' said Lance Jennings, a clinical virologist with the Canterbury District Health Board in Christchurch, New Zealand, who is chairman of the Asia-Pacific Advisory Committee on Influenza.
``We have a lot to learn about the molecular epidemiology of influenza viruses.''
To contact the reporter on this story: Jason Gale in Singapore at j.gale@bloomberg.net
Last Updated: August 22, 2008 03:27 EDT
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http://www.bloomberg.com/apps/news?p...d=aCs9Qp65uMk4
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
What would be of interest as well at this point would be some more information on the Relenza resistant strain(s).
Were they the dominant strain in an influenza sufferer;... the only strain? How severe are the symptoms they cause? How viable are they? How easily transmitted? Has there been an increase in identified cases?
The inference by linking Relenza resistance with H274Y Tamiflu resistance is that they are equally dire. If that's the case I'd like to know so I can factor more prayer into my pandemic planning.
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
Quote:
Originally Posted by miso
What would be of interest as well at this point would be some more information on the Relenza resistant strain(s).
Were they the dominant strain in an influenza sufferer;... the only strain? How severe are the symptoms they cause? How viable are they? How easily transmitted? Has there been an increase in identified cases?
The inference by linking Relenza resistance with H274Y Tamiflu resistance is that they are equally dire. If that's the case I'd like to know so I can factor more prayer into my pandemic planning.
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There isn't cross-resistance between oseltamivir and zanamivir. Thus, H1N1 with oseltamivir resistant motif retains sensitivity to zanamivir and vice-versa.
To date, clinical pattern of H1N1-oseltamivir-resistant seasonal human influenza strains mimic usual mild-self-limiting influenza-like illness, at least according WHO statements.
That said, it is possible that further clinical features will be highlighted in the near future, as investigation on the cases will proceed.
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
Quote:
Originally Posted by niman
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Commentary
100% H1N1 Tamiflu Resistance in Australia and South Africa
Recombinomics Commentary 21:44
August 21, 2008
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% were found to be resistant to oseltamivir by genotypic analysis.
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.
The above comments suggest that Tamiflu (oseltamivir) resistance (H274Y) is running at 100% in South Africa and Australia, strongly suggesting that similar levels will be seen in the upcoming flu season in the northern hemisphere.
The latest update extends earlier results from South Africa, which included analysis of the first 23 isolates. All contained H274Y, which was confirmed by the release of 16 HA and NA sequences. The sequences fell into two sub-clades and one of the sub-clades had 5 clustered polymorphisms near the receptor binding domain position of 190 (H3 numbering). Three of these five changes were non-synonymous, raising concerns that the H1 was rapidly evolving away from the Brisbane/59 sequences, which are the target of the northern hemisphere vaccine, which will be released in the next few months. Moreover, the two polymorphisms from the 3’ side of the cluster matched H1N1 sequences from the 1940’s
The detection of H274Y in all 107 isolates sequenced, coupled with 100% in Australian isolates, indicates that those isolates with H274Y are becoming dominant. These sequences may be linked to recent reports of high frequency pneumonia levels in Zimbabwe.
More information of the severity of the H1N1 cases in South Africa and Australia would be useful.
.
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
Thanks for the quick response ironorehopper.
My post was enquiring more in the line of " So you've announced there's a new bomb threat on the train,... is it also a couple of pounds of C4, or is it a Chinese New Year's cracker?"
Edit: Probably not the best metaphor but I'd really like to know more that "there are Relenza resistant strains too"
Last edited by miso; August 22nd, 2008 at 05:49 AM.
Reason: Clarification
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
Quote:
Originally Posted by ironorehopper
There isn't cross-resistance between oseltamivir and zanamivir. Thus, H1N1 with oseltamivir resistant motif retains sensitivity to zanamivir and vice-versa.
To date, clinical pattern of H1N1-oseltamivir-resistant seasonal human influenza strains mimic usual mild-self-limiting influenza-like illness, at least according WHO statements.
That said, it is possible that further clinical features will be highlighted in the near future, as investigation on the cases will proceed.
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The Relenza resistance is on the same Brisbane/59 genetic background (but at a much lower frequency).
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
The spread of H274Y will be included in the Keynote address in Beijing
http://www.recombinomics.com/presentations.html
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August 22nd, 2008, 11:15 AM
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
[ECDC] 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 be updated only 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
European Data Updated 7th August 2008 , Global Data August 20th – next update at the end of August
In late January 2008, antiviral drug susceptibility surveillance of seasonal influenza viruses was carried 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.
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.
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 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 was 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) weekly update as well as in Influenza News.
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) are currently assessing the significance of the data from the EISS VIRGIL network.
An interim European risk assessment has been published by ECDC 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.
The latest data were posted on August 20th http://www.who.int/csr/disease/influ...0082008_kf.pdf and now WHO is showing data separately for the 2007/8 winter season (Last Quarter 2007 to March 2008) and the 2008 season (Table 1 Second Quarter 2008 to August 20th).
At the global level the most recent notable finding was from South Africa where now all 107 influenza A/H1N1 specimens gathered since the start of the second Quarter 2008 showed the marker of resistance.
Their findings have been confirmed by WHO Collaborating Centres.
To date there have been 136 specimens influenza A/H1N1 specimens tested from WHO’s Africa Region but only nine of these have shown the markers of resistance apart from those from South Africa.
Other significant national proportions of A/H1N1 specimens for the Southern Hemisphere or Equatorial regions showing resistance for which there are data are from Australia (10 out of 10), Chile (4 out of 13), Argentina (2 out of 5) and the Hong Kong Region of China 97 out of 483 (17%). These are the first of these viruses reported from the Southern Cone of South America.
Looking back to the earlier period (Quarter 4 2007 to end of Quarter 1 2008 equivalent to the Northern Hemisphere winter season where there are data on more than 50 specimens the results are: 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).
As well as the WHO monthly table. WHO is publishing less frequent analytic summaries on the WHO web-site.
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.
These data are interesting because they firstly indicate that these A(H1N1) viruses are not going away and also that they seem to be following the pattern suggested for A(H3N2) viruses of spreading eventually to even the Southern Cone of South America.(1)
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 http://ecdc.europa.eu/Health_topics/..._seasonal.html is on the ECDC web-site this is also available in a pdf version as a briefing for policy makers http://ecdc.europa.eu/Health_topics/..._seasonal.html in the EU and EEA/EFTA Member States
1. Russell C, Jones T, Barr I et al The global circulation of seasonal influenza A (H3N2) viruses Science 2008; 320 340-6. http://www.sciencemag.org/cgi/conten...i;320/5874/340
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
Information on Antivirals and Antiviral Resistance http://ecdc.europa.eu/Health_topics/...ntivirals.html
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http://ecdc.europa.eu/Health_topics/...ntivirals.html
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
Tamiflu-Resistant Flu Is `Widespread' in South Africa (Update3)
By Jason Gale
Aug. 22 (Bloomberg) --
Roche Holding AG's Tamiflu may be ineffective in fighting this winter's dominant flu strain in South Africa, where studies found the highest level of resistance to the drug globally, World Health Organization data show.
Tests on 107 people with the H1N1 strain -- one of the three most common flu viruses in humans -- found all had a mutant bug that's likely to render Roche's medicine ineffective, the Geneva- based WHO said in an Aug. 20 statement. Only one person was taking Tamiflu at the time of sampling, the WHO said.
``The patients are from across the country, so the resistant strain is widespread,'' Terry Besselaar, director of South Africa's National Influenza Centre in Johannesburg, said in an e- mail today.
Tamiflu-evading flu has been reported in 40 countries in Europe, North and South America, Africa, Asia and Australia since widespread resistance to the pill was first reported to the WHO by Norway in January.
Its emergence has prompted doctors to consider other medicines, such as GlaxoSmithKline Plc's Relenza, to fight a disease that the WHO estimates causes 250,000 to 500,000 deaths annually.
Doctors ``and public health officials would be advised to know that one of their drugs might not be effective or is less effective in treating influenza,'' said Ian Barr, deputy director of the WHO Collaborating Centre for Influenza in Melbourne. Barr's lab tested some of the South African samples.
`Special Mutation'
``H1N1 is a seasonal influenza strain, and the H5N1 avian influenza strain remains sensitive to Tamiflu, so its stockpiling by governments remains appropriate,'' Roche spokeswoman Claudia Schmitt said in a telephone interview.
``It's a special mutation which was also observed in Norway, so you can't say that the use of Tamiflu led to the resistance.''
Roche plans to conduct a resistance surveillance study to collect information on both the sensitive and resistant influenza infections during the 2008-2009 flu season, Schmitt said.
Glaxo spokeswoman Claire Brough said the need to augment stockpiles to account for the possibility of resistant strains has been highlighted before, and is unlikely to change current demand. Stockpiling decisions in the future may boost demand, she said.
Roche's medicine, also known by the chemical name oseltamivir, is effective against type B influenza and the H3N2 strain that also commonly causes seasonal flu in people, according to the WHO.
Tamiflu Stockpiles
Tamiflu is being stockpiled by the 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 15 of them.
During the 2006-07 northern hemisphere winter, less than 1 percent of H1N1 virus samples in the U.S. showed Tamiflu resistance, and no resistant variants were detected in Japan or Europe, according to the WHO. Past studies had also found little evidence of spread of resistant H1N1 virus within the community.
``Laboratory experiments had previously demonstrated that flu viruses that have this mutation are not as fit,'' said Jennifer McKimm-Breschkin, a virologist at the Commonwealth Science and Industrial Research Organization in Melbourne.
``This is why it's a surprise. It's certainly looking like it's a robust enough virus to persist even between flu seasons in the northern and southern hemispheres.''
There is no evidence that the resistant viruses are causing more or less severe illness than other flu viruses, according to the WHO.
788 Samples
Tests on 788 samples taken from H1N1 flu patients in 12 countries, mostly in the southern hemisphere, from April 1 to Aug. 20 found that 242, or 31 percent, had the so-called H274Y mutation associated with Tamiflu resistance, the WHO said.
In the southern hemisphere, incidence of the mutation in tests on the H1N1 virus ranged from 100 percent in South Africa to 13 percent in Chile, according to the WHO.
That compares with a resistance rate of 16 percent found in 7,528 samples tested from the last quarter of 2007 to March 31 in 34 countries, mostly in the northern hemisphere.
``At this stage the significance of these findings remains uncertain,'' the European Centre for Disease Prevention and Control in Stockholm said in a statement today.
``The emergence of drug resistance in the context of limited drug use is unexpected, and the extent of future circulation is difficult to predict.''
There is no evidence that the appearance of Tamiflu- resistant viruses is related to use of the medicine, which is not widely prescribed in most European countries, the agency said. It's working with Basel, Switzerland-based Roche and national authorities to gather more information on routine Tamiflu use in Europe, ECDC said.
``What we're seeing is the evolution of the resistance gene and the distribution of it throughout the world,'' said Lance Jennings, a clinical virologist with the Canterbury District Health Board in Christchurch, New Zealand, who is chairman of the Asia-Pacific Advisory Committee on Influenza. ``We have a lot to learn about the molecular epidemiology of influenza viruses.''
To contact the reporter on this story: Jason Gale in Singapore at j.gale@bloomberg.net
Last Updated: August 22, 2008 10:15 EDT
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http://www.bloomberg.com/apps/news?p...d=aYJ463xrY_Oo
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
Quote:
Originally Posted by niman
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Commentary
Global Spread of H1N1 Tamiflu Resistance
Recombinomics Commentary 11:44
August 22, 2008
``The patients are from across the country, so the resistant strain is widespread,'' Terry Besselaar, director of South Africa's National Influenza Centre in Johannesburg, said in an e- mail today.
The above comments on Tamiflu (oseltamivir) resistance in H1N1 in South Africa represent a small subset of Tamiflu resistance spreading globally. Earlier reports on H1N1 in South Africa indicated that 23 of 23 H1N1 isolates had H274Y. Sequence data from these early isolates indicated all isolates were clade 2B (Brisbane/59), but the isolates fell into two sub-clades. The larger sub-clade had the same background as the dominant sequences in northern Europe and the United States reported in the 2007 / 2008 season. However, the South African isolates had a cluster of 5 polymorphisms on both sides of the receptor binding domain position 190 (using H3 numbers). One of the polymorphisms (G617A) was present on a subset of isolates from the United States and Europe. It had been in circulation in H1N1 isolates from the 1940’s. The polymorphism adjacent to this change (C610T) was also present on H1N1 isolates from the 1940’s, demonstrating sequential acquisition of adjacent polymorphisms via homologous recombination. These clustered changes will likely reduce the effectiveness of the northern hemisphere vaccine which will be introduced in the upcoming months and targets Brisbane/59.
However, H274Y is much more widespread the isolates in South Africa. All 10 of the H1N1 isolates from Australia this season also have H274Y. Similarly, recent data from a number of countries are reporting high frequencies of H274Y. Although the number of samples is low, H274Y is also being reported at 100% in Cameroon in west Africa and Montserrat in the Caribbean. High levels (5 of 8) are also being reported for the Seychelles off the coast of east Africa. Early reports on increased pneumonia rates have also been reported in nearby countries, including Zimbabwe in Africa as well as Honduras and Nicaragua in central America, raise concerns that these additional cases are also due to oseltamivir resistant H1N1.
The dramatic spread of H274Y is largely linked to its increased fixation on the Brisbane/59 strain which accounts for virtually all recent cases outside of Asia. H274Y was initially reported on New Caledonia (clade 1) in the United States and Hong Kong (clade 2C) in China, but the global spread has been fueled by clade 2B and involved multiple introductions. The initial sequence data from South Africa which has three non-synonymous changes flanking the receptor binding domain position 190 (N187S, G189A, A193T), raises concerns that the new northern hemisphere H1N1 vaccine will have limited utility, and Tamiflu resistance will continue on a global expansion.
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__________________
"The next major advancement in the health of American people will be determined by what the individual is willing to do for himself"-- John Knowles, Former President of the Rockefeller Foundation
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August 23rd, 2008, 01:56 PM
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Editor, Senior Moderator
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
Quote:
Originally Posted by niman
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Commentary
Recombination Drives Global Spread of H1N1 Tamiflu Resistance
Recombinomics Commentary 09:11
August 23, 2008
``What we're seeing is the evolution of the resistance gene and the distribution of it throughout the world,'' said Lance Jennings, a clinical virologist with the Canterbury District Health Board in Christchurch, New Zealand, who is chairman of the Asia-Pacific Advisory Committee on Influenza.
``We have a lot to learn about the molecular epidemiology of influenza viruses.''
The above comments on the dramatic emergence of oseltamivir (Tamiflu) resistance in H1N1 reflect the current state of confusion among those trying to understand the spread, based on the out-dated paradigm of selection of random mutations as a mechanism of antigenic drift. The application of this paradigm to antiviral resistance is conceptually straightforward, since the drug creates a strong selection pressure for the emergence of resistance.
Early reports on one such change, NA H274Y, indicated that this resistance would be limited to patients receiving oseltamivir. Although H274Y was said to generate significant resistance to the drug, influenza with H274Y would not be evolutionarily fit and would not compete favorably with wild type influenza in patients not receiving oseltamivir.
Initial data on H274Y seemed to support this paradigm, as initial reports of the emergence of H274Y was limited to patients in Vietnam who were being treated with Tamiflu, including one patient receiving a sub-optimal prophylactic dose in 2005, as well as a patient in Indonesia who stopped taking a treatment dose in 2006.
However, reports of H274Y in H5N1 in isolates from wild birds in late 2005 demonstrated that H274Y could compete with wild type H5N1 in hosts not taking oseltamivir.
The report of H274Y in H5N1 was then followed by H274Y in H1N1 in seasonal flu cases in the United States at the beginning of the 2006 season. These cases involved the dominant strain in the United States at the time, New Caledonia, which was clade 1. Similarly, in 2006 H274Y was also present in the Hong Kong strain (clade 2C) in China. In both cases, the resistance was found in patients who had not been receiving oseltamivir, demonstrating that H274Y was evolutionarily fit on two distinct H1N1 genetic backgrounds, although these isolates shared a region of identity adjacent to the polymorphisms, supporting distribution of the polymorphism via homologous recombination.
At the beginning of the 2007 season in the northern hemisphere, H274Y jumped to another H1N1 genetic background, Brisbane/59 (clade 2B) in Hawaii in the United States. These isolates were closely related to other isolates from Hawaii, but acquired H274Y and also matched the clade 1 and clade 2C sequences on the 3’ side of the acquisition. This acquisition was followed by a jump to another version of clade 2B, which became the dominant oseltamivir strain in the United States, and became the dominant H1N1 strain in Norway, where the high frequency caught the attention of surveillance groups. The presence o f H274Y on the “northern European” H1N1 background led to widespread reports of high frequencies of H274Y in early 2008.
Thus, the H274Y polymorphism was evolutionarily fit on a number of genetic backgrounds, including H5N1 in wild birds in 2005, followed by H1N1 on clade 1 and clade 2C in 2006, and the dramatic spread onto multiple versions of clade 2B in the 2007/2008 season.
Moreover, at the time of clade 2B expansion, the H1N1 vaccine target switched from clade 1 to clade 2A (Solomon Islands/3). However, in the 2007/2008 season Solomon Island had virtually disappeared, and there were no reports of H274Y on a Solomon Island genetic background. Therefore the mismatched H1N1 would have reduced effectiveness in blunting the spread of H274Y, and may have accelerated the H1N1 evolution away from the vaccine..
Recent reports of H274Y in the 2008 season in the southern hemisphere include multiple countries where H274Y is being reported on 100% of H1N1 isolates. The first sequences from a country with 100% resistance are from South Africa, where the first 107 H1N1 isolates have H274Y. The dominant sequence from South Africa has a cluster of five polymorphisms near position 190 (H3 numbering) in the receptor binding domain. One of these changes was seen earlier in the “northern European” lineage, and is also present in H1N1 from the 1940’s. The adjacent polymorphism, which is only in the South African isolates, is also in H1N1 isolates from the 1940’s further supporting acquisitions via homologous recombination.
The polymorphisms jumping from one genetic background to another, followed by expansion of the dominant strain, was reported earlier for a polymorphism on NA of H5N1, G743A. The spread of this polymorphism is also dramatic, in the absence of obvious selection, because it is synonymous and therefore does not change the NA sequence.
Like H274Y, G743A was initially reported on multiple genetic backgrounds (all major H5N1 sub-clades). The spread of clade 2.2 out of China in 2005 allowed for further analysis of G743A. In 2006 the polymorphisms was almost exclusively limited to one clade 2.2 sub-clade found in a limited geographical area (southern Germany, northern Switzerland and eastern France).
In early 2007, it appeared in bird isolates in the Nile Delta. The H5N1 in Egypt was well defined by 2006 isolates, which began to diversify in the 2006/2007 season. G743A appeared in multiple isolates in February in the Nile Delta. Plaque purified clones of isolates from one of the birds demonstrated that there were two readily distinguishable sub-clades and both had acquired G743A, which would have been difficult to explain by random mutations, because the parental sequences were present in 2006, and the number of new acquisitions on each background was limited, but included G743A in both instances. Shortly thereafter G743A appeared on additional genetic backgrounds in Egypt, including human isolates in southern Egypt, virtually eliminating the chances of coincidental copy errors on multiple isolates at the same time.
However, the G743A acquisitions were not limited to multiple H5N1 genetic backgrounds in Egypt. At the same time there was a H5N1 outbreak in Moscow and those sequences were closely related to clade 2.2.3 sequences which had been found in Azerbaijan in 2006, without G743A. However, the isoaltes from early 2007 had G743A.
The polymorphism also appeared on another clade 2.2.3 background in Kuwait. This clade 2.2.3 was the Uvs Lake strain which emerged in the summer of 2006 at Uvs lake in Mongolia. This H5N1, which evolved from a massive wild bird outbreak in Mongolai and Russia migrated to South Korea and Japan in late 2006 and none of the isolates had G743A. However, this genetic background acquired G743A in early 2007 in Kuwait.
The same scenario played out in western Africa. G743A was found in isolates in Ghana on an H5N1 genetic background that had been reported in 2006 in the Ivory Coast. G743 was also on another genetic background related to the H5N1 found in the first human H5N1 case in Nigeria. The presence of G743A is a subset of these related sequences in Nigeria also signaled acquisitions in early 2007.
These outbreaks in early 2007 were followed by outbreaks in Europe, beginning in the summer of 2007. These isolates were the Uvs Lake strain, which became dominant in Europe, and all reported sequences had G743A. Recently the Uvs Lake strain was reported in Nigeria for the first time, and it is likely that G743A will be reported in those sequences also.
Thus, the concurrent acquisition of G743A on multiple genetic backgrounds, and emergence on the dominant strain in Europe, parallels to emergence and spread of H274Y on H1N1 season flu. Neither polymorphism generated clear selection advantages in the avina or human hosts, but became fixed in the dominant clade in circulation, leading to dramatic spread.
These examples of genetic background jumping via homologous recombination are common, and the two examples above illustrate such acquisitions of single nucleotide polymorphism. This mechanism is the primary driver of influenza evolution and represents a paradigm shift.
These examples will be included in a keynote address to the drug discovery meeting in Beijing in the fall.
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__________________
"The next major advancement in the health of American people will be determined by what the individual is willing to do for himself"-- John Knowles, Former President of the Rockefeller Foundation
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August 25th, 2008, 08:31 PM
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
INFLUENZA A (H1N1) VIRUS, OSELTAMIVIR RESISTANCE (06): SOUTHERN HEMISPHERE
************************************************** ************************
A ProMED-mail post
< http://www.promedmail.org>
ProMED-mail is a program of the
International Society for Infectious Diseases
< http://www.isid.org>
Date: Mon 25 Aug 2008
Source: stuff.co.nz, New Zealand Press Association (NZPA) report [edited]
< http://www.stuff.co.nz/4667440a11.html>
Tamiflu [oseltamivir] resistant forms of the "ordinary" seasonal
influenza are rapidly spreading and the drug may be ineffective in
fighting the dominant flu strain in South Africa this winter
[2008-2009]. World Health Organisation (WHO) data show tests on 107
people in South Africa with the H1N1 strain, one of the 3 most common
flu viruses in humans, found all had a mutant [virus] resistant to
Tamiflu. Only one patient was taking Tamiflu at the time.
Tests on 788 samples taken from H1N1 flu patients in 12 countries,
mostly in the southern hemisphere, from 1 Apr to 20 Aug 2008 found
that 242, or 31 percent, had the H274Y mutation [in the neuraminidase
protein gene] associated with Tamiflu resistance, the WHO said.
Southern hemisphere incidence of the mutation in tests on the H1N1
virus ranged from 100 percent in South Africa to 13 percent in Chile,
compared with a resistance rate of 16 percent found in 7528 samples
tested from the last quarter of 2007 to [31 Mar 2008] in 34
countries, mostly in the northern hemisphere.
"What we're seeing is the [spread] of the resistance gene and the
distribution of it throughout the world," said Lance Jennings, a
clinical virologist with the Canterbury District Health Board [New
Zealand], who is chairman of the Asia-Pacific Advisory Committee on
Influenza. "We have a lot to learn about the molecular epidemiology
of influenza viruses." The Tamiflu-resistant form of flu has been
reported in 40 countries in Europe, North and South America, Africa,
Asia, and Australia since widespread resistance to the [drug] was
first reported to the WHO by Norway in January [2007].
Until bird flu vaccines are developed for the specific pandemic
influenza virus once it evolves and starts spreading, work likely to
take 3 months or more, Tamiflu and another retroviral treatment,
Relenza, are the main medical weapons to battle pandemic flu. Tamiflu
is being stockpiled by the WHO and governments around the world for
use in the event of a pandemic, and to treat the H5N1 avian flu
strain that has infected humans in 15 of the 60 countries to which it
has spread.
Last year [2007], Swedish researchers warned that sewage systems do
not break down Tamiflu, and that the drug was being discharged in
rivers and streams used by the waterfowl thought to be the main
carriers of avian flu. They urged doctors not to over-prescribe
Tamiflu to avoid creating resistance in avian flu carried by ducks.
If those viruses combined with other viruses that made humans sick
they could mutate into strains resistant to Tamiflu, they said early
in 2007.
Health Minister David Cunliffe said this year [2008] that 103 of the
1229 treatment courses of Tamiflu the Government had bought at a cost
of [USD] 300 000 had reached their expiry dates.
--
Communicated by:
ProMED-mail Rapporteur Mary Marshall
[Oseltamivir (brand name Tamiflu) is a medication that decreases the
spread of influenza A and B viruses. Neuraminidase is an enzyme that
enables the influenza virus to spread from infected cells to healthy
cells. Oseltamivir blocks the action of neuraminidase (that is,
Tamiflu is a neuraminidase inhibitor) thereby reducing the spread of
influenza. By preventing the spread of virus from cell to cell, the
symptoms and duration of influenza infection are reduced. On average,
oseltamivir reduces the duration of symptoms by one and a half days
if treatment is started within 48 hours after symptoms begin.
Thereafter it becomes less effective.
As far as is known Tamiflu-resistant influenza A virus does not
exhibit any enhanced or decreased virulence.
The final paragraph of the report above reveals a weakness inherent
in the strategy of maintaining stockpiles of Tamiflu to combat
seasonal and avian influenza; namely, the drug has a limited shelf
life. - Mod.CP]
[see also:
Influenza A (H1N1) virus, oseltamivir resistance (05): China (HK)
20080203.0438
Influenza A (H1N1) virus, oseltamivir resistance (04): CA, USA 20080202.0428
Influenza A (H1N1) virus, oseltamivir resistance (03): corr. 20080203.0430
Influenza A (H1N1) virus, oseltamivir resistance (03) 20080201.0399
Influenza A (H1N1) virus, oseltamivir resistance (02): Europe 20080129.0371
Influenza A (H1N1) virus, oseltamivir resistance - Norway 20080128.0361
2007
----
Avian influenza, human (101): Indonesia, Tamiflu resistance 20070622.2021
Influenza B virus, neuraminidase inhibitor resistance 20070404.1143
Avian influenza, human (15): Egypt, drug resistance 20070119.0253
Avian influenza, human (15): Egypt, drug resistance 20070118.0238
2006
----
Avian influenza, human (162): oseltamivir resistance 20061010.2907
2005
----
Avian influenza, human - East Asia (203): Tamiflu resistance 20051222.3659
Influenza viruses, drug resistance (06) 20051016.3021
Influenza viruses, drug resistance (05) 20051015.3014
Influenza viruses, drug resistance (04) 20051015.2999
Influenza viruses, drug resistance (03) 20051007.2924
Influenza viruses, drug resistance (02): RFI 20051001.2878
Influenza viruses, drug resistance 20050930.2863
2004
----
Avian influenza A (H5N1) virus, drug resistance (02) 20040127.0316
Avian influenza A (H5N1) virus, drug resistance 20040125.0298
2001
----
Influenza virus, neuraminidase inhibitor resistance (02) 20010928.2372
Influenza virus, neuraminidase inhibitor resistance 20010926.2350]
........................................cp/mj/jw
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August 25th, 2008, 08:32 PM
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
Quote:
Originally Posted by niman
INFLUENZA A (H1N1) VIRUS, OSELTAMIVIR RESISTANCE (06): SOUTHERN HEMISPHERE
************************************************** ************************
[Oseltamivir (brand name Tamiflu) is a medication that decreases the
spread of influenza A and B viruses. Neuraminidase is an enzyme that
enables the influenza virus to spread from infected cells to healthy
cells. Oseltamivir blocks the action of neuraminidase (that is,
Tamiflu is a neuraminidase inhibitor) thereby reducing the spread of
influenza. By preventing the spread of virus from cell to cell, the
symptoms and duration of influenza infection are reduced. On average,
oseltamivir reduces the duration of symptoms by one and a half days
if treatment is started within 48 hours after symptoms begin.
Thereafter it becomes less effective.
As far as is known Tamiflu-resistant influenza A virus does not
exhibit any enhanced or decreased virulence.
The final paragraph of the report above reveals a weakness inherent
in the strategy of maintaining stockpiles of Tamiflu to combat
seasonal and avian influenza; namely, the drug has a limited shelf
life. - Mod.CP]
...................................cp/mj/jw
*################################################# #########*
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More detailed analysis from CP.
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August 26th, 2008, 09:58 AM
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
H1N1 flu viruses growing more resistant to Tamiflu
By Robert Roos
CIDRAP News Editor
Aug 25, 2008 (CIDRAP News) – With influenza season well under way in the southern hemisphere, one of the three kinds of seasonal influenza virus is becoming increasingly resistant to the antiviral drug oseltamivir (Tamiflu), the World Health Organization (WHO) reported last week.
Thirty-one percent (242 of 788) of influenza A/H1N1 isolates from 16 countries that were tested in recent months carried a mutation associated with oseltamivir resistance, the WHO said. In South Africa, all of the 107 isolates tested had this mutation, known as H274Y, the agency reported.
Other countries and areas that tested 10 or more isolates and found resistance included Australia, 100% (10 of 10 isolates); Ghana, 20% (2 of 10) Hong Kong, 17% (97 of 583); and Chile, 13% (4 of 32 isolates).
The findings strengthen a trend that that was first observed last January in Norway and subsequently in many other countries. Overall for the last quarter of 2007 and the first quarter of this year, 16% (1,182 of 7,528) of tested H1N1 isolates carried the resistance mutation, according to WHO figures. Resistance was found in 35 countries, mostly in the northern hemisphere, including in 12% of tested US isolates and 26% of tested Canadian isolates.
"What we're seeing is the evolution of the resistance gene and the distribution of it throughout the world," said Lance Jennings, a clinical virologist with the Canterbury District Health Board in Christchurch, New Zealand, and chair of the Asia-Pacific Advisory Committee on Influenza, as quoted in an Aug 22 Bloomberg News report.
In South Africa, Terry Besselaar, director of the National Influenza Centre in Johannesburg, said, "The patients are from across the country, so the resistant strain is widespread," according to the Bloomberg report.
The WHO said only 1 of the 107 patients in South Africa was taking oseltamivir, and no unusual clinical features or underlying conditions were found.
No increase in oseltamivir resistance has been reported in the other two types of seasonal flu viruses, A/H3N2 and B. Recent WHO updates have not indicated which types are most common overall in the southern hemisphere this season, but the Aug 20 statement said flu was widespread in New Zealand, with H3 and B viruses predominant. The statement also cited sporadic flu activity in Argentina, with H1 viruses most common.
Many countries have stockpiled oseltamivir, which is used to treat people infected with the H5N1 avian flu virus and is generally considered the most promising antiviral to use in case H5N1 evolves into a human pandemic strain. The WHO statement did not mention any reports of resistance to zanamivir (Relenza), the other drug in the neuraminidase inhibitor class.
A spokeswoman for Roche, the maker of Tamiflu, said H5N1 viruses remain sensitive to the drug, according to the Bloomberg report. The spokeswoman, Claudia Schmitt, said the company plans to conduct surveillance on resistant and susceptible flu viruses during the 2008-09 flu season.
In a summary of H1N1 resistance to oseltamivir in the the 2007-08 flu season, the WHO said in June that no link between "oseltamivir exposure and resistance at the individual patient level was noted."
The increasing oseltamivir resistance in H1N1 viruses has puzzled experts. In an editorial published by Eurosurveillance in January, authorities said resistant viruses with the H274Y mutation had been seen in previous flu seasons but were rare and did not spread easily. But the more recent H1N1 isolates with the mutation were "fitter" and were spreading in the community, they wrote.
A recent update by the European Centre for Disease Prevention and Control (ECDC) observed, "At this stage the significance of these [resistance] 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."
See also:
Aug 20 WHO statement
http://www.who.int/csr/disease/influenza/H1N1webupdate20082008_kf.pdf
Aug 14 WHO update on global flu activity
http://www.who.int/csr/disease/influenza/update/en/index.html
Jun 13 WHO statement on H1N1 oseltamivir resistance in 2007-08 season
http://www.who.int/csr/disease/influenza/oseltamivir_summary/en/index.html
ECDC update
http://ecdc.europa.eu/en/Health_Topics/influenza/news/news_Influenza_080821.aspx#oseltamivir
Feb 1 CIDRAP News story " Europe says Tamiflu-resistant virus seen in 9 countries"
Provided by the Center for Infectious Disease Research and Policy (CIDRAP), University of Minnesota. © 2002-2008 Regents of the University of Minnesota.
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August 26th, 2008, 11:08 AM
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
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August 28th, 2008, 05:27 AM
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
Quote:
Originally Posted by niman
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Commentary
Dramatic Spread of H1N1 Tamiflu Resistance Puzzles Experts
Recombinomics Commentary 15:47
August 26, 2008
In a summary of H1N1 resistance to oseltamivir in the the 2007-08 flu season, the WHO said in June that no link between "oseltamivir exposure and resistance at the individual patient level was noted."
The increasing oseltamivir resistance in H1N1 viruses has puzzled experts. In an editorial published by Eurosurveillance in January, authorities said resistant viruses with the H274Y mutation had been seen in previous flu seasons but were rare and did not spread easily. But the more recent H1N1 isolates with the mutation were "fitter" and were spreading in the community, they wrote.
A recent update by the European Centre for Disease Prevention and Control (ECDC) observed, "At this stage the significance of these [resistance] 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."
The above summaries at the end of the most recent CIDRAP report on the spreading Tamiflu resistance, highlight the confusion linked to the reliance of influenza “experts” on a dying paradigm which uses selection of random mutations to explain antigenic drift in influenza. Consequently there is little understanding of how the resistance became widespread, and why it is unlikely that the trend will significantly reverse in the upcoming season.
The history of the emergence clearly demonstrates that the increasing dominance violates the old paradigm, leading to the conclusion that the recent isolates with H274Y are fit. However, the lack of the expected selection by Tamiflu use is the most striking aspect of they spread, as is the failure to look at the origins of the outbreak.
The earlier cases are largely ignored, even though the earlier cases were also in patients who had not taken recent Tamiflu. This condition applies to the wild birds infected with H5N1 in 2005, the clade 2C infected patients in China in the 2005/2006 season, the clade 1 infected patients in the United States in 2006/2007, or the early clade 2B patients in Hawaii in 2007/2008, which includes the region of identity downstream from the H274Y acquisition in all of the above human isolates.
The dramatic spread was not on the radar screen when the earlier cases were infected. Widespread discussion began after the rate in Norway exceeded 50%, as reported at the beginning of this year. All cases were H1N1, had the identical genetic change leading to H274Y, and were in patients not taking Tamiflu.
However, the failure to recognize the role of recombination in moving single nucleotide polymorphisms from one genetic background to another created more confusion. The concept of H274Y moving from a clade 2C background in China, to a clade 1 background in the US to a clade 2B background in the US, followed by movement to the dominant clade 2B background violated the random mutation aspect of the paradigm, and therefore was discounted.
Similarly, the reliance of poor reference anti-sera and target led to a misclassification of the H1N1 clades. In the past season the H1N1 vaccine target switched from New Caledonia (clade 1) to Solomon Island (clade 2A), but both targets had dead ended and were no longer in circulation. Instead they had been replaced by Brisbane/59 (clade 2B) and Hong Kong 2652 (clade 2C). However, Brisbane/59 was being called Solomon Island-like and Hong Kong 2652 was called New Caledonia-like, creating an illusion that the H1N1 was a match, when in fact it was a mismatch. Later in the season, classification of new Brisbane/59-like isolates were corrected, creating a second illusion, that Solomon Island was being replace by Brisbane during the season, when in fact Solomon Island was not in circulation anywhere in 2007/2008 and most countries were misreporting Brisbane as Solomon Island-like. Brisbane/59 grown on mammalian MDCK cells demonstrated the striking differences between immune recognition of Brisbane/59 and the target of the vaccine, Solomon Island/3. Mammalian Brisbane/59 generated a titer of 320 against the Brisbane anti-sera, which dropped to 40 for Hong Kong 2652, and was below the detection limits for Solomon Island/3 (and New Caledonia/20). Thus, the use of a New Caledonia target in 2006/2007 and Solomon Island/3 in 2007/2008 helped establish Brisbane/29-like as the dominant H1N1 strain in circulation, including the subset with H274Y.
The most recent sequences from South Africa had a cluster of additional changes near the receptor binding domain (position 190 in H3 numbering), raising concerns that the role out of the new trivalent vaccine, which includes Brisbane/59 as the new H1N1 target, will have limited utility, pushing the evolution of H1N1 carrying H274Y.
This evolution was supported by the Tamiflu resistance level of 100% in South Africa and Australia this season.
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"The next major advancement in the health of American people will be determined by what the individual is willing to do for himself"-- John Knowles, Former President of the Rockefeller Foundation
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
| 21: CY034601 | 
Reports |
| Influenza A virus (A/Germany/AF1975/2008(H1N1)) segment 4 sequence
gi|197323049|gb|CY034601.1|[197323049]
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
| 81: CY034541 |
Reports |
| Influenza A virus (A/Korea/AF1899/2008(H1N1)) segment 4 sequence
gi|197322929|gb|CY034541.1|[197322929]
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
Travel log
H274Y isolates in red bold
H274Y negative in black bold
gb|CY034621.1| Influenza A virus (A/Guatemala/AF1995/2008(H1N... 38.2 0.002
gb|CY034620.1| Influenza A virus (A/Honduras/AF1994/2008(H1N1... 38.2 0.002
gb|CY034619.1| Influenza A virus (A/Honduras/AF1993/2008(H1N1... 38.2 0.002
gb|CY034611.1| Influenza A virus (A/Germany/AF1985/2008(H1N1)... 38.2 0.002
gb|CY034604.1| Influenza A virus (A/Germany/AF1978/2008(H1N1)... 38.2 0.002
gb|CY034597.1| Influenza A virus (A/Germany/AF1971/2008(H1N1)... 38.2 0.002
gb|CY034596.1| Influenza A virus (A/Guatemala/AF1969/2008(H1N... 38.2 0.002
gb|CY034595.1| Influenza A virus (A/Honduras/AF1968/2008(H1N1... 38.2 0.002
gb|CY034591.1| Influenza A virus (A/Colorado/AF1961/2008(H1N1... 38.2 0.002
gb|CY034590.1| Influenza A virus (A/Texas/AF1960/2008(H1N1)) ... 38.2 0.002
gb|CY034589.1| Influenza A virus (A/Nevada/AF1959/2008(H1N1))... 38.2 0.002
gb|CY034583.1| Influenza A virus (A/Texas/AF1953/2008(H1N1)) ... 38.2 0.002
gb|CY034582.1| Influenza A virus (A/Alabama/AF1952/2008(H1N1)... 38.2 0.002
gb|CY034579.1| Influenza A virus (A/Maryland/AF1949/2008(H1N1... 38.2 0.002
gb|CY034554.1| Influenza A virus (A/Washington/AF1915/2008(H1... 38.2 0.002
gb|CY034553.1| Influenza A virus (A/Washington/AF1914/2008(H1... 38.2 0.002
gb|CY034543.1| Influenza A virus (A/Oklahoma/AF1901/2008(H1N1... 38.2 0.002
gb|CY034532.1| Influenza A virus (A/Washington/AF1889/2008(H1... 38.2 0.002
gb|CY034528.1| Influenza A virus (A/Washington/AF1885/2008(H1... 38.2 0.002
gb|CY034526.1| Influenza A virus (A/Washington/AF1883/2008(H1... 38.2 0.002
gb|EU914916.1| Influenza A virus (A/Johannesburg/46/2008(H1N1... 38.2 0.002
gb|EU914915.1| Influenza A virus (A/Johannesburg/35/2008(H1N1... 38.2 0.002
gb|EU914914.1| Influenza A virus (A/Johannesburg/34/2008(H1N1... 38.2 0.002
gb|EU914913.1| Influenza A virus (A/Johannesburg/28/2008(H1N1... 38.2 0.002
gb|EU914912.1| Influenza A virus (A/CapeTown/26/2008(H1N1)) h... 38.2 0.002
gb|EU914911.1| Influenza A virus (A/Johannesburg/25/2008(H1N1... 38.2 0.002
gb|EU914910.1| Influenza A virus (A/Johannesburg/21/2008(H1N1... 38.2 0.002
gb|EU914909.1| Influenza A virus (A/Johannesburg/10/2008(H1N1... 38.2 0.002
gb|EU551846.1| Influenza A virus (A/Paris/1208/2008(H1N1)) he... 38.2 0.002
gb|EU551842.1| Influenza A virus (A/Paris/1154/2008(H1N1)) he... 38.2 0.002
gb|EU551836.1| Influenza A virus (A/Paris/910/2007(H1N1)) hem... 38.2 0.002
gb|EU551835.1| Influenza A virus (A/Paris/577/2007(H1N1)) hem... 38.2 0.002
gb|EU551834.1| Influenza A virus (A/Paris/847/2007(H1N1)) hem... 38.2 0.002
gb|EU551833.1| Influenza A virus (A/Paris/644/2007(H1N1)) hem... 38.2 0.002
gb|EU551832.1| Influenza A virus (A/Paris/341/2007(H1N1)) hem... 38.2 0.002
gb|EU551831.1| Influenza A virus (A/Paris/749/2007(H1N1)) hem... 38.2 0.002
gb|EU685785.1| Influenza A virus (A/Paris/1170/2008(H1N1)) he... 38.2 0.002
gb|EU887034.1| Influenza A virus (A/South Carolina/01/2008(H1... 38.2 0.002
gb|EU887030.1| Influenza A virus (A/Wisconsin/01/2008(H1N1)) ... 38.2 0.002
gb|EU851990.1| Influenza A virus (A/Vermont/01/2008(H1N1)) se... 38.2 0.002
gb|EU851985.1| Influenza A virus (A/Minnesota/01/2008(H1N1)) ... 38.2 0.002
gb|EU851981.1| Influenza A virus (A/Hawaii/02/2008(H1N1)) seg... 38.2 0.002
gb|EU851979.1| Influenza A virus (A/Hawaii/01/2008(H1N1)) seg... 38.2 0.002
gb|EU851978.1| Influenza A virus (A/Wisconsin/36/2007(H1N1)) ... 38.2 0.002
gb|EU779629.1| Influenza A virus (A/Georgia/05/2008(H1N1)) he... 38.2 0.002
gb|EU779627.1| Influenza A virus (A/North Carolina/04/2008(H1... 38.2 0.002
gb|EU779626.1| Influenza A virus (A/North Carolina/02/2008(H1... 38.2 0.002
gb|EU779622.1| Influenza A virus (A/Wyoming/10/2008(H1N1)) he... 38.2 0.002
gb|EU779618.1| Influenza A virus (A/New Jersey/10/2008(H1N1))... 38.2 0.002
gb|EU779616.1| Influenza A virus (A/Memphis/03/2008(H1N1)) he... 38.2 0.002
gb|EU779615.1| Influenza A virus (A/Florida/09/2008(H1N1)) he... 38.2 0.002
gb|EU716598.1| Influenza A virus (A/Washington/01/2008(H1N1))... 38.2 0.002
gb|EU716578.1| Influenza A virus (A/South Dakota/06/2007(H1N1... 38.2 0.002
gb|EU716548.1| Influenza A virus (A/New Jersey/08/2008(H1N1))... 38.2 0.002
gb|CY031509.1| Influenza A virus (A/Texas/AF1324/2008(H1N1)) ... 38.2 0.002
gb|CY031491.1| Influenza A virus (A/South Dakota/AF1300/2008(... 38.2 0.002
gb|CY031490.1| Influenza A virus (A/South Carolina/AF1299/200... 38.2 0.002
gb|CY031488.1| Influenza A virus (A/South Carolina/AF1297/200... 38.2 0.002
gb|CY031485.1| Influenza A virus (A/North Carolina/AF1292/200... 38.2 0.002
gb|CY031484.1| Influenza A virus (A/New Jersey/AF1291/2008(H1... 38.2 0.002
gb|CY031483.1| Influenza A virus (A/Nebraska/AF1290/2008(H1N1... 38.2 0.002
gb|CY031482.1| Influenza A virus (A/Nebraska/AF1289/2008(H1N1... 38.2 0.002
gb|CY031480.1| Influenza A virus (A/Nebraska/AF1287/2008(H1N1... 38.2 0.002
gb|CY031479.1| Influenza A virus (A/Maryland/AF1286/2008(H1N1... 38.2 0.002
gb|CY031478.1| Influenza A virus (A/Maryland/AF1285/2008(H1N1... 38.2 0.002
gb|CY031475.1| Influenza A virus (A/Maryland/AF1282/2008(H1N1... 38.2 0.002
gb|CY031455.1| Influenza A virus (A/Alabama/AF1210/2008(H1N1)... 38.2 0.002
gb|CY031447.1| Influenza A virus (A/South Dakota/AF1303/2007(... 38.2 0.002
gb|CY031446.1| Influenza A virus (A/South Dakota/AF1302/2007(... 38.2 0.002
gb|CY031378.1| Influenza A virus (A/Sydney/142/2007(H1N1)) se... 38.2 0.002
gb|CY031304.1| Influenza A virus (A/Iraq/AF1204/2007(H1N1)) s... 38.2 0.002
gb|CY031303.1| Influenza A virus (A/Iraq/AF1203/2007(H1N1)) s... 38.2 0.002
gb|CY031302.1| Influenza A virus (A/Iraq/AF1202/2007(H1N1)) s... 38.2 0.002
gb|CY031301.1| Influenza A virus (A/Iraq/AF1201/2007(H1N1)) s... 38.2 0.002
gb|CY031300.1| Influenza A virus (A/Iraq/AF1200/2007(H1N1)) s... 38.2 0.002
gb|CY031299.1| Influenza A virus (A/Iraq/AF1199/2007(H1N1)) s... 38.2 0.002
gb|CY031298.1| Influenza A virus (A/Iraq/AF1198/2007(H1N1)) s... 38.2 0.002
gb|CY031296.1| Influenza A virus (A/Iraq/AF1196/2007(H1N1)) s... 38.2 0.002
gb|EU624319.1| Influenza A virus (A/England/557/2007(H1N1)) s... 38.2 0.002
gb|EU567013.1| Influenza A virus (A/New Jersey/05/2008(H1N1))... 38.2 0.002
gb|EU566982.1| Influenza A virus (A/New Jersey/20/2007(H1N1))... 38.2 0.002
gb|EU566979.1| Influenza A virus (A/New Jersey/06/2008(H1N1))... 38.2 0.002
gb|EU566976.1| Influenza A virus (A/Pennsylvania/02/2008(H1N1... 38.2 0.002
gb|EU566975.1| Influenza A virus (A/Indiana/01/2008(H1N1)) se... 38.2 0.002
gb|EU566970.1| Influenza A virus (A/Maryland/04/2007(H1N1)) s... 38.2 0.002
gb|EU566966.1| Influenza A virus (A/Arizona/15/2007(H1N1)) se... 38.2 0.002
gb|EU516279.1| Influenza A virus (A/South Dakota/06/2007(H1N1... 38.2 0.002
gb|EU516258.1| Influenza A virus (A/New Jersey/16/2007(H1N1))... 38.2 0.002
gb|EU516257.1| Influenza A virus (A/Illinois/10/2007(H1N1)) s... 38.2 0.002
gb|EU516243.1| Influenza A virus (A/Arizona/03/2007(H1N1)) se... 38.2 0.002
gb|EU516090.1| Influenza A virus (A/South Dakota/06/2007(H1N1... 38.2 0.002
gb|EU516083.1| Influenza A virus (A/New Jersey/15/2007(H1N1))... 38.2 0.002
gb|CY029828.1| Influenza A virus (A/Austria/404596/2008(H1N1)... 38.2 0.002
gb|CY029824.1| Influenza A virus (A/Austria/404342/2008(H1N1)... 38.2 0.002
gb|CY029823.1| Influenza A virus (A/Austria/404340/2008(H1N1)... 38.2 0.002
gb|CY029822.1| Influenza A virus (A/Austria/404339/2008(H1N1)... 38.2 0.002
gb|CY029821.1| Influenza A virus (A/Austria/404337/2008(H1N1)... 38.2 0.002
gb|CY029818.1| Influenza A virus (A/Austria/403918/2008(H1N1)... 38.2 0.002
gb|CY029817.1| Influenza A virus (A/Austria/403914/2008(H1N1)... 38.2 0.002
gb|CY029815.1| Influenza A virus (A/Austria/403908/2008(H1N1)... 38.2 0.002
gb|CY029807.1| Influenza A virus (A/Austria/402941/2008(H1N1)... 38.2 0.002
gb|CY029804.1| Influenza A virus (A/Austria/402931/2008(H1N1)... 38.2 0.002
gb|CY029802.1| Influenza A virus (A/Austria/402647/2008(H1N1)... 38.2 0.002
gb|CY029790.1| Influenza A virus (A/Austria/401513/2008(H1N1)... 38.2 0.002
gb|CY029785.1| Influenza A virus (A/Austria/400115/2007(H1N1)... 38.2 0.002
gb|CY021693.1| Influenza A virus (A/Memphis/15/2000(H1N1)) se... 38.2 0.002
gb|CY016683.1| Influenza A virus (A/South Australia/56/2005(H... 38.2 0.002
gb|CY003000.1| Influenza A virus (A/New York/239/2001(H1N1)) ... 38.2 0.002
gb|CY002672.1| Influenza A virus (A/New York/310/2001(H1N1)) ... 38.2 0.002
gb|CY009236.1| Influenza A virus (A/New York/441/2001(H1N1)) ... 38.2 0.002
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August 31st, 2008, 10:59 AM
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Retired
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Join Date: Feb 2006
Posts: 20,294
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Re: 100% oseltamivir resistant among H1N1 isolates tested in Australia and South Africa
gb|CY034621.1| Influenza A virus (A/Guatemala/AF1995/2008(H1N... 36.2 0.005
gb|CY034620.1| Influenza A virus (A/Honduras/AF1994/2008(H1N1... 36.2 0.005
gb|CY034619.1| Influenza A virus (A/Honduras/AF1993/2008(H1N1... 36.2 0.005
gb|CY034596.1| Influenza A virus (A/Guatemala/AF1969/2008(H1N... 36.2 0.005
gb|CY034595.1| Influenza A virus (A/Honduras/AF1968/2008(H1N1... 36.2 0.005
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