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

[ironorehopper]

Interim ECDC Risk Assessment - January 27th 2008
http://www.ecdc.europa.eu/pdf/080127_os.pdf
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Emergence of seasonal influenza viruses type A/H1N1 with oseltamivir resistance in some European Countries at the start of the 2007-8 influenza season

1. Summary Statement
Ordinary seasonal influenza viruses with significant resistance to the antiviral oseltamivir (Tamiflu) have been detected within the earliest part of this winter’s influenzas epidemics in Europe.
The viruses are known as influenza A/H1N1 (H274Y).
That is a type A influenza virus subtype H1N1 with a histidine to tyrosine amino-acid substitution at position 274 in the neuraminidase protein.
They were fully sensitive to other influenza antivirals.
These viruses have been detected by a European research and surveillance
project known as VIRGIL (supported by an EU grant) which has been underway since 2004-5. These viruses are a new phenomenon this winter. Specialist testing has been undertaken for ten countries and a proportion of A/H1N1 viruses detected in four countries Denmark, France, Norway and the UK, have been found resistant to oseltamivir. H1N1 viruses are predominant in this winters epidemics worldwide. Overall in Europe the proportion with oseltamivir resistant is around 13% but the proportions resistant are variable with Norway showing a markedly high proportion resistant (12 of 16). If the 16 Norwegian viruses are excluded the proportion with resistant would fall to around 5%. Data from Norway indicate that these viruses were transmitted in the country but they are not making people especially ill. Normally A/H1N1 viruses as a group cause milder disease than some other human influenza viruses. However it must be realised that all influenza A viruses are potentially lethal for vulnerable individuals (the old and the very young and those with chronic debilitating conditions). It also needs to be remembered that antiviral resistant is a relative not absolute term. Patients ill with resistant viruses often still seem to benefit when they receive antivirals. The source of these viruses is not known at present. It seems unlikely to have anything to do with antiviral use in Europe. Specifically the resistance is not explained by the source patients having taken any antivirals or any high levels of use of oseltamivir in Europe where generally the drug is used sparingly. These data come from around 150 viral isolates from very early in this winter epidemics in ten of the thirty European countries. However Norway is still seeing them in specimens collected this month. There are some
indications that A/H1N1 viruses with the same resistance mutation are being seen in some other countries, notably North America. However, Europe is showing the highest resistance levels at present. A conclusive risk assessment cannot be attempted at present and there seems little reason to change clinical guidance except possible where these new viruses predominate over all others. It could be that as the influenza season progresses these viruses will be overwhelmed by more fit and sensitive viruses (many resistant viruses lack ‘fitness’) Equally however the resistant viruses could come to spread and predominate. We simply do not know at present. There is considerable risk of confusion of this development with the separate issues of avian influenza, pandemic threat and antivirals stockpile. Information for the public and professionals has therefore been developed by ECDC and WHO for adaptation and use by countries. Intense virological
and epidemiological surveillance and other scientific investigations are now taking place in Europe and elsewhere. This is coordinated by WHO overall globally and this will in time allow for better descriptions and risk statement to be made. Therefore ECDC anticipates highlighting the results of these investigations and updating this assessment at intervals.
(....)

[tropical]

Ironorehopper -

"The source of these viruses is not known at present. It seems unlikely to have anything to do with antiviral use in Europe."

Very disturbing news.

[ironorehopper]

Disturbing! It is stated that H1 retains sensitivity to M2-inhibitors, and this is a partial contradiction with previous findings.
But, here is entire texts:
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2. Specific Questions
What are the implications for human health from the emergence and detection of oseltamivir resistant influenza A/H1N1 seasonal influenza viruses in some European countries this winter?
What are the options for further actions that could be taken?


3. What has been detected - What is new?
Surveillance for antiviral resistance in influenza has been undertaken in the European Union (EU) and European Economic Area (EEA) since the winter of 2005-5. this is undertaken by the EU supported VIRGIL project.

Following its agreed work-plan the central VIRGIL laboratories in London began testing specimens for the 2007-8 season in the week beginning January 23rd. These specimens came from people with proven human seasonal influenza in ten EU/EEA countries.

They represented the earliest viruses detected in November and December 2007 before transmission started in earnest this month. (EISS/ECDC Press Release, Arkema et al 2008).

Preliminary data shows that overall 19 of the 148 (13%) influenza A(H1N1) virus isolates predominantly collected in November and December 2007 from 10 European countries, carry an amino-acid mutation histidine to tyrosine at position 274 (H274Y) in the neuraminidase protein, which in previous studies has been associated with high level of resistance to oseltamivir.


An analysis by country shows that 12 of 16 Norwegian isolates, 4 of 19 French isolates, 2 of 75 United Kingdom isolates, and 1 of 10 isolates from Denmark carry the H274Y mutation.

No mutations were found in 3 specimens from Austria, 4 each from Germany and Latvia, 5 specimens from Slovakia, 1 from Slovenia and 11 specimens from Spain.
The concentration in Norway is striking but without the specimens from there the prevalence of this type among all H1N1 isolates in Europe would be only around 5%.


This is a new observation.

Although early in the influenza season, the presence of oseltamivir-resistant viruses circulating in the community in at least 4 European countries is unusual if compared to the previous winter seasons (2004/2005, 2005/2006 and 2006/2007), when little or no evidence of oseltamivir resistance was detected in over 900 isolates tested from 24 countries [Monto et al, 2006; VIRGIL 2008, personal communication].

However all the H1N1 viruses isolated and tested so far this year are sensitive to the other antineuraminidase drug zanamivir and to the anti-M2 drugs amantadine and rimantadine.

To date A/H1N1 have dominated the 2007-8 season in Europe and other parts of the Northern Hemisphere where surveillance is active (North America and Japan).(Arkema et al 2008)


Further testing and relevant investigations are now underway. This is involving WHO (European Region and Headquarters), EISS, ECDC and Member States. Investigations are well advanced in Norway and the information from the National Institute for Public Health (NIPH) is none of the 12 viruses were obtained from a person who has either been treated with oseltamivir, or knew they had been in close contact with another individual treated with oseltamivir.

This makes it very unlikely that the finding of the emergence of the mutated strains represent the selection of resistant strains that sometimes can be seen in people who are receiving oseltamivir.

Also none of the 12 cases report recent travel and there are no obvious epidemiological links between them. (NIPH personal communication)

Therefore it can be assumed that viruses carrying the H274Y mutation represent community influenza transmissions in Europe (rather than importations or a focused outbreak).

Certainly these viruses are to some extent fit and able to transmit and cause disease.

The specimens tested by VIRGIL came from November and december 2007, The Norwegian National Influenza Centre has sequenced some specimens from this month (January 2008) and finds evidence that the resistant virus is persisting.

To date there is no indication that the people with these infections are suffering from anything more than ordinary human influenza. While a few persons have been hospitalised that may be a surveillance artefact (in this case that people who are hospitalised are, in contrast to people who still at home, more likely to have a specimen taken and their influenza virus entering the surveillance system). However it must be realised that even ordinary seasonal influenza can be lethal, especially for those most
vulnerable (older people, people with debilitating diseases and the very young). ECDC estimates that each year ordinary seasonal influenza is responsible for around 40,000 deaths in the EU/EEA. [ECDC Influnenza Fact Sheets, 2007]


4. Scientific Background Information
4.1 Surveillance A series of systems deliver surveillance for influenza viruses worldwide.
These are choreographed by the World Health Organisation Global Influenza Surveillance Network (GISN). Central to it is the unrestricted sharing of information and viruses between countries. [ECDC Briefing 2007] In Europe there is the long-standing European Influenza Surveillance Scheme (EISS) which is currently integrating into other surveillance schemes with ECDC. In the Northern Hemisphere the season for intense clinical and virological influenza surveillance runs from Week 40 of one year in the Autumn to week 20 of the next year in the Spring. So seasons are referred to as Season 2004-5, Season 2006-7 etc. Background surveillance continues throughout the year. Monitoring of Influenza antiviral resistance in Europe is conducted as part of the European Surveillance Network for Vigilance against Viral Resistance (VIRGIL) in collaboration with the WHO Collaborating Centre at the MRC National Institute for Medical Research in London and the Community Network of Reference Laboratories for Human Influenza in Europe (CNRL) which is coordinated by EISS and is comprised of all the National Influenza Centres (NICs) in Europe [Meijer et al, 2005, 2006]. This central laboratory work on influenza for VIRGIL is undertaken at the Health Protection Agency Centre for Infection in London though this is supported by work across Europe and by the Neuraminidase Inhibitor Susceptibility Network (NISN) [Zambon M & Hayden FG, 2001]. Surveillance for antiviral resistance is carried out each winter influenza season and has been underway since 2004-5. The work is supported financially by the European Union though as it is based on a series of routine systems it also relies on considerable input and support from the countries concerned. Specimens are identified in EU member states and following initial work a subset of all virus isolates are sent centrally to the laboratories in London for full characterisation for the bi-annual WHO vaccine recommendations, and where they are tested for indicators of antiviral resistance [ Gerbil 2003, Meijer A et al, 2007]. At this time of year (January) surveillance work starts on the first specimens that have been gathered early in the season (November and December 2007). That is before proper transmission begins. This year transmission started in earnest in January 2008 [Arkema JMS et al, 2008].


4.2 Seasonal Influenza Epidemics

In temperate climates like Europe transmission of ordinary influenza (human seasonal influenza) takes place each year in the winter months with epidemics across Europe. In more tropical climates nearer the equator influenza transmission is thought to be more continuous through the year with over-laying epidemics. In the Southern Hemisphere the epidemics are the converse of those in Europe taking place in the period May to October. In recent years the European epidemics have rarely started in earnest before the New Year though early transmissions can always be detected in the late autumn. Human seasonal influenza is not caused by a single virus but by complex and variable mix of viruses the balance of which varies from year to year. Influenza viruses are inherently unstable and it is thought that small genetic changes are taking place in the viruses constantly (so called antigenic drift). This is the reason why there needs to be such careful surveillance of influenza and annual recommendations
made by WHO as to the composition of the influenza vaccines produced by industry.[Gerdil 2003] In the 2007-8 season the dominant virus has been of type A/H1N1 which is usually associated with milder disease in humans than say the A/H3N2 [Arkema JMS et al 2008, Simonsen L, 2005]. The drivers for the changes are not fully understood though an important element is the instability of the RNA at the heart of the influenza viruses, their tendency to mutate spontaneously and to occasionally exchange genetic material (reassortment) when two viruses infect the same human or animal. Of late work known as antigenic cartography has suggested that many of the new variants of human influenza viruses that have emerged recently come from the Far East and South East Asia [Smith et al 2004 & Smith 2006]. It is thought that subtly different influenza viruses are emerging constantly but many do not transmit efficiently (often they are said to lack fitness) and these then die out as they do not compete well with fitter viruses.


4.3 Influenza Pandemics

Very occasionally (four times since the late nineteenth century) larger changes led to the emergence of a new virus able to transmit efficiently from humans to humans and to which a large proportion of the population have no immunity. These spread as pandemics across the world.

It is important to bear in mind that when talking about these new H1N1-H247Y viruses there is no reason to imagine that they have any more pandemic potential than other influenza viruses. Equally it is important to appreciate that H1N1-H247Y is a human seasonal virus and must not be confused with avian influenza viruses notably the similarly named A/H5N1 which causes bird flu in poultry.


4.4 Antiviral Resistance

There are two main groups of antivirals used against influenza viruses. In order of discovery these are the M2 ion channel inhibitors (M2Is) adamantenes (amantadine and rimantadine), and the neuraminidase inhibitors (NIs) (zanamivir and oseltamivir). (Moscona 2005b) Amantadine and rimantadine were licensed in the US with antiviral indications in 1966 and 1993 respectively. Zanamivir and oseltamivir became available in the late 1990s. Oseltamivir is often preferred over zanamivir for treatment purposes as it is available as tablets while zanamivir has to be inhaled. Oseltamivir has a Europe-wide license (EMEA), whilst adamantenes and zanamivir need to be licensed by country, and are not licensed in all countries.

Resistant Viruses in People on Treatment

As influenza viruses continuously change through mutation and recombination, drug resistance viruses are occasionally detected briefly in infected individuals during treatment with antivirals. This is why information has to be gathered on what treatment if any people with resistant viruses have had, or whether they have been in contact with those on treatment. However these viruses usually lack fitness and do not transmit on. [Moscona 2005a]


Resistance to Neuraminidase inhibitors

This has been reported as occurring at very low level (<1%) in immunocompetent individuals screened during seasonal influenza epidemics [Monto AS, 2006] though cross resistance between oseltamivir and zanamivir is not common. Oseltamivir resistance in influenza viruses is relative and despite its presence patients with oseltamivir-resistant viruses may still benefit from receiving oseltamivir.[Moscona 2005a] Often the clinical outcome for patients with resistant viruses and treated with antivirals is not any different from patients carrying fully sensitive strains [De Jong MD et al, 2005 & Hayden FG, 2006] However, higher levels of antiviral resistance has been reported developing during treatment of children and immunosuppressed individuals [Kiso M et al, 2004; Hayden FG, 1997; Gubareva LV, 1998].


Types of Resistance

There are generally three levels of antiviral resistance according to the way that resistance can be detected or inferred:
a. Genotypic Resistance: detected through sequencing of the viral genome and identification of mutations previously associated with a certain level of drug resistance. Many national laboratories in Europe can undertake this testing
b. Phenotypic Resistance: resistance of the virus to drugs is tested in vitro (not in living systems) by measuring viral replication at different drug concentrations (IC50)
c. Clinical Resistance: based on animals (ferret or mice) and human patients and measuring or observing the actual response to treatment with antivirals.
Of course clinical resistance in humans is what is of most concern.[Moscona 2005b] Clinical resistance and the response to treatment with antivirals (the clinical response) remains the most important proof of antiviral effectiveness. A virus may have genetic markers associated with resistance (genotypic resistance) but still show satisfactory response either in the laboratory (phenotypic resistance) or when the antivirals are given
to patients (clinical resistance).
Genotypic mutations associated with drug resistance against oseltamivir are often observed to have defects in their basic virus characteristics including transmissibility and ability to replicate. This makes them “unfit”. However the most commonly observed mutations conferring adamantane resistance did not seem to affect the virus fitness, and hence naturally resistant viruses are circulating at variable levels during seasonal epidemics.
Until these observations no rise in resistance to oseltamivir for ordinary transmitting human influenza viruses had been observed over time. This might be due to the fact that some of the NI resistance associated mutations are also associated with reduced influenza virus transmissibility and this might partially explain the low prevalence of primary NI resistance in viruses isolated from clinical and animal model settings.
The H274Y mutation has only been observed in viruses of neuraminidase type 1 (N1).
This mutation has been associated with a 400-fold reduction in the sensitivity of the virus to oseltamivir in vitro. There is contradictory evidence on the role of such mutation in affecting the viral fitness with some studies showing reduced replicative capacity and transmissibility and other showing similar fitness than the wild type viruses [Hurt AC et al, 2006].


Resistance to the Adamantenes.

Influenza viruses resistant to the adamantenes emerged as early as the late 1960s. The drivers for this emergence are not clear. In some areas of the world, like North America the proportion of influenza strains naturally resistant to this drug class has recently become unacceptably high to the point where they are not always the drug of choice for seasonal influenza [Fiore AE et al, 2007].

4.5 What is known about A/H1N1 viruses and specifically A/H1N1-H247Y?
In general A/H1N1 viruses are associated with milder illness than other influenza A viruses though like all influenza A viruses they can cause severe disease and death, especially in some vulnerable individuals. A/H1N1 viruses with the H274Y mutation have been seen before when they were detected in Japan in patients treated with oseltamivir. Those viruses were not subsequently detected to be circulating in the community except at very low levels so they may be a somewhat different phenomenon.
However the earlier viruses were studied in animal models. This found that they could transmit from one animal to another but with lower efficiency than do ordinary A/H1N1 viruses. That said they are among the fitter of all antiviral resistant influenza viruses (FHayden personal communication 2008).


4.6 What is being observed elsewhere?
WHO is now working intensively with its partners across the world to determine whether these first European observations are unique or occurring elsewhere. There are some indications that some of the same virus oseltamivir-resistant A/H1N1 viruses are being observed at low levels in the United States.. However detailed surveillance for the 2007-8 season is only just starting and more information will become available later.


4.7 Oseltamivir use in Europe

It is important to bear in mind that apart from in Japan and to a lesser extent the United States oseltamivir is not much used for treatment of seasonal influenza. This is especially so in Europe where it seems that in most countries the numbers of prescriptions for treatment are negligible.(Communication from Roche 2007) There were many prescriptions in 2005 and 2006 in some countries but most reports suggest that these were driven by anxiety over the threat from bird flu and were stored in homes rather than used for treatment. This has two implications. Firstly it makes it even more unlikely that these viruses have emerged as a result of use of oseltamivir in Europe. Secondly it is not that the case that clinicians may be losing the utility of a widely used drug.


5. Risks of Misunderstanding – Risk Communication
Perhaps the greatest risk at present is that the information and risks are misunderstood, especially when WHO and ECDC lack the information to make definitive statements on risks. The possibility for confusion of these events with avian influenza (A/H5N1), pandemics and oseltamivir stockpiles is considerable. Therefore ECDC and WHO are preparing a series of Frequently Asked Questions and Answers (FAQs) and these will shortly be available on their web-sites. The ECDC FAQs are designed for adaptation and use by EU/EEA member states.


6. Formulation – What is likely to emerge?
These are early days in this new development and it really is too soon to undertake any proper risk assessment. There is only information for viruses detected early in the 2007- 2008 (actually from people who become ill in November and December) from a limited number of isolates from ten European countries. Numbers tested for any individual country are low. Hence this interim assessment will be reviewed in the coming weeks and months and updated as more information rapidly becomes available from more testing, from other countries and especially as a result of work and consultations organised by WHO with which ECDC is working closely. It could be that as the season progresses these particular viruses are overwhelmed by other, fitter viruses. Equally however they could spread to other countries and become more prevalent as seasonal influenza transmission spreads across Europe.


7. Risk Statement
It is also too early to make any definitive risk statement and more information will be gathered for this as time goes along. However the most important points to be born in are:
• There is no indication as yet that these oseltamivir resistant viruses (A/H1N1 H274Y) are more virulent or are causing more severe disease than wild type influenza viruses. Though A/H1N1 usually causes less severe disease than say the A/H3N2 viruses it still can have severe outcomes even death in vulnerable people.
• This high level of resistance to oseltamivir observed in a relatively small number of samples tested might not be confirmed when more samples are tested and when there is widespread circulation of flu in the community.
• A/H1N1 viruses are well matched with the current seasonal influenza vaccine and therefore patients who received vaccination are already at lower risk of contracting the disease or developing severe complications than people who have not been immunised.
• Oseltamivir is not much used in Europe at present.
• While there are no international or EU guidelines for use of antivirals there are national guidelines in some EU countries which often recommend that antivirals are reserved mostly for prophylaxis or early treatment among patient with risk factors or those who are older (variously defined as being over 60 or 65 years).[National Institute for Health and Clinical Excellence (NICE) UK, National Institute for Public Health and the Environment RIVM, The Netherlands]
Therefore the immediate implication of the reporting of oseltamivir resistance are limited and for those where antiviral prophylaxis or treatment is indicated alternative drugs can be used. However these national guidelines may need to be reviewed in the light of this development if the H1N1-H247Y viruses continue to appear and spread.


8. Important Links: [WHO etc when published]


9. Options for Action in the EU
a. Further typing of specimens especially those detected after transmission started in earnest including specimens from the other EU-EEA countries with the objectives of seeing and tracking how H1N1-H247Y matures and evolves in Europe.
b. Proactive communication of further results and information for the public and professionals including ‘rumour surveillance’ looking for misunderstandings and responding to them
c. Descriptive investigations of the initial cases especially concerning their disease and response to any treatment with antivirals that they happen to be given.
d. Consideration of review of national guidelines clinical advice by those experienced in developing such guidance.


10. When will be reviewed - One month after publication date (may be updated Earlier if need be)


References

1. Arkema JMS, Meijer A, Paget WJ et al. The influenza season has started in a number of European countries Euro Surveill 2008;13(4). Available online: LINK
2. De Jong MD, Tranh TT, Khanh TH et al. Oseltamivir resistance during treatment of influenza A(H5N1) infection. N Engl J Med 2005; 353: 2667-72.
3. ECDC Briefing European Centre for Disease Prevention and Control. Interim ECDC Scientific and Public Health Briefing: Sharing influenza Virus Samples – Version November 2007
4. ECDC Influenza Fact Sheet 2007
5. European Surveillance Network for Vigilance against Viral Resistance (VIRGIL)

6. Fiore AE, Shay DK, Haber P et al Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention (CDC). Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2007. MMWR Recomm Rep. 2007;56(RR-6):1-54.
7. Gerdil C. The annual production cycle for influenza vaccine. Vaccine 2003; 21: 1776-9.
8. Gubareva LV, Matrosovich MN, Brenner MK et al Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J Infect Dis. 1998;178(5):1257-62.
9. Hayden FG. Antiviral resistance in influenza viruses. Implications for management and pandemic response. NEJM 2006: 354: 785-8.
10. Hayden F, Klimov A, Tashiro M, et al. Neuraminidase Inhibitor Susceptibility Network position statement: antiviral resistance in influenza A/H5N1 viruses. Antivir Ther 2005; 10: 873-877.
11. Hayden FG. Prevention and treatment of influenza in immunocompromised patients. Am J Med. 1997;102(3A):55-60; discussion 75-6.
12. Hurt AC, Ho H, Barr I. Resistance to anti-influenza drugs: adamantanes and neuraminidase inhibitors. Expert Rev Anti Infect Ther 2006; 4:795-805.
13. Kiso M, Mitamura K, Sakai-Tagawa Y, et al Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet. 2004; 364 :759-65 10
14. Meijer A, Valette M, Manuguerra JC et al and Virology Working Group of the European Influenza Surveillance Scheme.. Implementation of The Community Network of Reference Laboratories for Human Influenza in Europe. J Clin Virol. 2005;34:87-96.
15. Meijer A, Brown C, Hungnes O et al and Virology Task Groups of the European Influenza Surveillance Scheme. Programme of the Community Network of Reference Laboratories for Human Influenza to improve Influenza Surveillance in Europe. Vaccine. 2006;24:6717-23.
16. Meijer A, Lackenby A, Hay A, Zambon M. Influenza antiviral susceptibility monitoring activities in relation to national antiviral stockpiles in Europe during the winter 2006/2007 season. Euro Surveill. 2007 Apr 1;12(4):E3-4.
17. Monto AS, McKimm-Breschkin JL, Macken C, et al. Detection of influenza viruses resistant to neuraminidase inhibitors in global surveillance during the first 3 years of their use. Antimicrob Agents Chemother 2006; 50:2395-402.
18. Moscona A. Oseltamivir resistance--disabling our influenza defenses. N Engl J Med. 2005a; 353: 2667-72.
19. Moscona A Neuraminidase Inhibitors for Influenza N Engl J Med 2005b; 353:1363-1373.
20. Simonsen L. Impact of influenza vaccination on seasonal mortality in the US elderly population. Arch Intern Med. 2005;165:265-272.
21. Smith DJ, A. S. Lapedes, J. C. de Jong et al. Mapping the Antigenic and Genetic Evolution of Influenza Virus. Science 2004, 305, 371-376
22. Smith DJ. Predictability and preparedness in influenza control. Science 2006, 312, 392-394.
23. WHO recommendation :Recommended composition of influenza vaccines for use in the 2007-2008 influenza season. Wkly Epidemiol Rec. 2007;82:69-76.
24. Yen HL, Herlocher LM, Hoffmann E et al Neuraminidase inhibitor-resistant influenza viruses may differ substantially in fitness and transmissibility. Antimicrob Agents Chemother 2005; 49: 4075-84.
25. Zambon M, Hayden FG. Position statement: global neuraminidase inhibitor susceptibility network. Antiviral Res 2001;49:147-156
26. Zurcher T, Yates PJ, Daly J, et al Mutations conferring zanamivir resistance in human influenza virus N2 neuraminidases compromise virus fitness and are not stably maintained in vitro. J Antimicrob Chemother 2006;58:723-32.

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[ironorehopper]

Originally Posted by tropical

Ironorehopper -

"The source of these viruses is not known at present. It seems unlikely to have anything to do with antiviral use in Europe."

Very disturbing news.

''12 to 16 isolates from Norway contain mutation''!

[tropical]

Originally Posted by ironorehopper

''12 to 16 isolates from Norway contain mutation''!

Thank you for the thread ironore.

Any released data about the habits of the patients with that mutation:
they traveled somewhere in the period previous the illness onset, job specifities, etc?

[Dutchy]

UPDATE 1-Some ordinary flu strains resist Tamiflu in study

Mon Jan 28, 2008

(adds details)

By Sarah Edmonds and Douwe Miedema

STOCKHOLM/ZURICH, Jan 28 (Reuters) - Some seasonal influenza viruses are resistant to Roche Holding AG's (ROG.VX: Quote, Profile, Research) Tamiflu, a study showed, but Roche said no doubts had been raised about the drug's power to combat any deadly bird flu pandemic.

Of 148 samples of influenza A virus isolated from 10 European countries during November and December, 19 showed signs of resistance to Tamiflu, the European Centre for Disease Control said on Monday, citing a preliminary survey.

Of 16 samples from Norway, 12 tested positive for resistance against Tamiflu, which is also known by the generic name oseltamivir, Stockholm-based ECDC said.

"Given the initial indication of a high level of resistance to oseltamivir in the A H1N1 viruses circulating in Norway, late last week ... the Norwegian authorities notified their EU partners and the World Health Organization (WHO) of this situation," the ECDC said.

Tamiflu sales have been lacklustre as Roche completed government orders for pandemic influenza stockpiles to fight a possible pandemic spread among humans of the deadly H5N1 virus, which so far has mainly killed birds.

The resistant strains found by the study were normal seasonal flu viruses, and not avian or pandemic flu, Roche said. The study was also too small to draw firm conclusions.

"These are preliminary results, which are in contrast to previous years, when little or no resistance to Tamiflu was observed," a spokeswoman said.

"More extensive surveillance globally is required to establish the relative prevalence and geographical distribution of the resistant viruses," she said.

Markets shrugged off the results of the study and Roche shares were down 0.7 percent by 1100 GMT, roughly in line with the Dow Jones Stoxx health index .

"The nature of the viruses does not make resistance surprising in our view," Landsbanki Kepler said in a research note, adding that the Tamiflu's limited usefulness against ordinary flu strains had long been known.

The H5N1 avian flu virus, wiping out bird flocks from Indonesia to Africa, rarely infects people but has killed 221 out of 353 people sick since the virus re-emerged in Hong Kong in 2003, according to the World Health Organisation.

The ECDC institute said the Norwegian Public Health Institute late last week published an advisory to doctors and the public on its website.

"At this stage it is impossible to say what the level of resistance is in influenza across Europe," it said.

"However from the limited data, the proportion of influenza viruses exhibiting resistance to oseltamivir must be significant, but not as high as in Norway."

It said the oseltamivir-resistant strain of A(H1N1) did not seem to make patients any sicker than non-resistant varieties.



http://www.reuters.com/article/rbssH...72811520080128

[tropical]

Originally Posted by tropical

... Any released data about the habits of the patients with that mutation:
they traveled somewhere in the period previous the illness onset, job specifities, etc?

When the above was wroted (by me), I did not saw the #3 post of iron.
(I shall must wrote the post in Word previous submiting).
___
Iron.:
"Also none of the 12 cases report recent travel and there are no obvious epidemiological links between them. (NIPH personal communication)

Therefore it can be assumed that viruses carrying the H274Y mutation represent community influenza transmissions in Europe (rather than importations or a focused outbreak). "
___
Dutchy:
"...Landsbanki Kepler said in a research note, adding that the Tamiflu's limited usefulness against ordinary flu strains had long been known."

I always (wrongly?) think that the Tamiflu potential of usage is on ALL kind of flu virus strains.

[ironorehopper]

Originally Posted by tropical

When the above was wroted (by me), I did not saw the #3 post of iron.
(I shall must wrote the post in Word previous submiting).
___
Iron.:
"Also none of the 12 cases report recent travel and there are no obvious epidemiological links between them. (NIPH personal communication)

Therefore it can be assumed that viruses carrying the H274Y mutation represent community influenza transmissions in Europe (rather than importations or a focused outbreak). "
___
Dutchy:
"...Landsbanki Kepler said in a research note, adding that the Tamiflu's limited usefulness against ordinary flu strains had long been known."

I always (wrongly?) think that the Tamiflu potential of usage is on ALL kind of flu virus strains.

-

EXCERPTS from Update on Avian Influenza A (H5N1) Virus Infection in Humans - Writing Committee of the Second World Health Organization Consultation on Clinical Aspects of Human Infection with Avian Influenza A (H5N1) Virus* (available also in FluTrackers)

Treatment
Antiviral Agents
Susceptibility to current antiviral agents varies among circulating strains of influenza A (H5N1) viruses.
Clade 1 viruses and most clade 2 viruses from Indonesia are fully resistant to M2 inhibitors, whereas clade 2 viruses from the lineages in other parts of Eurasia and Africa are usually susceptible (Klimov A: personal communication).
As compared with influenza A (H5N1) viruses from 1997 or influenza A (H1N1) viruses in vitro,55 clade 1 viruses generally show enhanced susceptibility to oseltamivir carboxylate, but the highlevel replication of some oseltamivir-susceptible strains requires higher doses or more prolonged administration, or both, in animal models.55,56
Clade 1 viruses appear to be 15 to 30 times more sensitive to oseltamivir than clade 2 isolates from Indonesia and Turkey,56,57 although the possible clinical relevance of such differences in oseltamivir susceptibility remains to be determined.
During oseltamivir therapy, the emergence of highly resistant variants with an H274Y neuraminidase mutation may be associated with a fatal outcome.58
Infection by influenza A (H5N1) viruses containing an N294S mutation that causes a reduction in oseltamivir susceptibility by a factor of 12 to 15 times was reported to be present in two Egyptian patients with fatal disease before therapy,59 and avian influenza A (H5N1) viruses with reduced susceptibility to neuraminidase inhibitors are occasionally detected.60

Early treatment with oseltamivir is recommended, 61,62 and data from uncontrolled clinical trials suggest that it improves survival (Table 4), although the optimal dose and duration of therapy are uncertain.
Mortality remains high despite administration of oseltamivir; late initiation of therapy appears to be a major factor.
Uncontrolled viral replication, as reflected in the detection of persistent pharyngeal RNA after completion of standard therapy, is associated with a poor prognosis. 58
Higher levels of viral replication and slower clearance of infection probably occur in the lower respiratory tract.3
The oral bioavailability of oseltamivir in patients with severe diarrhea or gastrointestinal dysfunction related to influenza A (H5N1) virus infection or those in whom the drug has been administered extemporaneously (e.g., by means of a nasogastric tube) is uncertain.
A higher dose of oseltamivir (e.g., 150 mg twice daily in adults) and an increased duration of therapy, for a total of 10 days, may be reasonable, given the high levels of replication of the influenza A (H5N1) virus, observations of progressive disease despite early administration of standarddose oseltamivir (75 mg twice daily for 5 days in adults) within 1 to 3 days after the onset of the illness, and the proven safety of higher doses in adults with seasonal influenza, especially if there is pneumonic disease at presentation or evidence of clinical progression.62
In mouse models of amantadine-sensitive influenza A (H5N1) virus infection, as compared with monotherapy, the combination of oseltamivir and amantadine significantly increased survival rates and inhibited viral replication in the internal organs.64
No adverse pharmacologic interactions have been shown in humans.65
In areas where influenza A (H5N1) viruses are likely to be susceptible to amantadine, combination treatment with oseltamivir would be reasonable, especially in seriously ill patients.
Although zanamivir is active against oseltamivir- resistant variants with N1 neuraminidase mutations at H274Y66 or N294S, the value of inhaled zanamivir has not been studied in human influenza A (H5N1) disease.
Suboptimal delivery to sites of infection in patients with pneumonic or extrapulmonary disease is a concern.
Parenteral delivery of zanamivir or the neuraminidase inhibitor peramivir results in antiviral activity in animal models of influenza A (H5N1) virus infection; these agents and others are under clinical development (Table 3 of the Supplementary Appendix).
(....)

[HenryN]

Rise in flu drug resistance worries experts TheStar.com - Canada - Rise in flu drug resistance worries experts
January 28, 2008
Helen Branswell
The Canadian Press

Influenza experts admitted today that they have been startled by the discovery this season of an unexpectedly high number of human flu viruses that appear to be naturally resistant to Tamiflu, the drug that countries around the world are stockpiling for use in the next flu pandemic.
The viruses have been isolated from people infected with influenza A viruses of the H1N1 subtype in a number of European countries.
And Canada's National Microbiology Laboratory in Winnipeg has reported finding one such virus, in a child who is believed to have been infected with influenza in Sudan before travelling to Canada.
The World Health Organization is convening a virtual meeting of experts tomorrow to try to get a handle on how far afield the resistant virus has been found, how common it is and what the findings signify.
"I think this is a very concerning change in influenza virus resistance patterns," Dr. Frederick Hayden, a leading antiviral expert and a member of the WHO's Global Influenza Program, said from Geneva.
"This is not only interesting, it's unusual and would not have necessarily been predicted by the necessary information. So it's certainly something we're taking seriously and trying to gather additional information (on)."
The reports relate only to human flu viruses of the H1N1 subtype. Most of the cases of resistance have occurred in people who were not treated with Tamiflu (oseltamivir), a fact that suggests viruses with this mutation may be more capable of spreading from person to person than had been previously thought.
It had been believed that viruses that acquired this resistance mutation would pay for that gain with a corresponding loss in their ability to transmit – that it would make them less able to compete with unaltered viruses in the race to infect and spread among human hosts.
"It's a bit of a surprise ... because several of the pre-clinical studies would suggest that this mutation does confer a biologic cost to the virus," said Hayden. "(But) it doesn't seem to reduce fitness very much."
A spokesperson for Hoffman-La Roche, the Swiss maker of Tamiflu, cautioned against over-interpreting the findings.
"These preliminary results are in contrast to previous years where little or no resistance to oseltamivir was observed," Laura Pagnotta, communications manager for Roche's Canadian operation, said via an e-mail.
"The clinical significance of these results is not yet known and more extensive surveillance is required."
The European Centre for Disease Control has reported that laboratory analysis of 148 H1N1 flu viruses so far this season turned up 19 viruses with a mutation on the neuraminidase protein – the N in a flu virus's name – at position 274.
The mutation does not render H1N1 viruses resistant to zanamivir (Relenza), another drug in the same class. Hayden said the viruses with this mutation are in fact susceptible to Relenza and to the only two other flu drugs on the market, amantadine and rimantadine.
Twelve of 16 H1N1 viruses from Norway tested positive for the mutation. Oseltamivir-resistant H1N1 viruses have also been found in Denmark, France and the United Kingdom.
Based on previous surveillance, fewer than one per cent of H1N1 viruses would be expected to be resistant to Tamiflu. But so far the EU as a whole is reporting a resistance rate of just under 13 per cent, though Hayden noted the rate would be around five per cent without the spike in cases in Norway.
The 274 mutation gives the H1N1 virus what's known as high-level resistance, meaning people infected with it would get little if any benefit if they were treated with Tamiflu.
The United States has also seen higher than expected rates, with six of 204 H1N1 viruses – 2.9 per cent – carrying this mutation, said Dr. Joe Bresee, chief of the epidemiology and prevention branch of the Influenza Division at the U.S. Centers for Disease Control.
But Bresee suggested it is too soon to say whether this is a trend, or a result of the fact that concern about influenza and the risk of a pandemic is spurring laboratories around the world to conduct more resistance testing.
"It's a somewhat higher proportion of resistance than we would have expected and (than) we've seen in the past," he said from Atlanta.
"But we don't know yet if it represents a trend upward or just we're doing a better job of doing surveillance."
Bresee said the CDC has no plan as yet to change its advice to doctors on how and when to use the drug. In 2006, soaring rates of resistance to amantadine and rimantadine prompted the CDC, the Public Health Agency of Canada and counterparts in other countries to advise against use of those drugs – advice that remains in effect.
Hayden said early data suggest this isn't yet a global phenomenon, and it isn't clear it will become one. "But it's something, obviously, that needs to be watched very carefully."
And he said it underscores the critical need for new classes of flu drugs.
"We've been concerned about this issue for a long time. And it's still not clear what's going to happen with this particular season, but I think that in general, this tells us that we really need to look at alternatives and try to understand really, whether we can come up with agents that are going to – I'm not sure help us overcome the problem of resistance – but help us cope in the future."

http://www.thestar.com/printArticle/298163

[HenryN]

H274Y travel log

		ISDN282211	A/Hawaii/21/2007	NA (6)	1413	2007	H1N1
		ISDN282224	A/Hawaii/28/2007	NA (6)	1413	2007	H1N1
		ISDN282222	A/Hawaii/28/2007	NA (6)	1413	2007	H1N1
		CY027037	A/Kansas/UR06-0104/2007	NA (6)	1427	2007	H1N1
		ISDN282240	A/Minnesota/23/2007	NA (6)	1413	2007	H1N1
		ISDN263890	A/Texas/31/2007	NA (6)	1413	2007	H1N1

[HenryN]

INFLUENZA A(H1N1) VIRUS, OSELTAMIVIR RESISTANCE - NORWAY
************************************************** ******
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: Sun 27 Jan 2008
Source: EpiNorth [edited]
<http://www.epinorth.org/eway/default0.asp?pid=230&oid=0&e=0&trg=Area_5328&MainArea_5260=5328:::::::&Area_5328=5273:45990::0:5326:1:5260;5328;::10:0:0>


Influenza virus in Norway resistant to oseltamivir
--------------------------------------------------
As the Norwegian Institute of Public Health reports, influenza activity in
Norway is currently at a low level but is increasing. Of 16 influenza
A(H1N1) viruses examined for resistance this season, 12 are resistant
against the anti-influenza drug oseltamivir (Tamiflu). The Norwegian
Institute of Public Health requests Norwegian physicians treating patients
with influenza to be aware of this if considering antiviral treatment.

The influenza activity in Norway is still low, but have increased since the
start of the year [2008] and further increase is expected in the comng
weeks. Influenza virus A(H1N1) that dominates this winter, usually gives a
milder disease than A(H3N2) which dominated the previous season.

Influenza may be a serious disease for certain groups of patients, who are
therefore offered vaccination. Antiviral treatment is mainly recommended
for patients with severe influenza and to patients with severe underlying
disease if they get influenza. Every season, the Norwegian Institute of
Public Health collects some influenza strains from the whole country for
closer analysis for surveillance purposes. Some of these viruses are sent
to the WHO influenza collaborating centre in London for resistance testing
and other analyses. [The] dominating virus this season, both in Norway and
the rest of Europe, is influenza A (H1N1) Solomon Islands. A total of 12 of
16 A(H1N1)-virus from different patients from various places around the
country have been shown to be highly resistant to oseltamivir (Tamiflu).
The virus is susceptible to other anti-influnza drugs [Relenza, amantadine,
rimantadine ? - Mod.CP]. The patients have not had more serious disease
than expected with influenza.

Norway is participating in international collaboration on surveillance and
advice on influenza with the European Centre for Disease Prevention and
Control (ECDC), the influenza network EISS and the World Health
Organization (WHO). This event has been notified to WHO under the
International Health Regulations.

--
communicated by:
Preben Aavitsland
<Preben.Aavitsland@fhi.no>

[The most recent weekly report [25 Jan 2008] of the European Influenza
Surveillance Scheme (EISS;
<http://www.eiss.org/cgi-files/bulletin_v2.cgi?display=1&code=250&bulletin=250>)
states that there is currently medium or high influenza activity in 16
European countries (Austria, Belgium, Bulgaria, France, Hungary, Ireland,
Italy, Lithuania, Luxembourg, Northern Ireland, Poland, Portugal, Romania,
Slovenia, Spain, and Switzerland). In week 03/2008, a further increase in
consultations for influenza-like-illness (ILI) and/or acute respiratory
infection (ARI) was reported by several countries and was most obvious for
Hungary, Luxembourg, Portugal, Slovenia, and Switzerland. Of the total
virus detections since week 40/2007 (n=3447), 81 per cent were influenza A
of which about 99 per cent were of the H1 subtype. For the intensity
indicator, the national network levels of influenza-like illness (ILI)
and/or acute respiratory infection (ARI) were high in Bulgaria, Luxembourg,
and Switzerland, medium in Austria, Belgium, France, Hungary, Ireland,
Italy, Lithuania, Northern Ireland, Poland, Portugal, Romania, Slovenia,
Spain, whilst they remained low in 11 other countries that reported this
indicator. For the geographical spread indicator, 11 countries (Austria,
Belgium, France, Hungary, Italy, Luxembourg, the Netherlands, Portugal,
Slovenia and Spain, Switzerland) reported widespread activity, 3 countries
regional activity, 5 countries local activity, 7 countries sporadic
activity and one country reported no influenza activity.

It remains to be established to what extent oseltamivir resistance is a
general phenomenon throughout Europe, or whether it is restricted to Norway
possibly as a consequence of greater availability of oseltamivir treatment
in Norway. The question of the degree of resistance is also of relevance;
whether resistance is complete or only partial as been has been observed in
the case of some isolates of H5N1 avian influenza virus from human
patients. - Mod.CP]

[see also:
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
2000
---
Influenza virus, neuraminidase inhibitor resistance 20010926.2350]

.................cp/ejp/sh

[HenryN]

Commentary at

http://www.recombinomics.com/News/01...amiflu_US.html

[gsgs]

they should make public the sequences ASAP.
It can't be kept secret anyway with so many countries
reporting it, although Norway may claim for copyright ;-)

[HenryN]

Originally Posted by gsgs

they should make public the sequences ASAP.
It can't be kept secret anyway with so many countries
reporting it, although Norway may claim for copyright ;-)

The sequences in the US are public.

[HenryN]

H5N1 travel log for H274Y

		EU146786	A/Indonesia/560H/2006	NA (6)	1353	2006	H5N1
		ISDN185497	A/Indonesia/560H/2006	NA (6)	1353	2006	H5N1
		DQ840522	A/swan/Astrakhan/Russia/Nov-2/2005	NA (6)	1014	2005	H5N1
		DQ493078	A/Vietnam/CL2009/2005	NA (6)	1332	2005	H5N1
		DQ250165	A/Vietnam/CL2009/2005	NA (6)	1333	2005	H5N1
		DQ320136		NA (6)	1013	2005	H5N1
		DQ250158	A/chicken/Hong Kong/3123.1/2002	NA (6)	1055	2002	H5N1

[tropical]

Thank you ironorehopper, and Dr. Niman:

"... Clade 1 viruses appear to be 15 to 30 times more sensitive to oseltamivir than clade 2 isolates from Indonesia and Turkey,56,57 although the possible clinical relevance of such differences in oseltamivir susceptibility remains to be determined.
During oseltamivir therapy, the emergence of highly resistant variants with an H274Y neuraminidase mutation may be associated with a fatal outcome. ..."
___
Influenza experts admitted today that they have been startled by the discovery this season of an unexpectedly high number of human flu viruses that appear to be naturally resistant to Tamiflu, the drug that countries around the world are stockpiling for use in the next flu pandemic.
The viruses have been isolated from people infected with influenza A viruses of the H1N1 subtype in a number of European countries.
And Canada's National Microbiology Laboratory in Winnipeg has reported finding one such virus, in a child who is believed to have been infected with influenza in Sudan before travelling to Canada.
___
"... At the Los Alamos sequence database, there are 1030 N1 sequences from H1N1 human isolates. 340 are from 2007 and all of the sequences below are from 2007.

Thus, although the percentage of samples was low, all were from 2007 and all were Solomon Island-like.

These Solomon-Island lake sequences trace back to Asia, where Tamiflu blankets are frequently applied in the treatment of H5N1.

The N1 in H5N1 has donor sequences for human N1 in the region adjacent to the acquisition which generates H274Y, which is the precise change found in the most common form of oseltamivir resistance in H5N1 patients, primarily in Vietnam. ..."
___

From the above, the Tamiflu blankets aplied on humans beeing infected also/only with seasonal flu, induced an insurgence of an Tamiflu resistant strain of human seasonal flu AH1N1, which is now disseminated in USA/Canada/Europe/.../.

On the other side EU wroted:
"... Therefore it can be assumed that viruses carrying the H274Y mutation represent community influenza transmissions in Europe (rather than importations or a focused outbreak).""

[HenryN]

Originally Posted by tropical

Thank you ironorehopper, and Dr. Niman:

"... Clade 1 viruses appear to be 15 to 30 times more sensitive to oseltamivir than clade 2 isolates from Indonesia and Turkey,56,57 although the possible clinical relevance of such differences in oseltamivir susceptibility remains to be determined.
During oseltamivir therapy, the emergence of highly resistant variants with an H274Y neuraminidase mutation may be associated with a fatal outcome. ..."
___
Influenza experts admitted today that they have been startled by the discovery this season of an unexpectedly high number of human flu viruses that appear to be naturally resistant to Tamiflu, the drug that countries around the world are stockpiling for use in the next flu pandemic.
The viruses have been isolated from people infected with influenza A viruses of the H1N1 subtype in a number of European countries.
And Canada's National Microbiology Laboratory in Winnipeg has reported finding one such virus, in a child who is believed to have been infected with influenza in Sudan before travelling to Canada.
___
"... At the Los Alamos sequence database, there are 1030 N1 sequences from H1N1 human isolates. 340 are from 2007 and all of the sequences below are from 2007.

Thus, although the percentage of samples was low, all were from 2007 and all were Solomon Island-like.

These Solomon-Island lake sequences trace back to Asia, where Tamiflu blankets are frequently applied in the treatment of H5N1.

The N1 in H5N1 has donor sequences for human N1 in the region adjacent to the acquisition which generates H274Y, which is the precise change found in the most common form of oseltamivir resistance in H5N1 patients, primarily in Vietnam. ..."
___

From the above, the Tamiflu blankets aplied on humans beeing infected also/only with seasonal flu, induced an insurgence of an Tamiflu resistant strain of human seasonal flu AH1N1, which is now disseminated in USA/Canada/Europe/.../.

On the other side EU wroted:
"... Therefore it can be assumed that viruses carrying the H274Y mutation represent community influenza transmissions in Europe (rather than importations or a focused outbreak).""

The startled "experts" should also be startled by the fact that H274Y is coded by C763T and the transition is IDENTICAL in human H1N1 and human/avian H5N1 (and is flying around in mute swans with Qinghai H5N1 in Astrakhan in 2005).

Just another of the "coincidences" of random mutations!

[HenryN]

Some ordinary flu strains resist Tamiflu in study


Sarah Edmonds and Douwe Miedema , Reuters


STOCKHOLM/ZURICH - Some seasonal influenza viruses are resistant to Roche Holding AG's Tamiflu, a study showed, but Roche said no doubts had been raised about the drug's power to combat any deadly bird flu pandemic.
Of 148 samples of influenza A virus isolated from 10 European countries during November and December, 19 showed signs of resistance to Tamiflu, the European Centre for Disease Control said on Monday, citing a preliminary survey.
Of 16 samples from Norway, 12 tested positive for resistance against Tamiflu, which is also known by the generic name oseltamivir, Stockholm-based ECDC said.
View Larger Image A warehouse manager takes a carton of Tamiflu, which contains the antiviral drug oseltamivir, for packing at a pharmaceuticals storage facility in Singapore March 21, 2007. Sewage systems do not break down Tamiflu, which means the main weapon against bird flu could seep into natural waters and make certain viruses resistant to the drug during a pandemic, Swedish researchers said on Wednesday. REUTERS/Nicky Loh




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• *
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"Given the initial indication of a high level of resistance to oseltamivir in the A H1N1 viruses circulating in Norway, late last week ... the Norwegian authorities notified their EU partners and the World Health Organization (WHO) of this situation," the ECDC said.
Tamiflu sales have been lacklustre as Roche completed government orders for pandemic influenza stockpiles to fight a possible pandemic spread among humans of the deadly H5N1 virus, which so far has mainly killed birds.
The resistant strains found by the study were normal seasonal flu viruses, and not avian or pandemic flu, Roche said. The study was also too small to draw firm conclusions.
"These are preliminary results, which are in contrast to previous years, when little or no resistance to Tamiflu was observed," a spokeswoman said.
"More extensive surveillance globally is required to establish the relative prevalence and geographical distribution of the resistant viruses," she said.
Markets shrugged off the results of the study and Roche shares were down 0.7 percent by 1100 GMT, roughly in line with the Dow Jones Stoxx health index.
"The nature of the viruses does not make resistance surprising in our view," Landsbanki Kepler said in a research note, adding that the Tamiflu's limited usefulness against ordinary flu strains had long been known.
The H5N1 avian flu virus, wiping out bird flocks from Indonesia to Africa, rarely infects people but has killed 221 out of 353 people sick since the virus re-emerged in Hong Kong in 2003, according to the World Health Organization.
The ECDC institute said the Norwegian Public Health Institute late last week published an advisory to doctors and the public on its website.
"At this stage it is impossible to say what the level of resistance is in influenza across Europe," it said.
"However from the limited data, the proportion of influenza viruses exhibiting resistance to oseltamivir must be significant, but not as high as in Norway."
It said the oseltamivir-resistant strain of A(H1N1) did not seem to make patients any sicker than non-resistant varieties.
(Editing by Rory Channing/Elizabeth Fullerton)

http://www.canada.com/topics/bodyand...a-f20dc8ddd44e

[HenryN]

Commentary at

http://www.recombinomics.com/News/01...iflu_H1N1.html

[HenryN]

INFLUENZA A (H1N1) VIRUS, OSELTAMIVIR RESISTANCE (02): EUROPE
************************************************** ***********
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: Tue 29 Jan 2008
Source: European Centre for Disease Prevention and Control (ECDC) [edited]
<http://ecdc.europa.eu/Press/press_releases/080127_pr.html>


Resistance to oseltamivir (Tamiflu) found in some European influenza virus
samples
---------------------------------------------------------------------------
Preliminary results from a survey of antiviral drug susceptibility among
seasonal influenza viruses circulating in Europe has revealed that some of
the A (H1N1) viruses in circulation this winter [2007-2008] are resistant
to the antiviral drug, oseltamivir (brand name Tamiflu). So far, 148
samples of influenza A(H1N1) viruses isolated during November and December
[2007] from 10 European countries [see comment below - Mod.CP] have been
tested by the EU funded VIRGIL [European surveillance network for vigilance
against viral resistance.] Of the 148 samples, 19 showed evidence of
resistance to oseltamivir.

Of the samples that tested positive for resistance to oseltamivir 12 came
from Norway. This was from a total of 16 virus samples sent for testing.
Given the initial indication of a high level of resistance to oseltamivir
in the A H1N1 viruses circulating in Norway, late last week [21-27 Jan
2008] once the information came to their attention, the Norwegian
authorities notified their EU partners and the World Health Organization
(WHO) of this situation. The Norwegian Public Health Institute also
published an advisory notice to doctors and the public on its website that
evening.

Experts from the European Centre for Disease Prevention and Control (ECDC),
the European Commission, and WHO are currently assessing the significance
of the data from the VIRGIL network. An interim joint assessment will be
published in the coming days, based on the limited data currently available.

At this stage it is impossible to say what the level of resistance is in
influenza across Europe. However from the limited data, the proportion of
influenza viruses exhibiting resistance to oseltamivir must be significant,
but not as high as in Norway. People who become ill with the oseltamivir
resistant strain of A(H1N1) do not appear to become any [sicker] than
people infected with "normal" seasonal influenza. That said, it should be
remembered that any influenza A can cause severe disease or death in
vulnerable people (older people, those with debilitating illnesses, and the
very young).

For further information see ECDC's Interim Risk Assessment available at
<http://ecdc.europa.eu/pdf/080127_os.pdf>.

--
communicated by:
Professor Angus Nicoll CBE
Senior Expert, Influenza Coordination
European Centre for Disease Prevention and Control (ECDC)
17183, Stockholm
Sweden
<Angus.Nicoll@ecdc.europa.eu>

[The Summary Statement of the ECDC Risk Assessment -- 27 Jan 2008 --
Emergence of seasonal influenza viruses type A/H1N1 with oseltamivir
resistance in some European Countries at the start of the 2007-2008
influenza season -- indicates that Denmark, France, and the United Kingdom
are the other countries in addition to Norway that have detected
oseltamivir-resistant A(H1N1) influenza virus.

The full Summary Statement reads: "Ordinary seasonal influenza viruses with
significant resistance to the antiviral oseltamivir (Tamiflu) have been
detected within the earliest part of this winter's influenza epidemics in
Europe. The viruses are known as influenza A/H1N1 (H274Y), and they were
fully sensitive to other influenza antivirals. These viruses have been
detected by a European research and surveillance project known as VIRGIL
(<http://www.virgil-net.org/>), which has been undertaking routine
surveillance for resistance in circulating influenza strains since
2004-2005. H1N1 viruses are predominant in this winter's epidemics
worldwide, and these resistant viruses are a new phenomenon this winter. A
limited amount of specialist testing has been undertaken for 10 countries
and a proportion of A/H1N1 viruses detected in 4 countries Denmark, France,
Norway, and the UK, have been found resistant to oseltamivir. Overall in
Europe the proportion with oseltamivir resistant is around 13 per cent but
the proportions resistant are variable with Norway showing a markedly high
proportion resistant (12 of 16). If the 16 Norwegian viruses are excluded
the proportion with resistant would fall to around 5 per cent. Data from
Norway indicate that these viruses were transmitted in the country. To date
there are no reports that they are making people any more ill than do other
influenza A viruses. Normally A/H1N1 viruses as a group cause milder
disease than some other human influenza viruses. However it must be
realised that all influenza A viruses are potentially lethal for vulnerable
individuals (the old and the very young and those with chronic debilitating
conditions). It also needs to be remembered that antiviral resistant is a
relative not absolute term. Patients ill with viruses that are deemed
resistant in the laboratory often still seem to benefit when they receive
antivirals." - Mod.CP]

[see also:
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
2000
---
Influenza virus, neuraminidase inhibitor resistance 20010926.2350]

...............cp/mj/sh

[AlaskaDenise]

Originally Posted by niman

Commentary at

http://www.recombinomics.com/News/01...amiflu_US.html

Commentary

H1N1 Tamiflu Resistance in the United States in 2007

Recombinomics Commentary 03:11
January 29, 2008

The European Centres for Disease Control said that while Tamiflu could still provide benefits, 13 per cent of samples of the H1N1 seasonal flu virus affecting Europe tested last November and December – most in Norway – contained a mutation associated with high levels of resistance.

The above comments describe the appearance of the oseltamivir resistance marker, H274Y, in recent H1N1 isolates in Europe.

However, a search of public sequences identifies H274Y suddenly appearing in 2007 H1N1 isolates from the United States (see list below. The number of complete human influenza sequences has grown steadily, largely because of the NIAID influenza sequencing project. At the Los Alamos sequence database, there are 1030 N1 sequences from H1N1 human isolates. 340 are from 2007 and all of the sequences below are from 2007. Thus, although the percentage of samples was low, all were from 2007 and all were Solomon Island-like.

These Solomon-Island lake sequences trace back to Asia, where Tamiflu blankets are frequently applied in the treatment of H5N1. The N1 in H5N1 has donor sequences for human N1 in the region adjacent to the acquisition which generates H274Y, which is the precise change found in the most common form of oseltamivir resistance in H5N1 patients, primarily in Vietnam.

In 2005 a milder version of H5N1 emerged in northern Vietnam. However, initial data supporting widespread mild infections of H5N1 were denied, even after initial results were independently confirmed.

Testing continued until negatives were achieved. The possibility of widespread H5N1 in people in Vietnam was largely discounted and use of Tamiflu in contacts of suspect patients was common.

Now Tamiflu chickens may be coming home to roost.

ISDN282211 A/Hawaii/21/2007 H1N1
ISDN282224 A/Hawaii/28/2007 H1N1
ISDN282222 A/Hawaii/28/2007 H1N1
CY027037 A/Kansas/UR06-0104/2007 H1N1
ISDN282240 A/Minnesota/23/2007 H1N1
ISDN263890 A/Texas/31/2007 H1N1


.

[AlaskaDenise]

Originally Posted by niman

Commentary at

http://www.recombinomics.com/News/01...iflu_H1N1.html

Commentary

H5N1 Tamiflu Blankets and Resistance in European H1N1

Recombinomics Commentary 16:58
January 29, 2008

Influenza experts admitted today that they have been startled by the discovery this season of an unexpectedly high number of human flu viruses that appear to be naturally resistant to Tamiflu, the drug that countries around the world are stockpiling for use in the next flu pandemic.

The viruses have been isolated from people infected with influenza A viruses of the H1N1 subtype in a number of European countries.

The World Health Organization is convening a virtual meeting of experts tomorrow to try to get a handle on how far afield the resistant virus has been found, how common it is and what the findings signify.

"I think this is a very concerning change in influenza virus resistance patterns," Dr. Frederick Hayden, a leading antiviral expert and a member of the WHO's Global Influenza Program, said from Geneva.

The above comments express surprise and concern regarding the sudden appearance of oseltamivir (Tamiflu) resistance in H1N1 seasonal flu, and fail to draw the connection between this dramatic change and the widespread use of Tamiflu blankets to treat H5N1. The change in the human N1 in H1N1 is identical to the avian/human N1 change in H5N1. Both N1’s have created H294Y via the identical nucleotide change, C763T. Although this change has been found in H5N1 patients in Vietnam and Indonesia treated with Tamiflu, it has also been found avian isolates, including mute swans in Astrakhan in 2005 (A/swan/Astrakhan/Russia/Nov-2/2005(H5N1) and A/swan/Astrakhan/1/2005(H5N1)) .

Question of fitness have been raised previously, but the presence of H294Y in wild birds flying around Europe as early as 2005 indicates the change does not carry a significant fitness penalty. Moreover, H294Y was found as early as 2002 in a chicken in Hong Kong, A/chicken/Hong Kong/3123.1/2002(H5N1).

H294Y can move from the N1 in H5N1 to the N1 in H1N1 via recombination. The opportunity for co-infections involving seasonal and pandemic influenza can be found in patients with mild H5N1 infections.

Such infections were suspect in 2005 in northern Vietnam. In contrast to outbreaks in 2004, the case fatality rates of H5N1 in northern and southern Vietnam were dramatically different in early 2005. In the north the clusters were larger and the infections were milder, suggesting H5N1 in humans was becoming more common, and transmitting more efficiently. Almost 1000 samples were collected for analysis. H5N1 was detected locally, so samples were sent to the CDC in Atlanta for confirmation. Positives were also seen in Atlanta, so samples were repeatedly tested until they turned negative. However, the lab results had little effect of the H5N1 in circulation, which was commonly treated with Tamiflu.

This treatment would select for human H1N1 or avian H5N1 with H294Y. This change began to appear in the United States in 2007. The isolates with H294Y were Solomon Island-like, which link back to Asia. Similarly, H5N1 outbreaks in the Middle East were also treated with Tamiflu. In Egypt, a scenario similarly to Vietnam developed in 2007. Early cases in the north were largely fatal, but outbreaks in southern Egypt were mild, again allowing for more efficient spread and co-infections with H1N1 seasonal flu. These co-infections would again create conditions for the movement of H294Y from H5N1 to H1N1 in areas where Tamiflu was used excessively.

Thus, the appearance of H294Y began in 2007 and now is becoming increasingly common in human H1N1 in 2008.

This increasing frequency of Tamiflu resistance in seasonal H1N1 is cause for concern, as is the potential for additional expansion in H5N1.


.

[tropical]

From Reveres EM:
http://scienceblogs.com/effectmeasur...n_seasonal.php

Tamiflu resistance in seasonal flu: the devil is in the details


"... The NA protein comes in 9 different forms. Humans are routinely infected with the N1 and N2 forms, and these aren't the same with respect to Tamiflu. The drugs were designed to work against the N2 form, which was the one where we had x-ray crystallography structures. Recently the N1 form was crystalized, permitting an investigation of the differences in how they react to these drugs. For Tamiflu to interfere with NA action it needs to nestle into a pocket. NA can change shape and for Tamiflu, but not Relenza, to work it needs to nestle into a pocket that forms during that shape change. It is thought the H274Y mutation causes Tamiflu resistance by preventing the formation of the pocket (the binding of Tamiflu is produced by rotating an amino acid near position 274 and its binding to another amino acid at position 224; it's complicated. See Moscona's Perspective in the New England Journal for more explanation). ..."

[HenryN]

Originally Posted by tropical

From Reveres EM:
http://scienceblogs.com/effectmeasur...n_seasonal.php

Tamiflu resistance in seasonal flu: the devil is in the details


"... The NA protein comes in 9 different forms. Humans are routinely infected with the N1 and N2 forms, and these aren't the same with respect to Tamiflu. The drugs were designed to work against the N2 form, which was the one where we had x-ray crystallography structures. Recently the N1 form was crystalized, permitting an investigation of the differences in how they react to these drugs. For Tamiflu to interfere with NA action it needs to nestle into a pocket. NA can change shape and for Tamiflu, but not Relenza, to work it needs to nestle into a pocket that forms during that shape change. It is thought the H274Y mutation causes Tamiflu resistance by preventing the formation of the pocket (the binding of Tamiflu is produced by rotating an amino acid near position 274 and its binding to another amino acid at position 224; it's complicated. See Moscona's Perspective in the New England Journal for more explanation). ..."

This is old news and there is no devil in the detail. H274Y knocks down the efficiency of Tamiflu by 500-1000X, and Tamiflu effectiveness is borderline for N1, without the resistance.

[tropical]

Thank you Dr. Niman.

From bad to worst.

P.S.
The EM news pasus intention was to additionaly auto-respond to an myself previously posed question (in a case anybody watching this thread was thinking also that Tamiflu can contrasted all NA's):
" I always (wrongly?) think that the Tamiflu potential of usage is on ALL kind of flu virus strains.""
with the cited excerpts from one EM post:
"... Humans are routinely infected with the N1 and N2 forms.
... Tamiflu. The drugs were designed to work against the N2 form, which was the one where we had x-ray crystallography structures.
... For Tamiflu to interfere with NA action it needs to nestle into a pocket.
... It is thought the H274Y mutation causes Tamiflu resistance by preventing the formation of the pocket, etc ..."

[HenryN]

Tamiflu-resistant flu viruses found in Canada

Updated Wed. Jan. 30 2008 8:19 AM ET
The Canadian Press

TORONTO -- Canada's National Microbiology Laboratory is reporting a high level of Tamiflu resistance among H1N1 viruses circulating so far this flu season in this country, one of a number of labs to see a phenomenon that is unsettling influenza experts. Nearly 10 per cent of H1N1 viruses tested so far this year by the Winnipeg lab are resistant to the drug, a cornerstone of pandemic planning for many countries around the globe. In the past, fewer than one per cent of circulating human flu viruses were thought to be resistant to Tamiflu.
"That's quite a surprise," the lab's scientific director, Dr. Frank Plummer, said, noting the resistance mutation spotted in the Winnipeg testing is the same one that has been reported over the past few days from Norway, several other European countries and the United States.
Eight of 81 H1N1 viruses tested carry the H274Y mutation - one each from British Columbia and Newfoundland and Labrador, and six from Ontario. Plummer said that total includes one virus (from British Columbia) recovered from a child who is believed to have been infected in Sudan.
His surprise is shared by experts with the World Health Organization's Global Influenza Program, which convened a teleconference of about 50 scientists from leading influenza laboratories around the world Tuesday to try to get a handle on how far this virus has spread, how common it is in places where it is being found and what is driving the spread.
Dr. Frederick Hayden, a leading antiviral expert working at the WHO, said the resistance virus has been reported over a broad geographic range, both in terms of countries and within countries themselves.
"We do know that again within the countries that have the information, it's not just focal pockets. There are multiple sites, for example, within France or within Norway where this has been detected," he said from Geneva.
The United States has reported that 5.5 per cent of tested H1N1 viruses there are resistant to the drug. European countries known to have found resistant viruses include Norway, Denmark, France and the United Kingdom. Hayden suggested more countries have found these viruses, but said he wasn't at liberty to name names.
Perplexingly, Japan - the country that uses more Tamiflu by far than any other in the world - has not found any of these resistant viruses this flu season, Hayden said.
Reports worldwide still number in the "few dozens." But that is enough to send up red flags, especially given that in all of the cases where details are known, people who caught the virus hadn't taken Tamiflu.
It wouldn't be startling to see people who've used the drug shedding viruses that are resistant to it. Like antibiotic resistance, resistance to antiviral drugs can develop in people who use them, though rates of drug-triggered resistance are low with Tamiflu.
But it had been thought that viruses that acquired this H274Y resistance mutation would pay for that gain with a corresponding loss in their ability to transmit. The belief was that if they developed in someone using Tamiflu, they would be unlikely to infect contacts of that person and start to circulate more widely - in essence, that they would be too weak to compete with regular flu viruses in the race to infect human respiratory tracts.
These recent findings suggest the drug is more vulnerable to the development of drug resistance than had been previously thought, experts fear.
"This mutation is not going to affect the fitness of the viruses as much as we thought," said Jennifer McKimm-Breschkin, a virologist with Australia's Commonwealth Science and Industrial Research Organization in Melbourne.
McKimm-Breschkin was one of the scientists involved in the discovery of Tamiflu's competitor, Relenza. Though the two drugs are in the same class, Relenza is still effective against viruses with the H274Y mutation.
"We're now seeing the ability of this virus that we thought would not have the ability to compete (with unmutated viruses) spreading globally," she said, suggesting that doesn't bode well if H5N1 avian flu starts a pandemic. The same mutation creates Tamiflu resistance in H5N1 viruses.
Hayden said the appearance of resistant H1N1 viruses across such a broad expanse "does raise a lot of questions."
Dr. Joe Bresee, chief of flu epidemiology and prevention at the U.S. Centers for Disease Control, questioned Monday whether there was a true rise in the number of resistant viruses.
Bresee cautioned that increased influenza surveillance prompted by concerns over the H5N1 virus may be turning a spotlight on something that always existed but went unnoticed in the past.
Hayden disagreed, saying an international network of antiviral experts has been watching for this resistance pattern but it has only been found rarely.
"Basically it was present at very low frequencies, less than a half per cent. In most studies, (it was) not even detected. So I think this is a new phenomenon and one that we need to understand better."
He said work is already underway to try to catalogue cases and to sequence resistant viruses to see if their genomes hold clues to how the resistance arose.

http://www.ctv.ca/servlet/ArticleNew...130?hub=Canada

[HenryN]

Commentary

http://www.recombinomics.com/News/01...274Y_H5N1.html

[Anty]

Just a short update and a question.

The use of Tamiflu in Norway is uncommon. Why do we see such high numbers of the mutation here?

70% (26 out of 37 ) viruses from different patients and from different parts of Norway have the mutation. (High level of resistance against Tamiflu)

This according to the latest update from The Norwegian Institute of Public Health(Folkehelsa)
(link)
http://fhi.no/eway/default.aspx?pid=...1:5569:1:::0:0

[gsgs]

the virus probably came from outside Norway.
Much (most?) flu is reintroduced each winter from the tropes.

It is unclear, whether some flu also "oversummers".

So the mutation may have been created elsewhere
and the virus reached Norway by airplane or ship.

Just bad luck, that they have so many resistant viruses this year.

[gsgs]

most Tamiflu is used in Japan
number of reported H1-seasonal flu samples:

2007,40,Japan,5
2007,41,Japan,10
2007,42,Japan,22
2007,43,Japan,22
2007,44,Japan,23
2007,45,Japan,46
2007,46,Japan,71
2007,47,Japan,58
2007,48,Japan,128
2007,49,Japan,145
2007,50,Japan,230
2007,51,Japan,163
2007,52,Japan,62
2008,01,Japan,14
2008,02,Japan,55
2008,03,Japan,13

so, the peak was in week 50.
Could those cases be linked to Japan travellers ?