Denmark - Dane with novel H1N1 found resistant to Tamiflu

[Giuseppe]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

(...)


ECDC Threat Assessment

First isolation of a secondary oseltamivir - resistant A(H1N1)v strain in Denmark, 29 June, 2009

SOURCE: Internal request following a EWRS message from Denmark health authorities
PUBLIC HEALTH ISSUE: Isolation of a mutant A(H1N1)v virus containing a genetic marker of resistance to oseltamivir.
CONSULTED EXPERTS: Internal experts

EVENT BACKGROUND INFORMATION:

Event reported by Danish EWRS Focal point on 29 July 2009 :

In the context of tracing contacts of a cluster of 3 imported cases in Denmark, a female contact who initially tested negative on PCR, was given prophylaxis with oseltamivir (75 mg per day). Five days later, despite reportedly having complied with treatment, she developed flu-like symptoms and was tested positive for A(H1N1)v. Sequencing of the virus showed a single mutation H275Y (H274Y in N2 nomenclature) in the neuraminidase gene. The presence of the resistance marker and the phenotypic (in vitro) resistance was confirmed by a WHO collaborating Centre. The virus is not a re-assortant and is presumed to remain susceptible to zanamivir (another neuraminidase inhibitor). All other virus isolated as part of this cluster investigation, including the presumed source patient, did not show the mutation.


ECDC THREAT ASSESSMENT FOR THE EU

The A(H1N1)v virus related to the ongoing pandemic has always be found sensitive to oseltamivir and zanamivir and resistant to adamantanes (M2 blockers). This is the first observation of a genetic marker of resistance to oseltamivir in a A(H1N1)v virus.

The mutation consists of the substitution of histidine to tyrosine at amino acid position 275 in the neuraminidase segment gene (position 274 in N2 nomenclature). This mutation has been described in the past, associated with secondary resistance to oseltamivir acquired during treatment. This was documented some years back in children in Japan where the drug was used more commonly than in Europe(1). The mutation was detected in up to 16% of oseltamivir-treated children in Japan, perhaps associated with under-dosing(2). Studies have shown that the virus containing this mutation is unfit in terms of transmissibility(3) and possibly also in terms of pathogenicity(4) as demonstrated in animal studies. Therefore, such mutation is of limited public health concern since it has not resulted in the past in a virus that demonstrated sustained person-to-person transmission.

According to the available epidemiological and virological data, this reported event in Denmark is almost certainly secondary resistance acquired during post-exposure prophylaxis. This is supported by the time sequence and the absence of similar genotypic markers in viruses isolated in the other cases of the cluster.

There is no evidence in this case that the isolated resistant virus has transmitted to other persons, meaning that the risk of spread of a resistant virus is nearly zero. It is however likely that such mutation will be observed again in the future. This observation does highlight the increased likelihood of such event arising from widespread use of anti-virals especially in prophylaxis.

Secondary resistance, arising due to treatment, must not be confused with more complex mutations including the H274Y substitution resulting from primary resistance. Such primary resistance was first observed in seasonal A(H1N1) influenza virus in the 2007-2008. It spread worldwide generally displacing other seasonal A(H1N1) viruses (98% resistance in EU in 2008-2009)(5). Following that phenomenon some EU countries have diversified their anti-virals stockpiles adding zanamivir to oseltamivir.

There is always a theoretical risk of re-assortment of A(H1N1)v with primary resistant seasonal viruses notably the seasonal influenza virus A(H1N1) containing the H274Y mutation.


CONCLUSIONS AND RECOMMENDATIONS

The emergence of secondary resistance while on antiviral treatment is a well recognised phenomenon in influenza viruses. As in the past, there is no evidence the mutation has led to a virus capable of transmitting from person to person. Therefore, though resistant viruses are always a concern, the emergence of A(H1N1)v resistant to oseltamivir does not represent a public health threat. It can be expected to happen again.

Surveillance of genetic resistance for detecting early primary resistance is of particular importance for the future course of the pandemic

CONTACT: support@ecdc.europa.eu


References

(1) Whitley RJ, Hayden FG, Reisinger K, Young N, Dutkowski R, Ipe D, et al. Oral oseltamivir treatment of influenza in children. Ped Infect Dis J 2001; 20(2):127-33.
(2) Ward P, Small I, Smith J, Suter P, Dutkowski R. Oseltamivir (Tamiflu(R)) and its potential for use in the event of an influenza pandemic. J Antimicrob Chemother 2005; 55(suppl_1): i5-21.
(3) Compromised transmission: Herlocher ML, Truscon R, Elias S; et al. Influenza viruses resistant to the antiviral drug oseltamivir: transmission studies in ferrets. J Infect Dis. 2004;190(9):1627-30
(4) Attenuated pathogenicity: Ives JA, Carr JA, Mendel DB; et al. The H274Y mutation in the influenza A/H1N1 neuraminidase active site following oseltamivir phosphate treatment leave virus severely compromised both in vitro and in vivo. Antiviral Res. 2002; 55(2): 307-17
(5) Meijer A, Lackenby A, Hungnes O, Lina B, van der Werf S, Schweiger B, et al. Oseltamivir-resistant influenza A (H1N1) virus, Europe, 2007?08 season. Emerg Infect Dis. 2009; 15(4):552-60

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http://www.ecdc.europa.eu/en/files/pdf/Health_topics/Situation_Report_090630_1700hrs.pdf
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[Mamabird]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

Please carefully read the ECDC assessment of the Danish resistant virus, appended to their daily Swine Flu update:

http://ecdc.europa.eu/en/files/pdf/Health_topics/Situation_Report_090630_1700hrs.pdf

This has been categorized as a secondary resistant virus due to the use of Tamiflu administered to the patient. It is not primary resistance, ie., one that was acquired from the virus of another infected person. This is based on the isolation of the viruses in the cluster of contacts around the Danish woman. None of those sequences revealed the NA mutation causing Tamiflu resistance.

 

[Mamabird]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

I guess we can expect the release of all the related Danish genetic sequences in very short order, expecially since this case apparently resolved itself earlier in the month.

 

[HenryN]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

Please carefully read the ECDC assessment of the Danish resistant virus, appended to their daily Swine Flu update:

http://ecdc.europa.eu/en/files/pdf/Health_topics/Situation_Report_090630_1700hrs.pdf

This has been categorized as a secondary resistant virus due to the use of Tamiflu administered to the patient. It is not a primary virus, ie., one that was acquired from another infected person. This is based on the isolation of the viruses in the cluster of contacts around the Danish woman. None of those sequences revealed the NA mutation causing Tamiflu resistance.

The report is rather vague on who and how many were in the cluster, as well as how hard they looked. If the overseas traveler had a mixture, the Tamiflu may have selected H274Y in the patient who developed symptoms after being on Tamiflu for 5 days, while the other isolates may have been collected prior to treatment, keeping the resistant sequence at a low level.

This is somewhat like the data for S227N in H5N1 in Tuirkey. The index case had S227N, but his sister didn't. Webridge said the S227N developed in the index case but subsequently two more sequences were release from others in Turkey (they would say from who) and one had S227N while the other didn't. In all likelihood all four had S227N and the published sequence represented what grew out in cluture. Of the four sequences two had S227N and two didn't.

The same thing happened in the SARS outbreak. All of the polymorphisms really originated with the index case, but many were absent from the sequence from the index case and many jumped contacts

I will still predict that H274Y will soon start appearing in swine H1N1, including patients who are NOT taking Tamiflu.

Notice that this group STILL can't explain how H274Y in seasonal flu managed to jump from genetic background to genetic background in the absence of Tamiflu and just calls it "complex".

 

[HenryN]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

I guess we can expect the release of all the related Danish genetic sequences in very short order, expecially since this case apparently resolved itself earlier in the month.

The tracing will likely be more informative than the sequence, unless the sequence has mixed signals. It is of note that this incident apparently happened some time ago, but to date there is a total of ONE sequence, collected in APRIL, that is public.

 

[HenryN]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

Please carefully read the ECDC assessment of the Danish resistant virus, appended to their daily Swine Flu update:

http://ecdc.europa.eu/en/files/pdf/Health_topics/Situation_Report_090630_1700hrs.pdf

This has been categorized as a secondary resistant virus due to the use of Tamiflu administered to the patient. It is not primary resistance, ie., one that was acquired from the virus of another infected person. This is based on the isolation of the viruses in the cluster of contacts around the Danish woman. None of those sequences revealed the NA mutation causing Tamiflu resistance.

I do not think that the three "cluster" members at the airport were necessarily contacts of the Danish woman. The text says the "presumed source contact" was negative, indicating the Danish woman only had one contact within the cluster. In fact the wording in the report suggest that the "import" cluster may simply be three individuals at the airport during some time frame who tested positive.
Of course if the one presumed contact did not have detectable H274Y, then there is still the issue of wild type, which could still be part of a mixture. Alternativly, since the contact cluster really only involves the two people (the absence of H274Y in the other two "cluster members" is really irrelvant), and it is likely that the sample of the traveling contact was collected prior to treatment, then the H274Y sample may have just been selected from a minor population, rather than a population generated by a de novo mutation. If the H274Y is just a minor population, then it is likely in patients at the origin of the flight and unaffected by the failure of the H274Y to transmit in Denmark.

 

[sharon sanders]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

Please carefully read the ECDC assessment of the Danish resistant virus, appended to their daily Swine Flu update:

http://ecdc.europa.eu/en/files/pdf/Health_topics/Situation_Report_090630_1700hrs.pdf

This has been categorized as a secondary resistant virus due to the use of Tamiflu administered to the patient. It is not primary resistance, ie., one that was acquired from the virus of another infected person. This is based on the isolation of the viruses in the cluster of contacts around the Danish woman. None of those sequences revealed the NA mutation causing Tamiflu resistance.

Thanks Mamabird for the explanation of the ECDC report.

 

[Mamabird]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

"By Christian Wienberg and Marthe Fourcade
June 29 (Bloomberg) -- Roche Holding AG said a swine flu patient treated with its Tamiflu drug in Denmark showed resistance to the antiviral medicine for the first time.
The patient was given a low dose of Tamiflu preventively after coming in contact with someone infected with the H1N1 pandemic virus, said David Reddy, who heads Roche?s influenza task force. The person developed flu symptoms and was found to have a virus mutation that evaded the drug, Reddy said on a conference call today. "

snip

The above was from an earlier post based on a conference call with the Roche official. As we know today based on the ECDC assessment, the patient was given 75mg of Tamiflu per day. This is the standard dosage recommended by Roche for both prevention and treatment of influenza.

 

[HenryN]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

"By Christian Wienberg and Marthe Fourcade
June 29 (Bloomberg) -- Roche Holding AG said a swine flu patient treated with its Tamiflu drug in Denmark showed resistance to the antiviral medicine for the first time.
The patient was given a low dose of Tamiflu preventively after coming in contact with someone infected with the H1N1 pandemic virus, said David Reddy, who heads Roche?s influenza task force. The person developed flu symptoms and was found to have a virus mutation that evaded the drug, Reddy said on a conference call today. "

snip

The above was from an earlier post based on a conference call with the Roche official. As we know today based on the ECDC assessment, the patient was given 75mg of Tamiflu per day. This is the standard dosage recommended by Roche for both prevention and treatment of influenza.

Standard treatment is 2 X 75 mg per day.

(A packet contains 10 pills. For prophylaxis it is one a day for 10 days. For treatment it is 2 a day for 5 days).

 

[Mamabird]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

Standard treatment is 2 X 75 mg per day.

(A packet contains 10 pills. For prophylaxis it is one a day for 10 days. For treatment it is 2 a day for 5 days).

That's correct. I misspoke.

The same total amount is used, but for prevention it is simply spread out over a longer time period. My point was that the dosage administered to the patient was that recommended by the manufacturer of the drug, not some lower dosage.

http://www.tamiflu.com/taking/default.aspx

 

[Shiloh]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

Source: http://www.cidrap.umn.edu/cidrap/content/influenza/swineflu/news/jun3009tamiflu-ms.html


Health officials say antiviral resistance likely in some pandemic flu cases

Jun 30, 2009 (CIDRAP News) ? A spokesman for Roche, the maker of oseltamivir (Tamiflu), said yesterday that Denmark's report of resistance to the drug in a patient with novel H1N1 (swine) influenza, the first reported finding of its kind, wasn't surprising and that the news underscores the importance of monitoring for any viral changes.

David Reddy, who leads Roche's influenza task force, told Bloomberg News that experts know that during seasonal influenza outbreaks, patients can develop resistance. "We fully expect that this can also occur during treatment with a new flu strain," he said.

He characterized what occurred in the Danish patient as "drug-induced resistance" that developed when a low dose of medication was used, as opposed to the more widespread resistance that occurs when a flu virus acquires new characteristics, which has happened over the past 2 years with the seasonal H1N1 strain.

World Health Organization (WHO) spokesman Dick Thompson said today that the Danish case is isolated and has no public health implications, Reuters reported. "But we must remain alert as the virus can change at any time and we must not be complacent," he added.

The antiviral resistance finding will not prompt any changes in the WHO antiviral recommendations, Thompson told Reuters.

Roche said it is monitoring drug resistance in several countries, and health officials in several nations, including the United States, are also watching for changes in the virus. The US Centers for Disease Control and Prevention (CDC) said in its most recent surveillance report, released Jun 24, that of 191 novel H1N1 isolates that have been tested for resistance to neuraminidase inhibitors, none showed resistance.

The CDC recommends treatment with oseltamivir or zanamivir for all patients who have confirmed, probable, or suspected novel H1N1 infections who are hospitalized or are at high risk for complications.

Carolyn Bridges, MD, associate director of epidemiologic science in the CDC's influenza division, told National Public Radio that though the United States hasn't detected any antiviral resistance in the new virus, it will likely occur here eventually. She said the novel flu virus has an "N1" gene that is very different than the "N1" of the seasonal H1N1 virus, so perhaps the pandemic virus isn't as susceptible to the antiviral resistance mutation seen with the seasonal H1N1 strain.

See also:

CDC influenza surveillance report for week ending Jun 20

 

[HenryN]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

That's correct. I misspoke.

The same total amount is used, but for prevention it is simply spread out over a longer time period. My point was that the dosage administered to the patient was that recommended by the manufacturer of the drug, not some lower dosage.

http://www.tamiflu.com/taking/default.aspx

Yes, the dosage was as recommended, but there is preceident for resistance in patients on a prophylactic does. The sister in Vietnam who had H5N1 with H274Y and N294S was also on a prophylactic dose initially. Although this level is approved, there are trials to test dosing at higher levels.

However, I still think that the H274Y was/is circulating and more examples will be announced in the not too distant future - they level is too high in seasonal flu to preclude acquistion by pandemic H1N1.

 

[the doctor]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

CDC oseltamivir recommendations: The CDC recommends treatment with oseltamivir or zanamivir for all patients who have confirmed, probable, or suspected novel H1N1 infections who are hospitalized or are at high risk for complications.

I think it is pretty unlikely that any patient meeting the criteria used by the CDC in their above recommendation would be able to obtain Tamiflu within the 48 hour treatment window from the onset of symptoms required for it to be an effective influenza treatment.

Most patients would not even show up in the doctor's office or ER until they had been sick for a few days at least.

This catch 22 recommendation is worthless. If followed, only patients who are least likely to benefit from Tamiflu because they have had influenza too long before receiving it will be treated with Tamiflu.

What an absurd situation. Does the CDC really carefully think out how their recommendations can actually be carried out in the real world before they issue them? Obviously not in this case.

Grattan Woodson, MD

 

[Mamabird]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

Yes, the dosage was as recommended, but there is preceident for resistance in patients on a prophylactic does. The sister in Vietnam who had H5N1 with H274Y and N294S was also on a prophylactic dose initially. Although this level is approved, there are trials to test dosing at higher levels.

However, I still think that the H274Y was/is circulating and more examples will be announced in the not too distant future - they level is too high in seasonal flu to preclude acquistion by pandemic H1N1.

Well, you know Roche needs to do one of two things. Reconcile themselves to the fact that this resistant strain may in fact be circulating, and therefore Tamiflu could not have aided the patient. Or, on the other hand, given the history of secondary resistance based on 75mg per day, increase the recommended dosage so that this will not likely be as big of an issue going forward.

Just sitting on top dead center making excuses is not leadership.

 

[Mamabird]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

From earlier post:

"David Reddy, who leads Roche's influenza task force, told Bloomberg News that experts know that during seasonal influenza outbreaks, patients can develop resistance. "We fully expect that this can also occur during treatment with a new flu strain," he said."

This is not a surprise, this is nothing new, we know it happens, everyone just needs to "be happy, don't worry". We at Roche, WHO and CDC have decided not to change our antiviral recommendations, but we will continue to monitor these evolving events very closely.

Sorry for brain warp - its been a long day.

 

[HenryN]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

<a rel="nofollow" href="http://www.recombinomics.com/News/07010901/H274Y_Swine_Acquisition.html">Commentary</a>

 

[kiwibird]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

So, Dr Niman, you believe this lady was the mixing vessel, one of the 5% who have 2 viral infections at the same time? If that happens here in NZ it would be one week of being ill, one week of tamiflu treatment to disclose the resistant virus - and then sick people needing ventilators. This would be week 4 of our flu season - the very peak. Already we have exceeded the ceiling for the last two years cases. Timely news from the local health boards would be appreciated.

 

[AlaskaDenise]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

<a rel="nofollow" href="http://www.recombinomics.com/News/07010901/H274Y_Swine_Acquisition.html">Commentary</a>

Acquisition of H274Y Tamiflu Resistance in Pandemic H1N1

Recombinomics Commentary 02:09
July 1, 2009

In the context of tracing contacts of a cluster of 3 imported cases in Denmark, a female contact who initially tested negative on PCR, was given prophylaxis with oseltamivir (75 mg per day). Five days later, despite reportedly having complied with treatment, she developed flu-like symptoms and was tested positive for A(H1N1)v. Sequencing of the virus showed a single mutation H275Y (H274Y in N2 nomenclature) in the neuraminidase gene. The presence of the resistance marker and the phenotypic (in vitro) resistance was confirmed by a WHO collaborating Centre. The virus is not a re-assortant and is presumed to remain susceptible to zanamivir (another neuraminidase inhibitor). All other virus isolated as part of this cluster investigation, including the presumed source patient, did not show the mutation.

According to the available epidemiological and virological data, this reported event in Denmark is almost certainly secondary resistance acquired during post-exposure prophylaxis. This is supported by the time sequence and the absence of similar genotypic markers in viruses isolated in the other cases of the cluster.

There is no evidence in this case that the isolated resistant virus has transmitted to other persons, meaning that the risk of spread of a resistant virus is nearly zero.

Secondary resistance, arising due to treatment, must not be confused with more complex mutations including the H274Y substitution resulting from primary resistance. Such primary resistance was first observed in seasonal A(H1N1) influenza virus in the 2007-2008. It spread worldwide generally displacing other seasonal A(H1N1) viruses (98% resistance in EU in 2008-2009

The above risk assessment by the European Centre for Disease Control indicates the oseltamivir resistance identified in a female <a rel="nofollow" href="http://www.recombinomics.com/News/06290902/Pandemic_H1N1_Resistance.html">contact</a> of a pandemic H1N1 confirmed traveler was due to the acquisition of H274Y. The report also indicates the sequence from the likely source of the pandemic H1N1 infection of the contact did not contain H274Y, supporting the acquisition during prophylactic treatment leading to a low risk assessment for spread.

However, there are alternate explanations for the failure to detect H274Y in the sequence from the traveling contact. If the contact was infected with two versions of H1N1, sample collection prior to oseltamivir treatment would generate the sequence of the dominant wild type species. The local contact, who developed symptoms five days after the start of treatment , would test positive for H274Y because the prophylactic treatment would lower the level of wild type RNA. Thus, potential spread of resistance would reside in patients in the originating country, who could travel to Denmark and re-introduce the H274Y.

Alternatively, the local contact could have been infected by another source in Denmark, since there were no symptoms during the first five days of prophylactic treatment. Although Denmark has reported a relatively low level of H1N1 in residents, like most countries in Europe, testing is focused on airport travelers and contacts, while testing for community spread is limited. However, since many passengers will be infected shortly before flight, many will be asymptomatic. Others will be asymptomatic because of an infection that does not produce a high fever, while others will have symptoms reduced because of medications. Thus, the number of passengers evading detection at airports will be large, leading to H1N1 spread in the community.

The evidence for H274Y acquisitions via recombination are linked to the recent patterns of spread in H1N1 seasonal flu. Although the report notes the dramatic primary spread of H274Y between 2007-2009, it simply calls such spread complex and fails to address the appearance of H274Y on multiple genetic backgrounds in the absence of Tamiflu treatment. It is the jumping of H274Y from one genetic background to another (recombination) that has raised concerns that such jumps will lead to acquisition of H274Y on a pandemic H1N1 background, because the H274Y level is near 100% in seasonal flu and pandemic H1N1 is accelerating its <a rel="nofollow" href="http://www.recombinomics.com/News/06300901/H274Y_Swine_Silent.html">spread</a> through the human population, increasing the frequency of dual infections involving swine and seasonal H1N1.

Thus, the acquisition of H274Y is expected and it is likely that there will be more examples of sequences like the resistance described in the above report. Release of the sequences from the cluster would be useful, as would the travel history of the traveler thought to have infected the contact who developed resistance via H274Y.

These data should launch more aggressive surveillance worldwide. Although countries have been promptly depositing sequences, the number of sequences remains low. Denmark has only deposited one sequence, which was from a patient infected in April.

The start of flu season in the southern hemisphere should lead to rapid evolution and the widespread acquisition of important polymorphisms, such as PB2 E627K, which was reported in Shanghai, but present only in the original sequence and the first clone, and NA H274Y, as found in the above patient from Denmark.

.

 

[AlaskaDenise]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

from post #131:

She said the novel flu virus has an "N1" gene that is very different than the "N1" of the seasonal H1N1 virus, so perhaps the pandemic virus isn't as susceptible to the antiviral resistance mutation seen with the seasonal H1N1 strain.

Is the N1 gene of novel H1N1 very different from seasonal?

Do the the words "isn't as susceptible to the antiviral resistance mutation" mean they believe it is less likely to reassort because it is so different?

If I remember correctly, the NA is swinish, so is there antiviral resistance in influenza commonly circulating in pigs?

.

 

[HenryN]

Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

So, Dr Niman, you believe this lady was the mixing vessel, one of the 5% who have 2 viral infections at the same time? If that happens here in NZ it would be one week of being ill, one week of tamiflu treatment to disclose the resistant virus - and then sick people needing ventilators. This would be week 4 of our flu season - the very peak. Already we have exceeded the ceiling for the last two years cases. Timely news from the local health boards would be appreciated.

The two sequences would be minor swine variants (with and without H274Y). The original mixing between swine and human H1N1 was likely upstream (in country where traveler was) and the mixture is widespread (in a very high percentage of patients - the mixing of closely related sequences is in almost all samples - the published sequence is a "consensus").