Hong Kong: Detection of human swine influenza virus resistant to Tamiflu in person from USA

[wotan]

Re: Hong Kong: Detection of human swine influenza virus resistant to Tamiflu in person from USA

I don't see any reports saying she was a resident of California. She could have been from HK and was visiting San Francisco. If she traveled with a group, someone else in that group could have infected her.

For that matter she could have been from anywhere and simply had a layover in San Francisco before traveling to HK.

.

Those may all be true, but there is a strong implication that the resistance at the least had its origins in the western hemisphere. Something tells me you don't fly from Berlin to HK by way of San Francisco.

[AlaskaDenise]

Re: Hong Kong: Detection of human swine influenza virus resistant to Tamiflu in person from USA

.....not only was in Hong Kong, but was also in San Francisco, the origin of the traveler.

I don't see any reports saying she was a resident of California. She could have been from HK and was visiting San Francisco. If she traveled with a group, someone else in that group could have infected her.

For that matter she could have been from anywhere and simply had a layover in San Francisco before traveling to HK.

.

[HenryN]

Re: Hong Kong: Detection of human swine influenza virus resistant to Tamiflu in person from USA

Niman, I know that in the past you have expressed the opinion that this pandemic will follow the pattern of the 1918 Spanish flu pandemic. I believe that the spring/summer outbreak in 1918 died down in August and peaked again in October and February. Do you envision that happening again, or do you believe that this novel H1N1 will be one continuous wave rather than the herald wave followed by subsequent second and third waves?

Also, what is your opinion regarding the virus circulating in Argentina and New Zealand and elsewhere in the southern hemisphere? Do you believe that it is a strain that has adapted to spread faster in humans (temperature adjustment) or the original strain? Do you think they are circulating simultaneously, one on the southern hemispehre and one in the northern? Have there been enough sequences published to determine which one is dominant now?

Thanks for your opinions.

The virus has a lot to work with and although sequences are being deposited promptly, there are many holes in the database as well as delays. Although H274Y has now been reported in Denmark, Japan, and Hong Kong (in a patient who arrived from San Francisco and didn't take tamiflu), the number of pandemic H1n1 sequences with H274Y remains are ZERO (as of this morning). The PB2 E627K was in the original and first clone from Shanghai, but not the second clone.
There are a lot of open issues with teh sequences.

Most deatsh in South America, including Argentina, were in the past week, so these sequences are not available.

The rapid rise in deaths in the southern hemisphere signals a change, but its not obvious in the database yet.

I expect the virus to evolve, and to evolve more rapidly as the flu season grows in the soiuthern hemisphere and more of the population develops antibodies to the current strain.

The virus is just starting to roll and one or two minor changes can have a MAJOR effect.

Right now it still looks like a 1918 train wreck between trains on the same track which are gathering speed and heading towards each other.

[AlaskaDenise]

Re: Hong Kong: Detection of human swine influenza virus resistant to Tamiflu in person from USA

<a rel="nofollow" href="http://www.recombinomics.com/News/07030903/H274Y_Lessons.html">Commentary</a>

Commentary

Lesson Not Learned in H1N1 Tamiflu Resistant Spread

Recombinomics Commentary 18:26
July 3, 2009

"Picking it up in a patient who was not treated is a cause for concern," Malik Peiris, professor of microbiology at Hong Kong University, said in an interview. "One case doesn't change the world, but if we are seeing more and more cases in patients who are not treated, then I think it would be more serious."

The patient, who was admitted to Queen Mary Hospital for isolation, tested positive for the new H1N1 flu strain and opted not to take Tamiflu, Hong Kong's health department said. She had mild symptoms and was discharged upon recovery on June 18.

"The key point is whether the strains will become dominant and then we will have a problem," he said. "At this moment, I don't think there is cause for alarm. There is certainly cause for heightened surveillance."

"Constant, random mutation is the survival mechanism of the microbial world," WHO Director-General Margaret Chan said in an address to a meeting on the flu pandemic in Cancun, Mexico, yesterday. "Like all influenza viruses, H1N1 has the advantage of surprise on its side."

Studies have shown that Tamiflu-resistant bugs develop in 0.4 percent to 4 percent of adults and children treated for seasonal influenza, Claudia Schmitt, a spokeswoman at Roche, said by phone from Basel today.

The above comments on the <a rel="nofollow" href="http://www.recombinomics.com/News/06290902/Pandemic_H1N1_Resistance.html">emergence</a> of H274Y and associated oseltamivir (Tamiflu) resistance clearly show that lessons were not learned from the spread of H274Y in seasonal flu (limited to H1N1). The spread of H274Y in seasonal flu destroyed the old paradigm of influenza evolution by selection of "random mutations", but as seen above, WHO is still citing that mechanism to try to explain the emergence of H274Y in pandemic H1N1 in Denmark, Japan, <a rel="nofollow" href="http://www.recombinomics.com/News/07030901/H274Y_HK_SF.html">Hong Kong and San Francisco</a>.

<a rel="nofollow" href="http://www.recombinomics.com/News/06290903/H274Y_Swine_Roche.html">Roche</a> is still citing old data on the emergence of resistance in Japan years ago, when children were treated with sub-optical doses. That data provided a classical example of resistance, which was linked to the sub-optimal dosing, as well as mutations in H1N1 and H3N2 at multiple locations within each sero-type. However, those changes were only viable in the presence of Tamiflu, which killed off the competing wild type strains.

In 2005 when resistance developed in treated patients or contacts infected with H5N1 the same assurances on lack of fitness and failure to spread were offered. The first example was a patient on a prophylactic dose because her brother was a confirmed case. She developed an infection, but responded to a therapeutic dose, even though H5N1 with H274Y as well as N296S was identified in sub-clones from the patient.

Although the spread of resistant H5N1 in patients was not reported, the appearance of H274Y in H1N1 in wild birds later that year was cause for concern. The wild birds in Russia were not given oseltamivir, yet H5N1 was isolated from dead birds indicating H5N1 with H274Y was evolutionarily fit, leading to transmission between birds and fatal infections.

Concerns of H274Y were increased the following year when it was reported in seasonal flu in China. The clade 2C (Hong Kong strain) with H274Y was found in patients who were not taking Tamiflu, again showing that evolutionarily fit could transmit to humans who were not taking Tamiflu.

The following season (2006/2007), H274Y jumped to another H1N1 sub-clade (clade 1 - New Caledonia strain) in the United States and United Kingdom. The multiple sub-clades within clade 1 signaled multiple introductions into patients not taking Tamiflu.

The following season (2007/2008), H274Y jumped again. Initial cases in the United States were in Hawaii were clade 2B (Brisbane strain), but did not spread. However, the H274Y jumped onto another clade 2B sub-clade which did spread in the United States and Europe. This sub-clade was initially reported in Norway in early 2008, but had been silently spreading throughout the fall.

In the summer of 2008 the H274Y in combination with HA A193T emerged, which then led to the fixing of H274Y at levels approaching 100&#37; of H1N1. The A193T, as well as several additional polymorphisms had been co-circulating on clade 2C. The acquisition of these polymorphisms, including three consecutive polymorphisms in NA signaled recombination, because the NA polymorphisms were not only consecutive, but included a synonymous change, which offered no obvious selection pressure.

Thus, the data was inconsistent with a "random mutation" mechanism. The key changes were co-circulating on a related sub-clade, and were appended onto a clade 2B backbone. The H274Y jumped from background to background in patients who were not taking Tamiflu. This spread of H274Y via recombination and genetic hitchhiking did not require de novo mutations. The key polymorphisms were already circulating in clade 2C, and had earlier been found in other H1N1 or H1N2 isolates.

The mechanism of evolution raised serious concerns when swine H1N1 acquire efficient transmission in humans. This transmission offered the opportunity of genetic exchanges between human seasonal H1N1 and swine H1N1 which was now also in humans. Dual infections would allow for H274Y jumping form seasonal flu to pandemic flu in patients infected with both viruses.

Thus, the detection of H274Y in Denmark this week was not a surprised. However, since the patient had been on a prophylactic dose of oseltamivir, the random mutation paradigm was used to explain the data and offer assurances that the resistance wouldn't spread. However, the appearance of H274Y in the treated patient raised concerns that H274Y was lurking in a minor sub-population that was missing in sequencing of untreated patients, and was detected only in treated patients.

The data from Denmark was repeated in Japan this week, when another patient being treated with a prophylactic dose of oseltamivir also gave rise to the detection of H274Y. However, the appearance of H274Y in the absence of other resistance changes raised concerns that H274Y had already been acquired via recombination and was silently spreading in association with wild type H1N1.

The concerns were increased by the announcement in Hong Kong at a traveler from San Francisco, who was not taking Tamiflu was harboring a resisitant sequence, which was almost certainly H274Y. The presence of resistance in a patient not taking Tamiflu indicated the pandemic H1N1 with H274Y was evolutionarily fit and not only was in Hong Kong, but was also in San Francisco, the origin of the traveler.

However, H274Y has not been reported in the United States, raising <a rel="nofollow" href="http://www.recombinomics.com/News/07030902/H274Y_Swine_Spread.html">serious surveillance concerns</a>. Most efforts are directed to hospitalized serious cases, and state across the country announced that they were no longer testing mild cases. However, the Hong Kong, ex-San Francisco case was mild, which may explain the lack of detection.

However, of greater concern is the ability of H274Y to jump from one background to another in the absence of oseltamivir selection.

However, statements above indicate the lesson from seasonal flu was not learned, and the old discredited random mutation explain is once again offered, along with assurances that the H274Y will not spread (even after it has been found or implied on three continents).

Increased surveillance will demonstrate not only that H274Y can spread, but that it has already spread, under the radar of the current surveillance system. Moreover, the reliance of the old "random mutation" paradigm will lead to more "surprises" but those who adhere to an paradigm which is inconsistent with the sequence data.

An increase in surveillance and sequencing will allow for more accurate products of future acquisitions, which are due to recombination and not due to de novo mutations, as repeated again and again by those who ignore the data, or quote those who ignore the data.

.

[AlaskaDenise]

Re: Hong Kong: Detection of human swine influenza virus resistant to Tamiflu (7/3/09)

<a rel="nofollow" href="http://www.recombinomics.com/News/07030902/H274Y_Swine_Spread.html">Commentary</a>

Commentary

Surveillance Flaws Drive Silent Spread of Tamiflu Resistant H1N1

Recombinomics Commentary 15:18
July 3, 2009


The virus was isolated from the specimen taken from a 16-year-old girl coming from San Francisco. She was intercepted by Port Health Office at the Hong Kong International Airport on June 11 upon arrival. The girl was then admitted to Queen Mary Hospital for isolation. She was tested positive to HSI but opted not to take tamiflu. She had mild symptoms and was eventually discharged upon recovery on June 18.


The above comments from a Hong Kong DOH press release on Tamiflu resistance in pandemic H1N1 highlight severe limitations in worldwide surveillance. Although this case was identified by routine surveillance of H1N1 positive patients in <a rel="nofollow" href="http://www.recombinomics.com/News/07030901/H274Y_HK_SF.html">Hong Kong</a>, it is an effort largely focused on travelers. Like countries outside of the Americas, most efforts have focused on travelers and largely ignored local community spread. The recent explosion in cases in the UK has led to a focus on the community spread there, but many other counties in Europe are reporting low numbers of confirmed pandemic H1N1 because of limited testing in the community.

In the US, efforts are focused on the community, but severe cases are targetted. Most states have stopped reporting and testing mild cases, so real monitoring of this group is minimal. However, the case in Hong Kong originated in San Francisco and was mild. The United States has not reported any Tamiflu resistance. The CDC has tested over 200 isolates and failed to identify H274Y.

This may be due in part to <a rel="nofollow" href="http://www.recombinomics.com/News/07010901/H274Y_Swine_Acquisition.html">virus mixtures</a>. In Denmark and Japan the H274Y was discovered in patients undergoing Tamiflu prophylactic treatment. The Tamiflu treatment would reduce wild type H1N1 and allow a minor population with H274Y to expand and be detected. Therefore, it is likely that the H274Y is spreading silently and under the radar of the sequencing efforts, which are focused on the dominant (consensus) sequence.

The acquisition of H274Y by pandemic H1N1 was not unexpected. H274Y has a history of jumping from one sub-clade to another, as well as jumping to multiple different backgrounds within a subclade via recombination and genetic hitchhiking. This has produced resistance that is limited to H1N1 and H274Y within H1N1. The co-circulation of human H1N1 seasonal flu with swine H1N1 in humans, has created a favorable environment for the jump of H274Y from seasonal flu to pandemic flu. Moreover, the widespread use of Tamiflu in patients infected with pandemic H1N1 will drive the rate of spread in pandemic H1N1.

Although countries have been placing sequences on deposit in a timely manner, there are still major deficiencies in the surveillance program, as described above. Moreover, the recent reports of Tamiflu resistance in isolates in Denmark, Japan, and Hong Kong have not lead to the release of these sequences.

An increase in surveillance and release of full sequences is still necessary. The pandemic H1N1 is now rapidly spreading in the southern hemisphere, which is just beginning its flu season. Sequences from fatal and mild cases are required to determine important changes in pandemic H1N1 associated with increased virulence as well as increased spread.

A serious comprehensive surveillance program is long overdue.

.

[DeniseMc]

Re: Hong Kong: Detection of human swine influenza virus resistant to Tamiflu in person from USA

Niman, I know that in the past you have expressed the opinion that this pandemic will follow the pattern of the 1918 Spanish flu pandemic. I believe that the spring/summer outbreak in 1918 died down in August and peaked again in October and February. Do you envision that happening again, or do you believe that this novel H1N1 will be one continuous wave rather than the herald wave followed by subsequent second and third waves?

Also, what is your opinion regarding the virus circulating in Argentina and New Zealand and elsewhere in the southern hemisphere? Do you believe that it is a strain that has adapted to spread faster in humans (temperature adjustment) or the original strain? Do you think they are circulating simultaneously, one on the southern hemispehre and one in the northern? Have there been enough sequences published to determine which one is dominant now?

Thanks for your opinions.

[HenryN]

Re: Hong Kong: Detection of human swine influenza virus resistant to Tamiflu in person from USA

<a rel="nofollow" href="http://www.recombinomics.com/News/07030903/H274Y_Lessons.html">Commentary</a>

[Commonground]

Re: Hong Kong: Detection of human swine influenza virus resistant to Tamiflu in person from USA

Has this been mentioned in earlier articles? I don't think so....

.....said Jennifer McKimm- Breschkin, a virologist at the Commonwealth Science and Industrial Research Organization in Melbourne.
?It?s very disturbing that, fresh into the human population, this one appears now to be able to retain fitness despite having the mutation and to be able to spread,? she said in a telephone interview today.

[HenryN]

Re: Hong Kong: Detection of human swine influenza virus resistant to Tamiflu in person from USA

Tamiflu-Resistant Swine Flu Virus Found in Hong Kong (Update2)


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By Nipa Piboontanasawat and Jason Gale
July 3 (Bloomberg) -- Tamiflu-resistant swine flu was found in a teenager who hadn?t taken Roche Holding AG?s best-selling antiviral medicine, Hong Kong?s health department said.
The city?s Public Health Laboratory Services Branch identified the drug-evading variant during routine surveillance of flu specimens, the department said in a statement today.
This marks the first known case of Tamiflu resistance in a swine flu patient not treated with the drug, which has been stockpiled by governments worldwide to fight pandemic influenza. The specimen was collected from a 16-year-old girl who flew from San Francisco and was intercepted by officials at Hong Kong International Airport on June 11, according to the statement.
?Picking it up in a patient who was not treated is a cause for concern,? Malik Peiris, professor of microbiology at Hong Kong University, said in an interview. ?One case doesn?t change the world, but if we are seeing more and more cases in patients who are not treated, then I think it would be more serious.?
The patient, who was admitted to Queen Mary Hospital for isolation, tested positive for the new H1N1 flu strain and opted not to take Tamiflu, Hong Kong?s health department said. She had mild symptoms and was discharged upon recovery on June 18.
Denmark, Japan
Basel, Switzerland-based Roche said on June 29 that a swine flu patient treated with Tamiflu in Denmark showed resistance to the drug for the first time. Japan?s health ministry reported a case of resistance yesterday in a woman from Osaka who had taken a 10-day course.
Studies have shown that Tamiflu-resistant bugs develop in 0.4 percent to 4 percent of adults and children treated for seasonal influenza, Claudia Schmitt, a spokeswoman at Roche, said by phone from Basel today.
It?s likely the few reported cases of drug-resistant swine flu emerged independently, Hong Kong University?s Peiris said.
?The key point is whether the strains will become dominant and then we will have a problem,? he said. ?At this moment, I don?t think there is cause for alarm. There is certainly cause for heightened surveillance.?
The new H1N1 pandemic virus and a seasonal H1N1 variant are more likely to develop resistance to Tamiflu than other common flu strains, Peiris said. About 95 percent of the H1N1 seasonal flu viruses circulating around the world evade the Roche pill, according to a March 21 World Health Organizationreport.
Glaxo?s Relenza
No widespread resistance to GlaxoSmithKline Plc?s flu drug Relenza has been reported in seasonal flu, and there have been no reports of resistance in swine flu.
?Constant, random mutation is the survival mechanism of the microbial world,? WHO Director-General Margaret Chan said in an address to a meeting on the flu pandemic in Cancun, Mexico, yesterday. ?Like all influenza viruses, H1N1 has the advantage of surprise on its side.?
Tamiflu and Relenza, an inhaled powder, reduce the severity and the duration of flu symptoms by 24 to 30 hours if treatment is started within the first two days of illness, according to the companies.
Both drugs work by blocking a protein on the surface of influenza particles called neuraminidase, which allows the virus to spread from infected cells to other cells in the body.
Scientists say mutant H1N1 viruses have evolved to evade Tamiflu through a single mutation in the neuraminidase that prevents the medicine from clinging to the viral protein, enabling the pathogen to spread.
The case in Hong Kong indicates that the mutant virus is capable of being transmitted among people, said Jennifer McKimm- Breschkin, a virologist at the Commonwealth Science and Industrial Research Organization in Melbourne.
?It?s very disturbing that, fresh into the human population, this one appears now to be able to retain fitness despite having the mutation and to be able to spread,? she said in a telephone interview today.
To contact the reporters on this story: Nipa Piboontanasawat in Hong Kong at npiboontanas@bloomberg.net; To contact the reporters on this story: Jason Gale in Singapore at j.gale@bloomberg.net.
Last Updated: July 3, 2009 07:46 EDT

http://www.bloomberg.com/apps/news?pid=20601202&sid=a9GPdD61pf30

[HenryN]

Re: Hong Kong: Detection of human swine influenza virus resistant to Tamiflu in person from USA

Hong Kong finds 1st case of Tamiflu-resistant H1N1

Fri Jul 3, 2009 8:39am EDT

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HONG KONG (Reuters) - Hong Kong's health department said on Friday it had detected a case of human swine influenza virus that was resistant to Tamiflu, the main antiviral flu drug.
The World Health Organization has declared a pandemic is under way from the new H1N1 virus, also known as swine flu.
"This is the first time Tamiflu resistance in HSI virus (was) found in Hong Kong," a spokesman for the health department said in a statement.
Only two other cases of Tamiflu-resistant H1N1 have been found so far, in Denmark and Japan.
According to the statement, the virus was isolated from a specimen taken from a 16-year-old girl coming from San Francisco, who was taken in by the Port Health Office at the Hong Kong International Airport upon arrival on June 11.
The virus was identified during the health department's routine sensitivity test of HSI virus to oseltamivir and zanamivir, the spokesman said.
Tamiflu, a tablet known generically as oseltamivir, is made by Switzerland's Roche AG and Gilead Sciences, while Relenza, an inhaled drug known generically as zanamivir, is made by GlaxoSmithKline under license from Australia's Biota Inc.
The department said that tests showed that the strain was sensitive to zanamivir.
Resistance to Tamiflu has been previously documented in the deadly bird flu virus H5N1 and seasonal H1N1 flu.
"You can always expect a certain number of resistances," said Roche spokeswoman Claudia Schmitt. "It does not necessarily mean that the strain is resistant to Tamiflu."
(Reporting by Michael Flaherty; Additional reporting by Sam Cage; Editing by Alex Richardson)

http://www.reuters.com/article/internal_ReutersNewsRoom_ExclusivesAndWins_MOLT/idUSTRE5622F720090703

[sharon sanders]

Re: Hong Kong: Detection of human swine influenza virus resistant to Tamiflu (7/3/09)

Tamiflu resistance in Swine flu in Denmark -

http://www.flutrackers.com/forum/showthread.php?t=113101

Tamiflu resistance in Swine flu in Japan

http://www.flutrackers.com/forum/showthread.php?t=113750

[HenryN]

Re: Hong Kong: Detection of human swine influenza virus resistant to Tamiflu (7/3/09)

<a rel="nofollow" href="http://www.recombinomics.com/News/07030902/H274Y_Swine_Spread.html">Commentary</a>

[Snicklefritz]

Re: Hong Kong: Detection of human swine influenza virus resistant to Tamiflu (7/3/09)

[St Michael]

Re: Hong Kong: Detection of human swine influenza virus resistant to Tamiflu (7/3/09)

<a rel="nofollow" href="http://www.recombinomics.com/News/07030901/H274Y_HK_SF.html">Commentary</a>

Thanks Dr. Niman:

<a rel="nofollow" href="http://www.recombinomics.com/News/07030901/H274Y_HK_SF.html">Commentary</a>


Recombinomics Commentary 13:36
July 3, 2009

The virus was identified during PHLSB's routine sensitivity test of HSI virus to oseltamivir and zanamivir, the spokesman said.

"This is the first time Tamiflu resistance in HSI virus found in Hong Kong," he said, adding that similar cases were also reported in Denmark and possibly Japan.

"Tests showed that this strain is sensitive to zanamivir (Relenza)," he said.

The virus was isolated from the specimen taken from a 16-year-old girl coming from San Francisco. She was intercepted by Port Health Office at the Hong Kong International Airport on June 11 upon arrival. The girl was then admitted to Queen Mary Hospital for isolation. She was tested positive to HSI but opted not to take tamiflu. She had mild symptoms and was eventually discharged upon recovery on June 18.

The spokesman noted that PHLSB conducted routine sensitivity tests on specimens taken from confirmed HSI patients.

The above comments from the Hong Kong Department of Health press release describe Tamiflu resistance (presumably H274Y, aka H275Y) in a patient arriving from San Francisco. The resistance was discovered during routine surveillance and there is no indication the patient was taking oseltamivir, indicating the pandemic H1N1 was evolutionarily fit.

The two other cases described this were (in Denmark and Japan) were in patients under prophylactic treat of Tamiflu. In both cases the resistance was due to H274Y (and discovered because of the prophylactic treatment).

Evolutionarily fit swine flu with H274Y is cause for concern. Last year seasonal H1N1 with H274Y spread worldwide. It had previous spread from one genetic background to another via genetic hitchhiking and recombination.

It is likely that H274Y in pandemic H1N1 will now follow a similar, but accelerated, pathway due to widespread use of oseltamivir to control the spread of pandemic H1N1.

The export of H274Y from San Francisco, and failure to identify the polymorphism in the United States, raises serious surveillance concerns.

[HenryN]

Re: Hong Kong: Detection of human swine influenza virus resistant to Tamiflu (7/3/09)

<a rel="nofollow" href="http://www.recombinomics.com/News/07030901/H274Y_HK_SF.html">Commentary</a>