New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

[Niko]

A strain of avian flu that is resistant to the antiviral drug oseltamivir has been isolated from two family members in Egypt, the World Health Organization said yesterday.

The development is potentially dangerous because oseltamivir, commonly sold under the name Tamiflu, is the chief weapon against the flu strain, H5N1, which many worry could mutate into a strain that could set off a worldwide pandemic.

The health organization emphasized that it was too early to tell whether the resistant strain had developed independently in the two patients, who were both under treatment with the drug, or whether they had picked it up from birds or from each other. The resistant strain did not spread to anyone else, including a third family member who also had avian flu.

?Given the information we have, we don?t see any broad public health implications,? said Dick Thompson, a spokesman for the organization.
Mr. Thompson was unsure which Egyptian cluster of flu infections the patients were part of. But another source said it was one in Gharbiya Province, roughly 50 miles north of Cairo, in which flu killed three people last month in a 33-member family living in one compound.

Oseltamivir-resistant strains were found in three unrelated patients in Vietnam in 2005 but did not spread.

The development ?is not a big surprise, but it certainly is disheartening,? said Dr. Anne Moscona, an expert on flu treatment at Weill Cornell Medical College.

The oseltamivir-resistant strain in Egypt was susceptible to zanamir, which is sold as Relenza, and to amantadine, which is from an older, cheaper and easier-to-use class of drugs but is not normally used as a first-line treatment because many avian flu strains are resistant to it.

The development, Dr. Moscona said, suggested that doctors might have to consider switching to a cocktail of drugs as first-line treatment, as is done with AIDS medications and sometimes with antibiotics.

Dr. Andrew T. Pavia, chairman of the pandemic influenza task force of the Infectious Diseases Society of America, said it was theoretically possible that resistant strains of the flu had developed simultaneously in two related patients, especially if they were very sick and had been treated with doses of oseltamivir that were too low.

But if one transmitted it to the other, ?it would be very worrisome,? he said, because previous resistant strains had been very weak at infecting new victims.

Scientists do not know exactly which mutations or how many of them would make the avian flu virus more dangerous, but they have some clues.

The virus now circulating in birds does not attach easily to cells inside human noses or throats. It reproduces more slowly at human temperatures than at bird temperatures, which are slightly higher. It does not detach easily from cells to infect new ones, and it is usually killed by oseltamivir.
Scientists are keeping an eye on the genes that code for those aspects of the virus ? for example, the shape of the spikes on its outer coating, where it binds to cells.

If an oseltamivir-resistant strain spreads, it will complicate the public health response. Governments have been stockpiling oseltamivir, not zanamir.
Zanamir is more expensive and also harder to use and to ship, because it is typically sold not as a pill but as a powder that comes in an inhaler resembling a small hockey puck.

An intravenous form exists but has not been approved for use in some countries, including the United States, Dr. Moscona said.
<nyt_update_bottom> </nyt_update_bottom>

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[4-ABBA]

Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

.... If an oseltamivir-resistant strain spreads, it will complicate the public health response. Governments have been stockpiling oseltamivir, not zanamir..... Zanamir is more expensive and also harder to use and to ship, because it is typically sold not as a pill but as a powder that comes in an inhaler resembling a small hockey puck.....

I think GaudiaRay said yesterday that governments have just now started stockpiling Relenza?

[Gert van der Hoek]

Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

Min of Health Egypt:


The Health Ministry starkly warned Tuesday 16/1/2007 that the deadly bird flu virus worldwide has mutated into a stronger strain.

Health Minister Hatem el-Gabaly said the virus is largely contained in Egypt, though.

He put at 18 the number of Egyptians who contracted the H5N1 virus since it first out broke in Egypt last February. He said 10 patients have died of the virus.

http://birdflu.sis.gov.eg/html/flu0102219.htm

[HenryN]

Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

Commentary at

http://www.recombinomics.com/News/01...ypt_N294S.html

[HenryN]

Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

Min of Health Egypt:


The Health Ministry starkly warned Tuesday 16/1/2007 that the deadly bird flu virus worldwide has mutated into a stronger strain.

Health Minister Hatem el-Gabaly said the virus is largely contained in Egypt, though.

He put at 18 the number of Egyptians who contracted the H5N1 virus since it first out broke in Egypt last February. He said 10 patients have died of the virus.

http://birdflu.sis.gov.eg/html/flu0102219.htm

N294S has been seen in H5N1 in ducks

<TABLE class=resultstable cellSpacing=0 cellPadding=4 width="100%" border=0><TBODY><TR bgColor=#a7c4ef><TD align=left><INPUT onclick=setAll(this.checked) type=checkbox value=212477 name=checkbox> </TD><TD class=displaytablerow align=left></TD><TD>DQ997411 </TD><TD>A/duck/Zhejiang/bj/2002 </TD><TD>NA (6) </TD><TD>1458 </TD><TD>2002 </TD><TD>H5N1 </TD><TD></TD></TR><TR bgColor=white><TD align=left><INPUT onclick=setAll(this.checked) type=checkbox value=14560 name=checkbox> </TD><TD class=displaytablerow align=left></TD><TD>AY075034 </TD><TD>A/Duck/Hong Kong/380.5/2001 </TD><TD>NA (6) </TD><TD>1427 </TD><TD>2001 </TD><TD>H5N1 </TD></TR></TBODY></TABLE>

[Anne]

Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

I tough tamiflu resistance was in 274 position of NA ( DE JONG/ NEW england J Med ) ?

[HenryN]

Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

I tough tamiflu resistance was in 274 position of NA ( DE JONG/ NEW england J Med ) ?

Commentary at

http://www.recombinomics.com/News/01...N294S_Fit.html

[HenryN]

Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

I tough tamiflu resistance was in 274 position of NA ( DE JONG/ NEW england J Med ) ?

That was the tease. N294S is the real deal.

[HenryN]

Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

Egyptian bird flu mutations suggest antiviral resistance

The Associated Press

Thursday, January 18, 2007

Mutations in the bird flu virus have been found in two people in Egypt, in a form that might be resistant to the medication most commonly used to treat the deadly disease, according to laboratory tests approved by WHO.
The mutations in the H5N1 virus strain were not drastic enough to make the virus infectious enough to spark a pandemic, said officials with the World Health Organization. But more such mutations could ultimately prompt scientists to rethink current treatment strategies.

Samples taken from two bird flu patients in Egypt ? a 16-year-old girl and her 26-year-old uncle ? were not as responsive as regular H5N1 viruses to Tamiflu, a drug also know as oseltamivir that is used to treat the disease, WHO officials said.

The girl and her uncle died in late December, as well as the man's 35-year-old sister, though she has not yet been confirmed as having had H5N1. The three ? who lived together in Gharbiyah province, 80 kilometers (50 miles) northwest of Cairo ? fell ill within days of one another after being exposed to sick ducks.

"Based on the information we have, we can't yet rule out human-to-human transmission," said Dr. Fred Hayden, a WHO bird flu and antivirals expert. "We need to better understand the dynamics of this outbreak."
Though people have passed the virus on to other people in the past, such infections are rare, and most patients have been infected by direct contact with sick birds.

Scientists fear, however, that the virus could mutate into a form more easily passed between people, which could spark a flu pandemic.
The drug-resistant strains found in Egypt likely developed after the patients were hospitalized and treated with Tamiflu, with the virus responding directly to the drug, Hayden said. It was not proven, however, that that was the case, and a more worrying scenario would be if drug-resistant strains were already circulating among birds.

Though Tamiflu remains the drug of choice to treat H5N1, experts may have to consider other options if they find more resistant viruses.
Because flu viruses evolve constantly, mutations are only worrisome if they are linked to the virus' transmissibility, lethality or drug susceptibility.
"What the resistance tests look for are markers associated with antiviral resistance," though finding the markers did not necessarily mean Tamiflu would not work, said Dr. Angus Nicoll, flu director at the European Centre for Disease Prevention and Control.

Hayden said the mutations found in Egypt were different from Tamiflu-resistant H5N1 viruses found in patients two years ago in Vietnam. The Vietnamese strains were definitely resistant to Tamiflu, whereas the Egyptian viruses have only proven they are not as susceptible to the drug, he said.

Tamiflu-resistant viruses such as those found in Vietnam are often treatable with an older, less expensive class of antivirals, known as amantadanes. Some bird flu virus strains from Indonesia and China have also proven susceptible to amantadanes.

H5N1 first hit Egypt last year, and has since infected 18 people, 10 of whom have died.

Since the H5N1 outbreak first began in late 2003, it has decimated the Asian poultry industry and infected at least 265 people worldwide, 159 of whom have died, according to WHO.

http://www.iht.com/bin/print.php?id=4248865

[Niko]

Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

For the benefit of those on dial-up connections, here is Dr. Niman's commentary referred to in previous posts:

<big><big></big></big>

<big><big>Commentary</big></big>

N294S Tamiflu Resistance is Evolutionarily Fit
Recombinomics Commentary
January 18, 2007

?Given the information we have, we don?t see any broad public health implications,? said Dick Thompson, a spokesman for the organization.
Mr. Thompson was unsure which Egyptian cluster of flu infections the patients were part of. But another source said it was one in Gharbiya Province, roughly 50 miles north of Cairo, in which flu killed three people last month in a 33-member family living in one compound.

Oseltamivir-resistant strains were found in three unrelated patients in Vietnam in 2005 but did not spread. [Media source: http://www.iht.com/bin/print.php?id=4248865]

The above comments on Tamiflu resistance in H5N1 are incomplete. Previously, H274Y has been found in H5N1 patients that have been treated with Tamiflu. However, this change appears to have developed during treatment. It was not detected in initial collections from the patient, or was initially present at low levels. This change is the only prior reported H5N1 oseltamivir resistant change in H5N1 in patients. However, data in the literature on H274Y indicates this change is not evolutionarily fit, and therefore H5N1 with this change has not been islated from sources other than patients undergoing Tamiflu treatment.

However, N294S has been detected previously in H5N1 in ducks in China (A/duck/Zhejiang/bj/2002(H5N1) and A/Duck/Hong Kong/380.5/2001(H5N1)). Both of these isolates were highly pathogenic with the common HA cleavage site, RERRRKKR), but did not have the 20 amino acid detection, which defines the Z genotype, including the Qinghai strain that is transmitted and transported by migratory birds, including the teal identified in Egypt in December, 2005.

However, N294S has not been previously reported in patients or the Qinghai strain of H5N1. Most of the NA Qinghai sequences have been sequestered in the private WHO database at Los Alamos. This private database is used by Weybridge, who has sequenced a large number of Qinghai isolates in Europe and the Middle East, as well as the CDC in Atlanta, which gets samples from NAMRU-3 in Cairo. Thus, N294S may have already been identified in Qinghai H5N1, but that information is not public.

The presence of N294S in H5N1 in ducks in China however, creates a source fro the acquisition of the change via recombination. The presence of N294S in both patients in samples collected within 48 hours of Tamiflu treatment suggests the sequences were present prior to Tamiflu treatment of the three cluster members. All three failed to respond to treatment and died.

More NA sequence data on additional patients and birds in Egypt would be useful.

http://www.recombinomics.com/News/01...N294S_Fit.html

[HenryN]

Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

Commentary at

http://www.recombinomics.com/News/01...94S_Ducks.html

[HenryN]

Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

Egyptian bird flu mutations suggest antiviral resistance
18/01/2007 - 13:59:02

Mutations in the bird flu virus have been found in two people in Egypt, in a form that might be resistant to the medication most commonly used to treat the deadly disease, according to laboratory tests approved by WHO.

The mutations in the H5N1 virus strain were not drastic enough to make the virus infectious enough to spark a pandemic, said officials with the World Health Organisation.

But more such mutations could ultimately prompt scientists to rethink current treatment strategies.

Samples taken from two bird flu patients in Egypt ? a 16-year-old girl and her 26-year-old uncle ? were not as responsive as regular H5N1 viruses to Tamiflu, a drug also know as oseltamivir that is used to treat the disease, WHO officials said.

The girl and her uncle died in late December, as well as the man?s 35-year-old sister, though she has not yet been confirmed as having had H5N1.

The three ? who lived together in Gharbiyah province, 50 miles north-west of Cairo ? fell ill within days of one another after being exposed to sick ducks.

?Based on the information we have, we can?t yet rule out human-to-human transmission,? said Dr Fred Hayden, a WHO bird flu and antivirals expert. ?We need to better understand the dynamics of this outbreak.?

Though people have passed the virus on to other people in the past, such infections are rare, and most patients have been infected by direct contact with sick birds.

Scientists fear, however, that the virus could mutate into a form more easily passed between people, which could spark a flu pandemic.

The drug-resistant strains found in Egypt likely developed after the patients were taken to hospital and treated with Tamiflu, with the virus responding directly to the drug, Hayden said.

It was not proven, however, that that was the case, and a more worrying scenario would be if drug-resistant strains were already circulating among birds.

Though Tamiflu remains the drug of choice to treat H5N1, experts may have to consider other options if they find more resistant viruses.

Because flu viruses evolve constantly, mutations are only worrisome if they are linked to the virus? transmissibility, lethality or drug susceptibility.

?What the resistance tests look for are markers associated with antiviral resistance,? though finding the markers did not necessarily mean Tamiflu would not work, said Dr Angus Nicoll, flu director at the European Centre for Disease Prevention and Control.

Hayden said the mutations found in Egypt were different from Tamiflu-resistant H5N1 viruses found in patients two years ago in Vietnam. The Vietnamese strains were definitely resistant to Tamiflu, whereas the Egyptian viruses have only proven they are not as susceptible to the drug, he said.

Tamiflu-resistant viruses such as those found in Vietnam are often treatable with an older, less expensive class of antivirals, known as amantadanes. Some bird flu virus strains from Indonesia and China have also proven susceptible to amantadanes.

H5N1 first hit Egypt last year, and has since infected 19 people, 10 of whom have died.

The latest case came to light this morning.

The reports, citing health authorities, said that a housewife from Beni Suef, about 60 miles south of Cairo, tested positive for the avian flu strain and was admitted to hospital for treatment.

The Middle East News Agency did not say how the woman contracted the virus.

Most people get it through contact with infected birds which they raise at home, or while slaughtering or cleaning chicken.

Meanwhile, three other bird flu cases in humans were suspected in the eastern province of Ismailiya and the southern city of Sohag, while three other provinces have declared a state of emergency after new bird flu cases were detected in domestic fowl, reported the independent al-Masri al-Youm daily.

Since the H5N1 outbreak first began in late 2003, it has decimated the Asian poultry industry and infected at least 265 people worldwide, 159 of whom have died, according to WHO.

http://breakingnews.iol.ie/news/stor...54&p=zx757yx6x

[HenryN]

Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

Moderately Tamiflu-resistant bird flu in Egypt--WHO
18 Jan 2007 14:49:57 GMT
<!-- 18 Jan 2007 14:49:57 GMT ## for search indexer, do not remove-->
By Stephanie Nebehay




GENEVA, Jan 18 (Reuters) - Two people who died of bird flu in Egypt last month had a strain of the H5N1 virus which has shown "moderate" resistance to the frontline antiviral Tamiflu, the World Health Organisation (WHO) said on Thursday.


Known as "294S", the mutated strain was first detected in 2005 in a teenage girl in Vietnam who survived, but this is the first evidence of it spreading beyond Asia, it said.


The United Nations agency said that the latest cases did not change its recommendation to treat bird flu patients with Tamiflu, known generically as oseltamivir. Made by Swiss-based Roche <ROG.VX>, the flu drug is being stockpiled by governments worldwide for use in the event of an influenza pandemic.


"What we've confirmed is that H5N1 viruses isolated from two patients in recent cases in Egypt both showed this so-called 294S change," Keiji Fukuda, coordinator for the WHO's global influenza programme, told Reuters.


He said that there was "no clinical information" upon which to base any change to the WHO's recommendations on treatment.


"But based on what we see from laboratory tests, we expect any reduction in sensitivity or increase in resistance is going to be on the moderate side," Fukuda said.


"We're not making any changes in recommendations for therapy because we don't have strong evidence this means oseltamivir should not be used."

The mutated strain was found in a 26-year-old Egyptian factory worker and his teenage niece in the Nile Delta province of Gharbia, both of whom died in December along with another female relative, according to Fukuda.

The uncle and niece were given Tamiflu in the second hospital in which they were treated, after the disease was already more developed, he said.


Egypt, which announced on Wednesday it was treating another bird flu patient, has recorded 10 deaths among 19 confirmed human cases -- the largest toll outside Asia.


Worldwide, there have been 161 fatalities among 267 known cases since 2003, according to the Geneva-based WHO.

"LESS EFFICIENT"


Laboratory tests on the two Egyptians' samples showed the 294S mutation, known to have levels of resistance which make oseltamivir "less efficient" in such cases, Fukuda said.


More research was needed, but for now there are "no wholesale recommendations on changes in treatment using oseltamivir," according to Fukuda, a U.S. influenza expert.


Governments wordwide have been stockpiling Tamiflu in case the H5N1 virus mutates and becomes easily transmissible among humans, sparking a pandemic which could kill millions of people.


The WHO reaffirmed last May that patients should get Tamiflu as a frontline treatment, but said that in certain cases, doctors may consider using it along with amantadine, an older class of effective flu drugs.


Its recommendations, based on a consensus of international experts, also said that zanamivir -- which is marketed as Relenza by GlaxoSmithKline <GSK.L> -- was a second choice.


Both Tamiflu and Relenza belong to a new drug class called neuraminidase inhibitors and can prevent the virus from infecting cells in the first place.

http://www.alertnet.org/thenews/newsdesk/L18932531.htm

[scottmcpherson]

question for the experts.....

OK, if we are steadily losing Tamiflu as a weapon, could it mean that the virus is losing its immunity to Amantadine? I recall Drs. Webster/Webby saying Amantadine was "off the table" in 2004. Could that be reversed?

The current Roche pitch to states is 80% Tamiflu/20% Relenza. That is the official ratio under the 25% off Federal "coupon plan," as I call it. I have suggested to State leaders that we may want to consider altering that ratio if Tamiflu resistance continues to develop.

[HenryN]

Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

Avian influenza - situation in Egypt - update
18 January 2007
Viruses with a genetic mutation, linked in laboratory testing to moderately reduced susceptibility to oseltamivir, have been discovered in two persons previously reported with H5N1 infections in Egypt. Both patients had been on treatment with oseltamivir for two days before the clinical samples that yielded the viruses were taken.
The two patients from whom samples were taken were a 16 year-old female and a 26 year-old male from Gharbiyah Province, Egypt.<SUP>1</SUP> They were a niece and uncle, respectively, who lived in the same house. The girl was admitted to a hospital on 19 December 2006, while the man was admitted on 17 December. On 21 December they began receiving 2 tablets per day of oseltamivir. On 23 December they were moved to a referral hospital. The samples which have so far been tested were taken from the two patients on 23 December. The girl died on 25 December and the man died on 28 December 2006.
In this and all other H5N1 investigations there is close, ongoing coordination between Egypt's Ministry of Health and Population (MOH&P) and WHO. It was Egypt's monitoring and rapid virological analysis conducted at the Central Public Health Laboratory in Cairo that initially allowed the diagnoses of H5N1 to be made. Confirmatory testing and genetic sequencing was done at NAMRU-3 and at two WHO Collaborating Centres located in Atlanta, USA and London, UK.
At this time there is no indication that oseltamivir resistance is widespread in Egypt or elsewhere. WHO is not making any changes in antiviral treatment recommendations for H5N1-infected persons published in June 2006 because the clinical level of resistance of these mutations is not yet well established. Current laboratory testing suggests that the level of reduced susceptibility is moderate. This mutation has previously been identified in Viet Nam in one case in 2005. Moreover, these mutations are not associated with any known change in the transmissibility of the virus between humans. Based on these considerations, the public health implications at this time are limited. Finally, these findings do not indicate a need for a change in phase level. The WHO pandemic preparedness level remains at three.
The Egyptian authorities, WHO and its Collaborating Centres will continue to share with the public all relevant information from the on-going investigations and analyses as soon as it becomes available.

<SUP>1</SUP>The ages and dates in this update related to the two patients, may differ slightly from earlier reports, but reflect the most recent information provided to WHO.

http://www.who.int/csr/don/2007_01_18/en/index.html