New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug
The development is potentially dangerous because oseltamivir, commonly sold under the name Tamiflu, is the chief weapon against the flu (http://topics.nytimes.com/top/news/health/diseasesconditionsandhealthtopics/influenza/index.html?inline=nyt-classifier) 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 (http://topics.nytimes.com/top/news/health/diseasesconditionsandhealthtopics/aids/index.html?inline=nyt-classifier) medications and sometimes with antibiotics (http://topics.nytimes.com/top/news/health/diseasesconditionsandhealthtopics/antibiotics/index.html?inline=nyt-classifier).
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 spect/'>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.
(http://www.nytco.com/)
It's hard enough to fight this ugly virus, and I would just as soon stick to the facts as we all work through the puzzel. I hope I have not misrepresented them in any of my posts.
The WHO update isuued today is quite clear. See bold below:
| |||||
It's hard enough to fight this ugly virus, and I would just as soon stick to the facts as we all work through the puzzel. I hope I have not misrepresented them in any of my posts.
Here is a 1, 2 3.
1. A new tamiflu resistant polymorphism is in both patients from the Gharbiya cluster.
2. Both patients have N274S.
3. Who issued a Situation update today on Egypt.
4. The situation update was devoted to N274S.
5. WHO indicates that the change has been seen in ONE patient in Vietnam in 2005.
6. The H5N1 from that ONE patient is not in the public domain.
7. The likely explation is that the private data base maintained by WHO for its network.
8. The hoarding continues (NAMRU-3 sends samples to CDC and Weybridge for sequencing - CDC has released ZERO sequneces from Egypt, Weybridge has released 2, NAMRU-3 has released 12).
Length=470
Score = 41.8 bits (91), Expect = 0.004
Identities = 11/11 (100%), Positives = 11/11 (100%), Gaps = 0/11 (0%)
..Query 1 CVCRDSWHGSN 11
Sbjct 290 CVCRDSWHGSN 300
is one of them? N294S
That is the human case (H1N1).
Resistant: LNAPNYYYEE
Correct. That is H274Y. However, that is in Vietnam in patients that developed Tamiflu resistance during treatment.
However, the change in Egypt is N294S, which is not in any public human sequence, which were was listed in the earlier post. All public sequences have N (and not S) at position 294.
Today's WHO update indocated that the change in Egypt (N294S) was in ONE patient in Vietnam. H274Y has been reported in several patients in Vietnam that developed resistance during Tamiflu treatment.
.
Length=470
Score = 41.8 bits (91), Expect = 0.004
Identities = 11/11 (100%), Positives = 11/11 (100%), Gaps = 0/11 (0%)
..Query 1 CVCRDSWHGSN 11
Sbjct 290 CVCRDSWHGSN 300
is one of them? N294S
The point is, and always has been, that when Tamiflu is given to infected patients, H5N1 quickly attempts to overt the roadblock that binds the new virons to the host cell. It has four different mutations that it uses to accomplish that, only one of which is N294S.
From the WHO update:
This mutation has previously been identified in Viet Nam in one case in 2005
http://www.recombinomics.com/News/01180703/H5N1_Egypt_N294S_Ducks.htmlCommentary
N294S Tamiflu Resistance Marker In H5N1 Ducks
Recombinomics Commentary
January 18, 2007
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.
"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 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.
The above comments provide additional detail on the isolates from the Gharbiya cluster, but fail to note that samples were collected with 48 hours of Tamiflu treatment, suggesting the changes did not develop in the patients (http://www.recombinomics.com/News/01180701/H5N1_Egypt_N294S.html). Although recent sequences from Qinghai isolates from birds in Egypt have not been reported, sequences in H5N1 infected ducks in China have been reported. (http://www.recombinomics.com/News/01180702/H5N1_Egypt_N294S_Fit.html)
Thus, the N294S change has already been found in the wild, indicating the change did not create a finess penalty that prevent the altered H5N1 from competing with wild type H5N1.
The N294S was found in all four sequences from the two Gharbiya cluster patients, which also suggests the changes were not linked to treatment of these patients. Additional sequences from Qinghai infected birds and patients in Egypt will help resolve these questions, but the available data points toward a circulating H5N1 with N294S.
The level of resistance can be influenced by the genetic background surrounding the change. The H5N1 in ducks in China provide donor sequences for the Qinghai sequences found in Egypt. Data on Tamiflu resistance levels on the duck isolates have not been reported. However, the H5N1 from the patients in Egypt has been tested and as indicated above, the H5N1 from Egypt were not as susceptible to the drug.
However, this is a major concern if the N294S is widespread because there have already been problems reported associated resistance of H5N1 to Tamiflu. H274Y (http://content.nejm.org/cgi/content/full/353/25/2633) has already developed in patients (http://content.nejm.org/cgi/content/full/354/13/1423) treated sub-optimally with Tamiflu, and many countries have increased the H5N1 treatment dosage. The newly reported change would raise serious questions about the use of Tamiflu for both treatment and prevention of H5N1 containing N294S.
Tamiflu blankets have been applied in prior outbreaks, including Turkey and Indonesia (http://www.recombinomics.com/News/08220602/H5N1_Cikelet_Tamiflu_Blanket.html), and suboptimal treatment may lead to additional isolates with N294S or a combination of resistance markers if N294S is already present.
More information on N294S frequencies of H5N1, including Qinghai H5N1 in Egypt, would be useful.
18 Jan 2007 14:49:57 GMT
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
"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
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
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
| DQ997411 (http://flu.lanl.gov/search/view_record.html?accession=DQ997411&database=fluA) | A/duck/Zhejiang/bj/2002 | NA (6) | 1458 | 2002 | H5N1 | |||
| AY075034 (http://flu.lanl.gov/search/view_record.html?accession=AY075034&database=fluA) | A/Duck/Hong Kong/380.5/2001 | NA (6) | 1427 | 2001 | H5N1 |
http://www.recombinomics.com/News/01190701/H5N1_Egypt_N294S_Transmission.html
Commentary
Transmission of N294S Tamiflu Resistance In Egypt
Recombinomics Commentary
January 19, 2007
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
The above comments from the WHO update (http://www.who.int/csr/don/2007_01_18/en/index.html) on the N294S Tamiflu resistance markers in the Gharbiya cluster, describe a patient (14F) in Hanoi in 2005, who developed Tamiflu resistance (http://www.recombinomics.com/News/10150501/H5N1_H2H_Tamiflu.html) via two markers, H274Y and N294S. H274Y was present at higher levels and was associated with a high level of Tamiflu inhibition in vitro, indicating the clinical role of N294S in that patient was minimal. The above case further suggests that the two patients in the Gharbiya cluster were infected with H5N1 that had already acquired N294S (http://www.recombinomics.com/News/01180701/H5N1_Egypt_N294S.html).
The evidence for N294S prior to Tamiflu use is significant. The NA sequences generated by US NAMRU-3 were from direct sequencing of samples collected two days after the start of Tamiflu treatment (2 X 75 mg). The two sequences had no evidence of the wild type N at position 294 or the common change associated with Tamiflu resistance in H5N1 (http://www.recombinomics.com/News/12220501/H5N1_Tamiflu_Resistance_Mutants.html) infected patients, H274Y. Since all four cluster members developed symptoms prior to Tamiflu treatment of any cluster member, the N294S would have had to have arisen independently in each patient. Moreover, N294S has been found in H5N1 infected ducks in China (http://www.recombinomics.com/News/01180703/H5N1_Egypt_N294S_Ducks.html) (Zhejiang and Hong Kong).
Therefore, the likelihood that N294S independently arose in both patients in response to Tamiflu treatment remains low.
Further testing of H5N1 patients and birds in Egypt will provide information of the frequency of N294S in Qinghai H5N1 in the region.
.
WHO is working hard to ascertain the facts and disseminate information.
They are bashed on other forums and blogs as if they hold the keys to all mysteries H5N1.
We support all international agencies in their efforts to solve the AI problems. Are they perfect? No.
No one is.
....Current laboratory testing suggests that the level of reduced susceptibility is moderate....
per Niman post above.....
The amount of resistance for N294S was about 10X (10X as much Tamiflu was require when treating H294S compared to wild type to get the same inhibition (IC50).
How can requiring 10X as much tamiflu be considered moderate resistance?
.
Try DQ250165 A/Vietnam/CL2009/2005
?????
The sequence position will vary depending on the presence or absence of the 20 aa deletion. For the human isolates from Vietnam in 2005, all have the deletion so the N -->S change would be around position 275b of the protein sequence. It is the lower case "s" in this seqence surrounding the change (VCRDsWHG). Wild type would be VCRDnWHG. All public sequences at Genbank or Los Alamos have an "n" at position 294.
It would seem that the sequence from the patient in Vietnam in 2005 is "hidden" in the WHO private database, if the WHO update is accurate.
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.
AND this one:
Actually, in one sense all are right. The Vietnam case the WHO mentioned in their update actually had both changes, H274Y and N294S. The patient was the 14F infected by her brother (who also infected his nurse and the grandfather had H5N1 antibodies). No one on that cluster died, although the index case was hospitalized for something like 85 days.
The case was written up in Nature in December 2005. Two sequences were deposited. One was wild type at both positions and the other had an ambiguous change (represent wild type and H274Y).
The amount of resistance for N294S was about 10X (10X as much Tamiflu was require when treating H294S compared to wild type to get the same inhibition (IC50).
Comparing that case of N294S to Egypt is apples and oranges. The Egyptian cases both had N294S without a hint of H274Y or wild type N at 294.
N294S was not due to tamiflu treatment of those two patients.
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 (http://www.who.int/csr/don/2006_12_27a/en/index.html)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.1 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 (http://www.who.int/medicines/publications/WHO_PSM_PAR_2006.6.pdf) 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.
http://www.who.int/sysmedia/images/rule.gif
1The 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
I understand this. There is some inconsistent data. There is a sequence mystery. There are missing sequences. Yes, we want them.
There are many dedicated individuals that work at the International agencies and Federal departments.
I am not going to argue about this. Publicly berating these groups does not result in release.
The point is, and always has been, that when Tamiflu is given to infected patients, H5N1 quickly attempts to overt the roadblock that binds the new virons to the host cell. It has four different mutations that it uses to accomplish that, only one of which is N294S.
Just to clarify, I have seen the sequences from the Gharbiya cluster. Both patients have N294S. 274 is H (wild type).
That is the point. The tamiflu resistance in Egypt is NOT the same as the resistance in the public sequences in Vietnam. The WHO update says ONE patient had it in Vietnem. For H274Y SEVERAL patients have had it.
N294S has never been reported (although WHO says they have seen it).
That was the tease. N294S is the real deal.
I apoligize, but I can find no statement by any WHO official that stated that a Vietnam patient had N294S. All I can locate is a statement by a reporter that the so called "294S" mutation was also in Vietnam. As everyone knows, that has never been the case, nor has WHO ever represented that to be the case as far as anyone knows.
The point is, and always has been, that when Tamiflu is given to infected patients, H5N1 quickly attempts to overt the roadblock that binds the new virons to the host cell. It has four different mutations that it uses to accomplish that, only one of which is N294S.
The sequence is wild type at postion 294 (has an N), but does have H274Y.
It's hard enough to fight this ugly virus, and I would just as soon stick to the facts as we all work through the puzzel. I hope I have not misrepresented them in any of my posts.
I would not want any statements to be misrepresented either. I simply seek the truth and know you do as well. I appreciate and welcome your comments.
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/story.asp?j=207570354&p=zx757yx6x
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
Resistant: LNAPNYYYEE
N294S has been seen in H5N1 in ducks (but not public human H5N1)
| DQ997411 (http://flu.lanl.gov/search/view_record.html?accession=DQ997411&database=fluA) | A/duck/Zhejiang/bj/2002 | NA (6) | 1458 | 2002 | H5N1 | |||
| AY075034 (http://flu.lanl.gov/search/view_record.html?accession=AY075034&database=fluA) | A/Duck/Hong Kong/380.5/2001 | NA (6) | 1427 | 2001 | H5N1 |
My only is interest is to properly represent the statements by WHO officials, and attempt to avoid the oft used easy way out: "If my theories are not supported by the data, then obviously someone is hiding the data."
It's hard enough to fight this ugly virus, and I would just as soon stick to the facts as we all work through the puzzel. I hope I have not misrepresented them in any of my posts.
Commentary
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] (http://www.iht.com/bin/print.php?id=4248865%5D)
The above comments on Tamiflu resistance in H5N1 are incomplete. Previously, H274Y (http://content.nejm.org/cgi/content/full/353/25/2633) has been found in H5N1 patients (http://content.nejm.org/cgi/content/full/354/13/1423) 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 (http://www.recombinomics.com/News/01180701/H5N1_Egypt_N294S.html) has been detected previously in H5N1 in ducks in China (A/duck/Zhejiang/bj (http://flu.lanl.gov/search/view_record.html?accession=DQ997411&database=fluA)/2002(H5N1) and A/Duck/Hong Kong/380.5 (http://flu.lanl.gov/search/view_record.html?accession=AY075034&database=fluA)/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 (http://www.recombinomics.com/News/11170602/H5N1_Teal_Egypt.html) 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 (http://www.fao.org/ag/againfo/subjects/en/health/diseases-cards/conference/documents/I.Brown.pdf) and the Middle East (http://www.recombinomics.com/phylo/Brown_Italy_2_Top.html), 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 (http://www.recombinomics.com/PR/060206.html).
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/01180702/H5N1_Egypt_N294S_Fit.html
WHO is working hard to ascertain the facts and disseminate information.
They are bashed on other forums and blogs as if they hold the keys to all mysteries H5N1.
We support all international agencies in their efforts to solve the AI problems. Are they perfect? No.
No one is.
The issue is what was stated in today's WHO update, which indicates N294S was seen in ONE patient in Vietnam in 2005. There is no public H5N1 sequence with N294S from a patient in Vietnam in 2005.
Tamiflu-resistant H5N1 strain surfaces in Egypt
Lisa Schnirring http://www.cidrap.umn.edu/cidrap/images/purple-speck.gif Contributing Writer
Jan 18, 2007 (CIDRAP News) – Two patients who recently died of H5N1 avian influenza in Egypt had a strain of the virus that was moderately resistant to oseltamivir (Tamiflu), the World Health Organization (WHO) announced today, but the finding has not prompted new health advisories.
News of the drug-resistant strain came as Egypt's health ministry announced a new human H5N1 case, involving a 27-year-old woman from the town of Beni Suef, about 62 miles south of Cairo. The report was carried today by IRIN, a United Nations news and information service.
Oseltamivir is recommended by the WHO as the first-line drug for H5N1 patients. The patients who had resistant infections were a 16-year-old girl and her 26-year-old uncle, who lived in the same house in Egypt's Gharbiyah province, in the Nile delta 50 miles northwest of Cairo. They got sick in December; the man was hospitalized on the 17th, followed by his niece 2 days later, the WHO said. Both received 2 tablets of oseltamivir on Dec 21 and were transferred to a referral hospital on Dec 23, the same day samples were taken.
The girl died Dec 25 and her uncle died Dec 28. They were part of a possible family cluster; H5N1 avian influenza was also confirmed in a 30-year-old woman in the household, said to be the man's sister, who died, though few details are available about her. The WHO said the patients reportedly had contact with sick ducks. The two cases boosted Egypt's avian flu total to 18 cases and 10 fatalities, all of which occurred in 2006.
Genetic sequencing was done at US Naval Medical Research Unit 3 in Cairo and at WHO collaborating centers in Atlanta and London, the WHO said.
Tests suggested that the virus had "moderately reduced susceptibility" to osteltamivir. The same type of mutation was previously identified in a Vietnamese case in 2005, the WHO said.
But in contrast to the Egyptian cases, the virus in the Vietnamese case appeared to be highly resistant to oseltamivir. The case, reported in December 2005 in the New England Journal of Medicine (NEJM), involved a 13-year-old girl who was started on oseltamivir the day she was hospitalized, receiving the recommended dose of 75 mg twice a day for 5 days.
The girl was one of 8 patients whose cases were analyzed after they were treated for H5N1 infection in Ho Chi Minh City in 2004 and 2005.
Researchers sequenced the H5N1 virus's neuraminidase gene to look for resistance, signaled by the substitution of tyrosine for histidine at amino acid position 274. The mutation was found in the 13-year-old girl, who died of severe pneumonia on her seventh day in the hospital.
The viral load in her throat was higher by the time of her death than it was earlier, which, with other laboratory evidence, suggested that drug resistance contributed to treatment failure and ultimately death, the NEJM report noted.
The mutation was also found in an 18-year-old girl, but the researchers said the relationship between the viral resistance and her death was less clear.
Fred Hayden, a WHO avian flu and antiviral expert, told the Associated Press (AP) today the drug-resistant strains in the Egyptian patients likely developed after they were treated with oseltamivir. He said a more worrying scenario would be if oseltamivir-resistant strains were circulating in birds.
The mutations in Egypt are different from the ones in Vietnam, Hayden told the AP. The Vietnamese strains were definitely resistant to oseltamivir, but the Egyptian ones were only shown to be less susceptible to the drug.
There is no evidence that oseltamivir-resistant strains are spreading in Egypt or elsewhere, the WHO said. The agency said it is not changing its antiviral treatment recommendations, because the clinical level of resistance of the mutations is not yet well established.
Public health implications of the findings are limited because the mutation is not associated with any known changes in transmissibility of the virus between humans, the WHO said, adding that it would not be raising the pandemic alert level.
Because of concerns about drug-resistant strains, avian flu experts have suggested that a higher dosage, longer treatment course, or combination therapy with other antiviral drugs may be needed to ensure the effectiveness of oseltamivir.
Terence Hurley, a US spokesperson for Roche, the maker of Tamiflu, told CIDRAP News by e-mail that studies are being conducted to gauge the optimal oseltamivir regimens for use in H5N1 flu cases. "These activities are based upon laboratory data and from information from patients infected with H5N1 who have been treated with Tamiflu," he said.
Roche is collaborating with the US National Institutes of Health on clinical studies to determine the efficacy of oseltamivir in the treatment of severe influenza, including H5N1, Hurley reported. "The NIH study is comparing standard doses of Tamiflu versus double doses for the treatment of people infected with avian influenza and other severe influenza infections in the Far East," he wrote. "Results of the study will be reported as soon as they are available."
The Egyptian woman reported today as a new H5N1 patient was admitted to a hospital Jan 11 after having given birth on Jan 2, IRIN reported. She initially denied contact with poultry, but WHO spokesman Hassan el-Bushra told IRIN that ducks and pigeons were found in her home and chickens had died nearby.
If her case is confirmed by the WHO, it will be Egypt's 19th.
See also:
Jan 18 WHO report (http://www.who.int/csr/don/2007_01_18/en/index.html)
Dec 27 WHO report (http://www.who.int/csr/don/2006_12_27a/en/index.html)
Dec 22, 2005 CIDRAP News article "Tamiflu resistance in avian flu victims sparks concern (http://www.cidrap.umn.edu/cidrap/content/influenza/panflu/news/dec2205tamiflu.html)"
De Jong MD, Thanh TT, Khanh TH, et al. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med 2005 Dec 22;353(25):2667-72 [Full text (http://content.nejm.org/cgi/content/full/353/25/2667)]
| DQ094290 (http://flu.lanl.gov/search/view_record.html?accession=DQ094290&database=fluA) | A/Viet Nam/BL-014/2005 | NA (6) | 1350 | 2005 | H5N1 | |||
| DQ094291 (http://flu.lanl.gov/search/view_record.html?accession=DQ094291&database=fluA) | A/Viet Nam/DT-036/2005 | NA (6) | 1350 | 2005 | H5N1 | |||
| DQ094292 (http://flu.lanl.gov/search/view_record.html?accession=DQ094292&database=fluA) | A/Viet Nam/HG-207/2005 | NA (6) | 1350 | 2005 | H5N1 | |||
| ISDN119679 (http://flu.lanl.gov/search/view_record.html?accession=ISDN119679&database=fluA) | A/Viet Nam/HN30408/2005 | NA (6) | 1350 | 2005 | H5N1 | |||
| ISDN117783 (http://flu.lanl.gov/search/view_record.html?accession=ISDN117783&database=fluA) | A/Viet Nam/JP14/2005 | NA (6) | 1350 | 2005 | H5N1 | |||
| ISDN117782 (http://flu.lanl.gov/search/view_record.html?accession=ISDN117782&database=fluA) | A/Viet Nam/JP4207/2005 | NA (6) | 1350 | 2005 | H5N1 | |||
| DQ493075 (http://flu.lanl.gov/search/view_record.html?accession=DQ493075&database=fluA) | A/Vietnam/CL105/2005 | NA (6) | 1350 | 2005 | H5N1 | |||
| DQ493076 (http://flu.lanl.gov/search/view_record.html?accession=DQ493076&database=fluA) | A/Vietnam/CL115/2005 | NA (6) | 1350 | 2005 | H5N1 | |||
| DQ250163 (http://flu.lanl.gov/search/view_record.html?accession=DQ250163&database=fluA) | A/Vietnam/CL115/2005 | NA (6) | 1350 | 2005 | H5N1 | |||
| DQ250164 (http://flu.lanl.gov/search/view_record.html?accession=DQ250164&database=fluA) | A/Vietnam/CL119/2005 | NA (6) | 1327 | 2005 | H5N1 | |||
| DQ493077 (http://flu.lanl.gov/search/view_record.html?accession=DQ493077&database=fluA) | A/Vietnam/CL119/2005 | NA (6) | 1326 | 2005 | H5N1 | |||
| DQ250165 (http://flu.lanl.gov/search/view_record.html?accession=DQ250165&database=fluA) | A/Vietnam/CL2009/2005 | NA (6) | 1333 | 2005 | H5N1 | |||
| DQ493078 (http://flu.lanl.gov/search/view_record.html?accession=DQ493078&database=fluA) | A/Vietnam/CL2009/2005 | NA (6) | 1332 | 2005 | H5N1 | |||
| DQ535726 (http://flu.lanl.gov/search/view_record.html?accession=DQ535726&database=fluA) | A/Vietnam/PEV16T/2005 | NA (6) | 1350 | 2005 | H5N1 |
http://www.recombinomics.com/News/01190701/H5N1_Egypt_N294S_Transmission.html
?????
Commentary at
http://www.recombinomics.com/News/01180702/H5N1_Egypt_N294S_Fit.html
I think GaudiaRay said yesterday that governments have just now started stockpiling Relenza?
Sensitive: LNAPNYHYEE
Resistant: LNAPNYYYEE
http://www.recombinomics.com/News/01180703/H5N1_Egypt_N294S_Ducks.html
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
per Niman post above.....
How can requiring 10X as much tamiflu be considered moderate resistance?
.
N294S has a weaker effect than H274Y, which is considered strong, but Tamiflu is already teetering, and N294S pushes it off the cliff (although Roche launched its damage control program today).
Instead of stockpilling an expensive patented organic chemistry molecule that exhibit some sign of neurotoxicity;
http://www.fda.gov/medwatch/safety/2006/safety06.htm#tamiflu
Instead of stockpilling only one expensive antiviral wh
The point is, and always has been, that when Tamiflu is given to infected patients, H5N1 quickly attempts to overt the roadblock that binds the new virons to the host cell. It has four different mutations that it uses to accomplish that, only one of which is N294S.
Either 2 reporters got it wrong or there is a piece missing from the public domain.
http://www.cidrap.umn.edu/cidrap/con...07tamiflu.html (http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/news/jan1807tamiflu.html)
Tamiflu-resistant H5N1 strain surfaces in Egypt
Lisa Schnirring http://www.cidrap.umn.edu/cidrap/images/purple-speck.gif Contributing Writer
**snipped**
Tests suggested that the virus had "moderately reduced susceptibility" to osteltamivir. The same type of mutation was previously identified in a Vietnamese case in 2005, the WHO said.
AND this one:
Moderately Tamiflu-resistant bird flu in Egypt--WHO
18 Jan 2007 14:49:57 GMT
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.
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 (http://www.who.int/csr/don/2006_12_27a/en/index.html) 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.1 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 (http://www.who.int/medicines/publications/WHO_PSM_PAR_2006.6.pdf) 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.
http://www.who.int/sysmedia/images/rule.gif
1The 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/print.html
http://www.recombinomics.com/News/01180701/H5N1_Egypt_N294S.html
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