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Flu Found Resistant to Main Antiviral Drug

Re: Flu Found Resistant to Main Antiviral Drug

Daiichi Sankyo to launch flu preventive drug-Nikkei | Reuters

Daiichi Sankyo to launch flu preventive drug-Nikkei

Sun Feb 22, 2009 10:51am IST
TOKYO, Feb 22 (Reuters) -

Japan's Daiichi Sankyo Co plans to launch as early as 2011 a new influenza preventive drug that could be effective against a strain unresponsive to widely used Tamiflu of Roche, the Nikkei business daily said.


Japan's third-largest drugmaker plans to seek regulatory approval for the drug by March 2011, the Nikkei said on Sunday.

It said animal testing has suggested the new drug under development is effective against a strain that has tolerance against Tamiflu, made by Swiss pharmaceutical company Roche.

A Daiichi Sankyo spokesman told Reuters the company is developing a new influenza treatment drug and it may seek regulatory approval in Japan by the end of calendar 2009, but declined to comment on Nikkei's report of the preventive drug.

(Reporting by Kiyoshi Takenaka; Editing by Anshuman Daga)
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​
<cite cite="http://in.reuters.com/article/asiaCompanyAndMarkets/idINT28150220090222">Daiichi Sankyo to launch flu preventive drug-Nikkei | Reuters</cite>
 
Re: Flu Found Resistant to Main Antiviral Drug

Killer flu H1N1 resistant to Tamiflu and flu jab vital

By Sue Dunlevy
The Daily Telegraph
March 05, 2009 12:00am
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<!-- // END story-tools ************************************** --><!-- // END article-header ************************************** --><!-- // article-body ************************************** --><!-- Image Caption ("image-lead") --><TABLE><TBODY><TR><TD>
Killer influenza strain resistant to drugs ... The only protection is a vaccination which Praveen Haider received from nurse Clare MacDuwell yesterday. Picture: Gary Ramage.


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<!-- // article intro ************************************** -->ONE of the killer influenza strains heading to Australia this winter is almost totally resistant to the only anti-viral tablet that can treat it - Tamiflu.
<!-- // END article intro ************************************** --><!-- // article corpus ************************************** -->This means having a vaccination may be the only way for many to beat the flu this year.
Just 10 years after the breakthrough flu drug hit the market the virus has fought back.
A study in this week's Journal of the American Medical Association found 98.5 per cent of the H1N1 influenza virus circulating in the US is now resistant to the antiviral drug Tamiflu.
The H1N1 form of influenza accounted for one in five flu infections in the United States between September 2008 and February 2009.
And four patients with this drug resistant flu died in the United States another two patients with the drug resistant flu died in the Netherlands.
Australia's expert Influenza Vaccine Committee has asked that the H1N1 strain be included in the 2009 flu vaccination available to people here.
The drug company which manufactures Tamiflu, Roche, says there is no evidence that the Tamiflu resistant virus results in more severe illness or that it is more easily transmitted.
Related Coverage
And it says the drug is still fully active against other types of influenza.
In the last 30 years influenza H3N2 has been the main strain circulating in Australia, the company says.
The World Health Organisation estimates around 500,000 people die every year from flu related health complications.
Before the 2007-08 season the level of resistance to Tamiflu among circulating flu viruses in the United States was less than 1 per cent.
By March last year 16 per cent of H1N1 influenza viruses tested had become resistant to Tamiflu, now 98.5 per cent of this strain of the flu is resistant.
The H1N1 virus is still susceptible to the flu medication Relenza but this inhaled product is not suitable for children, those with asthma or breathing problems or those with milk allergies.
The doctors who carried out the American study say it is unclear how H1N1 viruses had changed and become able to circulate between humans so successfully.
The mutation of this virus is of great concern because it has implications for a possible outbreak of the even more deadly birdflu some strains of which are also showing resistance to tamiflu.
The Australian Government has millions of doses of taxpayer funded Tamiflu stockpiled to use in the fight against a birdflu outbreak.
Tamiflu, taken in pill form, is the most commonly used flu treatment drug.
It has to be taken within 48 hours of the first onset of flu symptoms and studies show it speeds recovery from the flu by 30 per cent or 1.3 days.
It is suitable for adults and children aged over a year and requires a doctors prescription but is not subsidised by our drug subsidy scheme.
It won't work to fight off colds or other viruses.
Relenza is the only other flu medication available.
It too has to be taken within 48 hours of symptoms appearing and has to be inhaled so it can be delivered direct to the lungs.More than 500 Australians a week are having flu vaccinations in time for the onset of winter.
"We were early for vaccines this year, because last year's northern hemisphere vaccine was the same as the southern hemisphere - so we got a bit of a flying start," said Dr Tony Gherardin, from the Travel Doctor Group, specialising in vaccinations.
Dr Gherardin said vaccines were diverted from overseas to Australia to provide an early start to protecting against the flu season.
"There's increasing recognition that flu vaccines are safe, therefore increasing recommendation for a much wider group of people to be vaccinated including young children," he said.
Vaccines cost $25.50 each with people aged over nine needing a single shot while children aged between six months to nine needing two shots
"It's best that you crank up the immunity across the community before winter hits," Dr Gherardin said.
Parents are encouraged to vaccinate their children however doctors say people who are allergic to eggs should avoid the vaccine.
The numbers of vaccinations is expected to rise across Australia from next month.


http://www.news.com.au/entertainment/story/0,28383,25138931-5007185,00.html
 
Last edited by a moderator:
Re: Flu Found Resistant to Main Antiviral Drug

ECDC. Monitoring of Influenza antiviral resistance in EU during 2008-09 season (March 11, 2009)

Monitoring of Influenza antiviral resistance in EU during 2008-09 season

[Original text is available at this LINK. EDITED.]

Monitoring of antiviral resistance in EU for the season 2008-09 is currently ongoing. The coordinators of The Community Network of Reference Laboratories for Human Influenza in Europe (CNRL), routinely collect, analyze and disseminate information on antiviral resistance from Influenza viruses isolated from 25 European (European Union, EEA/EFTA) countries.

The analysis of resistance against Neuraminidase Inhibitors and Adamantanes is done by measuring IC50 values and/or by genotyping of viruses for detection of known drug resistance mutations.

Summary information on antiviral resistance in EU will be published weekly in the EISS bulletin (LINK) (also featured in the weekly ECDC influenza News)



<table style="width: auto;"><tbody><tr><td></td></tr><tr><td style="font-family: arial,sans-serif; font-size: 11px; text-align: right;">From TABLES</td></tr></tbody></table>
 
Re: Flu Found Resistant to Main Antiviral Drug

From EISS weekly bulletin (March 13, 2009. Post #412 Seasonal Influenza thread, http://www.flutrackers.com/forum/showpost.php?p=213746&postcount=412)

- Russian Federation. As a result of 21 strains of influenza A(H3) virus testing it was shown that all isolates from St. Petersburg and Kaliningrad were drift variants of the reference virus A/Brisbane/10/07 and reacted with antiserum to these strains up to 1/4 - 1/16 of homologous titer. All 19 isolates of influenza B virus belonged to the Victoria lineage. Four of ten influenza A(H1) viruses and 22 of 28 influenza A(H3) viruses isolated in Russia appeared to be resistant to rimantadine.
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Re: Flu Found Resistant to Main Antiviral Drug

Quote:

"CDC Update

http://www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4416B1-1.pdf"


Check out the CDC Update. The antiviral resistance table comparing Tamiflu with Relenza. Spot the antiviral that took 15 years of research and had over 12 published studies exploring resistance before it was on the market, and the other one (with no independent resistance studies) that was rushed to market in seven years, to beat it.
With a little flag waving, and some helpful nudges, it became the "Main Antiviral Drug."

Let's imagine a scenario in which Tamiflu was developed with as much care (and time) as Relenza.

Firstly Tamiflu would not have survived resistance trials, they would have mirrored what we are seeing now on a larger scale, and it would have been abandoned. Even if greed, or the need for a pill, overcame the evidence, Relenza would still have been on the market for eight years before Tamiflu.

In eight years Relenza would have made money to reward GSK for the effort of methodically bringing the first NI antiviral to market. It would have encouraged GSK to continue the lines of development already started in 1999. They would have,
-improved the inhaler for the original Relenza product.
-finished clinical trials, and had iv Relenza on the market.
-trialled the first and arguably best second generation LANI candidates, care of Biota. The best one of these could have been on the market now.


HOWEVER,


the reality is, some corners were cut, some men got rich, and the world stockpiled snake oil against a potent influenza pandemic, instead.
 
Re: Flu Found Resistant to Main Antiviral Drug

miso said:
Quote:

"CDC Update

http://www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4416B1-1.pdf"


Check out the CDC Update. The antiviral resistance table comparing Tamiflu with Relenza. Spot the antiviral that took 15 years of research and had over 12 published studies exploring resistance before it was on the market, and the other one (with no independent resistance studies) that was rushed to market in seven years, to beat it.
With a little flag waving, and some helpful nudges, it became the "Main Antiviral Drug."

Let's imagine a scenario in which Tamiflu was developed with as much care (and time) as Relenza.

Firstly Tamiflu would not have survived resistance trials, they would have mirrored what we are seeing now on a larger scale, and it would have been abandoned. Even if greed, or the need for a pill, overcame the evidence, Relenza would still have been on the market for eight years before Tamiflu.

In eight years Relenza would have made money to reward GSK for the effort of methodically bringing the first NI antiviral to market. It would have encouraged GSK to continue the lines of development already started in 1999. They would have,
-improved the inhaler for the original Relenza product.
-finished clinical trials, and had iv Relenza on the market.
-trialled the first and arguably best second generation LANI candidates, care of Biota. The best one of these could have been on the market now.


HOWEVER,


the reality is, some corners were cut, some men got rich, and the world stockpiled snake oil against a potent influenza pandemic, instead.
Click to expand...
The H1N1 Tamiflu resitance was not linked to Tamiflu treatment of seasonal flu.
 
Re: Flu Found Resistant to Main Antiviral Drug

niman said:
Commentary

http://www.recombinomics.com/News/03180901/H274Y_Predict_Evolution.html
Click to expand...
Commentary

Predictable Evolution in Tamiflu Resistant H1N1

Recombinomics Commentary 14:18
March 18, 2009

Recently released H1N1 sequences at Genbank and GISAID include multiple receptor binding domain changes in emerging Tamiflu resistant H1N1. The predictability of these changes is quite remarkable. The hitch-hiking paper is being updated with the more recently released sequences from this season, which describes the importance of the receptor binding domain changes. Some of these changes are detailed in the HA tree (slide 14) from the CDC, but that tree is not fully annotated. The emerging H1N1 isolates all have A193T, but each of the 5 newly formed branches is rooted in addition receptor binding changes, and all are at three flanking positions (187, 189, 196). There are two polymorphisms at 187 (N187S and N187D) and 196 (H196R and H196N), as well as four at position 189 (G189A, G189N, G189S, G189V).

The top branch in the CDC tree is labeled with G189A (as well as S145N). These acquisitions are widespread in Asia (including most isolates in Japan, South Korea, and Taiwan) and are associated with vaccine resistance. All five of the first H1N1 isolates from Italy had these acquisitions, and three of the isolates were from patients who had been vaccinated this season. Similarly, Taiwan reported that 70% of the H1N1 isolates there were vaccine resistant. These changes are also in US isolates, but are fairly rare.

The second branch in the CDC tree is labeled with G189V and H196R. All isolates are from the US and this is the dominant strain in the US. However, this sub-clade is also in Japan and was linked to school closings in Sendai last fall, as described earlier.

The third branch in the CDC tree is labeled N187S, but there are actually two sub-clades in this branch. One was detailed in the hitch-hiking paper and has N187S and G189N. These isolates were in South Africa and Australia in the summer of 2008 and are in Kenya in the fall. There are a few isolates in the US. However, a more common sub-clade in the US has N187S and G189S.

The fourth branch in the CDC tree only has two US isolates, and is not annotated. However, this sub-clade is fairly widespread in the US and is also in Argentina. These isolates have N187D.

The fifth branch in the CDC tree has one isolate from China (Jilin), but there are now multiple isolates from Jilin, as well as isolates from South Australia, which fall on this branch and these isolates have H196N.

Thus, every major branch that has emerged this season has A193T (and hitch-hiking H274Y on NA) as well as at least one adjacent HA change, which is limited to three positions (187, 189, 196).

As described in the paper, the changes for the acquisitions can be found in other H1N1 isolates that are co-circulating with the emerging H1N1, providing additional support for acquisitions via recombination, and for predictions based on such circulating polymorphisms.

.
 
Re: Flu Found Resistant to Main Antiviral Drug

Dr Niman,

With respect, I never said it was.

But everyone knows, when Tamiflu isn't being useless against a wild strain of influenza A with H274Y, it's generating it's own during treatment.
And not just H1N1 but H5N1 too.

Any further developments in Relenza resistance?
 
Re: Flu Found Resistant to Main Antiviral Drug

The problem with H1N1 with H274Y mutation is that its spread can be tracked enough well to define a clear track of evolution, without any noticeable connection with antiviral drug oseltamivir usage during seasonal influenza epidemics.

So, the stability and fintness of H1N1 with this mutation could have been taken into account by national and supernational health agencies BEFORE this virus strain would become dominant, in order to update trivalent inactivated vaccines and treatment protocols for high risk population.

It isn't happened. So, for many patients - immunocomprised or critically ill with underlying conditions - very few alternatives have remained to protect from influenza H1N1 infections.

These way of tracking viruses could be useful although may not improve our ability to understand HOW this particular strain has overcome structural hurdles that previously impaired the stability.

Some researchers have also suggested to decode entire viral genome to explore other possible changes or acquisitions.

Nonetheless, I would express my admiration for this theory of ''elegant evolution'' suggested by dr Niman.
 
Re: Flu Found Resistant to Main Antiviral Drug

For me the key question about the potential for Relenza resistance to develop is whether there are any studies that show a treated patient generates resitant virus over the course of treatment, (as does tamiflu on treatment, occasionally) even if the resulting variant is not a 'fit' virus for onwards transmission
 
Re: Flu Found Resistant to Main Antiviral Drug

Zanamivir intermediate resistant viruses or with reduces sensitivity were surely isolated in the past, mainly H3N2 and B. I think in Scientific Library should be present some abstract, but I don't know for sure at the moment.
 
Re: Flu Found Resistant to Main Antiviral Drug

Found!

Emergence of Influenza B Viruses With Reduced Sensitivity to Neuraminidase Inhibitors

Context
Very little is known about the frequency of generation and transmissibility of influenza B viruses with reduced sensitivity to neuraminidase inhibitors. Furthermore, transmission of resistant virus, whether influenza A or B, has not been recognized to date.

Objective
To assess the prevalence and transmissibility of influenza B viruses with reduced sensitivity to neuraminidase inhibitors.

Design, Setting, and Patients
Investigation of the neuraminidase inhibitor sensitivity of influenza B isolates from 74 children before and after oseltamivir therapy and from 348 untreated patients with influenza (including 66 adults) seen at 4 community hospitals in Japan during the 2004-2005 influenza season. Four hundred twentytwo viruses from untreated patients and 74 samples from patients after oseltamivir therapy were analyzed.

Main Outcome Measure
Sialidase inhibition assay was used to test the drug sensitivities of influenza B viruses. The neuraminidase and hemagglutinin genes of viruses
showing reduced sensitivity to neuraminidase inhibitors were sequenced to identify mutations that have the potential to confer reduced sensitivity to these drugs.

Results
In 1 (1.4%) of the 74 children who had received oseltamivir, we identified
a variant with reduced drug sensitivity possessing a Gly402Ser neuraminidase substitution.
We also identified variants with reduced sensitivity carrying an Asp198Asn,
Ile222Thr, or Ser250Gly mutation in 7 (1.7%) of the 422 viruses from untreated patients.
Review of the clinical and viral genetic information available on these 7 patients indicated that 4 were likely infected in a community setting, while the remaining 3 were probably infected through contact with siblings shedding the mutant viruses.

Conclusions
In this population, influenza B viruses with reduced sensitivity to neuraminidase inhibitors do not arise as frequently as resistant influenza A viruses. However, they appear to be transmitted within communities and families, requiring continued close monitoring.

JAMA. 2007;297:1435-1442
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