UK's RS & AMS Experts call for better flu plans

[GaudiaRay]

Experts call for better flu plans

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The UK government is stockpiling millions of courses of Tamiflu

</td></tr> </tbody></table> <!-- E IIMA --> <!-- S SF --> Leading scientists say the UK government is failing to take advantage of scientific developments in the fight to prevent a flu pandemic. A report from the Royal Society and the Academy of Medical Sciences says it is inadequate to stockpile just one anti-viral drug.
It warns the H5N1 virus can develop resistance to Tamiflu, and says the drug Relenza should also be stockpiled.
It also calls for special scientific advisor to help plan for pandemic flu. <!-- E SF -->
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We are concerned that it is not updating its plans as the landscape of what we know about influenza changes

Sir John Skehel

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It also said the expert should work alongside the Chief Medical Officer and the Chief Scientific Adviser, to advise ministers.
And it calls on the government to work more with industry on vaccine production.
Sir John Skehel, chair of the report's working group, said: "We are concerned that decisions are being made, as the UK prepares for a possible pandemic, that fail to take account of expert advice.
"For example, the decision to continue to stockpile just one antiviral drug is a major concern. This needs to be reconsidered.
"New evidence that H5N1 can develop resistance to Tamiflu indicates that a combination of antivirals should be stockpiled by the UK for the most effective management of a pandemic."
He said the government was right to order Tamiflu in early 2005 - a stockpile of 14.6 million courses of anti-viral drugs is being built up
But Sir John added: "We are concerned that it is not updating its plans as the landscape of what we know about influenza changes."
The RSM said the government should consider increasing the size of the stockpile and should think about using the drug as a prophylaxis, a preventative treatment.
'Most prepared'
The report calls on the Department of Health to bring together academic researchers and pharmaceutical companies to develop vaccines which could be used to protect the public in the event of a pandemic.
It says it would not be possible to manufacture enough influenza vaccines globally in a pandemic - because experts will not know the make-up of a pandemic virus until it starts to spread meaning it would not be possible to immunise everyone.
However, the report adds that limited vaccine supplies can "go-further" if they are combined with adjuvants - agents which boost the effectiveness of a vaccine.
Sir John said: "We find limited evidence that the UK government is engaging with industry to research and develop new vaccines.
"Encouraging researchers and drug manufacturers to share information would speed up the development of adjuvants and vaccines to make the UK more responsive during a pandemic."
He added: "The UK is recognised as one of the most prepared countries in the world however research in this area must continue and up-to-date scientific information should be central to the government's decision making process.
"It will ensure we are prepared not only for a possible influenza pandemic, but also for any future emerging infectious diseases which may affect the UK."
'Adequate stockpile'
But Professor Lindsey Davies, the Department of Health's Director of Pandemic Influenza Preparedness, said: "We are already addressing many of the report's recommendations in our ongoing pandemic preparedness planning.
"We will consider the recommendations of the report as we continue to develop this work."
She said the UK would continue to work with international partners, including the European Union and the WHO, on preparedness vaccine development.
Professor Davies added: "Our antiviral strategy is informed by international consensus and expert advice, and the current stockpile should be adequate to treat all those who fall ill in a pandemic of similar proportions to those in the 20th Century."
Shadow health secretary Andrew Lansley said further action was needed.
"If you believe, as I do, that there's a major risk of a pandemic flu on the scale of the 1918 pandemic of Spanish flu, we should think about stockpiling more antiviral drugs, stockpiling face-masks.
"And we should think about getting an H5N1 vaccine now, on the basis it will offer limited protection.
Liberal Democrat health spokesman Steve Webb said: "A national bird flu strategy must take into account the latest scientific advice on what will best tackle any pandemic.
"We cannot wait until after a case has been discovered to check if our contingency plans are the most effective to deal with this potential threat."
http://news.bbc.co.uk/2/hi/health/6158310.stm


GR: Let the record reflect: NOT A SINGLE MENTION OF RECOMBINATION AS A WAY TO DISCERN PROBABIILTY OF THE VIRAL EVOLUTION. This is now late 2006.

 

[Mingus]

New Strategy on Bird Flu Is Needed, Experts Say

New Strategy on Bird Flu Is Needed, Experts Say

http://www.spotlightingnews.com/article.php?news=3277



New Strategy on Bird Flu Is Needed, Experts Say

Experts from the Royal Society and the Academy of Medical Sciences issued a report saying that new measures should be taken regarding the anti-bird flu plan.

The scientists believe that the UK government is not taking into consideration the new discoveries in flu pandemic prevention. The experts say that stockpiling just one anti-viral drug is not enough to prevent the diseases.

"We are concerned that decisions are being made, as the UK prepares for a possible pandemic, that fail to take account of expert advice," Sir John Skehel, chair of the report's working group said.

"For example, the decision to continue to stockpile just one antiviral drug is a major concern. This needs to be reconsidered."

The group of experts also warned that the H5N1 virus can develop resistance to Tamiflu and also sustained Relenza as an anti-viral drug.

"New evidence that H5N1 can develop resistance to Tamiflu indicates that a combination of antivirals should be stockpiled by the UK for the most effective management of a pandemic," Sir John Skehel added. "We are concerned that it is not updating its plans as the landscape of what we know about influenza changes."

In the past few months Britain has stockpiled about 14.6 million treatment courses of Tamiflu at a cost of around $380 million. That is the only treatment the UK ordered until now.

 

[JJackson]

Re: UK's RS & AMS Experts call for better flu plans

I have now had a chance to read all of this report and most of its recommendation are to do with trying to get a more structured approach to the use of research, and the advice of scientists, by politicians and other decision makers. It also push (gently) for more openness and information sharing (no overt call for release of DVLA Wadbridge's sequestered sequences). As a poster, ad nauseam, on the dangers of reliance on Tamiflu which I am convinced will quickly become useless due to the emergence of a resistant form which the volume of the existing stockpile (now 400,000,000 Std. treatments) will make the dominant strain I was delighted to see the report bring this to a wider audience. One thing they did say, which was new to me, was that the mutation that leads to Tamiflu resistance tends to create a less robust virus. Does anyone know what research caused them to state this and if so please could you supply a link? If I am right in my views about Tamiflu resistance then this is potentially very good news.

 

[AlaskaDenise]

Re: UK's RS & AMS Experts call for better flu plans

...... One thing they did say, which was new to me, was that the mutation that leads to Tamiflu resistance tends to create a less robust virus. Does anyone know what research caused them to state this and if so please could you supply a link? .......

I found this article which seems to contradict that statement...

https://content.nejm.org/cgi/content/full/353/25/2633

[FONT=Arial, Helvetica, sans-serif]Oseltamivir Resistance ? Disabling Our Influenza Defenses[/FONT]
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<CENTER>[SIZE=+1]Anne Moscona, M.D.[/SIZE]</CENTER>

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.
To accommodate the bulky side chain of oseltamivir in the active<SUP> </SUP>site, the neuraminidase molecule must undergo rearrangement<SUP> </SUP>to create a pocket (Panel A). Zanamivir, by contrast, binds<SUP> </SUP>to the active site without any rearrangement of the molecule.<SUP> </SUP>Several mutations that limit the necessary molecular rearrangement<SUP> </SUP>may diminish the binding of oseltamivir (Panel B). Molecular-level<SUP> </SUP>analysis (Panel C) shows that the amino acid termed E276 must<SUP> </SUP>rotate and bond with R224 to form a pocket for the side chain<SUP> </SUP>of oseltamivir. The mutations R292K, N294S, and H274Y inhibit<SUP> </SUP>this rotation and prevent the pocket from forming, resulting<SUP> </SUP>in resistance to oseltamivir. The mutations nonetheless allow<SUP> </SUP>the binding of natural sialic acid substrate, so mutated virus<SUP> </SUP>can survive and propagate. In contrast, the binding of zanamivir<SUP> </SUP>does not require any reorientation of amino acids, so these<SUP> </SUP>mutated viruses remain sensitive to that drug. An E119V mutation<SUP> </SUP>also interferes only with oseltamivir binding, possibly because<SUP> </SUP>a water molecule can fit between oseltamivir and valine at the<SUP> </SUP>active site but cannot insinuate itself between zanamivir and<SUP> </SUP>valine at residue 119.....
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[AlaskaDenise]

Re: UK's RS & AMS Experts call for better flu plans

....... Does anyone know what research caused them to state this and if so please could you supply a link? ........

The story is referenced in an Effect Measure story. Since I believe it's against FT policy to post a blog article, I won't post in it's entirety. see http://effectmeasure.blogspot.com/2005/10/tamiflu-resistance-revisited.html

in part...

...there are some biological reasons to believe influenza/A would not show the kind of resistance to Tamiflu characteristic of the other main influenza/A anti-viral, amantadine because the genetic mutations required to make the virus resistant also made it less fit. Yesterday's paper shows data consistent with that idea.

It's in Nature (20 October 2005)

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[kent nickell]

Re: UK's RS & AMS Experts call for better flu plans

Also related to above...

http://www.bloomberg.com/apps/news?pid=20601102&sid=apT0bMPgell0&refer=uk

Glaxo's Relenza Is Less Likely to Cause Resistant Flu Strains

By Jason Gale

Aug. 18 (Bloomberg) -- GlaxoSmithKline Plc's Relenza antiviral treatment is less likely to lead to drug-resistant flu strains than Roche Holding AG's Tamiflu, giving the product an edge against a feared pandemic, a Glaxo-sponsored study found.

Tamiflu is recommended by the World Health Organization as the first choice for doctors treating human cases of avian influenza. A Tamiflu-resistant strain of the H5N1 virus killed at least three people in Vietnam, raising concern about the drug's potency should H5N1 spark a pandemic.
Human flu strains created to be resistant to Relenza were weakened and less viable when studied test tubes in the laboratory. The study, to be published in this month's edition of the Journal of Antimicrobial Chemotherapy, was undertaken by Glaxo's Medicine Research Centre in Stevenage, England, and an Australian government scientific organization.

``It appears that mutations that confer Relenza resistance compromise the ability of the virus to survive and multiply,'' said Jennifer McKimm-Breschkin, a virologist at the Commonwealth Science and Industrial Research Organization in Melbourne. The finding may explain why no cases of Relenza-resistant flu have been found in normally healthy adults, she said in a telephone interview yesterday.

McKimm-Breschkin was a member of a team that developed London-based Glaxo's Relenza, which is also known by its chemical name, zanamivir.

Relenza and Tamiflu, known scientifically as oseltamivir, both work by blocking neuraminidase -- one of the two surface proteins in influenza viruses and the ``N'' in H5N1 -- that allows the virus to spread from infected cells to other cells in the body.

Different Molecules

The two drugs have a different molecular structure. Zanamivir more closely resembles the sugars coating cells which the virus has to remove in order to spread, McKimm-Breschkin said. Mutant flu viruses that lose the ability to bind with zanamivir also lose the ability to remove the sugars and subsequently can't spread and reproduce, she said.

``It has always been more difficult to get zanamivir resistant mutants than oseltamivir-resistant mutants in the laboratory,'' said K.Y. Yuen, head of the microbiology department at the University of Hong Kong.

Hong Kong has a policy of recommending Relenza as a safeguard to any health care worker caring for an avian flu patient being treated with oseltamivir, Yuen said in an e-mail yesterday.

For health workers, ``Relenza should be considered as a prophylaxis since they may have a risk of getting an oseltamivir- resistant flu virus from these patients who may be brewing them up during treatment,'' he said.
Preferred Choice

Oseltamivir, taken orally in capsules, is the preferred drug for treating avian flu cases because the medicine is easier to administer than zanimivir, which is inhaled. It also is circulated in the bloodstream around the body, unlike zanamivir, which is taken up by tissues mostly in the upper airway and may not kill virus outside the lungs.

Only 4 percent to 17 percent of the total amount of the orally inhaled Relenza is absorbed by multiple organs, according to a study published in 1999 in the journal Clinical Pharmacokinetics.

Infection caused by seasonal flu is typically confined to the upper respiratory system. Avian flu has been shown to infect numerous parts of the body, including the gastrointestinal system, blood and cerebral spinal fluid, according to Menno de Jong, head of the virology department at the Oxford University Clinical Research Unit in Ho Chi Minh City, Vietnam.

De Jong's team was the first to report human avian flu cases caused by Tamiflu-resistant H5N1 strains.

New Version?

Relenza isn't made in pill form because the drug can't enter human cells and tissues properly by that route, Jennifer Armstrong, a Glaxo spokeswoman said last month. Glaxo is in the early stages of studying the possibility of a version that could be administered directly into the bloodstream, she said.

``If an intravenous or oral preparation of zanamivir is finally available, it will replace oseltamivir whose only superiority is good systemic blood level,'' said Yuen.

Relenza sales rose 70 percent to 5.2 million pounds ($9.8 million) in 2005. Roche's Tamiflu brought in 1.6 billion Swiss francs ($1.3 billion) last year.

To contact the reporter on this story: Jason Gale in Singapore at j.gale@bloomberg.net

Last Updated: August 18, 2006 05:56 EDT

 

[AlaskaDenise]

Re: UK's RS & AMS Experts call for better flu plans

Also related to above........

Glaxo's Relenza Is Less Likely to Cause Resistant Flu Strains

By Jason Gale

Aug. 18 (Bloomberg) -- .......Last Updated: August 18, 2006 05:56 EDT

Just to clarify the dates.

.

 

[JJackson]

Re: UK's RS & AMS Experts call for better flu plans

Thanks AD and Kent.

From The excellent Influenza report (2006) http://www.influenzareport.com/ir/drugs/oselta.htm

Resistance

In vitro, the NA mutations E119V, R292K, H274Y, and R152K are associated with resistance to oseltamivir (McKimm-Breschkin 2003). Viral strains containing the R292K mutation did not replicate as well as the wild-type virus in culture and were 10,000-fold less infectious than the wild-type virus in a mouse model (Tai 1998). Likewise, the H274Y mutation reduced the replicative ability in cell culture by up to 3 logs (Ives 2002), required a 100-fold-higher dose for infection of donor ferrets, and was transmitted more slowly than was the wild type (Herlocher 2004).

It has been suggested that if mutations compromise viral fitness, they might be without clinical significance. The recently published cases of high-level resistance to oseltamivir in an H5N1 strain shed some doubt on this hypothesis (Le 2005, de Jong 2005). In this case, treatment with the recommended dose of oseltamivir, although started one day after the onset of symptoms, did not suppress viral replication efficiently and eventually led to the development of a drug-resistant strain. The cause for this - overwhelming viral replication or altered pharmacokinetics in severely ill patients - is unclear.

Whereas the incidence of development of resistant strains of seasonal H1N1 and H3N2 influenza has been low among adults and adolescents (0.3 %), paediatric studies have demonstrated higher rates. One study found neuraminidase mutations in viruses from 9/50 patients (18 %), six of whom had mutations at position 292 and two at position 119 (Kiso 2004). As children can be a source of viral transmission, even after 5 days of treatment with oseltamivir, the implications of these findings need to be investigated.

Cross-resistance between oseltamivir-resistant influenza mutants and zanamivir-resistant influenza mutants has been observed in vitro. Two of the three oseltamivir-induced mutations (E119V, H274Y and R292K) in the neuraminidase from clinical isolates occur at the same amino acid residues as two of the three mutations (E119G/A/D, R152K and R292K) observed in zanamivir-resistant virus (Tamiflu 2005).

I am not sure that any of this data is strong enough to rely on H5N1 being significantly weakened to a '57 / '68 level but given it's current CFR the enormous Tamiflu investment will have been worth it if it nudges the CFR down even a little in the Advent of a pandemic strain emerging.

I do not think the relationship between virulence and pandemic collateral damage (economic & fabric collapse, as opposed to deaths from flu) will be linear, or anything close. As the CFR rises absenteeism, SIP, post pandemic personal and business bankruptcy, economic depression etc. will rise geometrically IMO.

 

[JJackson]

Re: UK's RS & AMS Experts call for better flu plans

The annex to the report lists those consulted and states that the evidence presented by these individuals could be viewed on the RS site (http://www.acmedsci.ac.uk/). As I could not find it I phoned the RS and spoke to one of the authors (Dr Simon Edwards) who said this is being collated and will be up shortly.

He was very helpful and a we discussed the content and he asked about things I hoped might be in it but weren't. I bought up the use of the older ion channel blockers as a combination therapy, stockpiles of drugs for secondary pneumonia and sequence releases from the DVLA lab in Wadebridge, all of which were apparently discussed but ended up on the cutting room floor. Such is the reality of trying to shoehorn everything into a report.

 

[JJackson]

Re: UK's RS & AMS Experts call for better flu plans

http://www.royalsoc.ac.uk/page.asp?id=5573&tip=1

Now has the evidence presented to the panel (see also http://www.flutrackers.com/forum/showthread.php?t=13995)