AFD - Antivirals

[sharon sanders]

Japan: No Link Between Tamiflu And Abnormal Behavior



# 2135

http://afludiary.blogspot.com/2008_07_01_archive.html

For nearly two years the antiviral drug Tamiflu (oseltamivir) has been indirectly linked, solely through anecdotal reports, to aberrant behavior in teenagers and children.

In Japan, where the drug is used widely for seasonal influenza, there have been scattered reports of delirium, and even suicidal behavior, among teenagers while taking Tamiflu.

Today, after a year of study, a Japanese government backed research group has announced that they have found no evidence that the flu drug was the cause of this behavior.

Japan finds no Tamiflu link to abnormal behavior

Fri Jul 11, 2008 6:19am BST

TOKYO (Reuters) - A Japanese government-backed research group has found no evidence that flu drug Tamiflu causes abnormal behavior in young people, a health ministry official said on Friday.

The study, which could lead to the lifting of warnings in Japan on the prescription of the drug to those between the ages of 10 and 19, was carried out in response to incidents that came to light last year in which young people jumped from buildings while taking Tamiflu.

The drug is distributed in Japan, a heavy user of Tamiflu, by Chugai Pharmaceutical Co Ltd through its partnership with developer Roche.

The findings will be presented to a drug safety panel at the ministry, which may decide to withdraw warnings against Tamiflu use in young people, which were introduced in March last year, the ministry official said.
(Cont.)

posted by FLA_MEDIC @ 10:05 AM

[Oracle]

Re: AFD - Antivirals

Study consisted of private interviews of physicians and families of young patients who used Tamiflu. Results suggests study design bias; one would expect 'no effect' or 'negative effects'. But positive effect on mental health?

Non.

Busy physicians are quite unlikely to be able to recall mental health status of individual patients during an unusually heavy flu season in 2006-07. Patients were UNLIKELY to report mental health problems when Tamiflu is prescribed for influenza-like illness and during follow-up visits (if infection or drug complications arose. Parents and family members are also not likely to report patient behavioral issues, out of concern for potential negative social consequences (for instance, later admission to elite high schools and colleges).

Many Japanese who have migrated to the US, whom I know personally, have reported significant peer/social pressure for conformity to rigidly proscribed role and social class expectation. They describe this as a feeling of being constantly monitored for correct behaviors - be it school or work environments, or within formal, semi-casual or casual social networks of family and peers.

Chugai Pharmaceuticals is half-owned by Hoffman-LaRoche. Japan has stockpiled a LOT of oseltamivir.

[sharon sanders]

Re: AFD - Antivirals

Increased Tamiflu Resistance In Seasonal Influenza



# 2157


Roughly 6 months ago an increased number of H1N1 influenza samples with resistance to Tamiflu began showing up in Norway. These viruses carried a specific neuraminidase mutation called H274Y that results in a decreased sensitivity to oseltamivir (Tamiflu).

Prior to this time, very few instances of tamiflu resistance among seasonal flu samples had been detected. In the 2006-2007 flu season, laboratories found no resistant strains in Europe or Japan, and in less than 1% of samples from the United States.


This year, we've seen a sudden surge of Tamiflu resistance, and this has many scientists worried. Thus far, we are talking about the H1N1 seasonal flu virus. Widespread resistance has not shown up in the H5N1 avian flu virus, nor is it being seen in the H3N2 seasonal flu.


It was just three years ago that Amantadine resistance suddenly exploded, and in 2005 the CDC recommended that it no longer be prescribed for influenza.

That pretty much left Tamiflu and Relenza as our only alternatives.

The WHO (World Health Organization) is now actively analyzing virus samples from all over the world, looking to see how many have this H274Y mutation, and attempting to figure out why it is happening.

Last month we learned that roughly 25% of European samples tested this spring showed this mutation. Yesterday, a new report was released showing that 100% of South African samples tested now carry this mutation.

Here is the analysis from this month's WHO report (reparagraphed for readability).

Influenza A(H1N1) virus resistance to oseltamivir - 2008 influenza season, southern hemisphere


18 July 2008

During weeks 26?27 (15 -28 June), the level of overall influenza activity in the world increased reflecting the situation in southern hemisphere. However, influenza A(H1N1)virus circulation remains generally low in all countries reporting influenza activity at this time (see Seasonal influenza activity in the world, 2008)


WHO has received several reports from National Influenza Centres in the southern hemisphere regarding influenza A(H1N1)virus resistance to oseltamivir.

In South Africa, a total of 90 A(H1N1) viruses have been isolated during the 2008 influenza season to date, and all of the 23 influenza A(H1N1) viruses tested by the WHO collaborating Centres in London and Melbourne were found to have resistance to oseltamivir by neuraminidase enzyme-inhibition assay.

None of these patients were receiving oseltamivir at the time of sampling, and no unusual clinical feature or underlying conditions have been found.

To date, preliminary test results show that the viruses carry the specific neuraminidase mutation (H274Y) that confers oseltamivir resistance in N1, while no sign of adamantane resistance by genetic analysis have been found. From Chile, three of the 24 A(H1N1) viruses tested showed the specific neuraminidase mutation (H274Y).

Oseltamivir resistance, at least among the H1N1 viruses, seems to be spreading rapidly. The numbers from South Africa, showing 23 out of 23 samples tested with the mutation are particularly surprising.

And the lack of Amantadine resistance in these samples, something that was running as high as 90% three years ago, is also a bit of a surprise.

None of this means that Tamiflu has become useless against a pandemic virus, but it is worrisome that the same mutation now being seen in the H1N1 virus is identical to the mutation seen in a handful of H5N1 cases that turned out to be resistant to Tamiflu.

posted by FLA_MEDIC @ 9:44 AM

[gsgs]

Re: AFD - Antivirals

90% Amantadine resistance was in H3N2, not H1N1

[tropical]

Re: AFD - Antivirals

Why things must go Murphy way ...

[HenryN]

Re: AFD - Antivirals

Increased Tamiflu Resistance In Seasonal Influenza




And the lack of Amantadine resistance in these samples, something that was running as high as 90% three years ago, is also a bit of a surprise.

None of this means that Tamiflu has become useless against a pandemic virus, but it is worrisome that the same mutation now being seen in the H1N1 virus is identical to the mutation seen in a handful of H5N1 cases that turned out to be resistant to Tamiflu.

posted by FLA_MEDIC @ 9:44 AM

This season H1N1 Amantadine resistance (S31N) is solely in clade 2C (Hong Kong), while oseltamivire resistance (H274Y) is solely in clade 2B (Brisbane/59).
The story is in the sequence. No surprises required. No isolates with resistance to both. The level of Amantadine resiatnce (S31N) in H3N2 remains at levels above 90% this season.

[Michael Coston]

Re: AFD - Antivirals

Thanks for the clarification, Dr. Niman.

[HenryN]

Re: AFD - Antivirals

Thanks for the clarification, Dr. Niman.

Relenza resistance (Q136K) is also beginning to emerge. It had been seen previously in Asia, but this year it appeared in Pennsylvania and a related change (Q136R) has appeared in New Jersey (other than position 136, both NA sequences are identical and isolated in January, 2008).

[gsgs]

Re: AFD - Antivirals

searching google...

----------------------------

A recent study in Australia published by Hurt et al (2007) identified several H1N1 strains that demonstrate significant resistance to zanamivir (up to 250 fold) through Q136K and K150T mutations. These 4 zanamivir resistant virus strains showed little or no change in susceptibility to oseltamivir.

http://lib.bioinfo.pl/pmid:9656997/pmid/cit

RG R292K-NA virus showed cross-resistance to zanamivir

of A/Fujian/411/02 in eggs could be improved by either changing minimum of two HA residues (G186V and V226I) to increase the HA receptor-binding ability or by changing a minimum of two NA residues (E119Q and Q136K) to lower the NA enzymatic activity

E119Q was resistant to zanamivir

A Hurt (WHO, Australia): mutations in N1
4 A(H1N1) strains detected with reduced NAI sensitivity
3 novel mutations in NA gene: Q136K, K150T, K143R
All affect the recently identified ?150-cavity?


1. Gubareva L. abstract O66, Options VI, 2007.
2. Hurt A. abstract O67, Options VI, 2007.

[sharon sanders]

Re: AFD - Antivirals

Seven Days Without Antivirals Makes One Weak





# 2232



A recent article in The Lancet medical journal focuses our attention, once again, on the incredibly high fatality rate among H5N1 patients in Indonesia. As followers of the bird flu story are well aware, more than 80% of Indonesian's known to have contracted the virus, have died.


In Egypt, where 50 people have been identified as having the virus, the fatality rate is a far lower (but still dismally high) 44%. Whether this is due to there being different strains of the virus circulating in Egypt, or victims getting quicker, or better, medical care - or just of generally better health among Egyptians - is unknown.

The difference is dramatic, however.

And according to this article, a major factor in the high fatality rate in Indonesia may be that on average, it took 7 days for a bird flu patient to received antivirals.


The Lancet article, at the time of this writing, was offline (technical difficulties according to their website), but will presumably be available later today.

Human H5N1 virus: epidemiological and clinical data from case-investigation reports in Indonesia, a country which has had the most patients with H5N1 influenza and one of the highest case-fatality rates.

In the meantime we have this Reuters' article available, which ran in The Straits Times.

More than 80% of Indonesia bird flu cases die


WASHINGTON - LATE diagnosis and treatment means that more than 80 per cent of people infected with H5N1 avian influenza in Indonesia have died, researchers reported on Wednesday.


An analysis of outbreaks in Indonesia, the country hardest hit by bird flu, affirms that quick treatment with anti-viral drugs can save lives. But local health care workers are not properly trained in diagnosing bird flu and often do not have the needed drugs to treat it.


Indonesia has had one-third of the world's known cases of human infection with H5N1 avian influenza. It rarely infects people but globally has killed 243 out of 385 sickened since 2003. In Indonesia, 135 people have been infected and 110 have died, according to the World Health Organisation.


Dr Toni Wandra of the Ministry of Health in Jakarta and colleagues analysed the known cases as of February and found it took on average six days for patients to be admitted to a hospital.

By the time they were admitted, 99 per cent had a fever, 88 per cent were coughing and 84 per cent had breathing problems, they reported in the Lancet medical journal.

(Continue . . .)

The lancet article goes on to say that of patients who received antivirals (generally Tamiflu) within 6 days of falling ill, more than 1/3rd survived.


While patients who did not receive antivirals for more than 7 days saw a greater than 80% mortality rate.


It is generally assumed that to be really effective, Tamiflu needs to be administered within 48 hours of infection.


It makes sense that when you use a medicine that is designed to interrupt the replication of a virus, the sooner you introduce it, the lower the viral load the patient will have to combat.


Of course we are dealing with a limited set of patients, under less than ideal conditions, and with far too few seeking early medical care to draw very many conclusions.


Early diagnosis, and antiviral treatment, does appear to increase one's survivability when infected with this virus.


Good news.


But only for those who live in countries where the drug, and prompt medical care, are readily available.

posted by FLA_MEDIC @ 7:04 AM

[sharon sanders]

Re: AFD - Antivirals

Wednesday, September 03, 2008

GSK Offers Corporate Purchase Plan For Relenza




# 2273




The following decision chart comes from the Proposed Considerations for Antiviral Drug Stockpiling by Employers In Preparation for an Influenza Pandemic released in June of this year by the HHS.







As you can see, the HHS is recommending that `very high' and `high' risk employees be provided prophylactic antivirals by their employers during a pandemic crisis.


Additionally, some companies that are part of the critical infrastructure are also encouraged to strongly consider providing antivirals to their key employees.



Last June Roche, manufacturers of Tamiflu, unveiled a corporate reservation and purchase plan for large corporations wishing to ensure they can access antivirals quickly during a pandemic crisis.


Details of the Roche plan may be read here.


Today, GSK (GlaxoSmithKline), manufacturers of the other primary antiviral available today, Relenza, have unveiled a similar corporate purchase/reservation plan.


Here is how Maggie Fox of Reuters reports this story.

Glaxo offers corporate plan for its flu drug



Wed Sep 3, 2008 3:23pm EDT
By Maggie Fox, Health and Science Editor

WASHINGTON, Sept 3 (Reuters) - GlaxoSmithKline (GSK.L: Quote, Profile, Research, Stock Buzz) released a new plan on Wednesday for companies to stockpile its influenza drug Relenza in case of a pandemic.

The plan gives businesses two options: to buy Relenza now at a discount with free storage, or to pay an annual fee to reserve the flu drug for future purchase at a capped rate.

"We are committed to helping employers and other business leaders prepare for an influenza pandemic and its impact on the health of their employees and the operational integrity of their organizations," Chris Viehbacher, president for North American pharmaceuticals at the company, said in a statement.

In June, rival Roche AG (ROG.VX: Quote, Profile, Research, Stock Buzz), which makes the flu drug Tamiflu, offered a similar plan.

Most experts agree that a pandemic of some type of influenza is certain, although no one can predict when or what strain might strike.
(Continue. . . )

Posted by FLA_MEDIC at <a class="timestamp-link" href="http://afludiary.blogspot.com/2008/09/gsk-offers-corporate-purchase-plan-for.html" rel="bookmark" title="permanent link"><abbr class="published" title="2008-09-03T16:11:00-04:00">4:11 PM</abbr>

[sharon sanders]

Re: AFD - Antivirals

Pandemic PEP Talk



# 2296


PEP, or Post-Exposure-Prophylaxis, is one strategy of how we might best use antiviral medications (ie. Tamiflu/Relenza) during a pandemic.


The idea behind PEP is that once someone is identified as having pandemic influenza in a family (or a business, nursing home, etc.), that those people who have been exposed to the patient are given a 10-day prophylactic course of antiviral medications.

There are basically three uses for antivirals:

• Treatment of those infected
• Outbreak Prophylaxis for people who are likely to be exposed
• PEP (Post Exposure Prophylaxis) - giving antivirals to those exposed, but not yet symptomatic to prevent infection.

In the HHS's Proposed Guidance on Antiviral Drug Use during an Influenza Pandemic, released in June of this year, the concept of PEP was discussed, but the idea was not officially endorsed.


The limiting problem is the amount of antiviral medications it would require.


Without adding PEP, the HHS working group has determined that the number of courses of antivirals the United States needs on hand for a pandemic would be at least 195 million

Roughly 2.4 times more than the government intends to purchase.

They urge that the private sector, mostly businesses - but `families and individuals as appropriate' - stockpile the rest.

This would provide:

• 6M doses for deployment overseas to try to stop an outbreak
• 79M treatment courses for the infected here in the United States
• 103M courses to provide prophylaxis for healthcare and emergency service workers
• 5M courses for outbreak control in Nursing homes, prisons, and other closed settings
• 2M courses for people who are severely immuno-compromised

With an anticipated Federal and State Stockpile (currently lagging behind the goal) of 81 million courses, this means that the private sector would have to make up the 114 million course shortfall.

The authors of this HHS document point out that more than 150,000 American lives could be saved if households had antivirals available for PEP, or Post Exposure Prophylaxis.

The working group falls short of actually recommending household PEP, explaining:

Despite these potential benefits, however, further work is needed to assess the feasibility of this strategy and identify approaches for purchasing and stockpiling the antiviral drugs to support its implementation. Therefore, the working group makes no recommendation for household antiviral PEP at this time.

To implement household PEP would require another 106 million courses of antivirals, bringing the total needed to just over 300 million courses.


Today we get a press release announcing the publication of what the authors refer to as the first study on the cost-effectiveness of PEP in the United States.

Cost-Effective Antiviral Strategy Could Halve Pandemic Deaths


Article Date: 14 Sep 2008 - 9:00 PDT Treatment with the oral antiviral oseltamivir combined with post-exposure prophylaxis (PEP) of people exposed to infected individuals could be one of the most cost-effective strategies for reducing illness and death during an influenza pandemic according to recent modeling research published in Value in Health by Beate Sander et al., University of Toronto, Ontario, Canada.


The objective of the study was to analyze, from a US societal perspective, the potential economic impact of a number of key mitigation strategies that may be considered in the event of a pandemic.


Combined targeted antiviral treatment / PEP is a cost-saving strategy and the most effective single approach for mitigating pandemic influenza. The addition of school closure provides greater benefit. Although this remains cost-effective from a societal perspective, school closure will most likely be an attractive strategy when transmission / mortality rates are high.


This analysis is the first economic evaluation to be performed using a dynamic model to predict influenza transmission, the model being based on a "typical" American community of 1.6 million individuals. The study evaluated the use of 16 alternate strategies based on the use of oseltamivir for both treatment and post-exposure prophylaxis (PEP), the use of pre-vaccination in 70% of the population, the use of school closure to reduce the spread of disease and the absence of any intervention.

(Continue . . .)

ABSTRACT
http://www.ispor.org

It should be noted that the author's of this study have extrapolated a much higher number of lives saved by the use of PEP than did the HHS working group.


These sorts of models all depend on the numbers you feed into them. Attack rates, transmission rates (R0 number), and CFR (Case fatality ratios). Right now, all of these numbers are guesses. No one really knows what the next pandemic will bring.

As statistician George E. P. Box told us, "All models are wrong, but some are useful".

But even the more conservative estimates from the HHS indicate that having enough antivirals on hand to implement a PEP strategy could save 155,000 lives.


Cost effective or not, the real barrier here is the `will', on the part of the public or private sector, to invest in hundreds of millions of additional courses of antivirals before a pandemic starts.


And right now, relatively few appear anxious to do so.

Posted by FLA_MEDIC at <a class="timestamp-link" href="http://afludiary.blogspot.com/2008/09/pandemic-pep-talk.html" rel="bookmark" title="permanent link"><abbr class="published" title="2008-09-14T13:16:00-04:00">1:16 PM</abbr>

[sharon sanders]

Re: AFD - Antivirals

Sunday, September 14, 2008

Antiviral Resistance Worries For Upcoming Flu Season




# 2297


Last winter, for the first time, widespread influenza virus resistance to the antiviral oseltamivir (Tamiflu) was reported . . . first from Norway and then from many other monitoring countries.


You can find earlier coverage of this story here, here, and here.


The resistant virus is H1N1, which is only one of several circulating strains of flu viruses. The H3N2 virus, thus far, remains sensitive to the drug, as does the influenza B virus in circulation.


This resistance is caused by a mutation, known as H274Y, where a single amino acid substitution (histidine (H) to tyrosine (Y)) occurs at the neuraminidase position 274.


In some nations, the percentage of H1N1 viruses carrying this mutation has risen to as high as 100%, although most nations are reporting much lower incidences.


Scientists will be watching closely to see if this antiviral resistance is picked up by the H3N2 virus this flu season (which already has become largely resistant to Amantadine).






This story is from the Canadian Press, and is by Helen Branswell - which means that it is clear, concise, expertly written . . . and well worth your time to follow the link and read it in its entirety.

Health officials watching whether flu viruses are becoming resistant to drug


Helen Branswell, THE CANADIAN PRESS


TORONTO - As flu season approaches, public health authorities will be keeping an anxious eye on one family of flu viruses to see if an unwelcome phenomenon that cropped up last winter will stage a repeat performance.

To the surprise and dismay of scientists and governments, H1N1 viruses that were resistant to Tamiflu suddenly appeared in high numbers in Northern Europe.

Testing elsewhere has since shown viruses resistant to the key drug - whose generic name is oseltamivir - have spread to North and South America, the Caribbean, Africa, parts of Asia, Australia and New Zealand.

North American officials say they will quickly test for resistance once the northern hemisphere flu season begins and H1N1 viruses start to spread. And in the U.S. at least, authorities are entertaining the possibility they may have to tweak the advice they give doctors on which flu drugs to use should - as most expect - the problem recur.

"We are thinking about the various sorts of scenarios that might occur," says Dr. Tony Fiori, who develops antiviral drug and vaccine policy in the influenza division of the U.S. Centers for Disease Control in Atlanta, Ga.

"It's hard to imagine we'd be at a point of telling people not to use oseltamivir. We might look at possibilities like pushing people towards using zanamivir when they can, since there hasn't been resistance seen to that."

Zanamivir is the generic name for GlaxoSmithKline's Relenza, which, like Tamiflu, belongs to a class of drugs called neuraminidase inhibitors.

(Continue)

Posted by FLA_MEDIC at <a class="timestamp-link" href="http://afludiary.blogspot.com/2008/09/antiviral-resistance-worries-for.html" rel="bookmark" title="permanent link"><abbr class="published" title="2008-09-14T15:33:00-04:00">3:33 PM</abbr>