How much human bird flu in Indonesia?

And when we say nothing out of the ordinary, we of course mean BUSINESS as usual, patient catches bird flu, is treated with Tamiflu (oseltamivir), patient lives or patient dies.

"Patient 1 was treated with doses of oseltamivir
that were relatively high for her weight, especially
during the first day of treatment. Moreover,
in this patient, unlike most patients with influenza
A (H5N1) virus infection, treatment was
started when the greatest clinical benefit could
be expected: within 48 hours after the onset of
symptoms. Indeed, her clinical condition remained
stable during the first three days of treatment
without the need for supplemental oxygen. However,
on the fourth day of treatment she became
progressively dependent on oxygen, her white-cell
and platelet counts fell, and there was laboratory
evidence of hepatitis. At the time of her death,
the viral load in her throat had increased. These
observations suggest that the development of drug
resistance contributed to the failure of therapy
and, ultimately, the death of this patient. In the
second patient, the viral RNA load declined during
treatment, but not to undetectable levels.
Whereas only wild-type 274H virus was detectable
after two days of treatment, 274Y mutant virus
was isolated shortly after treatment. Although a
direct relationship between the emergence of resistance
and this patientâs death was less clear, the
presence of replicating virus after 14 days of illness
suggests an effect on the outcome.
The emergence of resistant influenza A (H5N1)
variants during oseltamivir treatment should not
be surprising. In adults with influenza A (H1N1)
or (H3N2) virus infection, the development of resistance
to oseltamivir is rare, but resistant viral
variants have been detected in up to 18 percent
of children who receive oseltamivir.12-14 The difference
in resistance rates between adults and
children may be explained by the occurrence of
a primary infection in children associated with
higher rates of viral replication owing to a lack of
previous immunity. Since humans have no previous
immunity to influenza A (H5N1) virus, all
human infections with this virus are primary
infections."

Oseltamivir Resistance during Treatment of Influenza A (H5N1) Infection

Source:http://www.wnysmart.org/Documents/Influenza/Tamiflu%20Resistance%20NEJM…

With all due respect the bottom line isn't the cover-up of the true number of cases occurring in Indonesia, it's why is Tamiflu being used exclusively in what are effectively clinical trials using bird flu victims when we could use better results from Relenza, injectable zanamivir, injectable peramivir, or CS-8958, before the shit hits the fan and there's nowhere to "recall all dependents of employees" to.

I completely agree.

However, at least Indonesia is dumb enough to tell us they are not reporting while at the epicenter and the source of the next pandemic, China, they aren't reporting and not talking...per usual.

Most of the compounds I've mentioned are still in clinical trials you say. What about Relenza (zanamivir) then?
The best I can find is this quote from the WHO's latest (15 August 2007) "Clinical management of human infection with avian influenza A (H5N1) virus", explaining why Relenza isn't used,
"Oseltamivir remains the primary recommended antiviral treatment....Limited information is available about the utility of other antivirals in the treatment of A(H5N1) disease. Although highly active in vitro and in animal models of A(H5N1) virus infection, including that due to oseltamivir-resistant A(H5N1) virus (23), topically applied (inhaled) zanamivir has not been studied in human A(H5N1) illness."

The logic is, the WHO isn't using Relenza to treat H5N1 because,...it hasn't been used to treat H5N1 (Joseph Heller would be proud). Fortunately not the same logic they used when they started using Tamiflu.

Revere, you wrote:

[Indonesian] government control efforts (except on the information front)[have been] ineffective.

I agree. On the information front, Indonesia has been exceptionally effective: The country has transparently and successfully conveyed its key message to the world. The message? "You should not trust anything we say about avian influenza."

Message received.

I am sad for some of the truly excellent communication officers in Indonesian ministries who are in agony about their government's anti-public health policies.

Good point, Path Forward.

Government policy doesn't indict all of Indonesia, or even all of Indonesian public health.

Path F/ Dem:

Thanks for giving us hope.

How to help them, then?

Secretary Clinton just visited, it is important to have a moderate Muslim friend; so politically impossible.

Economic sanction? Then, it would be like Burma. Singaporean companies will flood in. Moreover, now everyone catches fire. No.

How about to institute the quarantine routine of outbound passengers in the consensus of decent countries to give the pressure on Indonesian minister? Yes, but it is a big engineering.

Indonesia is likely being set up to blame for the coming pandemic. Panasonic apparently "knows" something is up. Czech newspapers are questioning if vaccines contaminated with the H5N1 to 18 countries by Baxter was part of a conspiracy to provoke a pandemic. Indonesias health minister has not cooperated because she has expressed fears the US wanted samples in order to re-engineer the virus to ethnically target them. This is something the Project For A New American Century, signed off by Rumsfeld and his Gilead Tamiflu connections, had said would be a convenient political tool.

pft: Can you take your tinfoil had off long enough to explain to me -- scientifically -- how having isloates of Indonesia's H5N1 would ethnically target Indonesians? (I'm not aware that sven she was dumb enough to say that, although maybe I have underestimated her).

Revere, Miso raised the overarching issue no global government or WHO authority wishes to discuss (they have the sequence samples) -- human H5N1 infection treatment protocols midst the hyper-evolutionary emergence of 2008/9 H1N1 containing the antiviral resistance mutation H274Y.

Antiviral (Oseltamivir/Tamiflu) resistant H5N1strains will logically emerge due to flu patients being co-infected with H274Y-H1N1+ H5N1 and then treated exclusively with Tamiflu... But, let's not talk about that, shall we:*)

Honchos in government and WHO don't desire us to think or talk about this issue -- so, they collude together in undereporting the actual H5N1 infections/fatality case numbers.

Revere, "Because not announcing the true number of bird flu cases when the number is known to you is a cover-up. Maybe it's a cover-up that is doing little damage because nothing out of the ordinary is happening. [Certainly not the horror story of collected human H5N1 viral sequences from 2008/9 showing H274Y mutations!] But how are we to know?"

Effect Measure -- "Misleading bird flu press release (aka, Gideon's strumpet)" By Revere (February 9, 2009)
http://scienceblogs.com/effectmeasure/2009/02/misleading_bird_flu_press…

Excerpt from reader posting by: Jonathon Singleton | February 11, 2009:

Dr Berger you write in your EM response that, "GIDEON does not seek to editorialize or explain the fact that lower numbers were reported in a given year, but merely to report the numbers themselves."

There appears to be an obvious "reality disconnect" between the ideals of your database's [purported goal] -- "providing doctors with accurate and current information" -- and enacted practice...

Utilizing a very basic media research-analysis of global H5N1 news reports from the last several years clearly raises evidence of governmental/WHO undereporting of actual H5N1 infections/fatalities...

Do you believe Gideon Informatics has a "duty of care" to accurately report ALL the facts of a given infectious disease eg. multi-strain (clade) H5N1 to those individuals who utilize your database for professional medical purposes!?!

Jonathon,

Are we in Stage 4?

What is becoming increasingly obvious is that Tamiflu should never have been approved for use against influenza A. It has failed against H1N1 and H5N1. When it's not creating resistant strains during treatment, it's prone to resistance in strains that already exist in the wild. Rushing it to market to compete with Relenza has had dire consequences.
The WHO is continuing to recommend Tamiflu as treatment against H5N1, while health professionals refuse to acknowledge the problem (no-one other than J.S. has even reacted to my deliberately nutty posts here or in the child flu death thread http://scienceblogs.com/effectmeasure/2009/03/flu_deaths_in_children.php ) How can they tell the public they were conned, and all the money was spent on a dud, Tamiflu.

Even GSK is part of the conspiracy. What else explains their behaviour towards Relenza, for example their refusal to support an injectable zanamivir?

Victoria, a British scientist, Dr MaeWan Ho, whom I hold in high regard, has often used the following term, "Absence of evidence is not evidence of absence!"

The most rational way of answering your question midst this governmental/WHO cover-up -- where "absence of evidence" is created by official censorship of the full facts -- is thru Revere's edited words:

Revere, "Because not announcing the true number of bird flu cases when the number is known to you is a cover-up. Maybe it's a cover-up that is doing little damage because nothing out of the ordinary is happening. [Certainly not the horror story of national government/WHO collected human H5N1 viral sequences from 2008/9 showing H274Y mutations!] But how are we to know?"

http://www.americanstudents.us/Pages%20from%20Kamen.pdf

Eyes on the ICC -
"Prosecuting the Pandemic:
Strengthening International Public Health Law"

Justin Kamen

Thank you revere for not pulling the plug on my conspiracy theory.

Here's the final instalment,...I'm done.

The background,
The history of Tamiflu is worth closer inspection.

I'm not going to rant about evil American capitalist greed, I'll quote the "The race to develop GS4104" article instead.
http://www.nzzfolio.ch/www/d80bd71b-b264-4db4-afd0-277884b93470/showart…

"The history of the drug that is now sold in pharmacies under the name of Tamiflu began on October 14, 1992."
"On that day Norbert Bischofberger was in Los Angeles for the annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)."
"Bischofbergerâs attention was drawn by a poster that reported the results of an animal experiment. Researchers at Monash University, in Parkville, Australia, had discovered a molecule that stopped the proliferation of influenza virus in mice. This research had been supported by the small Australian company Biota, which then joined forces with the British pharmaceutical giant Glaxo, which wanted to develop and market GG 167, the substance concerned."
"In 1983, Australian scientists elucidated the spatial arrangement of the thousands of atoms that make up the neuraminidase molecule. The scientists saw how the surface of the molecule changed with each new influenza season, but they also found a site that always looked exactly the same: this was a deep cleft in which, apparently, the sialic acid was dissolved. This cleft was potentially the Achilles heel of the influenza virus. If it could be plugged with another molecule, the sialic acid would remain undissolved and the virus, on attempting to leave the host cell, would remain stuck. The Australian researchers had in fact discovered just such a molecule and had already tested it in mice. Bischofberger studied the results reported on the poster and became convinced that the molecule GG 167 could in fact become the first real anti-influenza drug. Then, however, he realised what had been bothering him: since the structure of the GG 167 molecule prevented the drug from being transported from the mouseâs stomach into its bloodstream, the drug would be ineffective if swallowed. Instead, it had been inhaled. The scientists from Biota and Glaxo felt that this could even be an advantage. After all, the cells most affected by the virus are situated in the throat and lungs. Bischofberger thought otherwise, namely that given a choice between swallowing and inhaling a medicine, people would prefer to swallow it. And, he decided, he would make it his business to ensure that they had something to swallow. Within a short time after the conference, ten people were working on the influenza project at Gileadâs headquarters in Foster City, California. "
"Like all new drugs, GS 4104 had to undergo three phases of clinical trials. In phase I, tests are conducted on a small group of healthy individuals to determine the optimal dose range and to detect any unexpected side effects. In phase II, a small group of influenza patients are given the drug. In phase III, the drug is tested under realistic conditions on hundreds of influenza patients."
"Normally, the three phases take seven years to complete. However, in view of the lead enjoyed by Glaxo Wellcome, whose drug had already completed the phase II clinical trials, Rocheâs management boldly scheduled the introduction of GS 4104 for the year 2000. That left just three years for the clinical trials and the marketing authorisation process, which generally takes about a year by itself. "
"On September 24, 1999, just in time for the coming influenza season, Tamiflu was approved for use in Switzerland. Four weeks later it was granted a licence in the USA. Almost seven years had passed since Norbert Bischofberger of Gilead Sciences spurred on the development of the influenza drug â an uncommonly short time, given that the process normally takes ten to fifteen years. Glaxo Wellcomeâs drug GG 167, which had given Bischofberger the original idea, was now called Relenza and had been approved for use in Switzerland three months previously."

There you have it, the Relenza compound survived 15 years of trials and development, including at least 13 studies of resistance (2), and Tamiflu took seven years, and honestly, I could only find one study of resistance, and that was by Roche (1). Unfortunately Relenza development still had a way to go. The inhaler needed improving, so younger children and the elderly could be more successfully treated. Injectable Relenza worked, but formal clinical trials for FDA approval were needed. GSK even had working LANI compounds lined up.

The overwhelming success of Tamiflu ended all that.

Instead of GSK being rewarded for methodical developing the first neuraminidase inhibitor, Relenza was rejected. Lack of demand forced GSK to lock the gates of all Relenza manufacturing plants (only reopening them when some governments wanted to stockpile token amounts of Relenza) ,and cured GSK of any interest in picking up where Relenza development left off.

Bravo Tamiflu, a success story, not greed (3) .

The irony,
here's an extract from an article in the Scientific American, January 1999 from the team that brought Tamiflu to market ,

"As many people know, two anti-flu
drugs, amantadine and rimantadine, are
already on the market. But those agents,
which work by a different mechanism,
have serious flaws. They can cause confusion
and other neurological side effects,
and they are ineffective against one
of the two major influenza classes (type
B) that afflict people. Moreover, influenza
viruses seem to become resistant to
the drugs fairly easily. Therefore, individuals
treated in the first phases of an epidemic
can spread a drug-resistant version
of the virus to other people, who
will then prove unresponsive to the
medicines....

Scientists have tried
diligently to produce strains of influenza
in the laboratory that are resistant to
zanamivir and GS 4104. So far they
have had only limited success. Some
strains gained resistance, as might be
anticipated, by altering amino acids in
the active site of neuraminidase. But
these changes made the enzyme less stable
or less active than usual, suggesting
that viral survival in the body would
be impaired."

http://birdflubook.com/resources/laver78.pdf

The reality,
They claimed particular concern over resistance, and yet soon after Tamiflu was on the market it was clearly generating viable resistant strains with ease,

"Volunteers experimentally infected with influenza A/Texas/36/91 (H1N1) virus and treated with the neuraminidase (NA) inhibitor oseltamivir were monitored for the emergence of drug-resistant variants. Two (4%) of 54 resistant viruses were detected by NA inhibition assay among last-day isolates recovered from 54 drug recipients. They bore a substitution His274Tyr in the NA."

Selection of Influenza Virus Mutants in Experimentally Infected Volunteers Treated with Oseltamivir
The Journal of Infectious Diseases 2001;183:523â531
http://www.journals.uchicago.edu/doi/full/10.1086/318537#tb4

Perhaps the pressure to select, trial, and quickly bring an oral antiviral to market resulted in a less than ideal choice. You think?

The dodgy reassurances,
Roche did some research published in 2002 "The H274Y mutation in the influenza A/H1N1 neuraminidase active site following oseltamivir phosphate treatment leave virus severely compromised both in vitro and in vivo". (Antiviral Res. 2002 Aug;55(2):307-17 ) which assured us "Virus carrying a H274Y mutation is unlikely to be of clinical consequence in man".
http://www.ncbi.nlm.nih.gov/pubmed/12103431

Unfortunately influenza A viri carrying a H274Y mutation include seasonal flu and bird flu.

OOPS!

(1) Tamiflu resistance research

Tai CY, Escarpe PA, Sidwell RW, et al. Characterization of human influenza virus variants selected in vitro in the presence of the neuraminidase inhibitor GS 4071. Antimicrob Agents Chemother 1998;42:3234â41.
http://aac.asm.org/cgi/content/full/42/12/3234

(2) Relenza resistance research

Staschke KA, Colacino JM, Baxter AJ, et al. Molecular basis for the resistance of influenza viruses to 4-guanidino-Neu5Ac2en. Virology 1995; 214:642â6.

Blick TJ, Tiong T, Sahasrabudhe A, et al. Generation and characterization of an influenza virus neuraminidase variant with decreased sensitivity to the neuraminidase-specific inhibitor 4-guanidino-Neu5Ac2en. Virology 1995;214:475â84.

Gubareva LV, Bethell R, Hart GJ, Murti KG, Penn CR, Webster RG. Characterization of mutants of influenza A virus selected with the neuraminidase inhibitor 4-guanidino-Neu5Ac2en. J Virol 1996;70:1818â27.

McKimm-Breschkin JL, Blick TJ, Sahasrabudhe A, et al. Generation and characterization of variants of NWS/G70c influenza virus after in vitro passage in 4-amino-Neu5Ac2en and 4-guanidino-Neu5Ac2en. Antimicrob Agents Chemother 1996; 40:40â6.

Penn, C. R., J. M. Barnett, R. C. Bethell, R. Fenton, K. L. Gearing, N. Healy, and A. J. Jowett. 1996. Selection of influenza virus with reduced sensitivity in vitro to the neuraminidase inhibitor GG167 (4-guanidino-Neu5Ac2en): changes in haemagglutinin may compensate for loss of neuraminidase activity, p. 735-740. InL. E. Brown, A. W. Hampson, and R. G. Webster ed.), Options for the control of influenza III. Elsevier, Amsterdam, The Netherlands.

McKimm-Breschkin, J. L., M. McDonald, T. J. Blick, and P. M. Colman. 1996. Mutation in the influenza virus neuraminidase gene resulting in decreased sensitivity to the neuraminidase inhibitor 4-guanidino-Neu5Ac2en leads to instability of the enzyme. Virology 225:240-242

Sahasrabudhe, A., T. Blick, and J. McKimm-Breschkin. 1996. Influenza virus variants resistant to GG167 with mutations in the haemagglutinin, p. 748-752. In L. E. Brown, A. W. Hampson, and R. G. Webster (ed.), Options for the control of influenza III. Elsevier, Amsterdam, The Netherlands.

Gubareva LV, Robinson MJ, Bethell RC, Webster RG. Catalytic and framework mutations in the neuraminidase active site of influenza viruses that are resistant to 4-guanidino-Neu5Ac2en. J Virol 1997;71:3385â90.

Colacino, J. M., W. G. Laver, and G. M. Air. 1997. Selection of influenza A and B viruses for resistance to 4-guanidino-Neu5Ac2en in cell culture. J. Infect. Dis. 176(Suppl. 1):S66-S68.

McKimm-Breschkin, J. L., A. Sahasrabudhe, T. J. Blick, M. McDonald, P. M. Colman, G. J. Hart, R. C. Bethell, and J. N. Varghese. 1997. Mutations in a conserved residue in the influenza virus neuraminidase active site decreases sensitivity to Neu5Ac2en-derived inhibitors. J. Virol. 72:2456-2462

Blick TJ, Sahasrabudhe A, Mcdonald M, et al. The interaction of neuraminidase and hemagglutinin mutations in influenza virus in resistance to 4-guanidino- Neu5Ac2en. Virology 1998;246:95â103.

Gubareva LV, Matrosovich MN, Brenner MK, Bethell RC, Webster RG. Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J Infect Dis 1998;178:1257â62.

Barnett JM, Cadman A, Burrell FM, et al. In vitro selection and characterisation of influenza B/Beijing/1/87 isolates with altered susceptibility to zanamivir. Virology 1999;265:286â95.

(3) Not greed

Patent Nonsense
http://birdflubook.com/a.php?id=85

Edited copy of email sent to: "Justin Kamen, Founder and President StudentsPrepAmerica"

Sunday, March 8, 2009

Howdy Justin,

I've read the Google html version of the file http://www.americanstudents.us/Pages%20from%20Kamen.pdf you linked at the Effect Measure posting -- How much human bird flu in Indonesia? by Revere (March 6, 2009) (don't get me started on why I can't read pdf's on AdobeReader:*)

Really Justin, in simple terms your paper describes a fragmented international situation vis a vis protecting the public against emerging pathogens such as H2H-H5N1. Like headless chickens, our national government health leaders and international organisations like WHO are lacking a co-ordinating central nervous system keeping the proverbial "show" cohesive whilst it travels along the road. So, you raise the International Criminal Court (ICC) as that mechanism which could become the spinal attachment "glue" holding together the severed heads of all those wonderful "cluckers" in positions of public health authority.

I'm in complete agreeance with you Justin, if you read the attached email you can see I'm beyond frustrated by the incredible naivety our political and public health honchos hold and display re: this "snap of fingers" history changing issue.

The simple reality is, like the U.S. Senator for Maine, Susan Collins, many folk are unable to comprehend the seriousness of the issue due to fear. It's psychologically easier to live within denialist behavioral patterns. This, of course, makes our job protecting public health much more difficult.

Cheers Then:*) Jonathon

Excerpt from Justin Kamen's political science paper, "Prosecuting the Pandemic: Strengthening International Public Health Law":

"[This] paper proposes an additional coercive mechanism that takes advantage of an existing international legal instrument that has so far not surfaced in discussions of global health: the International Criminal Court.

To wit, using the legal framework established by the Rome Statute in regards to crimes against humanity, individuals who would withhold vital public health information for political or economic advantage should be held accountable for their actions in an international court. By standing in the way of global preparation efforts, leaders and officials in these countries doom the international community to helplessness in the face of an emerging public health threat.

Therefore, with-holding accurate and timely information on dangerous infectious diseases, particularly H5N1, should be constituted as a crime against humanity in the jurisdiction of the International Criminal Court under Article 5 of the Rome Statute..."