Effect Measure

Since the antiviral agent oseltamivir (Tamiflu) has been touted as the global savior should a bird flu pandemic materialize the idea has been haunted by the specter of Tamiflu resistance. What if H5N1 becomes resistant to the drug? Is all lost? Now it is being reported in the media that the European Centre for Disease Control and Prevention has found that the predominant circulating seasonal flu virus in Europe this year, H1N1, is showing an unexpectedly high rate of Tamiflu resistance (19/148 isolates tested). This is much more than what has been seen in the past and was from patients not treated with the drug, leading to the fear that a mutation conferring resistance also has some survival advantage leading to this sudden emergence and spread. US CDC data reported in the same news article suggests a much lower (2.2%), but still appreciable level of the same resistance associated mutation in the US during this flu season. This sounds like pretty bad news, and it may very well be, but as with everything connected with H5N1 and influenza in general, things are more complicated than they appear at first.

Consider what is meant by “Tamiflu resistance” in these reports. As best I can make out from the Reuters report the resistance was signaled by finding a resistance-associated mutation, H274Y, in the viral isolates (more on the mutations associated with drug resistance here). This particular mutation is thought to interfere with a necessary change in the place where the drug binds to the viral neuraminidase (NA) enzyme. NA is one of two major proteins on the surface of the virus, the other being hemagglutinin (HA). HA is the key player in viral entrance to host cell. Once inside the cell the virus hijacks the host cell’s protein making machinery to make copies of itself. These copies than bud off the surface of the host cell to infect other cells. But in order to cut loose from the surface of the host cell it needs its other protein, NA, which frees it by slicing a connection to the cell’s sialic acid tipped glycan (see our posts here on the subject). Tamiflu gets into a key region of the NA and prevents it from letting the virus shed from the host cell. Tamiflu is a pill. Another neuraminidase inhibitor, zanamivir (trade name Relenza) only is active in inhaled form.

Now things start to get a little more complicated. The NA protein comes in 9 different forms. Humans are routinely infected with the N1 and N2 forms, and these aren’t the same with respect to Tamiflu. The drugs were designed to work against the N2 form, which was the one where we had x-ray crystallography structures. Recently the N1 form was crystalized, permitting an investigation of the differences in how they react to these drugs. For Tamiflu to interfere with NA action it needs to nestle into a pocket. NA can change shape and for Tamiflu, but not Relenza, to work it needs to nestle into a pocket that forms during that shape change. It is thought the H274Y mutation causes Tamiflu resistance by preventing the formation of the pocket (the binding of Tamiflu is produced by rotating an amino acid near position 274 and its binding to another amino acid at position 224; it’s complicated. See Moscona’s Perspective in the New England Journal for more explanation).

All of this was predicted by analyses of the molecular structure of oseltamivir, zanaivir and neuraminidase. But those predictions were also based on snapshots of structures. New work by Landon et al. and Russell reveals the N1 version is more flexible than thought and that once bound the shape can change from a form similar to N2 behavior to a more open form in N1. Thus the tidy story may not be so tidy after all, or at least our explanations need some modification. The claim of increased resistance to oseltamivir in H1N1 is based on the appearance of H274Y, not yet on the demonstration that H274Y is of clinical importance in the treatment of influenza. Is there evidence that would mitigate its importance? Not much, but there is some. There is a body of work to show that the viruses that carry H274Y are not as fit as the ones that don’t. Unfortunately some of this published work comes from the maker, Roche, so there will be well founded suspicion (this is a burden Roche scientists must bear as a result of the behavior of their employer and the whole industry of which it is a part). What that work seems to show (subject to the qualifications just stated) is that H1N1 carrying H274Y replicates a thousand times less well than the unmutated version and that its ability to cause disease in the ferret model (thought to mimic human infection) is also significantly compromised (see Ives et al.). There are little clinical data shedding light on the efficacy of Tamiflu in H274Y carrying H5N1 viruses, although the mutation has been found there in some patients. A paper by de Jong et al. in 2005 described two fatal cases of H5N1 in Vietnamese patients where H274Y viruses replicated to produce moderate to high viral loads even during timely Tamiflu treatment.

An additional argument against the claim that H274Y mutants are less fit is the fact that they are showing up in Europe where use of the drug for treatment of flu is much less common than in Japan where the mutant has been previously seen. This has led to the speculation the mutation might be conferring some survival advantage. However there has also been major and sudden increases in resistance to the older influenza antivirals, Amantadine and Ramantadine (they work by a different mechanism) and this also has happened without much selective pressure. The thought has been that they are hitchhiking (are linked with) other changes that are important to survival and that the resistance is not itself causing incrased replicability or transmissibility of the virus.

So is this new finding of an increased prevalence of H274Y mutations in H1N1 of epidemiological and clinical importance? It certainly could be but we can argue this both ways. Roche obviously doesn’t want this to be the case, nor, for that matter, does anyone else. Now is the time to do some clinical and epidemiological studies on patients infected with H274Y H1N1 in Europe. You would think that is happening.

But often what you would think and what is actually happening are two different things. I hope that is not the case here.

Comments

  1. #1 Shannon
    January 29, 2008

    Tamiflu resistance in seasonal flus makes me shiver, Tamiflu resistance in H5N1 makes me faint. Our flu arsenal is limited and now perhaps somewhat shaky. I wait with baited breath two studies. The one in Europe and the one Indonesia.

    INDONESIA: Scientists worry bird flu strain is drug resistant – 28/01/2008

    Indonesia has the world’s highest number of bird flu deaths and now scientists are trying to find out why. One theory being tested is that the Indonesian strain of the H5N1 virus is less susceptible to conventional antivirals.

    Presenter – Joanna McCarthy Speaker – Professor Anne Kelso from the WHO Collaborating Centre for Influenza in Melbourne, Dr Deoraj Caussy, Epidemiologist, World Health Organisation.

    listen windows media >

  2. #2 Shannon
    January 29, 2008

    link correction for,
    INDONESIA: Scientists worry bird flu strain is drug resistant – 28/01/2008

    http://www.radioaustralia.net.au/connectasia/stories/s2147920.htm

  3. #3 phytosleuth
    January 29, 2008

    What do you mean? Our flu arsenal has always been shaky. Antivirals and vaccines are valuable, but limited. They’ve always been limited.

    Resistance strategies have been honed for 3.8 billion years. We are infants in the contest and still haven’t figured it out because we think we are strong. Reminds me of a Star Trek Next Generation episode where the aliens say, “We are strong.”

  4. #4 paiwan
    January 29, 2008

    Revere:

    My stupid question- Phuket is a tourists place; every day has thousand European visitors come in (2,000 SquareKm). In terms of transmission, H274Y H1N1 can be here in Phuket and anchoring here locally? Or it is location specific?

    Thanks.

  5. #5 Marissa
    January 29, 2008

    My major concern is that using Tamifly willy-nilly in cases of flu in which the patient doesn’t need it will help the virus develop cross-resistance in strains of H5N1, although this would require recombination, and perhaps, that is a relatively low probability.

    My other comment relates to why the resistance should be mostly related to Norway. Anyone have any ideas?

  6. #6 revere
    January 29, 2008

    Marissa: It’s not just Norway. It’s Denmark, France and the UK, too. The Norway results that have been in the news were results released by the Norway Labs. As for using Tamiflu when it’s not needed, the problem is that by the time you know you need it it’s probably too late.

  7. #7 phytosleuth
    January 29, 2008

    Reliance on attack strategy results in resistance. The challenge is to find strategies in which the virus cannot build resistance.

    How do some organisms protect themselves without creating resistance? What conditions encourage virulence? What conditions encourage benign-ness?

  8. #8 herman
    January 29, 2008

    http://www.int.iol.co.za/index.php?set_id=1&click_id=31&art_id=nw20080129105410220C432363
    With all humility I request you read the above referenced article. It’s implications are profound. As everything in relation to H5N1, there is no magic bullet, including the use of Tamiflu. The article starts:
    “Confirmation of the 100th bird flu death in Indonesia shows the virus is out of control…, experts said on Tuesday.”
    So humans are trying to stop a virus that is out of control in Indonesia, with Tamiflu. Does anyone see how ludricuos that is? This virus is more than capable of rapidly mutating to overcome any protection Tamiflu may have provided in the past. As it is used as a magic bullet, it will become impotent to stop the virus.
    Ngurah Mahardika, the virologist on the resort island of Bali said:
    “The virus is uncontrollable in Indonesia. It means the viral contaminates in the environment are quite high. The reason is the virus is not under control in animals right now.”
    Now comes the wake up call. He then said:
    “(Exterminating poultry) is not possible anymore, you can only do that when there is a small outbreak, when it first begins. It is now endemic.”
    And now goats in India are dying. I do not know if they are infected with H5N1; but if they are, the virus has overcome another species barrier, meaning it will have more and more chances to unlock the glycan lock, and kill humans in exactly the same way, and with exactly the same deadly efficiency it is not killing birds. And humans will only stare in disbelief as they see friends and family members dying a horrible death, in which the patient coughs up blood and the body changes to the color blue.
    Let me ask you this: If culling is now useless in India, because the virus is now endemic in birds, what should be done? Will not the cullers be exposed to the virus and possibly assist the virus to unlock the glycan lock and open the fatal door that leads to massive human death?
    Our hospitals do not have enough N-95 masks to protect our medical staff. Will the medical staff disappear from hospitals when they know there is not protection for them, and they may die. Would you go to work in a hospital if you did not have protection? So who will care for the patients?
    Tamiflu is not a magic bullet. This virus has already caused a bird pandemic. It is a vicious killer. As dead birds are thrown into wells, rivers, and lakes in India and elsewhere; as starving and sick people eat the dead birds, as cullers who cannot afford masks and gloves become infected, as children play with the dead birds, the virus will sooner or later unlock the glycan lock. And when it does, there will be no way to stop it. At that moment the massive death will begin, with a possible motality rate of 40% or more. Then humans will struggle with all the human bodies, like they are now struggling with all the bodies of the dead birds.
    And if the virus penetrates other species barriers, and starts massively killing dogs and cats, will you want your pet culled? Will it be acceptable to you to burn the dog or cat alive, or bury them alive, as they do now with the sick birds? Would you want that for your pet. Would you hide your sick pet to protect it, knowing it may infect humans and kill them?

  9. #9 Chris
    January 29, 2008

    When I first heard about Tamiflu I thought why aren’t they talking about amantadine, another antiviral drug. It’s been around for a while. So I looked it up. It turns out the Chinese already ruined amantadine for us by using on their poultry to protect against bird flu. It’s only approved for human use, at least in the US.

    This is someone disturbing but it seems these antiviral drugs become resistant faster than bacteria become resistant to antibiotics.

  10. #10 revere
    January 29, 2008

    Chris: Resistance to M2 inhibitors like amantadine started before the Chinese (and possibly others) used it in poultry. It turns out that this resistance can develop easily and quickly, often in the course of treatment of a single patient. It also spread widely without much selective pressure, so the resistance phenotype may just be linked to another survival feature. The NI drugs are quite different than the M2 inhibitors, however. Also the dynamics of the spread of drug resistance mean that even very rare variants will spread throughout the population. See my (17 part!) series: http://scienceblogs.com/effectmeasure/math_model_series/

  11. #11 herman
    January 29, 2008

    Tamiflu is being used in India. But here is a report about the virus spreading from rural to urban areas. Of course I have reference to the spread in birds. But plenty of humans are taking tamiflu. I am not so sure it helps. And in regard to the reference to the culler, when they say the test results are negative, don’t be so sure. Testing in India is a disaster in itself.

    “In Kolkata, the health department had a harrowing time after a member of the culling team in Budge Budge, South 24-Parganas, was admitted to MR Bangur hospital with suspected bird flu. Blood samples of Dipankar Dey were sent for tests to three labs. “All came back negative. He is suffering from an infection of the upper respiratory tract,” said Sanchita Bakshi, director health services.

    Culling has been ordered in Baduria, North 24-Parganas, after half the stock of poultry died at a farm. The government decided not to wait for the test reports from Bhopal, said animal resources development minister Anisur Rahman. He refuted corruption charges pressed against some culling officials but admitted that the state had lodged a police complaint against staff who left midway through the culling operation in Birbhum without informing their superiors.

    In Midnapore town, there was panic after seven goats dropped dead. The owner claimed he had buried the animals but couldn’t show the burial place raising fear that the infected meat was sold.”

    Does this report make you feel bird flu is under control in India?

  12. #12 Carl
    January 29, 2008

    Not to be stupid here, but presumably the pharma makers are at least looking at follow on drugs? I don’t think anyone ever thought Tamaflu was supposed to be a magic bullet. It’s purpose, I thought, was to buy time until we could look at other approaches to this problem (perhaps genetic engineering or whatever). If one way of addressing aproblem is ineffective we look for new approaches we don’t just say the problem is impossible. It sounds like the emerging resistance is a clarion call to get moving on this.

  13. #13 Gaudia Ray
    January 29, 2008

    Let’s see… Tamiflu resistance began in chickens in India and was carried to chickens in the West. And now, somehow humans ate the Tamiflu-resistant chicken, in the West, and now they have got into their systems this Tamiflu-resistance.

    Is this it?

    Or was it magic?

    I don’t get it. And moreover, why should I “get it”? Instead, I’ll wait for the experts to figure it out and tell me how it occurs. Yes, that’s it! I’m gonna sit here and wait until some lab guru is going to prove to me how it happens.

  14. #14 revere
    January 29, 2008

    Carl: Big Pharma didn’t develop either Tamiflu or Relenza. They couldn’t care less. Both drugs were developed by small companies and licensed to the big guys. I’m guessing some company is working on some new drugs (see the Landon paper I linked to in the post on new “druggable hot spots” in N1) but that will take time.

    GR: WTF are you talking about? That was incomprehensible.

  15. #15 neil
    January 29, 2008

    Gaudia Ray,

    You’ve got it all bass-ackwards and made a mixed metaphor outta it!

    Revere explained it earlier, I think. Tamiflu inhibits the virus from being able to use it’s Neuraminidase to do it’s replicating thing. It fits in a receptor and the virus fails to bind.

    A mutation in the virus makes it so the tamiflu no longer fits the neuraminidase receptor. So a virus with resistance can go about it’s thing un-inhibited.

    The resistance is NOT in the humans, it’s in the virus.

    (Tamiflu resistance may have started in Vietnam, btw.)

  16. #16 Shannon
    January 29, 2008

    Carl:
    The following is a list of areas being investigated. There is also a lot of interest in phytochemicals. Some show antiviral potential.

    DNA vaccines: Research is ongoing on DNA vaccine technology which injects the flu viral nucleotides – usually the ones that code for the protein haemgluttin – directly into a person’s Langhans cells in the skin. The person’s cell then reads that DNA and transcribes it into viral proteins, which allows the body to develop an immune response.
    Genetically engineered live and killed influenza virus vaccines: It permits the construction of high-yield 6:2 seed viruses by mixing the 6 plasmid DNAs from a good-growing laboratory strain with the HA and NA DNAs obtained by cloning relevant genes from currently circulating viruses. Thus, within a 1-2 weeks period, the appropriate seed viruses could be generated for distribution to the manufacturers.
    Protein vaccines: Virus-Like Particle (VLP) vaccine comprises 3 co-expressed virus proteins – hemagluttin, neuraminidase and matrix M1 – which are injected into the body. The VLP lacks genetic material, so it cannot replicate. But animal studies have shown that it triggers an immune response.
    Cell-culture vaccines: Methods are under development for vaccine production using cell cultures instead of embryonic chicken eggs. Mammalian cell substrates can save 1-2 months of the egg production time.
    Viral-vectored vaccine: Researchers are working on adenoviral-vector vaccine for H5N1 for the past 3 years. The production process involves attaching part of the bird flu gene, extracted through standard molecular techniques, to a relatively benign adenovirus. The vaccine is then injected into the host where in only it replicates as influenza proteins, without harming the host.
    Replication-defective vaccines: Virus particles, which lack the gene for the nuclear export protein, will go through a single cycle of replication without forming infectious particles. Mass production of defective viruses can be achieved using complementing cell lines.
    Nano viricides: Also called chemical viruses, these are synthetic chemicals which destroy specific targets while remaining invisible in their hydrophilic shells to the host’s immune system.
    Universal vaccines: Influenza viruses continue to undergo antigenic drift, which is mostly reflected in accumulating changes in the HA. This fact requires a change in the vaccine formulation or a re-examination of the seed strains, on an annual basis. A realistic approach is the design of more cross protective vaccines for use in interpandemic years and during pandemics. A study has been done to show the effects of vaccines based on the conserved extracellular portion of the M2 protein fused to the hepatitis B core protein.[48] Such an immunogen may induce a cross-reactive response in the vaccinated host. Similarly, immunisation with the NA antigen is likely to induce responses that are more cross-reactive than those by the more variable HA. In both cases, protection will require immune responses which are more vigorous than what is seen after natural infection. Antibodies against NA and M2 proteins in infected humans are generally not protective. Thus, vaccines consisting of NA or M antigens would need to be made to induce a dramatically enhanced immune response.
    http://www.bioline.org.br/request?ph06112

  17. #17 Gaudia Ray
    January 30, 2008

    R, now you know what it’s like to read the postings of those who continue to choose to remain in the dark as to how the virus evolves. WTF.

    Welcome to my world.

    neil, I was joshing. Your point is the point: “A mutation in the virus makes it so the tamiflu no longer fits the neuraminidase receptor.”

    And just how does this “mutation” take place?

    Thank you Shannon for posting that broad overview of the alternative pro-active, pre- and concurrent avoidance approaches developed over the past few years.

    I really hope one of those will become human approved and mainstream rather rapidly. If something will come to market that will replace this “chase the HA evolutionary race car”, it would sure bring peace of mind to billions of folks.

    However, at this time, it’s not time to toss out the baby with the bathwater. There is no reasonable explanation for the “mutations”, except imo, one.

    What I don’t yet, seriously, understand is why single nucleotide point mutations are not explored much more fully as to why they occur, because this Tamiflu resistance SNP is now one of them; it was seen in Japan in the past, and now is being seen in another first world country.

    It must have crossed over on a chicken’s moustache, under the seat of one of those chicken veternarians.

  18. #18 Gaudia Ray
    January 30, 2008

    IMO, and I’m trained as a business lawyer, after reading a fair bit in this field, the H274Y is doing what every previous SNP has done. It’s appearing because it’s in the environment, and it transmits the same way all the others do, via a method that is predictable.

    How in heaven’s name was it not obvious that when it appeared in Japan, it would spread and appear everywhere Tamiflu is used, and everywhere Japanese people who used Tamiflu, travelled and transmitted their flu in the ordinary distribution of virus around the world?

    This is not random. It is not reassortment. It is not abracadbra.

    So, what is the method of transmission at the viral molecular level?

    It was obvious to Revere hizzelf years ago that Tamiflu would become ineffectual.

    The big heads up here is that the environmental pressure necessary to cause the expansion of anti-viral resistance is stunningly low! There’s no need for a sea of N274Y to be concentrated, and then to run over its levy walls.

    This new discovery of a fact that every person who thinks in terms of recombination would easily conclude had a very high probability to have happen is therefore not big news.

    Not one smart person prepping for pandemic has considered the frontline defense to be Tamiflu, except the British who have bet their entire nation-state farm on their warehouses full of Tamiflu, and the other countries who signed up like lemmings to subscribe to Master Roche’s drug. (My larder has less than a handful of Tamiflu in it, and that from when I first saw pandemic on the high probability horizon.)

  19. #19 revere
    January 30, 2008

    GR: Mutations occur by different mechanisms and while you may think the one that produced H274Y is obvious (and let’s be clear, you are a business lawyer who has invested in a company that hopes to make money selling predictions from one particular mechanism, which may or may not be correct and whose method of prediction may or may not work), but this is an empirical question. You are wondering why what is so clear to you, as a business lawyer, when you read the scientific literature, is not so clear to the scientists who write the papers and publish them for others to see, and the same question may have occurred to others. I took the trouble to write a 17 part series explaining at least one way that a rare mutation could spread throughout the population. It did not depend on the mechanism being recombination. That’s just one explanation, not necessarily the right one, but the idea you and your company are the only ones who know what is going on is ludicrous and preposterous. I have remained agnostic on the mechanisms, which is reasonable I think, although in this case much more plausible ones are available. But then I have no financial stake in the answer and in this case most readers are probably wondering, “Why should I care?” I am just telling them why you care.

  20. #20 anon.yyz
    January 30, 2008

    This looks like a race against time. A new anti-viral is needed. Peramivir once looked promising until they flunked the Phase II Trial and will no longer continue with Phase III.

    http://www.fiercebiotech.com/story/biocrysts-peramivir-flunks-trial/2007-09-20

    http://www.biospace.com/news_story.aspx?StoryId=83699

    Is there another anti-viral on the horizon?

    In Egypt they use amatadine/Tamiflu cocktail since only some strains are Tamiflu resistant. Will this work in Europe and Canada for H1N1?

  21. #21 neil
    January 30, 2008

    Hmmmm..,

    Is it so hard to understand HOW the tamiflu resistance SNP got into (according to Niman) WIDESPREAD distribution?

    In a tamiflu flooded environment, it’s the selective advantage that allows the virus to procreate selectively and thus survive to breed another day.

    As simple as that.

    The mechanisims of the whole process can be described by a vast network of grant papers, research, and scholarly works. However it boils down to survival of the fittest.

    The virus seems to be good at it’s job, even though it’s got a primitive and sloppy replication transcription method.

  22. #22 revere
    January 30, 2008

    neil: The added wrinkle here (and with Amantadine resistance) is that there is not much selective pressure. Tamiflu is not used that much in the European areas where it has been found (and wasn’t used in many of the patients where it was found). The additional issue is that there is a literature saying that H274Y isn’t as genetically fit as the wild type, so why is it persisting?

  23. #23 Shannon
    January 30, 2008

    A flu virus is inherently unstable. It makes changes on the coat all the time under pressure and not under pressue. This new wrinkle may not have been driven from Tamiflu use. It simply may have been a spontaneous change. It could then have been have remained because of limited use of the antiviral. It doesn’t take much of an edge to make it successful.

  24. #24 revere
    January 30, 2008

    Shannon: But that’s the wrinkle. It wasn’t supposed to have an edge but a deficit and it was found in areas and patients not under selective pressure.

  25. #25 Shannon
    January 30, 2008

    Obviously that isn’t the case. It is not only surviving but thriving. Methinks something is rotten in Denmark. Either the researchers were dead wrong or, there is something going on we aren’t aware of. One aspect in particular disturbs me greatly. This is already all over one geographical area and we didn’t even know it. Our early warning systems are flawed. We trusted the makers of the drug with nothing in place to verify the veracity of their research nor, did we put in place any kind of monitor to verify if the changes would indeed mean a reduction in the viruses ability to thrive.

  26. #26 revere
    January 30, 2008

    Shannon; There is a working global surveillance system for oseltamivir resistance and this report is a product of that. So it is being looked for. The data on genetic fitness comes from lab work,much done by Roche and published in the peer reviewed literature. What the explanation for the discrepancy is isn’t know at this point. But it is a legitimate question to ask. There are several possible answers.

  27. #27 Shannon
    January 30, 2008

    I should warn you one of my pet peeves is the peer review system. We only get a portion of what they find. Roche may or may not be telling us everything they know or, suspect. A flawed product that makes them billions may be worth the loss in revenue farther down the line. I understand they need to protect their patents but, I also know we are bamboozled occasionally. The market will right the wrong in lost sales eventually but, not until we are well down the road to loss of productivity, income, and lives. And in this case, perhaps pandemic. I don’t know how we can fix the problem either. I just remain highly sceptical of all manufactured drugs and their touted use and safety.

  28. #28 revere
    January 30, 2008

    Shannon; I don’t disagree with you. I do a lot of peer review and I’m a journal editor but it can’t stop the practices of companies that decide not to publish data that is inconvenient for them. I think I noted that in my original post on this.

  29. #29 Shannon
    January 30, 2008

    Revere, I know that. Sorry my rant sounded as if I didn’t. I am angry and frustrated. It isn’t you and, it isn’t totally them (Roche) either. The system needs to be revamped somehow. The consequences of a Tamiflu resistant H5N1 virus right or, nearly right out of the starting gate, buys us no time. I am concerned. The revelation the virus wasn’t made impotent gave me a nasty shock. It also means that the seasonal flu will have one less weapon and an increased morbidity and mortality.

  30. #30 Gaudia Ray
    January 30, 2008

    Shannon, of all people, you should not be shocked. In CE discussions, years ago, idiots like me, business lawyers, recognized that Tamiflu had lots of hope associated with it, but it would probably fail as a defense against H5N1 or whatever the mysterious magic pandemic flu will be (that too is held in the squeaky car of top scientists who are sure it is evolving some way, but not via recombination).

    I recognized it because the must diss’d virological thinker, Niman, said it didn’t stand much of a chance of holding the integrity of its antiviral position because of recombination. Others, including most of the scientists who Revere refers to, above, who had access to the scientific papers, refused to make the same bold claim. Nope; they didn’t know then, and they don’t know now.

    It’s amazing to me the incapacity or unwillingness of the much touted, much accoladed, much-useless-when-it-comes-to-reasonable-probability-projections-over-time scientists to speak to the future.

    What are the reasons you are so shocked?

    If one of them is the devastating consequence of the king being exposed in his underwear, now, with Tamiflu in his counting house and little else, that is not a reason to be shocked. You knew this to be true. You better than most all here know that Tamiflu was and is a thin thread of hope in which minimal investment would be worthwhile.

    I have advocated from day one for the construction of vax plants, including the vax packaging facilities, the skeletons to be set in place, to be fleshed out with staff and the latest vax production front nearer the time of level 6, like NOW. But the answer has been, “We don’t know what vax to produce”, which is itself non-responsive. However, for the ilk of the “scientists” who Revere referenced, that was sufficient to support their silence. The crown of thorns rests clearly on those people who are supposedly dedicating their lives, those bleeding hearts who annoint themselves as socially responsible. They have failed to indefatigably lobby for the Manhattan Project-like need which faces all mankind due to H5N1, our we-don’t-know-if-this-is-it pandemic precursor, if not the early stage pandemic virus itself.

    But what do I know. I’m just a business lawyer. The readership knows those who remain silent, those who banish, ban, and claim the anointment jar.

  31. #31 Shannon
    January 31, 2008

    GR, I must tell you I almost feel I am in a Jane Austin novel. Do I get to be the heroine? I do hope so. Although, the work I have done sometimes feels feeble. I know it has been read but, what for Gods sake is being done with it? Well over 7,000 hits now on one thread alone. Let’s pray they find a few valuable attributes and candidates amongst the litter. I think they are there but will they be tested in time and pan out?

    As for my shock, yes, I confess I knew we would at some point reach this cliff. But, I too can hope for more time even if I worked my backside off to find alternatives. I would very much like to know why the damned drug failed to make the virus more impotent. I am also shocked as it appears it isn’t only in Norway we see the changes. It felt like I’d plunged unexpectedly into frigid water. I am also in a snit the testing didn’t find the critical change in a more timely manner. How long have these changes been out there? Given the extent of the range I suspect for at least several months. I think I’d feel a tad better about the fiasco, if we weren’t in the middle of flu season, with thousands of chickens dying in India and Bangladesh. The good news is it seems the Indian debacle heralds from the Middle East and, not the deadlier virus we see in Indonesia or, from Europe. The other good news is I haven’t read anything to make me think the Indian virus is Tamiflu resistant.

    Now I just have to get over being livid and go back to being my charming self. LOL And go back to my own searching.

  32. #32 highflyer
    January 31, 2008

    Its certainly not good news (particularly with the findings now from Canada too) but thats about it. Far too early for any more conclusions.

    And then laywers and herbalists on a mission, but without any idea of the basics, take over. Sigh.

  33. #33 anon
    January 31, 2008

    hmm, one of the 1918-viruses also had that mutation,
    also viruses from the 30s.

  34. #34 anon
    January 31, 2008

    sorry, I made a mistake. Cancel that previous post.

  35. #35 Shannon
    January 31, 2008

    Highflyer I am going to assume you meant me in your post. I am an herbalist, but I am also a scientist who graduated summa cum laude. Your bias is showing. As for taking over, my research is reviewed by a great many but, they are under no obligation to do so. I can only assume that after more then 10,000 hits on my threads they are getting something out of it. Then, it wasn’t meant to interest you, it was done to facilitate drug companies and researchers. My hope was they would explore options they haven’t yet tried. Since I have seen my work copied verbatim from the forum by biochemists in institutions of higher learning, I think it is safe to assume I have been at least moderately successful.

    I have to laugh here because I was turned down to join an herbalists forum because my work was too scientific. The price for being multi-talented. ROFLMBO

  36. #36 miso
    February 1, 2008

    Shannon,
    Your list is missing research into second generation neuraminidase inhibitors. Clinical trials are progressing (at the usual snails pace) using dimeric zanamivir, also called LANI: long acting neuraminidase inhibitors.

    http://aac.asm.org/cgi/content/full/48/12/4542

    Research into an injectable peramivir is progressing but it looks like it is also useless against the H274Y mutation.

    Characterization of drug-resistant recombinant influenza A/H1N1 viruses selected in vitro with peramivir and zanamivir
    Mariana Baza, Yacine Abeda and Guy Boivin

    Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, Quebec City, Que., Canada

    Abstract

    “There is a limited information with regard to the neuraminidase (NA) mutations conferring resistance to peramivir and zanamivir in the influenza N1 background. In this study, an influenza A/WSN/33 (H1N1) recombinant virus was passaged under peramivir or zanamivir pressure. The peramivir-selected variant had a H274Y mutation in the neuraminidase (NA) gene conferring resistance to peramivir and oseltamivir but susceptibility to zanamivir. The zanamivir-selected variant had a massive deletion in the region encoding the NA active center and an A200T hemagglutinin mutation. This variant exhibited reduced susceptibility to zanamivir with a drug-dependent phenotype.”

    Antiviral Research
    Volume 74, Issue 2, May 2007, Pages 159-162

    Promising research into an injectable Relenza was abandoned by GSK in the late 90’s.

    “Safety and Efficacy of Intravenous Zanamivir in Preventing Experimental Human Influenza A Virus Infection”

    ABSTRACT

    Zanamivir is a potent inhibitor of influenza A and B virus neuraminidases and is active topically in experimental and natural human influenza. We conducted this double-blinded, placebo-controlled study to evaluate the safety and efficacy of intravenously administered zanamivir. Susceptible volunteers were randomized to receive either saline or zanamivir (600 mg) intravenously twice daily for 5 days beginning 4 h prior to intranasal inoculation with ~105 50% tissue culture infectious doses (TCID50) of influenza A/Texas/36/91 (H1N1) virus. Reductions in the frequency of viral shedding (0% versus 100% in placebo, P < 0.005) and seroconversion (14% versus 100% in placebo, P < 0.005) and decreases in viral titer areas under the curve (0 versus 11.6 [median] log10 TCID50 � day/ml in placebo, P < 0.005) were observed in the zanamivir group, as were reductions in fever (14% versus 88% in placebo, P < 0.05), upper respiratory tract illness (0% versus 100% in placebo, P < 0.005), total symptom scores (1 versus 44 [median] in placebo, P < 0.005), and nasal-discharge weight (3.9 g versus 17.5 g [median] in placebo, P < 0.005). Zanamivir was detectable in nasal lavage samples collected on days 2 and 4 (unadjusted median concentrations, 10.5 and 12.0 ng/ml of nasal wash, respectively). This study demonstrates that intravenously administered zanamivir is distributed to the respiratory mucosa and is protective against infection and illness following experimental human influenza A virus inoculation.

    http://aac.asm.org/cgi/content/full/43/7/1616

    I’ll believe things are getting serious when GSK are forced to re-instate their injectable Relenza trials,… until then it’s business as usual.

  37. #37 Shannon
    February 1, 2008

    Miso,
    http://aac.asm.org/cgi/content/full/48/12/4542
    Made interesting reading. Lots of questions going through my head. Wonder how expensive it is to produce? I also wonder if it depends on a scarce resource? As for the snails pace, unless there is a critical and immediate need need for the product, caution, peer review, expense are always going to be higher priorities. I am of two minds here. I would certainly like the process to speed up given the potentially grave possibility of pandemic however, the possibility of something with the disastrous side-effects of thalidomide, as an extreme example, always needs to be examined and that takes time.

    [snip]
    In summary, we have identified dimeric NA inhibitors that show remarkably high levels of and prolonged anti-influenza virus activities. We believe that, relative to zanamivir, the superior in vivo prophylactic activities of dimers such as compound 9 can be attributed to a combination of the improved antiviral potency and higher level of compound retention in the lung. These compounds provide a clear example of how suitable multivalent derivatives of a known therapeutic compound can introduce an extra mode of binding and, hence, give dramatically improved activity in vivo. These results raise the prospect for a new type of anti-influenza drug that could be used at very low doses administered once weekly, such that a single dose could be suitable for the treatment of influenza or such that treatment just once a week could be suitable for the prevention of infection.

    [snip]

  38. #38 highflyer
    February 1, 2008

    Shannon: It has nothing to do with bias. No matter how good you might be in your “graduation” field or work (whichever that is), with regards to flu/medicine/biology/virology/pharmacology, herbalist describes the expertise you demonstrate and not expertise in the afformentioned fields.

  39. #39 Shannon
    February 1, 2008

    Highflyer, I’m sorry I didn’t realize you needed to be an expert in the field of biochemistry, epidemiology, etc…, to post here. My mistake. I also didn’t realize you were a gatekeeper. Just for my own edification before I toddle off, what is your field of expertise?

  40. #40 revere
    February 1, 2008

    Shannon: I’m not following your conversation, but we are the gatekeepers here and for the most part (rare exceptions) the gates are open to all.

  41. #41 miso
    February 2, 2008

    Apologies for the cut off quote regarding injectable Relenza, it contained “less than” symbols that html interprets as formatting brackets. it should have read,

    “Zanamivir is a potent inhibitor of influenza A and B virus neuraminidases and is active topically in experimental and natural human influenza. We conducted this double-blinded, placebo-controlled study to evaluate the safety and efficacy of intravenously administered zanamivir. Susceptible volunteers were randomized to receive either saline or zanamivir (600 mg) intravenously twice daily for 5 days beginning 4 h prior to intranasal inoculation with ~105 50% tissue culture infectious doses (TCID50) of influenza A/Texas/36/91 (H1N1) virus. Reductions in the frequency of viral shedding (0% versus 100% in placebo, P less than 0.005) and seroconversion (14% versus 100% in placebo, P less than 0.005) and decreases in viral titer areas under the curve (0 versus 11.6 [median] log10 TCID50 � day/ml in placebo, P less than 0.005) were observed in the zanamivir group, as were reductions in fever (14% versus 88% in placebo, P less than 0.05), upper respiratory tract illness (0% versus 100% in placebo, P less than 0.005), total symptom scores (1 versus 44 [median] in placebo, P less than 0.005), and nasal-discharge weight (3.9 g versus 17.5 g [median] in placebo, P less than 0.005). Zanamivir was detectable in nasal lavage samples collected on days 2 and 4 (unadjusted median concentrations, 10.5 and 12.0 ng/ml of nasal wash, respectively). This study demonstrates that intravenously administered zanamivir is distributed to the respiratory mucosa and is protective against infection and illness following experimental human influenza A virus inoculation.”

    P.S. Keep up the good work Shannon.

  42. #43 miso
    February 2, 2008

    anon,

    this is what is with “super-relenza” (=LANI) taken from ASX announcements from Biota Holdings. Note that seven months passed between the end of Phase I and the beginning of Phase II clinical trial – that’s what I was referring to as a snails pace. Interestingly GSK had the rights to develop one of the LANI compound but gave it back to Biota – probably a good thing considering their woeful handling of Relenza.

    LANI completes Phase I in Japan and to commence Phase I in UK
    19 April 2007 – Biota Holdings Limited today announced that its long acting
    neuraminidase inhibitor (LANI), CS8958, an anti-influenza treatment, has:
    1. demonstrated effectiveness against the avian flu virus H5N1;
    2. completed Phase I studies in Japan; and
    3. received ethics approval to commence comparable studies in the UK.
    Biota’s partner for LANI, Daiichi-Sankyo, overnight announced that laboratory studies had confirmed CS8958�s effectiveness against the avian flu virus H5N1 in addition to its effectiveness against influenza A and B type non-avian viruses.
    Daiichi-Sankyo also announced that it has completed a Phase I clinical trial in Japan on CS8958 and expects to start Phase II studies in October.

    The UK studies will extend the safety and pharmacokinetics studies of CS8958 in man. The double-blinded study will involve up to 40 healthy volunteers using a single dose, and will trial up to four separate, single dose levels. The study is being funded as part of a US$5.6 million grant provided by the US National Institutes of Health. The studies will utilise a newly licensed inhaler designed by Hovione and complement the studies completed by Daiichi-Sankyo in Japan. The UK studies will generate data in western subjects and lay the basis for further clinical development outside Japan.
    CS8958 is an inhaled long acting neuraminidase inhibitor and offers higher potency and a lower dose than zanamivir and oseltamivir, the currently available products.
    CS8958 offers the potential for once only treatment and once weekly prophylactic protection from influenza, known consumer advantages over existing inhaled and oral therapies.
    CS8958 and a range of other LANI type compounds are co-owned by Biota and Daiichi-Sankyo.

    LANI Phase II clinical trials commence
    22 November 2007 – Biota Holdings Limited today announced that its long acting
    neuraminidase inhibitor (LANI), CS8958, an anti-influenza treatment, has commenced Phase II clinical evaluation. The first patient has commenced treatment. The study is being carried out by Daiichi-Sankyo in the northern hemisphere influenza season.
    Key aspects of the Phase II clinical trials are as follows:
    – Two trials are planned, one in Japan and the other elsewhere in Asia;
    – The studies aim to test the effectiveness of CS8958 in adult patients who have naturally acquired influenza A or B;
    – Fever resolution after a single inhaled dose of CS8958 will be the primary end point, although influenza carries a range of symptoms in addition to fever. The reduction in these other symptoms will also be measured;
    – The double blind trials will examine the safety and efficacy of CS8958 and assist in selecting the best doses for treating influenza; and
    – The duration of the trial will depend on the severity of the influenza season and hence the availability of patients for the trial.

    I feel uncomfortable quoting share market announcements (compared to scientific papers), but you’ve got to take information from anywhere you can find it.

  43. #44 David Pawlowski
    April 29, 2009

    Fast forward to 29 April 2009, Swine Flu makes a come back and Tamiflu will be used (hopefully) agressively early on in an attempt at holding the line on the emerging global pandemic while folks rush about trying to make a vaccine. In Campeche (Pomuch) Mayan region of Mexico an old custom is practiced where in the living dig up the remains of the dead. It is hoped that some poor fool did not dig up the remains of a relative who died from the 1918-1920 Spanish Flu epidemic and scrapped and cleaned his bones from the dry cool earth of South East Mexico. While no one has asked this question, it begs consideration given the exponential growth in flu perhaps starting with a rash of pneumonia related deaths in the Mexican state of Campeche from November 2008 on. It is interesting to note that the claimed case #2 fatality in Mexico was apparently a mother (39) who was working in some capacity for the National Institute of Statistics and Geography as a public health poll taker apparently tracking the progress of the Swine Flu. The Mexican government knows far more than it is revealing. The Pandemic is shaping up to be a possible repeat of the 1918 global pandemic and one would assume the virus will mutate and escape effective control of Tamiflu at some point when the weather becomes cool and dry in North America in the fall.

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