Effect Measure

CDC guidelines for antiviral therapy for swine flu infection:

This swine influenza A (H1N1) virus is sensitive (susceptible) to the neuraminidase inhibitor antiviral medications zanamivir and oseltamivir. It is resistant to the adamantane antiviral medications, amantadine and rimantadine. (CDC)

What are these antiviral drugs and how do they work? Over the years here we’ve discussed this pretty often, so I went back and retrieved one of our older posts (from 2007). I’ve done some editing but it’s pretty much the same as when I wrote it about bird flu. Same principles.

Oseltamivir (which we will call by its trade name, Tamiflu) belongs to a class of flu antivirals called neuraminidase inhibitors. Neuraminidase (NA) is a protein that acts like an enzyme (it catalyzes a specific biochemical reaction) and it is present on the virus in the form of a glycoprotein, one of the two glycoproteins that stud the viral surface (for more on the basics of glycoproteins in lay language see our series that starts here). The other glycoprotein is hemagglutinin (HA). There are 9 immunologically distinct classes of NA and 16 of HA and the specific HA/NA combination of these types are what distinguish the various influenza A subtypes named for them (e.g., H1N1, H3N2 or H5N1). These are also the main elements that our own immune systems recognize and it is the HA glycoprotein that is the basis for the current seasonal influenza vaccines (some newer experimental vaccines are now using other viral proteins).

The HA protein plays an important role at two critical points in viral infection of a host cell. The first comes when it binds to a host cell receptor of the right kind. Currently we believe the main receptor is something called a sialylglycan (we have discussed details in the glycoprotein series linked above). Once docked to the receptor the virus is “taken into” the cell by being enveloped by the cell’s membrane in a process called endocytosis. Think of a closed bag of liquid you push a small stone into the side of, making an indented pocket with a sort of “neck” to the outside. Now pinch off the neck part so that the stone is now inside the bag surrounded by its own little piece of the bag wall. It still isn’t really inside the bag yet because of the surrounding coating of bag wall, but if it could get through that it would be bathed by the liquid in the bag and truly “inside.” That’s what the virus needs to do because it requires to give its genetic material access to the cell’s genetic and protein-making machinery so it can make copies of itself, its only real function. HA takes part in this process, too, helping the virus “fuse” with the surrounding little bit of bag wall and exit from its internal bubble into the cell proper. In addition, there is a viral protein (M2, called an ion channel protein) that allows the virus to “uncoat” and release the genetic material in more or less naked form (I say more or less because the genetic material is complexed with three other proteins but free of its viral coat). An older class of viral drugs, the adamantane class (amantadine and rimantadine) works by inhibiting the M2 protein and preventing the internalized virus from exposing its genetic material for us by the host cell’s protein making and replication machinery. The current swine flu virus is completely resistant to the adamantane drugs.

But it is sensitive the the neuraminidase inhibitors that involve NA, not HA. After the virus makes copies of its genetic material and its various parts all is fully assembled again at the inside cell surface and then budded from the outside surface of the host cell. But it is stuck to the service by the same HA that enabled its entrance, so it has to be cut loose from the same sialylglycans it used to attach, on entry. That is what NA does. Neuraminidase inhibitors like Tamiflu work by decreasing NA function, making it hard for them to exit after budding at the surface (I’m simplifying, so see the original post if you want more gory details about the complications; for most people this is already too much).

Antiviral drugs like Tamiflu and Relenza (generic name zanamivir) work because they look like the sialylglycan the virus is trying to find for its initial attachment, acting like decoy host cell receptors. The drugs bind in a chemical recognition site, a sort of “pocket” on the NA glycoprotein. In order for the drug to bind, there must be a fairly specific set of attachment points in the pocket and this is determined by the sequence of amino acids that make up the NA protein. which in turn is determined by the genetic sequence in the viral RNA. So if that genetic material changes (a mutation) it can alter the attachment points the drug needs and produce an NA that no longer binds the drug.

That’s the back story of antiviral drug resistance. The bottom line, as published officially by CDC last night is this:

Since April 21, 2009, CDC has reported cases of respiratory infection with a swine-origin influenza A (H1N1) virus (S-OIV) that is being spread via human-to-human transmission (1). As of April 28, the total number of confirmed S-OIV cases in the United States was 64; these cases occurred in California (10 cases), Kansas (two), New York (45), Ohio (one), and Texas (six). The viruses contain a unique combination of gene segments that had not been reported previously among swine or human influenza viruses in the United States or elsewhere (1). Viruses from 13 (20%) of 64 patients have been tested for resistance to antiviral medications. To date, all tested viruses are resistant to amantadine and rimantadine but are susceptible to oseltamivir and zanamivir. (Morbidity and Mortality Weekly Report Dispatch, Update: Drug Susceptibility of Swine-Origin Influenza A (H1N1) Viruses, April 2009)

Now you know a little more what this means.

Comments

  1. #1 webtax
    April 28, 2009

    this is interesting.

    guys just a little question about the diagnosis:
    when with it says that the classic RT-PCR kit cannot detect the new H1N1, it means that it results negative, or that its also positive for “h1n1″ so you can’t tell between the old and new?

    because then you can , by discarding, tell that you have the new h1n1… but i guess its the second situation.

  2. #2 revere
    April 28, 2009

    webtax: You need a specific swine flu primer. If you use the usual seasonal flu primers you don’t get anything (unsubtypable).

  3. #3 Steven R
    April 28, 2009

    So it’s not Swine Flu = Man+Bird+Swine; rather it’s Swine Flu = Swine Flu 1930’s + Swine Flu 1979.

    http://www.wired.com/wiredscience/2009/04/swinefluupdate/

    Neither of the strains have ever proven contagious in humans. One of the genes inherited from the Eurasian strain has reportedly never been seen in humans. It codes for the neuraminidase enzyme — the N1 in H1N1 — which controls the expansion of the virus from infected cells.

    “The new neuraminidase gene that came in from Eurasian swine is one we’ve never before seen circulating in humans,” said Rambaut. “That’s one of the reasons it’s spreading rapidly. Very few people will have any immunity to this particular combination, which is what gives the concern that this will be a pandemic rather than just a normal seasonal flu outbreak. It remains to be seen how much and to what extent there is existing immunity.”

    Does this effect the response or potential?

  4. #4 dmv
    April 28, 2009

    Nice post. The 4-part series linked to is helpful as well. For some good graphics, with more technical explanations, your readers may want to check out:

    http://www.reactome.org

    And then click on “Influenza Infection” (4th entry in the 2nd column).

  5. #5 Hesam
    April 28, 2009

    You mentioned your 4 part Influenza series. Could you make it available as a single printer friendly document?

  6. #6 webtax
    April 28, 2009

    @revere: i have been reading and see that most probably there’s no primer capable of distinguish between old and new H1N1 (because of similarity), but theres gona be probes in the PCR kit for that matter, to be able to make difference. (now the only way is through nucleotid secuencing) that is what WHO is apparently mentioning is going to be at least.

    specifics aside, my question remains : could be that if you get an unsubtypable diagnosis (but knowing its influenza A), you could tell with high probability % that is a new h1n1 confirmed case, because by discarting the two other Influenza A subtypes ? as theres litlle probability theres a new subtype or its another virus

    regards

  7. #7 Pierce R. Butler
    April 28, 2009

    Breakthrough! The cause of the Mexico swine flu outbreak has been identified:

    Mexico City Sees Swine Flu Virus on Second Anniversary of OKing Abortion

    How could we ever get along without hyperchristians?

  8. #8 Phila
    April 28, 2009

    New Zealand is allegedly offering Tamiflu OTC, which doesn’t seem like a very good idea.

  9. #9 webtax
    April 29, 2009

    OTC, over the counter, means without needing recipe right?

  10. #10 Houston
    April 29, 2009

    recipe is what they tried to use in Florida when they killed the polo ponies, for Tamiflu we need a prescription

  11. #11 Revere
    April 29, 2009

    Revere

    Both these drugs are NA antivirals. You have lumped Relenza and Tamiflu together under the NA blanket. One would get the impression they are the same. Why is it that Tamiflu, this season, has a 98 % resistance to H1N1 strains where Relenza has been shown to be 100 % effective.

    I know each drug is designed differently but why is tamiflu resistant and Relenza isnt !!! Is Relenza inherently a better design hence the recent stockpile changes around the world. Does anyone know.

  12. #12 webtax
    April 29, 2009

    @Houston: thanks for the clear up, that was i meant- idiomatic barriers always stalking.

  13. #13 attack rate
    April 29, 2009

    @Phila

    New Zealand sells Tamiflu OTC every seasonal influenza season (May-September in the Southern Hemisphere). It’s not truly OTC – you must consult with a pharmacist and have signs of influenza, otherwise you still need a prescription.

    This has been the case for a few years, and isn’t really anything to do with the H1N1 situation.

  14. #14 Phila
    April 29, 2009

    New Zealand sells Tamiflu OTC every seasonal influenza season (May-September in the Southern Hemisphere). It’s not truly OTC – you must consult with a pharmacist and have signs of influenza, otherwise you still need a prescription.

    OK, good. Thanks for the info!

  15. #15 pft
    April 29, 2009

    Seasonal H1N1 was already pretty much resistant to Tamiflu. Yet this new strain of H1N1 is not resistant. Curious, no?

  16. #16 Miroslav
    April 29, 2009

    Hmmmm,

    “ONLY” Tamiflu!!!

    Again????

  17. #17 Paul Browne
    April 29, 2009

    “I know each drug is designed differently but why is tamiflu resistant and Relenza isnt !!! Is Relenza inherently a better design hence the recent stockpile changes around the world. Does anyone know.”

    From what I’ve read on the subject (and I’ll admit that I’ve barely skimmed the surface of the literature) the reason for the slower evolution of resistance to Relenza is that while both Relenza and Tamiflu bind strongly to the neuraminidase pocket, the the binding of relenza more closely mimics the binding of sialylglycan to the same pocket. What this means is that there is a high probability that if the virus mutates so that it will no longer bind Relenza it will no longer be able to bind sialylglycan either, so it won’t be able to infect cells. With Tamiflu the probability of this happening is a bit lower, though of course many mutations will still block sialylglycan binding, and resistance evolved more quickly. Relenza does look like being the better drug.

    It’s also worth mentioning that even before the problem of resistance developed neuraminidase N1 was found to be somewhatmore sensitive to Relenza, while neuraminidase N2 was a little more sensitive to Tamiflu, again this would argue that Relenza would be the better drug to use in this outbreak, though both are certainly helpful.

    If I may shamelessly highjack the thread I’d like to urge you to sign the Pro-Test petition at:
    http://www.amprogress.org/site/c.jrLUK0PDLoF/b.5110163/k.1BA4/Show_Your_Support_for_Medical_Progress.htm

    Animal research played a very important role in the later stages of the development of both Relenza and Tamiflu, as the in vivo anti-viral activity and pharmokinetics of candidates were being evaluated, changes made and the candidates and then re-evaluated before selection for clinical trials.

  18. #18 revere
    April 29, 2009

    webtax: Things untypable with the kits CDC gives to state labs are often still typable at CDC labs as seasonal flu. That’s been the experience. So untypable at state labs could mean either it is novel but not swine flu, swine flu or still typable as seasonal flu by CDC.

    Other questions on tamiflu and relenza: these are different drugs and bind to NA in different ways. Tamiflu was designed for group 2 NA, but a conformation change (an internal rotation) when tamiflu binds makes it look more like group 2 and allows it to bind to N1, too. A common mutation (H274Y) prevents the rotation. Relenza, however, can still bind. But Relenza cannot be absorbed orally so it has to be inhaled with a special inhaler. It is not a pill. Children have difficulty getting this into their lungs as do people with breathing difficulty and asthmatics.

    Seasonal H1N1 this year carries the H274Y mutation, but the NA in swine flu, so far, does not. It is not at all anomalous because the NA in the swine flu virus is not derived from the NA in H1N1, it is a swine, not a human NA.

  19. #19 miso
    April 29, 2009

    “I know each drug is designed differently but why is tamiflu resistant and Relenza isnt !!! Is Relenza inherently a better design hence the recent stockpile changes around the world. Does anyone know.”

    Are you implying revere completely glossed over the well documented differences in the way Tamiflu and Relenza bind in the “pocket” on the NA glycoprotein; fundamental to the understanding of antiviral drug resistance?

    That would be admitting Relenza is inherently better.

    Try reading here, it’s old, but thanks to the usual bias inthe media, it’s still fresh,

    Oseltamivir Resistance – Disabling Our Influenza Defenses by Anne Moscona, M.D.
    http://content.nejm.org/cgi/content/full/353/25/2633

    There is no evidence of zanamivir resistance in viruses isolated from normal healthy patients after treatment with the drug. The only case of in vivo zanamivir resistance is that of an 18-month-old immunocompromised child, who acquired an influenza B virus infection and failed to respond to ribavirin treatment. The child was subsequently treated with zanamivir and after 12 days of treatment a virus containing an R152K NA mutation was isolated. This virus also contained a mutation in the HA protein, T198I, which had appeared prior to the NA mutation. In contrast, resistance to oseltamivir occurs in 1%-4% of adults and 4%-8% of the paediatric population.

    http://jac.oxfordjournals.org/cgi/content/full/55/2/162?ijkey=d0c8f4f3e2bf2822989791388539886104f542f3

    Here’s something no-one ever criticizes Tamiflu for. It’s all well and good that it is take orally, but IT CAN”T BE INJECTED.

    “zanamivir is not used because it is an inhaler and patients in the recent Asian outbreak were too ill to inhale even though laboratory tests show it has some effects on H5N1. Manufacturers should think about producing an injectable form. Drugs that are administered intravenously can be better absorbed in patients who have stomach and acidity problems. We don’t have to worry about absorption, injections take drugs right in. But if the patient takes them orally, maybe some amounts won’t be absorbed or some may be destroyed by stomach acids. Intravenous zanamivir would also ensure faster onset, which would be critical in patients who are seriously ill. Orally taken drugs take 3-4 hours to reach maximum blood concentration and 3-4 hours is very critical in severe cases. But injectable zanamivir takes only 30 minutes to reach maximum blood concentration, this is a huge difference. With an intravenous antiviral, doctors can also vary the doses.”

    Source: http://focosi.altervista.org/pathoviruses_influenzaA.html

    Q. So where’s iv zanamivir?
    A. We don’t need it because we worship the sun god Tamiflu… hang on it’s just gone supanova…what are we going to do n

  20. #20 GeorgeT
    April 29, 2009

    Is it possible for a virus to be resistant to Relenza but not Tamiflu?

  21. #21 engstudent
    April 29, 2009

    How useful is 1 out of 66 confirmed cases, as the initial CFR in the US? As far as statistics go. An initial rough estimate of total fatilities with a lot of other assumptions with this number says there could be 150000 to 462000 fatalities in the US. The other assumptions are that 10% of the population infected.

    The first thing that comes to my mind is that there couldve been hundreds of other mild cases of the virus already in the US and not even reported much less confirmed that would scewer this number much lower.

  22. #22 revere
    April 29, 2009

    engstudent: You need to know where the numerator and denominator come from to know what it means. In this case, though, the numerator is a child who got sick in Mexico and was brought to Texas for treatment, so it isn’t even part of the denominator. See our earlier post on CFR.

  23. #23 engstudent
    April 29, 2009

    oh my

    Thanks for clarifying that. I didnt know he was brought here for treatment. And Ill go re-read that post now pbbbbbbbbbbbbbt sorry (:

    Out of curiousity where can I get more information about these individual cases, the media has been almost void of relavent, real information.

    thanks again

  24. #24 Patch
    April 29, 2009

    Revere,

    More speculation…..

    I saw on the news this morning, that Mexico, for many reasons, has water shortages and it was suggested that the large number of infected people may be a result of their inability to properly wash their hands.

    We’ve talked about this before, but if that stands to reason, then would it also stand to reason that perhaps the virulence is much more dramatic in Mexico simply because of viral load?

  25. #25 Science Teacher
    April 29, 2009

    Thank you for this excellent primer, Revere!

  26. #26 Paul Browne
    April 29, 2009

    Good point about the need to use an inhaler with Relenza Revere, I’d forgotton about that.

  27. #27 GeorgeT
    April 29, 2009

    Patch: there are numerous factors on the larger number of infected people in Mexico:

    1. Mexico City is very crowded.
    2. They didn’t know they had a problem. It spread before any containment and education could be done.
    3. Speculation that the Mexico City climate is ideal for the virus.
    4. Extended families living together.
    5. They are a more socially oriented culture than the US so more chances for spread.
    6. Since the average Mexican is less educated, they may not have the same level of understanding of need for cleanliness.
    7. A poorer health system.
    8. The poor in Mexico don’t have access to luxuries like hand sanitizer and disinfecting wipes.

    IMHO, Lack of water would be pretty far down the list of reasons. I wasn’t aware of a water shortage in Mexico City (though I’m no expert). I thought northern Mexico was more problematic for that.

  28. #28 miso
    April 29, 2009

    Revere,
    rejecting posts because they point out your anti Relenza bias is weak. You’ve got my e-mail address use it.

  29. #29 Dylan
    April 29, 2009

    Personally, I think that Revere simply articulated the obvious, with regard to Relenza. I hardly think that his observation is going to shut the factories down; decrease production; or impede sales. Do you?

  30. #30 miso
    April 29, 2009

    Dylan,
    my point is you don’t know what I think, because it was censored. I posted it twice, in two hours and it’s still being “considered” by revere.

    I’ll give it one more go because I always keep copies of my posts. Here goes…

  31. #31 miso
    April 29, 2009

    “I know each drug is designed differently but why is tamiflu resistant and Relenza isnt !!! Is Relenza inherently a better design hence the recent stockpile changes around the world. Does anyone know.”

    Are you implying revere completely glossed over the well documented differences in the way Tamiflu and Relenza bind in the “pocket” on the NA glycoprotein; fundamental to the understanding of antiviral drug resistance?

    That would be admitting Relenza is inherently better.

    Try reading here, it’s old, but thanks to the usual bias inthe media, it’s still fresh,

    Oseltamivir Resistance – Disabling Our Influenza Defenses by Anne Moscona, M.D.
    http://content.nejm.org/cgi/content/full/353/25/2633

    There is no evidence of zanamivir resistance in viruses isolated from normal healthy patients after treatment with the drug. The only case of in vivo zanamivir resistance is that of an 18-month-old immunocompromised child, who acquired an influenza B virus infection and failed to respond to ribavirin treatment. The child was subsequently treated with zanamivir and after 12 days of treatment a virus containing an R152K NA mutation was isolated. This virus also contained a mutation in the HA protein, T198I, which had appeared prior to the NA mutation. In contrast, resistance to oseltamivir occurs in 1%-4% of adults and 4%-8% of the paediatric population.

    http://jac.oxfordjournals.org/cgi/content/full/55/2/162?ijkey=d0c8f4f3e2bf2822989791388539886104f542f3

    Here’s something no-one ever criticizes Tamiflu for. It’s all well and good that it is take orally, but IT CAN”T BE INJECTED.

    “zanamivir is not used because it is an inhaler and patients in the recent Asian outbreak were too ill to inhale even though laboratory tests show it has some effects on H5N1. Manufacturers should think about producing an injectable form. Drugs that are administered intravenously can be better absorbed in patients who have stomach and acidity problems. We don’t have to worry about absorption, injections take drugs right in. But if the patient takes them orally, maybe some amounts won’t be absorbed or some may be destroyed by stomach acids. Intravenous zanamivir would also ensure faster onset, which would be critical in patients who are seriously ill. Orally taken drugs take 3-4 hours to reach maximum blood concentration and 3-4 hours is very critical in severe cases. But injectable zanamivir takes only 30 minutes to reach maximum blood concentration, this is a huge difference. With an intravenous antiviral, doctors can also vary the doses.”

    Source: http://focosi.altervista.org/pathoviruses_influenzaA.html

    Q. So where’s iv zanamivir?
    A. We don’t need it because we worship the sun god Tamiflu… hang on it’s just gone supanova…what are we going to do n

  32. #32 revere
    April 29, 2009

    miso: I’m not censoring anything. I’m desperately trying to check these threads, hold down a day job and travel (I’m typing this from an airport lounge). I can’t always see what is being held and not held. If yours was held it was probably because it had a lot of links in it. But I’m not censoring you. I am frantic with media calling, trhying to get my flight, so business not connected with flu, etc. Many things slip past me and I can’t help it. You’ll just have to be patient or

  33. #33 Lily
    April 29, 2009

    revere:
    In your replies you sound as if you were one (1) person while the blog explains that THE editorS sign their posts with “revere”.
    Are you a board of editors or are you one person?

  34. #34 miso
    April 29, 2009

    “…You’ll just have to be patient or…”

    …post it somewhere it won’t get lost,

    http://www.flutrackers.com/forum/showthread.php?p=225147#post225147

    I’ll know next time not to link to sources.

  35. #35 Arkady
    April 29, 2009

    “It is resistant to the adamantane antiviral medications, amantadine and rimantadine.”

    Bugger. So my secret personal stock of lab-research grade rimantadine is useless ;-) (I work on a viroporin similar to ‘flu M2 protein)

    If all else fails we can seal ourselves into the containment labs I suppose…

  36. #36 Heraclides
    April 29, 2009

    Lily,

    In most blogs run by a group, each member of writes articles by themselves and that person looks after any comments resulting from their article. So while the website as a whole might have articles by several people, each article is looked after by one person.

  37. #37 lisaintassie
    May 3, 2009

    Can direct competition be used? Can a large insoluable molecule with an irrisistable sialic acid molecule attatched, be used as a treatment to slow infection? It could be inhaled and swallowed so as to work at the sites in our bodies have the protease involved in the viral cleavage. Being large, it will not be easily incorporated into our cells easily (coughed up & pooed out). In this way virises trying to enter our cells (lung/gastro-intestinal)as well as newly replicated ones will be competatively attatched and expelled?

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