Tamiflu resistance of influenza H1N1 strains

9 January 2009

124790416_5dc7e07b8f_mYesterday the New York Times ran an article on the resistance to Tamiflu of current influenza H1N1 strains circulating in the US. I wrote a post about this issue on 22 December 2008, so I’m happy to see the Times following my lead. But there is an issue with the Times article that I’d like to address here. According to the article:

The single mutation that creates Tamiflu resistance appears to be spontaneous, and not a reaction to overuse of the drug.

Drug-resistant viruses are not ‘reactions’ to overuse of the drug. The drug selects, from the diverse viral population in an individual, those viruses that can multiply in its presence. Usually the drug-resistant mutants are already in the host, and outpace other drug-sensitive viruses. Is that what the writer means by ‘spontaneous’? Not in this case. What apparently happened is that the mutation that causes drug-resistance, a change from histidine to tyrosine at position 274 of the viral NA protein, emerged in parts of the world were little Tamiflu is used. There was some other reason why this change was selected for in those populations. The article implies that the his->tyr change accompanied a second amino acid change at position 193 of the HA protein which improved the ability of the virus to infect people. This change did not affect resistance to Tamiflu, but apparently it only persisted when the change at 274 was also present. It so happened that the 274 change also conferred resistance to Tamiflu. Thus, when this virus arrived in parts of the world where Tamiflu is used, the resistance was noted. None of this is made particularly clear from the article.

I also have an issue with the author describing the amino acid changes in the ‘N’ and ‘H’ genes. The correct nomenclature is NA and HA. The author might have been mislead by the strain designation which uses only ‘H’, e.g. H1N1. It’s a small point but I believe that the devil is in the details.

What about the two other anti-influenza drugs? And the other strain currently circulating, H3N2?

Most of the flu in the US now is caused by H1N1 strains. So although the H3N2 strains are sensitive to Tamiflu, it’s not much help.

The Tamiflu-resistant H1N1 strains are sensitive to another drug, Relenza (zanamivir). But that drug must be inhaled and is not appropriate for everyone. However, these H1N1 strains are sensitive to Rimantadine, so its use is a good alternative. Most H3N2 strains are resistant to Rimantadine, which is why it has not been used much in recent years.

Nevertheless, our anti-influenza drug arsenal is much too small. It’s worth recalling the following information from Principles of Virology (ASM Press):

With about 1016 human immunodeficiency virus (HIV) genomes on the planet today, it is highly probable that somewhere there exist HIV genomes that are resistant to every one of the antiviral drugs that we have now or are likely to have in the future.

AIDS is no longer a death sentence because we have a deep arsenal of antiviral drugs that can control the infection. Patients are treated with a combination of three anti-HIV-1 drugs at a time. When resistance inevitably emerges, the patient is switched to another combination of three. The high levels of HIV-1 replication in many hosts, coupled with the large numbers of viral mutants that are produced, ensure that resistance will emerge.

Influenza virus shares similar features as HIV-1: high replication rates in many hosts, and the generation of large numbers of viral mutants. Therefore any antiviral strategy that employs only three drugs  is bound to fail. The difference with influenza, of course, is that an excellent vaccine is available, and should be used whenever possible. The antiviral compounds should only be used in the face of an outbreak when immunization has not been sufficiently comprehensive. However, I suspect that the use of Tamiflu and Relenza is far more prevalent than desired. How many people rush for a prescription at the first signs of a respiratory infection? And how many of those have already been immunized? This was not the intended use for these antiviral compounds.

If we want to seriously use antiviral to treat influenza (which I don’t think is a good idea except in certain cases), we need to have a far deeper arsenal of antiviral drugs.

  • ET

    Is amantadine ( the original one I mean) still used as an antiviral, and is it efficacious against influenza?

  • profvrr

    Because of the central nervous system side effects of amantadine is less frequently used to treat influenza. Rimantadine has fewer side effects. I suspect the H1N1 strains are susceptible to amantadine as it is very similar to rimantadine. In recent years the CDC has recommended the use of amantadine, but this year, the recommendation is zanamivir or a combination of oseltamivir and rimantadine.

  • ET

    If the technique for an HIV vaccine is to find a glycoprotein that is always present, then is it not possible to do the same with Influenza?

  • profvrr

    In theory, yes…but individual glycoproteins are not always as immunogenic as the whole virion. As you know, there is an effective vaccine for influenza which consists of whole, inactivated virions (or in some cases whole virions which are then disrupted with detergent). These vaccines are immunogenic and protective. Glycoprotein vaccines against influenza have been tested but are far less effective than the current vaccines. Which is not to say the situation will not improve with futher research.

  • ET

    To switch topics if I may;

    frequently there is reference to women 'along the road to Kinshasha' who, despite being exposed to HIV presumably repeatedly since the beginning of the epidemic, have no trace of the virus. I suppose my first question is a) are their such women (who seem to have achieved a folklore-like status), and b) if they have no trace what so ever of the virus, then are they controlling it in a way different from the elite controllers?

    And finally, Is it possible that HERV's play a role here? These are records of our previous battles with retroviruses are they not? So then, by default, does that mean that there must be some segment of the population that is completely immune to this disease somewhere?

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  • profvrr

    I'm not aware of any such HIV-resistant prostitutes. The road to
    Kinshasha has a huge death rate because over 90% of the prostitutes
    who work there are infected. But I will ask Jeremy Luban who is
    joining me in the next TWiV this week.

    The HERVs in humans are retroviruses, not lentiviruses and thus would
    not be expected to interfere with HIV replication.

  • Jonathon Singleton

    ’Spontaneous’ — perhaps an evolutionary paradigm consistent with the flawed science of genetically modified crops and organisms using unstable viral promoters!?! Horizontal gene transfer and recombination working at an accelerated pace — not unlike the premise of a science fiction disaster novel, where corporate greed and nu science in its longitudinal tested infancy is thrown out into the commercial world and… Hey cliche, a few years later we have what we are now experiencing re: Tamiflu resistance at 100% in H1N1 which may cross over into other H/N viruses shortly!?! Just a thought — I've been researching this area for nine years…

  • profvrr

    You are right. The combination of RNA virus + just a few antiviral
    compounds = guaranteed resistance. But I understand that new flu
    antivirals are being tested, so that perhaps in the future we will use
    combinations as is done for HIV.

  • money prof

    Raivo Pommer
    raimo1@hot.ee

    Depfa Bank Krise

    Es handelt sich dabei um eine nachrangige Anleihe über 500 Millionen Euro. Die für den 21. März geplante Zinszahlung falle nach einem Beschluss des Verwaltungsrats der Depfa aus.

    Eine Entscheidung zu ähnlichen Papieren der Depfa stehe noch aus. “Diese Nachricht könnte das Vertrauen in das Marktsegment erschüttern”, kommentierten Anleihenhändler.

    “Das ist ein politisches Debakel”, sagte Bankenprofessor Klaus Fleischer von der Fachhochschule München. Schließlich seien die Garantien und Hilfen des staatlichen Rettungsfonds Soffin in Höhe von mehr als 102 Milliarden Euro in die HRE-Gruppe geflossen, “um Schaden vom Kapitalmarkt abzuwenden”.

    Nach Angaben der HRE hat die Bankengruppe vier Nachranganleihen im Volumen von insgesamt 1,55 Milliarden Euro ausstehen. Zinstermine sind im März, im Juni und im Oktober. Der Analysedienst Dealogic gibt den Gesamtmarkt vergleichbarer Nachranganleihen in Europa mit 300 Milliarden Euro an.

  • pum

    Raivo Pommer
    raimo1@hot.ee

    Gegen krise

    Die norddeutschen Länder wollen gemeinsam beim Bund für ihre Verkehrsprojekte kämpfen. Hamburgs Bürgermeister Ole von Beust (CDU) sagte heute nach einem Treffen mit den Regierungschefs von Schleswig-Holstein, Niedersachsen, Bremen und Mecklenburg-Vorpommern, Berlin müsse sich der Hinterlandanbindung der Häfen und der Infrastruktur mehr widmen: “Wichtig ist uns, dass der Bund verstärkt einsteigt.” Aus dem Konjunkturprogramm I sei nicht genug angekommen. “Da geht es darum, das aufzustocken.” Bremens Bürgermeister Jens Böhrnsen (SPD) betonte: “Dazu gehört auch, dass wir (…) deutlich machen, dass der Anteil des Bundes an Hafeninvestitionen und vor allem auch an der Hafenunterhaltung viel zu gering ist.”

  • american dream

    Raivo Pommer
    raimo1@hot.ee

    HEDGE-FOND

    Die Kapitalabflüsse gestalteten sich in der Branche in Europa und den Vereinigten Staaten allerdings sehr unterschiedlich: Während amerikanische Hedge-Fonds in großem Umfang juristische Sperren nutzten, die eine sofortige Rückzahlung von Anlagegeld an die Kunden beschränkten oder hinauszögerten (Gates), ist dies bei europäischen Hedge-Fonds weniger üblich. Auch gibt es in Europa mehr Dachfonds, in die Privatinvestoren investieren. Diese hatten die erste Kündigungswelle bei Hedge-Fonds im Herbst 2008 ausgelöst. Die Kapitalabflüsse aus Hedge-Fonds waren daher in der zweiten Jahreshälfte vor allem in Europa relativ hoch. Die Mittel europäischer Hedge-Fonds schrumpften nach Einschätzung von Morgan Stanley um 25 bis 30 Prozent.

    In den Vereinigten Staaten beliefen sich die Mittelabflüsse zunächst „nur“ auf 15 bis 20 Prozent. Dies erklärt, warum der weltweite Verband der Hedge-Fonds, die Alternative Investment Management Association (AIMA), kürzlich bekanntgab, dass das Anlagekapital der 1200 bei der AIMA registrierten Mitglieder jetzt zum Großteil von institutionellen Investoren gehalten werde und nicht mehr von vermögenden Einzelpersonen, wie dies früher der Fall gewesen war.

  • drC

    the anti-virals we currently have demonstrate 8-10% rate of mutation at baseline, greater percentages in the pediatric population for some reason. Anyway, using these meds on a population scale response to influenza is irresponsible at least and criminal at worst.

  • Matt

    Aggravating our susceptibility to becoming ill, there is the stress in our society due to an almost unique confluence of record unemployment, insolvency, bankruptcy with war and pandemics— Not to mention the general lack of affordability in health-care

  • robert

    Swine flu is man made…follow the money

  • robert

    Swine flu is man made…follow the money

  • DSS

    Finally, an educated san opinion
    Congratulations

    Dr D S S

  • Kumar

    Is the current h1n1 epidemic could again rise the tamiflu resistance?

  • Tom

    A popular health website (http://www.everydayhealth.com) provides the following Q&A:

    “Should I take Tamiflu or Relenza to prevent swine flu?
    According to the CDC, Tamiflu and Relenza can be used to prevent influenza in a person who is not ill but who has been or may be near a person with swine influenza. These antiviral drugs are 70 to 90 percent effective, and the dosage depends on an individual's particular situation. The average person does not need to take either Tamiflu or Relenza at this time, and it is likely that pharmacists will not fill prescriptions unless you already have confirmed swine influenza.”
    If most North American H1N1 is highly resistant to Tamiflu, presumably this advice is dead wrong; or am I missing something? Thanks

    Tom

  • http://www.virology.ws profvrr

    The H1N1 influenza virus strain of the past season was highly
    resistant to Tamiflu. The 2009 pandemic H1N1 strain, however, is
    susceptible to the antiviral drug. The blog post you are reading here
    concerns the previous season's H1N1 strain; it was written before the
    new H1N1 strain emerged.

  • Tom

    Thanks!

  • siam_spearo

    Dear Profvrr,

    I am not a Doctor or a specialist in medicine. I am living in Thailand and the doctors here are less educated than those on the front line, they tend to copy the trends and go with second opinions from the states, europe and WHO.
    It is very confussing for me as these opinions seem to change as quickly as the Virus does.
    My Partner tested positive to type A and negative to type B, we have been told that this means there is a chance that she may have H1N1, I am now online a few hours later after putting her in bed looking for help on the internet as the academics of Thailand seem to have little to no help for us.
    She has been given TAMIFLU 75MG (Oseltamivir) BISOLVEN 8MG (Bromhexine Hydrochloride) ROTUSS CAPSULE and CLARINASE (5MG LORATADINE & 120MG PSEUDOEPHEDRINE SULFATE)

    From what little I have learnt on the net this evening it looks as though she should be taking Tamiflu and Relenza and not either or, could you confirm this for me? I noticed your most recent post mentioning the previous strains resistance to Tamiflue, is it possible that we are suffering from the same strain of tamiflu resistant H1N1 and is there anyway to tell the seperate strains from one another?
    We have been told that she will be better in 5 days of treatment and that there is nothing to worry about but after living here for a decade I know that this is just another way of saying they don't know what will happen.
    I'm sorry to trouble you but i Love her very very much I hope to hear from you soonest.

    Regards,
    Craig

  • http://www.virology.ws profvrr

    Either Tamiflu or Relenza should be taken, not both. It's highly
    unlikely that last year's H1N1 virus is causing the infection,
    although there is still some of that virus circulating. The strains
    can be differentiated from one another, but it requires sophisticated
    lab tests which cannot be done in a doctor's office. Tamiflu should
    lead to improvement within a few days.

  • Anurag

    how is H1N1 different from Swine Flu … and how is it that an article on H1N1 was published in Jan 09 whereas it was only in March 09 when the 1st cases were registered with WHO ??

  • http://www.virology.ws profvrr

    There are many different 'vintages' of influenza H1N1 viruses. Since
    1977 an H1N1 strains (“Russian flu”) has been circulating globally.
    That strain was the subject of this blog post. In March 2009 a very
    different strain of influenza H1N1 virus emerged, the swine-origin
    strain that is causing the current pandemic.

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  • Jako

    It's all very sad. I am from Brazil, we have a lot of people die, the government does nothing. We do not really buy Tamiflu, my sister, my brother bought the medicine at the pharmacy USA. The medicine helped, during the week my sister recovered. I personally do not believe in these conversations that Tamiflu does not help. Usli who need, then his brother was there to buy (not advertising) http://www.ekpharm.org

  • CommentReader

    I think you need to re-read the conversations. The replies clarify that the current H1N1 strain is NOT showing resistance to Tamiflu… This article was posted before the swine-origin strain emerged.

  • akshay

    is blood transfusion of an recovered human to the resisting individual can b effective
    so tht the antibodies can transfuse to it ??????????

  • http://www.virology.ws profvrr

    In theory such passive transfer of antibodies would be protective. An
    excellent example from the 1960s is how serum from a nurse who
    recovered from Lassa fever was used to save Jordi Casal's life after
    he acquired a laboratory infection. But this is not likely to be done
    for influenza.

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  • Donna

    Does the use of antiviral medications such as Tamiflu prevent a person infected with H1N1 from producing antibodies to prevent reoccuring infection?

  • http://www.virology.ws profvrr

    Tamifly doesn't completely block viral replication so there will still be an immune response to infection.

  • hadi

    Could the human genome contribute to the viral H1N1 resistance to Tamiflu?

  • http://www.virology.ws profvrr

    Interesting question. I don't believe so. Viral resistance is a
    consequence of mutation in the viral genome, and I'm not aware of any
    human proteins that influence resistance to Tamiflu. I wouldn't rule
    out the possibility for other viruses, though.

  • Yoly

    Will the current vaccine protect against this mutated strain?

    Called the CDC and representative couldn't answer the question even after consulting with others.

  • http://www.virology.ws profvrr

    Yes, the current vaccine will definitely protect even against a H1N1
    strain resistant to Tamiflu. I'm shocked that the CDC rep didn't know
    that.

  • Yoly

    Will the current vaccine protect against this mutated strain?

    Called the CDC and representative couldn't answer the question even after consulting with others.

  • http://www.virology.ws profvrr

    Yes, the current vaccine will definitely protect even against a H1N1
    strain resistant to Tamiflu. I'm shocked that the CDC rep didn't know
    that.

  • Mohamed

    Hey

    Maybe it’s been mentioned before, but is this article about the recent swine-flu H1N1?

  • http://www.virology.ws profvrr

    No, this article refers to the seasonal H1N1 strain that circulated before the emergence of swine-origin H1N1.

  • ranjani

    i just chkd ur article…i m just curious to know….is dere chances of treatng tamiflu resistant strains???? is it by giving relenza…do reply

  • aylabr

    relenza, also called zananivir, has demonstrated to be able to treat tamiflu resistant strains of influenza

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