Effect Measure

Swine flu and Tamiflu resistance

Currently the only antiviral drugs effective against the swine flu (novel H1N1) virus are the two neuriminidase inhibitors, oseltamivir (trade name Tamiflu) and zanamivir (trade name Relenza). Relenza is in active form at the outset and cannot be absorbed orally. It must be inhaled, leading to asthmatic reactions in some, ineffective dosage in those with breathing difficulties, and no drug at sites beyond the respiratory tract. Despite these drawbacks, it has so far produced little or no viral resistance. Tamiflu is absorbed orally and converted by the liver into the active form, so it gets to other organs and can be taken by people unable to inhale Relenza. But it has other problems. One is a tendency for the flu virus to become resistant to it. Until today, however, there have been no reports of Tamiflu resistance in swine flu isolates, although most flu experts were waiting for the other shoe to drop. Today may have been the day we heard it fall:

Scientists have established the first case of the new H1N1 influenza strain showing resistance to Tamiflu, the main antiviral flu drug, Danish officials and the manufacturer said on Monday.

It was expected that the strain would at some point show resistance to Tamiflu, Denmark’s State Serum Institute said. The patient was now well and no further infection with the resistant virus had been detected.

“It does not constitute a risk to public health and does not cause changes to the recommendations for the use of oseltamivir (Tamiflu),” the institute said in a statement. (Reuters)

It’s not exactly clear what a lack of risk to public health means in this context. I agree at this point it doesn’t affect the extent of infection in the population, but if Tamiflu resistance becomes widespread it will alter treatment options for those who are infected and since Tamiflu treatment can reduce viral shedding also affect transmission within small groups, like households. Still, we don’t know much about the reported resistance. Seasonal H1N1 is already resistant, so if novel H1N1 reassorted and swapped out its own H1 for a seasonal H1 when both viruses co-infect a host cell, that would be one mechanism. More likely, the HA of the the swine flu virus suffered a mutation that produces Tamiflu resistance (H274Y is the commonest, but others are possible). We don’t know any details yet.

Details aside, this development is not a surprise, although its ultimate significance is unclear. Antivirals, especially when given early in the course of the illness, do seem to be of some benefit, but it’s not dramatic. They reduce the symptomatic duration of illness by a day or two and with it viral shedding. They may also have some prophylactic effect for those known to be exposed. But if your model is the often dramatic effect that antibiotics have on bacterial infections, these antivirals are effective only on the margins and they are not without adverse reactions.

So the other shoe may have dropped but if it did, we don’t yet know the consequences. People get over flu because their bodies are able to do it on their own. For some, although not most, an antiviral might make a vital difference. But the main protections are not to get infected to begin with, and if you do, to be in good shape, to have good care, and to have good luck. If you have the last of these, you don’t need antivirals. If you don’t, they probably won’t help.

Meanwhile, it is what it is. Whatever that is.

Comments

  1. #1 cpg
    June 30, 2009

    Revere

    You talk about how effective an antiviral really is in the context of flu treatment. Shouldnt the focus be on what an antiviral can do for the majority of the population.

    With regards to the normal or ”mild” A/H1N1 flu you are right, antivirals are supposed to reduce shedding so make you better sooner. This is a mute point for the majority of us except for say the japanese who dont like taking ”sickies”. The rest of us ride it out.

    Government stockpiling of Antivirals is really for the vulnerable or for when a real nasty pandemic virus hits. In this scenario reducing of viral shedding may then save your life or to put it another way make you less sick.

    There are some promising second generation antivirals currently being tested right now that will leave relenza and tamiflu in their wake. I believe they have moved pass phase 3 onto approvals.

    http://www.abnnewswire.net/press/en/59483/Biota_Holdings_Limited_ASX:BTA_LANI_Phase_III_Clinical_Trials_Set_For_Enrolment.html

    http://www.medpagetoday.com/MeetingCoverage/ACIP/14896

  2. #2 Tom DVM
    June 30, 2009

    The funny-ironic thing is that in 2006, Dr. Osterhaus et al (many of the world’s most knowledgable on influenza) requested 40 million dollars to initiate what they considered vital research to find new antivirals.

    At the time, the ‘powers that be’ were pushing-selling their new panacea…it was ‘all Tamiflu all the time’…and I guess they decided for whatever reason that we had all the antiviral we need because the small request for funds were turned down.

    OF course many of the same experts warned that we were in an outlier position and that was also played down as well.

    The same bunch is still running things and their latest scheme is the ‘mild’ scenario..,.and deliberately delayed calling it a pandemic, delaying the production of vaccines.

    I wonder how different things would be if they had approved and fully funded the antiviral research effort in 2006.

  3. #3 Alex R
    June 30, 2009

    My question is related to cpg’s comment: What is the effect of Tamiflu on *severe* — fatal or near-fatal — flu cases? Does it have a significant effect on mortality rate?

  4. #4 raven
    June 30, 2009

    requested 40 million dollars to initiate what they considered vital research to find new antivirals.

    I’ve been saying that for years.

    Biomed 001 remedial. We are always in a race with pathogens. They will become resistant to any antiviral/antibiotic/antianything sooner or later. TB, malaria, and Staph have made most previously effective drugs useless for many cases. There is a TB, XDR-TB resistant to all known drugs. Mortality runs 50-90%.

    This is straight, simple minded evolutionary biology.

    Even if someone had started antiflu drug screening in 2006, it wouldn’t help us now. It still takes 6-10 years to get a new drug approved. Even a crash emergency program like AZT for HIV took years.

    It is too late for swine flu. but we all know that pandemics are like buses, sooner or later another one will come along. George Sanyana had it right. “Those who ignore the lessons of history are doomed to repeat them.” We should start developing new flu antivirals now.

  5. #5 MarkS
    June 30, 2009

    What concerns me is that while Tamiflu and Relenza are effective (for now) in treating the virus infection, they don’t have any effect on the pneumonia which actually causes death. There have been studies which show that various agents (statins, COX-2 inhibitors, antihistamines, fibrates, glitazones, etc.) can have an effect in treating the pneumonia. Since they are generic, none of them have been studied extensively and it is currently not clear what role they could play.
    However, this interesting article proposes a research protocol which could help provide answers and lead to understanding of effective treatment modalities.
    Meeting the Challenge of Influenza Pandemic Preparedness in
    Developing Countries, Emerging Infectious Diseases.
    http://www.cdc.gov/eid/content/15/3/365.htm2009;15(3):365-371.

  6. #6 raven
    June 30, 2009

    Relenza has its problems. It is an aerosol drug with lung delivery. This can be difficult for patients with lung infection and problems in a hospital setting.

    In this case, for seriously ill patients, an injectable would work. I know this drug isn’t orally active but can it be injected? Anyone know? If so, a new formulation would buy some time.

    Also, just because a Tamiflu isolate has been seen, this doesn’t make Tamiflu useless. Yet. It will take a lot of time for resistance to spread through the viral pool and displace the parent strain. In a lot of patients, Tamiflu resistance will be a dead end.

    No idea how long that will take. Based on Tamiflu resistance and seasonal flu, it could take years. Based on seasonal flu, it will eventually happen.

  7. #7 revere
    June 30, 2009

    MarkS: If you use the Google search bar on our site you will find a number of posts on statins. Dave Fedson has also noted that Avandia may be even more effective, but except for observational studies of gram neg. sepsis and pneumonia we don’t have info at the moment. I believe there are some RCTs in progress. But I am persuaded by the statin data. However it is not pneumonia, per se, but the sepsis it brings (or the primary viral pneumonia cytokine storm), and that is still a minority of cases (fortunately).

    raven: Just remember, though, that these antivirals are therapeutic measures and don’t have the effect that measures applied on a population basis would have. Historically such measures don’t affect the epidemiology much.

  8. #8 melbren
    June 30, 2009

    How common is it for patients to die with the swine flu in the E.R.? This is the second such case within two weeks in San Diego County. Any chance this is a nastier strain?

    http://www3.signonsandiego.com/stories/2009/jun/30/2-more-swine-flu-deaths-reported

  9. #9 Cynthia
    June 30, 2009

    Here is some good information on anti-virals, such as Tamiflu, and the recent resistant case of Swine Flu;
    Tamiflu-Resistant Swine Flu Emerging: http://www.newsinferno.com/archives/7582

  10. #10 Dylan
    June 30, 2009

    “How common is it for patients to die with the swine flu in the E.R.? This is the second such case within two weeks in San Diego County. Any chance this is a nastier strain?”

    melbrin: My own view is that what we are observing is an indication that the system is being swamped. It would not require any change in the virus to do this. Just a greater patient load could accomplish this outcome. A sign of things to come; it is altogether possible that we are in for a very bad late summer, or early fall.

  11. #11 phytosleuth
    July 1, 2009

    “How common is it for patients to die with the swine flu in the E.R.? This is the second such case within two weeks in San Diego County. Any chance this is a nastier strain?”

    I also suggest that most people are not watching for serious symptoms nor do many people recognize them before late in the process. People may be waiting too long to ask for help.

  12. #12 Dylan
    July 1, 2009

    phytosleuth: Your explanation is clearly the better one. I agree.

  13. #13 phytosleuth
    July 2, 2009

    See also Effect Measure: Swine flu: warning signs that someone is going sour

    http://scienceblogs.com/effectmeasure/2009/06/swine_flu_warning_signs_that_s.php

  14. #14 miso
    July 2, 2009

    “Relenza has its problems.”

    Revere,
    Still using the Roche handbook to describe the limits of zanamivir? Well at least you won’t catch the flu considering where you’ve kept your head for years.

    I gave up beseeching alternatives to Tamiflu which was stamping out research in alternatives like weeds (especially zanamivir i.e. I.V.relenza, and third generation NIs, Biota’s LANI compound snipped in the bud TEN YEARS AGO) assisted by bigoted Flag waving Tami-nazis.

    You got any pure science/research behind Roche’s anti-zanamivir propaganda, or haven’t you ever needed it?

    I’m three words into “I told you so”, if I wait much longer I’ll have all four words, but not many to tell it to.

  15. #15 Tom dVM
    July 2, 2009

    miso.

    You deserve your ‘due’…whether you get it or not is another matter…but thanks anyway!!

    The problem with Relenza as I see it is it will be usueless with any severe form of influenza.

    1) I don’t think you can administer it.

    2) It won’t get into a severly effected lung…it will never reach therapeutic blood concentrations.

    Have they come up with an injectable or other format yet?

  16. #16 M. Randolph Kruger
    July 2, 2009

    UT continues their little statin test Revere. No results yet.

    They better come up with something damned fast as the UK health minister said that there will be 100,000 cases a day by the end of August.

    http://www.theherald.co.uk/news/news/display.var.2517930.0.UK_braces_for_up_to_100_000_flu_cases_every_day.php

    A slightly different read….

    BRITAIN TO EXPERIENCE 100,000 SWINE FLU CASES A DAY
    Maria Cheng
    AP-Medical Writer
    7/2/09

    LONDON (AP) – Britain faces a projected 100,000 new swine flu cases a day by the end of August and must revamp its flu strategy, the nation’s health minister said Thursday.

    Britain has officially reported 7,447 swine flu cases and three deaths, but officials acknowledge the real number of cases is far higher, since many with the virus have not been tested.

    Britain is the hardest-hit nation in Europe amid the global swine flu epidemic. Many flu experts believe numbers could jump exponentially now that the virus is entrenched. Because swine flu, or H1N1, is a new virus, few people have any natural immunity, allowing the virus to spread rapidly.
    Cases are doubling every week and on this trend we could see over 100,000 cases per day by the end of August,” Health Minister Andy Burnham told the House of Commons on Thursday.

    Britain has been reporting several hundred new swine flu cases daily for the last several weeks. If that surges to 100,000 cases a day by the end of August, there could be 6 million people infected by the fall, or 10 percent of Britain’s 60 million population.

    Since flu spreads more quickly in densely populated areas, cases will probably be concentrated in cities like London, Birmingham and Manchester.

    Britain had been trying to contain the disease by liberally giving out the drug Tamiflu to all suspected swine flu cases and their contacts. Yet many experts have criticized Britain’s attempt to contain the outbreak, saying it wastes resources, drugs and could promote antiviral resistance.

    Burnham said Britain will now only give the antiviral to people believed to have the virus.

    The World Health Organization has said that 2 billion people could eventually be infected with swine flu worldwide. Most cases are mild and require no medical treatment. More than 77,000 cases, including 332 deaths, have been reported worldwide.

    Other countries including Australia, Japan and the United States initially tried to contain swine flu by giving out Tamiflu widely, but dumped the strategy within weeks.

    Still, Britain’s top medical officer defended the country’s earlier approach.

    “We’ve been fighting this pandemic very aggressively,” Sir Liam Donaldson said during a press conference. “We’re unapologetic about that.”

    Donaldson said Britain probably had the world’s largest stockpile of Tamiflu. The antiviral can alleviate swine flu symptoms and shorten the course of illness by about a day if patients take it within 48 hours of getting sick.

    Earlier this week, health officials reported the first instance of Tamiflu resistance, in a Danish patient who had been taking the drug. Experts worry that if Tamiflu is given out widely—as per Britain’s earlier approach—that could make it easier for the virus to develop resistance.

    Burnham said people with swine flu symptoms should check health services websites or call flu hotlines to get help before seeing their doctors. He said patients should stay at home and have friends pick up drugs for them from designated community centers.

    The sharp jump in Britain’s numbers may also reflect the country’s previous refusal to look for the disease. When swine flu arrived in the U.K., officials only tested people who had traveled to North America, where the epidemic began, or those in contact with a confirmed swine flu case.

    That meant the testing system did not pick up the virus’ spread into communities.

    WHO’s declaration in June that swine flu was a pandemic—a global epidemic—was made partly because the agency felt some countries, including Britain, were not accurately reporting their swine flu outbreaks.

    Burnham also predicted the first doses of swine flu vaccine would arrive in Britain in August. Britain has ordered 60 million doses of vaccine, enough to cover the entire population.

    Other experts, however, doubt the vaccine will be available that quickly, since it needs to be produced, tested in humans and meet regulatory approval—a process that may take longer than two months.

  17. #17 miso
    July 3, 2009

    Tom dVM,
    I.V. Relenza was dumped by GSK in clinical trials a few years ago, the reason wasn’t failed tests, it was lack of market demand.

    Soon after GSK dropped the trials the South East Asian Infectious Disease Clinical Research Network (http://www.seaicrn.org/)took up the lip service of trialling I.V. zanamivir in the early 2005. SEAICRN polished its protocol for years and did NOTHING, while all Tamiflu trials were activated and completed. GSK did it’s bit by sabotaging zanamivir supply and sabotaging financial support.

    IV Relenza wouldn’t be my first choice (injection treatment is daily for treatment, but drip in hospital would be practical), but it’s the only zanamivir compound anywhere along testing.

    Ideally the Biota LANI compound should have been tested twenty years ago, but the funds dried up when Tamiflu sucked the oxygen out of GSK’s research fund for zanamivir (Relenza) and the glossy advertising campaign for Tamiflu, meant Roche educated medical intellectuals (like Revere) what to think.

    The best available compound anywhere along clinical trials would be the Daiichi-Sankyo LANI compound (CS8958) which has not been tested with injectable versions, but which has reached successful phase III clinical trials and requires only one puff weekly.
    If the D.S. compound fails then it’s ironic to think the ORIGINAL,TWENTY YEAR OLD, Biota LANI compound should have had a fair chance to complete clinical trials and save lives, and might still be needed for trials.

    I suspect there was a gentleman’s agreement years ago when Roche and GSK were fighting out NI antivirals about 2000-1, and before bird flu made it a deadly serious choice.
    GSK gave a wink, and stopped competing against Tamiflu, and Roche let GSK concentrate on influenza vaccines without competition from Roche.

  18. #18 Tom DVM
    July 3, 2009

    Thanks Miso.

    Yes, there may be an incestous relationship between Roche and the WHO…but you can bet we will never find out about it.

    If we pay the wages of the World Health Organization, then we should have the right to know if:

    1) senior WHO decision makers pushing Tamiflu had or have shares in Roche

    2) Any and all ‘gifts’ given by Roche (nudge nudge wink wink) to WHO employees.

    3) If they or their family members have jobs on a part or full-time basis with Roche at the same time they are employed with the WHO.

    4) How many senior supervisors ‘retired’ from the World Health Organization go on to work at Roche… then in the perfect position to influence people they hired previously at the WHO.

    The World Health Organization has no code of ethics, no oversight and no consequences…just like its parent…as in ‘food for oil’.

    In the end, as in all things, the truth may will out…just before they do what they are best at…revisionist history.

  19. #19 miso
    July 4, 2009

    I’m wondering when the so called medical intellectuals are finally going to realise that Tamiflu was always less about treating influenza and saving lives, and more about making money; originally by copying the pioneering research of zanamivir(Relenza) but with the aim of working as a pill, even if the compound was prone to RESISTANCE TO H274Y FROM THE FIRST CLINICAL TRIALS, and a string of “little white lies”.

    Laboratory tests on H274Y variants were no less viable then than they are now, good science doesn’t bend to your hypnotic will, you have to fudge it yourself, the way Gilead/Roche must have done.

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

    Once Tamiflu was a cash cow, Roche made sure it would spend whatever was needed to keep TAMIFLU NUMBER ONE, no matter the cost or consequences.
    Roche is hell bent on using every gimmick possible to sell Tamiflu even now, as its lack of worth is becoming evident to the Tamiflu incredulous groupies, even if the lack of an alternative might KILL MILLIONS OF INFLUENZA victims and has no effect preventing a plague to spread.

    I hope the gullible still worshipping Tamiflu are the first to use it to treat the flu on themselves, at least then, Tamiflu will have enriched the soil, and raised the average I.Q. of the rest of the population.

  20. #20 Claire
    July 21, 2009

    It is kind of worrying… there’s roughly, what? 7 Billion people in the world and the mortality is around 1% at the moment so that means 70 million people will die worldwide of swine flu if everyone catches it. That’s 700,000 in the UK and 3 million in the US alone which is a lot of people! There’s a very up to date outbreak map tracker and news links on http://www.flutrack.info, seems to be updated several times a day.

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