Drug-Resistant Flu Strain Turns Up In Denmark but Doesn't Last Long - page 3

June 30, 2009 Global Update Drug-Resistant Flu Strain Turns Up In Denmark but Doesn't Last Long By DONALD G. McNEIL Jr. The first case of swine flu resistant to the antiviral drug Tamiflu has... Read More

  1. by   indigo girl
    Another case of Tamiflu resistance found in Japan


    From a Japanese translation:

    Quote from www.flutrackers.com

    The Ministry of Health Labor and Welfare announced Friday that another oseltamivir-resistant virus was found in Yamaguchi prefecture from a patient of novel influenza after prophylaxis of oseltamivir.
    The patient has already recovered and no further infection from the patient has been confirmed.

    According to the National Institute of Infectious Diseases, a spot mutation at H275Y of Neuraminidase was confirmed in the virus. No reassortment with the seasonal influenza virus was found.

    Source: http://www.mhlw.go.jp/kinkyu/kenkou/...fuh0717-04.pdf
  2. by   indigo girl


    Much as I admire Helen Branswell's work, this is not the 4th case of resistance to Tamiflu. There have been other cases that were noticeable by the lack of fanfare, just little blurbs of info describing what happened to these patients, and btw, they were still testing positive for swine flu despite Tamiflu treatment. Yes, it was expected that this would happen, just not this soon...

    Quote from www.google.com

    Canada has recorded a case of Tamiflu-resistant swine flu virus, in a Quebec man who had been given the drug to prevent infection.

    The case is the fourth reported globally since the new H1N1 virus was discovered in April.
    The man, 60, was given the flu antiviral after his son fell ill with the pandemic virus. It's believed the resistance arose in the man and there is no evidence he transmitted resistant virus to anyone else.

    "It appears to be an isolated case," said Jirina Vlk, spokesperson for the Public Health Agency of Canada.
    "Although the strain does not appear to have spread beyond the reported individual case we continue to be vigilant on this front."
    Use of Tamiflu to prevent infection - a procedure called prophylaxis - has been seen on occasion to give rise to resistant viruses.
    "We know that it was going to happen and it's not good news that it's happening," said Dr. Allison McGeer, an influenza expert at Toronto's Mount Sinai Hospital.

    But she said given the amount of Tamiflu being used in the world right now, such cases are bound to arise.
    Last edit by indigo girl on Jul 21, '09
  3. by   indigo girl
    More Tamiflu resistance in Japan


    This patient was being treated prophylactically after being exposed to a positive case in the workplace. He got sick anyway on day 5 after the exposure despite treatment. His virus was sampled and sent off to be tested revealing that he had a Tamiflu resistant virus.

    Not so surprising as Japan has always used more Tamiflu than any other country, Dr. Niman over at Recombinomics believes that there will be many more cases out there because Tamiflu resistance has been flying under the radar in many countries and not just in Japan. Whether he is right or not remains to be seen so stay tuned...


    H274Y is the polymorphism associated with Tamiflu resistance in influenza viruses.

    Quote from www.flutrackers.com

    This case is virtually IDENTICAL to the Osaka case, down to the FIFTH day. The patient is started on a 10 day course of Tamiflu. However, the patient gets infected because the H1N1 with H274Y is at a relatively high level, but just below detection by the sequencers (unless they look closley). The published sequences are just "consensus" sequences and represent the dominant strain. If the strain with H274Y is 20% or less, it won't won't show up in the sequence (if it is 20-50% the sequence will have mixed signals).

    The fact that the patient become symptomatic five days after the start of treatment, means the level of H274Y is relatively high (normally it takes 2-4 days to develop symptoms), because the delay in disease onset date is small.

    The H1N1 at day 5 is exclusively virus with H274Y, so the sequencers are stuck with H274Y and announce the "discovery".

    H274Y is WIDESPREAD and below the sequencer's radar becasue they are not looking very hard.

    Japan has a high level of H1N1 and frequently uses Tamiflu, so 3 of the 5 isolates from treated patients are in Japan.
  4. by   indigo girl

    h274y is a genetic marker indicating that a strain of virus is resistant to treatment with tamiflu. according to this commentary, tamiflu resistant strains of swine flu may be circulating along the texas/mexico border.

    zanamivir is the only available alternative antiviral drug but it must be inhaled. not every patient will be able to use it, and it only hits the respiratory tract. tamiflu treats systemically which is more useful considering that swine h1n1 also affects other body systems such as the gi tract.

    Quote from www.recombinomics.com

    "we have found resistance to tamiflu on the border. we have observed some cases, few to be sure, in el paso and close to mcallen, texas," said maria teresa cerqueira, head of the local paho office.

    cerquiera said one patient diagnosed with a tamiflu-resistant strain had been treated with zanamivir -- an anti-viral made by glaxosmithkline -- and another was given no alternative medication. both survived.

    the above comments describe at least two oseltamivir resistant patients along the texas / mexico border. the cases are at opposite ends of the border (see map) and raise concerns that the resistance developed in the absence of tamiflu treatment. one patient had "diagnosed" resistance and was treated with zanamivir, while the other wasn't treated with zanamivir, leaving open the possibility that neither were treated with oseltamivir. moreover, the wording left open the possibility that there were more than two patients, suggesting fit swine h1n1 with h274y was circulating over a wide area.

    the emergence of fit swine h1n1 with h274y is not a surprise. a case has already been reported in hong kong in a traveler from san francisco. the precursor for this strain has been reported worldwide, although the only case reported in the us was in april in new jersey, raising concerns that the fit strain was circulating silently, in part because the cases were mild and not being tested. the patient in hong kong, like one of the patients recovered without treatment with relenza, indicating the cases were relatively mild.

    the fact that these cases were reported simultaneously also raises concerns that a fit h274y is circulating in the area.

    details on the number of cases, and release of sequences, would be useful.
  5. by   indigo girl
    reports from vietnam


    these notes are from a very patient translator over at flutrackers. she has reported many interesting things going on over there where tamiflu resistance is just one of their problems. actually, it's our problem as well. we are no longer routinely testing for swine flu, but they still are. that is the reason why they are aware of the prevalance of tamiflu resistance in their country.

    we only test people sick enough to be hospitalized or those that we think may need tamiflu. does anyone still think tamiflu resistance is only occurring outside of the us?

    Quote from www.flutrackers.com

    august 4th & 5th, we get a few articles on patients reacting slowly to tamiflu:

    at the hospital in private nguyen khuyen, because only 1 patient (test results 3 times still positive for h1n1) should the student has transferred to bv tropical diseases treated from 1 / 8. at the health of students and this stability will be in a few days.

    5 influenza a/h1n1 patients over 10 days still positive


    on august 8th....it has progressed to "many" patients [their words, not mine]....and the first mention of tamiflu resistance

    the treatment of influenza a/h1n1 in vietnam has recorded the patient's treatment time longer unusual, then many times the test is positive for influenza virus a/h1n1.

    dak lak province in a patient is admitted and have positive results for influenza a/h1n1 from 24 / 7. treated properly exposed it after 5 days, the test on 29 / 7, the result is not negative. 2 days later, patients continue to be tested and continue positive.

    "this is the first patient to test the 4 th, after almost 10 days with new negative influenza virus a/h1n1," mr. tran quy tuong, deputy director general management treatment (ministry of health ) said.

    in tien giang, 5 patients with influenza a/h1n1 also fell into a similar situation.

    mr. trinh quan huan, deputy minister of health explained: "previously, when other types of flu appear (h5n1, h3n2, influenza b), we have used to treat tamiflu. frequency use tamiflu more likely resistance tamiflu growing. "
    commonground's full thread on swine flu in vietnam is worth reading:

  6. by   indigo girl

    Quote from www.thestar.com

    More cases of Tamiflu resistant swine flu viruses have come to light, the World Health Organization said today.

    China and Singapore have found Tamiflu-resistant pandemic viruses, Charles Penn, a scientist with the Geneva-based agency, said in an interview with The Canadian Press.

    He revealed that the WHO has also been alerted informally to the discovery of a small number of other Tamiflu-resistant viruses. He would not say where they were found or how many there were in total.
    (hat tip Avian Flu Diary)

    I really have a problem with the withholding of certain aspects of this information. Sorry, but if it is not that important, then he should have no problem with details of where these cases were, how many there are, and just how they were discovered. It makes a difference. He is being deliberately evasive about information that WHO obviously is privy to, but we are not.

    Quote from www.thestar.com

    Formal notification involves reporting on details of the case, including whether the patient was taking Tamiflu for treatment of flu or prophylaxis (prevention).

    The WHO also wants to know whether the virus has been checked to see if all the genes are those of the pandemic virus or whether the pandemic virus might have swapped genes with the seasonal H1N1 virus.

    That would be an unwelcome turn of events: virtually all the human H1N1 viruses circulating over the past year or so have been resistant to Tamiflu. It's an attribute public health authorities would not like to see the pandemic virus acquire.

    Penn said to date there is no evidence of that kind of gene swapping – called reassortment. Nor is there any sign that the resistant pandemic H1 viruses are spreading from person to person, he said.

    "Basically what it looks like is they are all individual isolated cases. No onward transmission and no suggestion or implication of them having originated, if you like, from a common source," he said.

    It has always been expected that some degree of resistance to the drug would arise. Studies done years ago by the drug's maker, Roche, found that in rare cases people taking the drug either for treatment or prevention develop resistance.

    "It's been there all the time as an event which can happen with a low frequency. And therefore what we're seeing now is no more or less than we would have expected from those early data," Penn said.

    It was long thought Tamiflu-resistant flu viruses would not spread and so didn't pose much of a threat. But in the winter of 2008, the explosive development of resistance in seasonal H1N1 viruses showed the conventional wisdom was unfounded.
    Me thinks, he doth protest too much.

  7. by   indigo girl
    WHO Failure to See Spread of Tamiflu Resistant Pandemic H1N1


    Quote from www.recombinomics.com

    ...the rationale behind the withholding of additional cases remains unclear. At the time Thailand had already acknowledged at least one case, and additional reports from Hong Kong and an MMWR Dispatch describing two immuno-compromised patients in Washington State were made public on Friday. Cases in Texas along the border with Mexico area till being denied, although the initial report included detail on two of the cases, suggesting the denials were largely based on semantics.

    The cases in Texas would change the inferred scale, because the cases were at opposite ends of the border and had much in common with the initial H1N1 described in southern California. Those cases were unlinked to each other or swine, yet the sequences were virtually identical, indicating the virus was widespread. The same conclusion could be made from the cases in Texas, which may be related to the withholding of the information associated with these cases.

    However, the detail that has come out in the past few days has left little doubt that the WHO's "scale of what we are seeing" is false. The failure to see the true scale of the H274Y spread is due to the limited testing, which is largely focused on samples collected prior to Tamiflu treatment, which can be "seen" in results from patients on prophylactic Tamiflu treatment or in samples collected a few days after the start of Tamiflu treatment in symptomatic patients.
  8. by   indigo girl
    tamiflu resistance in northern california


    i have not been posting every case of tamiflu resistance found, but will occasionally do so as a reminder that they are continuing to occur. we probably are not hearing about all of them. and, since most people are never tested anymore, the true extent of resistance is unknown, but may be significantly higher than many would like to believe.

    it is only a matter of time before we lose this drug. this might not be so important if swine flu remains relatively mild for most of the cases. we still have relenza, and at some point peramavir should also be approved for use. if case loads climb this winter in the northern hemisphere, cases of resistance may increase as well in the hospitalized patients, and this could be troublesome.

    h274y is a genetic marker indicating that a strain of virus is resistant to treatment with tamiflu.

    Quote from www.recombinomics.com

    during this week, the cdph viral and rickettsial diseases laboratory detected a specimen with the h275y resistance mutation (associated with oseltamivir resistance); the result was confirmed by the cdc. this is the first time that this mutation has been detected by the vrdl and provides strong evidence for the importance of enhanced surveillance for antiviral resistance testing. the specimen was obtained from a hospitalized patient in northern california.

    the above comments are from the latest report from the california department of public health and may be the first example of a hospitalized patient in the us who has h274y and is not immuno-compromised. earlier two immuno-compromised cancer patients were described in seattle, in addition to two summer campers in north carolina who were on prophylactic tamiflu

    earlier a traveler from san francisco was h274y positive in hong kong, and had no reported tamiflu exposure, raising concerns of an evolutionarily fit pandemic h1n1 circulating in northern california, since the infected traveler was symptomatic during or shortly after deplaning from a non-stop flight originating in san francisco.

    the above description does not include tamiflu use in the hospitalized patient, so it is unclear if the h274y was detected prior to treatment or if treatment selected for h274y. prior cases developed resistance shortly after the start of treatment, raising concerns of h274y circulation as minor component in worldwide infections, leading to increases in deaths as seen in california, or widespread outbreaks as seen in schools in the southern united states.

    moreover, the number of cases of resistance continues to rise. the latest who update on reported cases cites four for japan, indicating another patient on prophylactic tamiflu developed an infection which was h274y positive.

    more information on tamiflu exposure linked to the hospitalized patient in northern california, as well as sequence data on the growing number of h274y positive cases would be useful.
  9. by   indigo girl

    Quote from www.recombinomics.com
    The patient without documented exposure to Tamiflu is likely to be the hospitalized patient described in the latest weekly report from California. The northern California patient was hospitalized, suggesting H274Y was identified through routine surveillance. Earlier, a San Francisco traveler to Hong Kong also had no documented exposure to Tamiflu, but had a mild case of pandemic H1N1 with H274Y. Thus, the H1N1 was evolutionarily fit and could produce mild disease in patients not taking Tamiflu.
    How does it happen that a person who has never taken Tamiflu can have a case of Tamiflu resistant swine flu?

    You have to look at some history to understand why. Seasonal H1N1, one of the influenzas that vaccination is provided for each year, is now resistant to Tamiflu. This did not happen overnight but rather through many recombinations of viruses exchanging genetic information with each other. By now if you have been folowing this thread, you know that H274Y is the SNP (single nucleotide polymorphism) that is associated with Tamiflu resistance in flu viruses. This change was accelerated by the joining of H274Y with HA A193T. It is as if H274Y got a ride in a fast car because HA A193T really gets around. Once they began teaming up together, Tamiflu became useless in treating seasonal flu, H1N1. It was very unfortunate timing that this just came to fruition in the last year prior to the outbreak of the current pandemic with swine flu.

    Quote from www.recombinomics.com
    In seasonal flu, recombination moved H274Y from one genetic background to another until the H274Y paired up with HA A193T and other key changes acquired from clade 2C via recombination. The genetic hitchhiking of H274Y lead to fixing in seasonal H1N1, which created a large genetic reservoir for the transfer of H274Y from seasonal H1N1 to pandemic H1N1.
    This has "created a large genetic reservoir for the transfer of H274Y from seasonal H1N1 to pandemic H1N1". When two influenza viruses co-infect the same host, they exchange information. We can therefore expect that this is going to occur this flu season many, many times over, and we will see further cases of Tamiflu resistance.
  10. by   indigo girl

    despite the official denials of tamiflu resistance along the texas-mexican border reported in the media:

    Quote from www.recombinomics.com

    influenza a/h1n1 (novel) 5 2 (40%) 0 (0) 5 5 (100%)

    the above description is from the week 32 mmwr surveillance report from the texas department of state health services. the number of h1n1 isolates tested for oseltamivir resistance rose for 3 to 5, and both new isolates were resistant (presumably h274y). it is likely that these two cases are those on the mexican border which were disclosed and denied earlier this month.

    although both cases were on the mexican border (see map), they were at opposite ends of the texas border, raising concerns that resistance in texas was widespread. indeed, as noted above, the rate to date in texas is 40% (2/5). initial reports speculated that the resistance was linked to cross-border access to tamiflu in mexico. however, the us border with mexico extends well beyond texas, so cross border traffic is not limited to texas, or the two locations described.

    the clustering of these cases in texas, but at widely separated locations is similar to the first two pandemic h1n1 cases in southern california. both were reported at the same time, but were not linked, raising concern that the h1n1 tamiflu resistance was widespread.

    two cases in texas in the same report raise similar concerns. texas has only tested five pandemic h1n1 samples, so the two positives clearly dictate more aggressive testing is warranted.

    there has been a recent resurgence of cases in mexico, and these two resistant cases raise concerns that the resurgence is linked to resistance, which may be circulating as a minor species or may be evolutionarily fit, as suggested for the two isolates from northern california.

    release of the sequences from the texas isolates would be useful, as would more testing of cases pre and post oseltamivir treatment.

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