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Denmark - Dane with novel H1N1 found resistant to Tamiflu

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  • Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

    <a rel="nofollow" href="http://www.recombinomics.com/News/07010901/H274Y_Swine_Acquisition.html">Commentary</a>

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    • Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

      So, Dr Niman, you believe this lady was the mixing vessel, one of the 5% who have 2 viral infections at the same time? If that happens here in NZ it would be one week of being ill, one week of tamiflu treatment to disclose the resistant virus - and then sick people needing ventilators. This would be week 4 of our flu season - the very peak. Already we have exceeded the ceiling for the last two years cases. Timely news from the local health boards would be appreciated.
      "The only security we have is our ability to adapt."

      Comment


      • Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

        Originally posted by niman View Post
        <a rel="nofollow" href="http://www.recombinomics.com/News/07010901/H274Y_Swine_Acquisition.html">Commentary</a>
        Acquisition of H274Y Tamiflu Resistance in Pandemic H1N1

        Recombinomics Commentary 02:09
        July 1, 2009

        In the context of tracing contacts of a cluster of 3 imported cases in Denmark, a female contact who initially tested negative on PCR, was given prophylaxis with oseltamivir (75 mg per day). Five days later, despite reportedly having complied with treatment, she developed flu-like symptoms and was tested positive for A(H1N1)v. Sequencing of the virus showed a single mutation H275Y (H274Y in N2 nomenclature) in the neuraminidase gene. The presence of the resistance marker and the phenotypic (in vitro) resistance was confirmed by a WHO collaborating Centre. The virus is not a re-assortant and is presumed to remain susceptible to zanamivir (another neuraminidase inhibitor). All other virus isolated as part of this cluster investigation, including the presumed source patient, did not show the mutation.

        According to the available epidemiological and virological data, this reported event in Denmark is almost certainly secondary resistance acquired during post-exposure prophylaxis. This is supported by the time sequence and the absence of similar genotypic markers in viruses isolated in the other cases of the cluster.

        There is no evidence in this case that the isolated resistant virus has transmitted to other persons, meaning that the risk of spread of a resistant virus is nearly zero.

        Secondary resistance, arising due to treatment, must not be confused with more complex mutations including the H274Y substitution resulting from primary resistance. Such primary resistance was first observed in seasonal A(H1N1) influenza virus in the 2007-2008. It spread worldwide generally displacing other seasonal A(H1N1) viruses (98&#37; resistance in EU in 2008-2009

        The above risk assessment by the European Centre for Disease Control indicates the oseltamivir resistance identified in a female <a rel="nofollow" href="http://www.recombinomics.com/News/06290902/Pandemic_H1N1_Resistance.html">contact</a> of a pandemic H1N1 confirmed traveler was due to the acquisition of H274Y. The report also indicates the sequence from the likely source of the pandemic H1N1 infection of the contact did not contain H274Y, supporting the acquisition during prophylactic treatment leading to a low risk assessment for spread.

        However, there are alternate explanations for the failure to detect H274Y in the sequence from the traveling contact. If the contact was infected with two versions of H1N1, sample collection prior to oseltamivir treatment would generate the sequence of the dominant wild type species. The local contact, who developed symptoms five days after the start of treatment , would test positive for H274Y because the prophylactic treatment would lower the level of wild type RNA. Thus, potential spread of resistance would reside in patients in the originating country, who could travel to Denmark and re-introduce the H274Y.

        Alternatively, the local contact could have been infected by another source in Denmark, since there were no symptoms during the first five days of prophylactic treatment. Although Denmark has reported a relatively low level of H1N1 in residents, like most countries in Europe, testing is focused on airport travelers and contacts, while testing for community spread is limited. However, since many passengers will be infected shortly before flight, many will be asymptomatic. Others will be asymptomatic because of an infection that does not produce a high fever, while others will have symptoms reduced because of medications. Thus, the number of passengers evading detection at airports will be large, leading to H1N1 spread in the community.

        The evidence for H274Y acquisitions via recombination are linked to the recent patterns of spread in H1N1 seasonal flu. Although the report notes the dramatic primary spread of H274Y between 2007-2009, it simply calls such spread complex and fails to address the appearance of H274Y on multiple genetic backgrounds in the absence of Tamiflu treatment. It is the jumping of H274Y from one genetic background to another (recombination) that has raised concerns that such jumps will lead to acquisition of H274Y on a pandemic H1N1 background, because the H274Y level is near 100% in seasonal flu and pandemic H1N1 is accelerating its <a rel="nofollow" href="http://www.recombinomics.com/News/06300901/H274Y_Swine_Silent.html">spread</a> through the human population, increasing the frequency of dual infections involving swine and seasonal H1N1.

        Thus, the acquisition of H274Y is expected and it is likely that there will be more examples of sequences like the resistance described in the above report. Release of the sequences from the cluster would be useful, as would the travel history of the traveler thought to have infected the contact who developed resistance via H274Y.

        These data should launch more aggressive surveillance worldwide. Although countries have been promptly depositing sequences, the number of sequences remains low. Denmark has only deposited one sequence, which was from a patient infected in April.

        The start of flu season in the southern hemisphere should lead to rapid evolution and the widespread acquisition of important polymorphisms, such as PB2 E627K, which was reported in Shanghai, but present only in the original sequence and the first clone, and NA H274Y, as found in the above patient from Denmark.

        .
        "The next major advancement in the health of American people will be determined by what the individual is willing to do for himself"-- John Knowles, Former President of the Rockefeller Foundation

        Comment


        • Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

          from post #131:

          She said the novel flu virus has an "N1" gene that is very different than the "N1" of the seasonal H1N1 virus, so perhaps the pandemic virus isn't as susceptible to the antiviral resistance mutation seen with the seasonal H1N1 strain.
          Is the N1 gene of novel H1N1 very different from seasonal?

          Do the the words "isn't as susceptible to the antiviral resistance mutation" mean they believe it is less likely to reassort because it is so different?

          If I remember correctly, the NA is swinish, so is there antiviral resistance in influenza commonly circulating in pigs?

          .
          "The next major advancement in the health of American people will be determined by what the individual is willing to do for himself"-- John Knowles, Former President of the Rockefeller Foundation

          Comment


          • Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

            Originally posted by kiwibird View Post
            So, Dr Niman, you believe this lady was the mixing vessel, one of the 5% who have 2 viral infections at the same time? If that happens here in NZ it would be one week of being ill, one week of tamiflu treatment to disclose the resistant virus - and then sick people needing ventilators. This would be week 4 of our flu season - the very peak. Already we have exceeded the ceiling for the last two years cases. Timely news from the local health boards would be appreciated.
            The two sequences would be minor swine variants (with and without H274Y). The original mixing between swine and human H1N1 was likely upstream (in country where traveler was) and the mixture is widespread (in a very high percentage of patients - the mixing of closely related sequences is in almost all samples - the published sequence is a "consensus").

            Comment


            • Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

              Originally posted by AlaskaDenise View Post
              from post #131:



              Is the N1 gene of novel H1N1 very different from seasonal?

              Do the the words "isn't as susceptible to the antiviral resistance mutation" mean they believe it is less likely to reassort because it is so different?

              If I remember correctly, the NA is swinish, so is there antiviral resistance in influenza commonly circulating in pigs?

              .
              All 8 gene segments in swine are quite a bit different than human. Even the PB1, which is human, is close to H3N2 PB1 from 5-15 years ago.

              Comment


              • Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

                So are you in agreement with Carolyn Bridges's statement that the N1 gene is different from the seasonal version, therefore " the pandemic virus isn't as susceptible to the antiviral resistance mutation" ?

                .
                "The next major advancement in the health of American people will be determined by what the individual is willing to do for himself"-- John Knowles, Former President of the Rockefeller Foundation

                Comment


                • Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

                  Originally posted by AlaskaDenise View Post
                  So are you in agreement with Carolyn Bridges's statement that the N1 gene is different from the seasonal version, therefore " the pandemic virus isn't as susceptible to the antiviral resistance mutation" ?

                  .
                  No. There has already been one report from a VERY limited dataset. Now that H274Y in swine H1N1 has been reported, I expect more sequences and more examples. Although sequences are deposited promptly, surveillance, even for pandemic H1N1, still has some VERY serious issues (the grand total for Denmark remains at ONE, which is one more than many countries).

                  Comment


                  • Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

                    Related thread:

                    Japan Reports Tamiflu-Resistant H1N1 Influenza Case

                    Comment


                    • Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

                      Originally posted by kent nickell View Post
                      If H274Y takes hold and takes out both tamiflu and peramivir it does seem that for all practical purposes we would be left with inhaled Relenza (and its inherent problems of being able to be inhaled deep enough in young children and in people with lung problems)... 2 other drugs in the pipeline A-315675 (a possible oral alternative to tamiflu) and long acting zanamivir dimers also both look like they have their problems in development .. A-315675 though may be worth some clinical trials as it appears to have some effectiveness against H274Y although it appears difficult to sort out its in vitro and in vivo effectiveness (in mice)...




                      ""These results confirm the potent inhibitory effect of A-315675 against oseltamivir-resistant influenza viruses of the N1 and N2 subtypes and support the clinical development of its bioavailable prodrug A-322278.""




                      """Finally, we confirmed that the A/H1N1 H274Y mutant virus is as virulent as the WT virus, at least in this mouse model and in the A/WSN/33 background (2), which correlates with its natural occurrence and high transmissibility in humans during the 2007 to 2008 influenza season. Of note, A-322278 appears to be somewhat less effective in protecting mice challenged with the NA H274Y mutant virus than those infected with the WT virus. As we have previously reported similar 50% lethal dose values for the two viruses in mice (i.e., 103 PFU) (2), it is possible that such differences in activity could be attributable to low-level cross-resistance between the two drugs that is not measurable in in vitro assays. Clinical trials of A-322278 are warranted in the context of an eventual pandemic and in consideration of the limited alternatives to oseltamivir. """
                      Resisatnce discover in Hong Kong in patient from San Francisco who was NOT taking Tamiflu. It is fit.

                      Comment


                      • Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

                        Originally posted by pjie2 View Post
                        Please. Drug resistance is a phenotype. This is high school definition time.

                        Phenotype = the observable characteristics and traits of an organism. In this case, we observe drug resistance.

                        Genotype = the genetic makeup of an organism. H274Y is one of several genotypes that can confer the phenotype of drug resistance.

                        Until and unless the sequences from the Danish patient are published, we do not know the genotype of the flu strain she had, but we do know that the phenotype was a drug resistant one. There are no grounds for the assertion that the resistance is due to H274Y. However, if the patient she caught it from had a non-resistant strain, then that would constitute very good evidence that the resistance is due to a de novo mutation in this individual patient, and not indicative of wider circulation of a resistant strain.
                        H274Y has now been confirmed in Denmark and Japan, and the resistance in Hong Kong (from San Franciso) is in patient NOT taking Tamiflu, so it is almost CERTAINLY H274Y and is spreading silently in the United States due to poor surveillance (at best).

                        Comment


                        • Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

                          Originally posted by niman View Post
                          Google translation

                          - He had to start with no ill. That was in the preventive treatment with Tamiflu, because he had been in close contact with a swine influenza hit abroad. Since there had been five days of Tamiflu, the person suddenly ill with H1N1, but it not appear that the medicine worked.
                          Symptoms five days after the start of prophylatic treatment matches the most recent case in Japan.

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