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Anti-viral resistance in 2009 A/H1N1 flu - historical compilation of news

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  • #16
    Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

    Meanwhile, lab workers in Denmark are reporting the first known case of swine flu that is resistant to Tamiflu, the main anti-viral drug that governments have been stockpiling in case this strain of H1N1 turns nasty this summer. The single case of drug resistance is worth noting but not yet cause for alarm, according to the CDC. NPR's Richard Knox sent this background note to explain why:
    "It's not good. But experts say it doesn't necessarily mean all or even most swine flu viruses will soon become resistant to the mainstay antiviral.
    The Danish patient reportedly has recovered from the flu. And as far as anyone knows, he or she did not pass the resistant virus on to anyone else.
    Experts have been worried swine flu might become Tamiflu-resistant because many of the ordinary seasonal flu viruses that circulated in North America this past season were unfazed by the drug. One of these unfazed seasonal strains is also from the H1N1 family.
    Roche, which makes Tamiflu, says the Danish patient's virus had only one genetic mutation, called H-274-Y. That mutation has long been known to arise in the viruses infecting a small percentage of people on Tamiflu, in response to treatment. But here's the difference: The Tamiflu-resistant seasonal flu virus has a half-dozen mutations, including H-274-Y. Scientists don't know if the swine flu virus can or will acquire this suite of resistance mutations.
    Actually, it's pretty surprising that the pandemic virus hasn't acquired the H-274-Y mutation more often, given the thousands of people treated with Tamiflu lately.
    "It's certainly likely that we will see this in the United States," says Dr. Carolyn Bridges of the Centers for Disease Control. But so far the CDC has tested almost 200 swine flu viruses for Tamiflu resistance and hasn't found any.
    One reason, Bridges says, is that the new H1N1 virus has an "N1" gene that's very different from the corresponding gene of the seasonal H1N1. That's significant, because Tamiflu works by blocking neuraminidase --- that's what the "N" stands for. So maybe the pandemic virus's N-gene isn't as susceptible to the Tamiflu resistance mutation as the analogous gene in its very distant cousin, the seasonal H1N1 virus.
    But the Danish case shows that it can happen.

    Battling infectious disease is more like a tense negotiation than a scorched earth battle, as this update on contaminated cookie dough and drug-resistant swine flu shows.

    Comment


    • #17
      Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

      (...)


      ECDC Threat Assessment

      First isolation of a secondary oseltamivir - resistant A(H1N1)v strain in Denmark, 29 June, 2009

      SOURCE: Internal request following a EWRS message from Denmark health authorities
      PUBLIC HEALTH ISSUE: Isolation of a mutant A(H1N1)v virus containing a genetic marker of resistance to oseltamivir.
      CONSULTED EXPERTS: Internal experts

      EVENT BACKGROUND INFORMATION:

      Event reported by Danish EWRS Focal point on 29 July 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.


      ECDC THREAT ASSESSMENT FOR THE EU

      The A(H1N1)v virus related to the ongoing pandemic has always be found sensitive to oseltamivir and zanamivir and resistant to adamantanes (M2 blockers). This is the first observation of a genetic marker of resistance to oseltamivir in a A(H1N1)v virus.

      The mutation consists of the substitution of histidine to tyrosine at amino acid position 275 in the neuraminidase segment gene (position 274 in N2 nomenclature). This mutation has been described in the past, associated with secondary resistance to oseltamivir acquired during treatment. This was documented some years back in children in Japan where the drug was used more commonly than in Europe(1). The mutation was detected in up to 16% of oseltamivir-treated children in Japan, perhaps associated with under-dosing(2). Studies have shown that the virus containing this mutation is unfit in terms of transmissibility(3) and possibly also in terms of pathogenicity(4) as demonstrated in animal studies. Therefore, such mutation is of limited public health concern since it has not resulted in the past in a virus that demonstrated sustained person-to-person transmission.

      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. It is however likely that such mutation will be observed again in the future. This observation does highlight the increased likelihood of such event arising from widespread use of anti-virals especially in prophylaxis.

      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% resistance in EU in 2008-2009)(5). Following that phenomenon some EU countries have diversified their anti-virals stockpiles adding zanamivir to oseltamivir.

      There is always a theoretical risk of re-assortment of A(H1N1)v with primary resistant seasonal viruses notably the seasonal influenza virus A(H1N1) containing the H274Y mutation.


      CONCLUSIONS AND RECOMMENDATIONS

      The emergence of secondary resistance while on antiviral treatment is a well recognised phenomenon in influenza viruses. As in the past, there is no evidence the mutation has led to a virus capable of transmitting from person to person. Therefore, though resistant viruses are always a concern, the emergence of A(H1N1)v resistant to oseltamivir does not represent a public health threat. It can be expected to happen again.

      Surveillance of genetic resistance for detecting early primary resistance is of particular importance for the future course of the pandemic

      CONTACT: support@ecdc.europa.eu


      References

      (1) Whitley RJ, Hayden FG, Reisinger K, Young N, Dutkowski R, Ipe D, et al. Oral oseltamivir treatment of influenza in children. Ped Infect Dis J 2001; 20(2):127-33.
      (2) Ward P, Small I, Smith J, Suter P, Dutkowski R. Oseltamivir (Tamiflu(R)) and its potential for use in the event of an influenza pandemic. J Antimicrob Chemother 2005; 55(suppl_1): i5-21.
      (3) Compromised transmission: Herlocher ML, Truscon R, Elias S; et al. Influenza viruses resistant to the antiviral drug oseltamivir: transmission studies in ferrets. J Infect Dis. 2004;190(9):1627-30
      (4) Attenuated pathogenicity: Ives JA, Carr JA, Mendel DB; et al. 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; 55(2): 307-17
      (5) Meijer A, Lackenby A, Hungnes O, Lina B, van der Werf S, Schweiger B, et al. Oseltamivir-resistant influenza A (H1N1) virus, Europe, 2007?08 season. Emerg Infect Dis. 2009; 15(4):552-60

      -

      ------

      Comment


      • #18
        Re: Denmark - Dane with novel H1N1 found resistant to Tamiflu

        Source: http://www.cidrap.umn.edu/cidrap/con...amiflu-ms.html


        Health officials say antiviral resistance likely in some pandemic flu cases

        Jun 30, 2009 (CIDRAP News) ? A spokesman for Roche, the maker of oseltamivir (Tamiflu), said yesterday that Denmark's report of resistance to the drug in a patient with novel H1N1 (swine) influenza, the first reported finding of its kind, wasn't surprising and that the news underscores the importance of monitoring for any viral changes.

        David Reddy, who leads Roche's influenza task force, told Bloomberg News that experts know that during seasonal influenza outbreaks, patients can develop resistance. "We fully expect that this can also occur during treatment with a new flu strain," he said.

        He characterized what occurred in the Danish patient as "drug-induced resistance" that developed when a low dose of medication was used, as opposed to the more widespread resistance that occurs when a flu virus acquires new characteristics, which has happened over the past 2 years with the seasonal H1N1 strain.

        World Health Organization (WHO) spokesman Dick Thompson said today that the Danish case is isolated and has no public health implications, Reuters reported. "But we must remain alert as the virus can change at any time and we must not be complacent," he added.

        The antiviral resistance finding will not prompt any changes in the WHO antiviral recommendations, Thompson told Reuters.

        Roche said it is monitoring drug resistance in several countries, and health officials in several nations, including the United States, are also watching for changes in the virus. The US Centers for Disease Control and Prevention (CDC) said in its most recent surveillance report, released Jun 24, that of 191 novel H1N1 isolates that have been tested for resistance to neuraminidase inhibitors, none showed resistance.

        The CDC recommends treatment with oseltamivir or zanamivir for all patients who have confirmed, probable, or suspected novel H1N1 infections who are hospitalized or are at high risk for complications.

        Carolyn Bridges, MD, associate director of epidemiologic science in the CDC's influenza division, told National Public Radio that though the United States hasn't detected any antiviral resistance in the new virus, it will likely occur here eventually. 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.

        See also:

        CDC influenza surveillance report for week ending Jun 20

        Comment


        • #19
          Re: Japan Reports Tamiflu-Resistant H1N1 Influenza Case

          Japan finds first case of H1N1 resistant to Tamiflu
          Thu Jul 2, 2009 11:19am EDT

          TOKYO, July 2 (Reuters) - Japan has confirmed its first case of a genetic mutation of the new H1N1 influenza that shows resistance to antiviral drug Tamiflu, a health ministry official said on Thursday.
          Takeshi Enami, an official at the health ministry, said that the patient's sensitivity to Tamiflu had yet to be tested.

          The patient, who was confirmed in May with the H1N1 strain of the flu in the Osaka prefecture of western Japan, has recovered since then and that no cases of the new flu have been confirmed around the patient, Enami said.

          He could not confirm the age or the sex of the patient. (Reporting by Yoko Kubota; Editing by Alex Richardson)

          Comment


          • #20
            Re: Japan Reports Tamiflu-Resistant H1N1 Influenza Case

            Tamiflu-resistant swine flu patient found in Japan: govt
            Thursday, July 2, 2009 - 20:21
            AFP News Briefs List

            A genetic mutation of swine flu that is resistant to the anti-viral Tamiflu has been discovered in Japan, the first such case in the country, the health ministry said.

            It was the second reported case of Tamiflu resistance linked to swine flu in less than a week.

            The latest case was found in a patient who had been given the drug since first being diagnosed with A(H1N1) around two weeks ago, Kyodo news agency reported Thursday, citing the Health, Welfare and Labour Ministry.

            The patient -- a woman in Osaka prefecture -- was recovering after having been given Ralenza, an alternative anti-flu medication, the report said.

            A spokeswoman for Swiss pharmaceuticals giant Roche, which makes Tamiflu, said the company had been informed of the case and called it "normal."

            "It is absolutely normal
            ," she said, adding that "0.4 percent of adults develop resistance" to Tamiflu.


            She said the case does not indicate Tamiflu has become less effective against swine flu.

            Danish authorities announced earlier this week they had discovered resistance to Tamiflu in a female patient. Ralenza was also used successfully to treat her.

            According to the latest World Health Organization figures, Japan has 1,266 reported cases of swine flu, but has so far recorded no fatalities.

            Comment


            • #21
              Re: Japan Reports Tamiflu-Resistant H1N1 Influenza Case


              Oseltamivir in Osaka Press Release (Products: Tamiflu) for the avian flu virus was detected indicating the mutant gene from Osaka ○ resistance, indicating that the H275Y Tamiflu-resistant isolates with a mutated avian flu virus genes were reported on the Summary, as attached, to provide information.

              ○ The virus, now, WHO, National Institute of Infectious Diseases in collaboration center, is scheduled to be implemented and drug susceptibility testing.

              In Japan, about 500 nationwide surveillance by the virus are carried out in cooperation with the medical institution where the future for the new influenza virus, and not knowing what is expected from the drug-resistant gene mutation .

              ○ In addition, gene mutations that are resistant to Tamiflu, the severity of the virus (pathogenic) is a direct influence is not.

              Oseltamivir in Osaka (product name: Tamiflu) Description of a new flu virus was detected in a mutant gene be resistant.

              ○ Description of patients from patients living in Osaka, with the avian flu virus resistant to Tamiflu indicates the gene mutation.

              If this is to begin on May 15, May 17, concentrated contacts of patients confirmed that the avian flu patients.

              ○ 5 prophylactic administration of the drug from the Monday 18 days (10 days) were made,

              May 24 with a fever on May 28 to contact the Counseling Center, fever, and on May 29 in the diagnosis of avian flu.

              Sunday May 29 from 5-day Zanamivir (Product name: Relenza) treated by recovery.

              The samples were collected from patients in the Osaka Prefectural Institute of Public Health,

              After separation of the virus culture, the gene sequence was confirmed, June 18,

              Be resistant to Tamiflu H275Y mutant gene was confirmed.

              ○ In addition, the May 15 analysis has been similar for patients who develop the virus strain, indicating the mutant gene was confirmed Tamiflu resistant.

              ○ then spread to the surrounding, including the Family is not approved.

              ○ neuraminidase was carried out by the Osaka Prefectural Institute of Public Health (NA) part of the gene (250bp) and the analysis of mutations in the gene (point mutation)(A/H1N1; mutation) which arises, seasonal influenza (A/H1N1;Soviet-type) which is caused by hybridization of the year.


              ○ 6 Monday 30 of the European Center for Disease Control (ECDC) said, in Denmark, as the avian flu patients contact the rich history of travel abroad, who had prophylactic administration of Tamiflu, the drug administration 5 The tests for flu-like symptoms after day, is found to be infected with avian flu.

              Then I check the status of drug-resistant, and has been recognized that drug-resistant mutation.

              ○ For this case, ECDC will never be shown to isolate the virus-resistant gene mutations full TAMI patients are given Tamiflu, a phenomenon that is observed in the seasonal flu, Tamiflu will be resistant For influenza virus, has not been confirmed to be infected by the surrounding public health risk and are not considered.

              ※ In addition, ECDC's report, in Japan, found that children infected with seasonal flu are being treated by a full TAMI, the 16

              The virus was separated from the TAMI shows the percent of full immunity, the infection is introduced, studies that were low.

              Comment


              • #22
                Re: Japan Reports Tamiflu-Resistant H1N1 Influenza Case

                <TABLE class=lan18 border=0 cellSpacing=0 cellPadding=0 width="97%" align=center><TBODY><TR><TD class=hei22 height=25 vAlign=bottom>Japan reports first case of Tamiflu-resistant H1N1 flu
                </TD></TR><TR><TD bgColor=#ffffff height=4></TD></TR></TBODY></TABLE><TABLE border=0 cellSpacing=0 cellPadding=0 width="50%" align=center><TBODY><TR><TD height=8></TD></TR></TBODY></TABLE><TABLE border=0 cellSpacing=0 cellPadding=0 width="97%" align=center><TBODY><TR><TD width="48%">www.chinaview.cn 2009-07-03 09:10:07</TD><TD class=hui12 width="26%" align=middle> </TD><TD class=hui12 width="12%" align=middle> Print</TD></TR></TBODY></TABLE><TABLE border=0 cellSpacing=0 cellPadding=0 width="80%"><TBODY><TR><TD height=20></TD></TR></TBODY></TABLE><TABLE class=lt14 border=0 cellSpacing=0 cellPadding=0 width="97%" align=center><TBODY><TR><TD class=lt14>


                TOKYO, July 3 (Xinhua) -- Japanese has detected the first genetic mutation of the new H1N1 strain of influenza A that develops resistance to the anti-flu drug Tamiflu, the health ministry said late Thursday.

                The Tamiflu-resistant virus was detected in a woman in her 40s infected with the new influenza in Osaka Prefecture, it said.
                The ministry added she is already recovering after being administered Relenza, another anti-flu drug.
                The female patient had been administered Tamiflu since May 18 as a preventive measure after she was found to have had close contact with another confirmed infected patient the previous day. She was confirmed infected with A/H1N1 influenza on May 28. An analysis of a virus taken from her detected the genetic mutation that does not respond to Tamiflu on June 18. The first case of HINI that showed resistance to Tamiflu was reported in Denmark at the end of last month.



                </TD></TR></TBODY></TABLE>

                Comment


                • #23
                  Re: HONG KONG, PRC SAR: RESPONSE AND TRACKING (by Govt Agencies) [857 cases, 0 deaths, 3 in hospital, as 07/02/09]

                  Hong Kong: Detection of human swine influenza virus resistant to Tamiflu (7/3/09)

                  A spokesman for the Department of Health (DH) said the department's Public Health Laboratory Services Branch (PHLSB) today (July 3) detected a strain of human swine influenza (HSI) virus which was resistant to oseltamivir (Tamiflu).


                  The virus was identified during PHLSB's routine sensitivity test of HSI virus to oseltamivir and zanamivir, the spokesman said.

                  "This is the first time Tamiflu resistance in HSI virus found in Hong Kong," he said, adding that similar cases were also reported in Denmark and possibly Japan.

                  "Tests showed that this strain is sensitive to zanamivir (Relenza)," he said.


                  The virus was isolated from the specimen taken from a 16-year-old girl coming from San Francisco. She was intercepted by Port Health Office at the Hong Kong International Airport on June 11 upon arrival. The girl was then admitted to Queen Mary Hospital for isolation. She was tested positive to HSI but opted not to take tamiflu. She had mild symptoms and was eventually discharged upon recovery on June 18.

                  The spokesman noted that PHLSB conducted routine sensitivity tests on specimens taken from confirmed HSI patients.

                  "This is the only Tamiflu-resistant strain so far among some 200 HSI samples tested in Hong Kong. Further tests are underway," he said.

                  Hong Kong has maintained an antiviral stockpile of both Tamiflu and Relenza.

                  The case will be reported to the World Health Organization (WHO), the spokesman said. He reiterated that Hong Kong had an intensive influenza surveillance system on antiviral resistant influenza viruses.

                  "We will closely liaise with WHO and overseas health authorities and monitor the global development of antiviral resistant HSI virus," he said.
                  -

                  View Original Article

                  Comment


                  • #24
                    First Tamiflu-resistant swine flu case found in teenager (Hong Kong ex San Francisco)

                    <TABLE class=bodyCopy border=0 cellSpacing=1 cellPadding=1 width=500 align=center><TBODY><TR><TD>First Tamiflu-resistant swine flu case found in teenager
                    (10 mins ago)
                    A 16-year-old girl was found to be infected with a mutation of the swine flu virus that is resistant to the antiviral Tamiflu soon after arriving from San Francisco, the Department of Health said today.

                    It is the first such case in Hong Kong. Similar cases have been reported in Denmark and Japan.

                    The teenager was intercepted at the airport on June 11 and admitted to Queen Mary Hospital.

                    She opted not to be put on a course of Tamiflu before testing positive for the swine flu strain, which is known to be resistant to the antiviral.

                    She had mild symptoms and was discharged on June 18.

                    The case will be reported to the World Health Organization.

                    Danish health authorities have used Relenza, an alternative anti-flu medication, to successfully treat a female patient with the same strain.

                    The Japanese said a patient was found to be resistant to Tamiflu after being put on the drug since she was being diagnosed with the H1N1 virus around two weeks ago, Kyodo news agency reported yesterday.

                    The Osaka prefecture patient was recovering after having been given Relenza.

                    A spokeswoman for Swiss pharmaceuticals giant Roche, which makes Tamiflu, said the company had been informed of the case and described as ''normal'' such resistance to the drug.

                    ''It is absolutely normal,'' she said, adding that ''0.4 percent of adults develop resistance'' to Tamiflu.

                    She said such cases do not indicate Tamiflu has become less effective against swine flu.

                    http://www.thestandard.com.hk/breaki...l.asp?id=15461</TD></TR></TBODY></TABLE>

                    Comment


                    • #25
                      Re: Hong Kong: Detection of human swine influenza virus resistant to Tamiflu in person from USA

                      Tamiflu-Resistant Swine Flu Virus Found in Hong Kong (Update2)


                      Share | Email | Print | A A A



                      By Nipa Piboontanasawat and Jason Gale
                      July 3 (Bloomberg) -- Tamiflu-resistant swine flu was found in a teenager who hadn?t taken Roche Holding AG?s best-selling antiviral medicine, Hong Kong?s health department said.
                      The city?s Public Health Laboratory Services Branch identified the drug-evading variant during routine surveillance of flu specimens, the department said in a statement today.
                      This marks the first known case of Tamiflu resistance in a swine flu patient not treated with the drug, which has been stockpiled by governments worldwide to fight pandemic influenza. The specimen was collected from a 16-year-old girl who flew from San Francisco and was intercepted by officials at Hong Kong International Airport on June 11, according to the statement.
                      ?Picking it up in a patient who was not treated is a cause for concern,? Malik Peiris, professor of microbiology at Hong Kong University, said in an interview. ?One case doesn?t change the world, but if we are seeing more and more cases in patients who are not treated, then I think it would be more serious.?
                      The patient, who was admitted to Queen Mary Hospital for isolation, tested positive for the new H1N1 flu strain and opted not to take Tamiflu, Hong Kong?s health department said. She had mild symptoms and was discharged upon recovery on June 18.
                      Denmark, Japan
                      Basel, Switzerland-based Roche said on June 29 that a swine flu patient treated with Tamiflu in Denmark showed resistance to the drug for the first time. Japan?s health ministry reported a case of resistance yesterday in a woman from Osaka who had taken a 10-day course.
                      Studies have shown that Tamiflu-resistant bugs develop in 0.4 percent to 4 percent of adults and children treated for seasonal influenza, Claudia Schmitt, a spokeswoman at Roche, said by phone from Basel today.
                      It?s likely the few reported cases of drug-resistant swine flu emerged independently, Hong Kong University?s Peiris said.
                      ?The key point is whether the strains will become dominant and then we will have a problem,? he said. ?At this moment, I don?t think there is cause for alarm. There is certainly cause for heightened surveillance.?
                      The new H1N1 pandemic virus and a seasonal H1N1 variant are more likely to develop resistance to Tamiflu than other common flu strains, Peiris said. About 95 percent of the H1N1 seasonal flu viruses circulating around the world evade the Roche pill, according to a March 21 World Health Organizationreport.
                      Glaxo?s Relenza
                      No widespread resistance to GlaxoSmithKline Plc?s flu drug Relenza has been reported in seasonal flu, and there have been no reports of resistance in swine flu.
                      ?Constant, random mutation is the survival mechanism of the microbial world,? WHO Director-General Margaret Chan said in an address to a meeting on the flu pandemic in Cancun, Mexico, yesterday. ?Like all influenza viruses, H1N1 has the advantage of surprise on its side.?
                      Tamiflu and Relenza, an inhaled powder, reduce the severity and the duration of flu symptoms by 24 to 30 hours if treatment is started within the first two days of illness, according to the companies.
                      Both drugs work by blocking a protein on the surface of influenza particles called neuraminidase, which allows the virus to spread from infected cells to other cells in the body.
                      Scientists say mutant H1N1 viruses have evolved to evade Tamiflu through a single mutation in the neuraminidase that prevents the medicine from clinging to the viral protein, enabling the pathogen to spread.
                      The case in Hong Kong indicates that the mutant virus is capable of being transmitted among people, said Jennifer McKimm- Breschkin, a virologist at the Commonwealth Science and Industrial Research Organization in Melbourne.
                      ?It?s very disturbing that, fresh into the human population, this one appears now to be able to retain fitness despite having the mutation and to be able to spread,? she said in a telephone interview today.
                      To contact the reporters on this story: Nipa Piboontanasawat in Hong Kong at npiboontanas@bloomberg.net; To contact the reporters on this story: Jason Gale in Singapore at j.gale@bloomberg.net.
                      Last Updated: July 3, 2009 07:46 EDT

                      Comment


                      • #26
                        Re: Hong Kong: Detection of human swine influenza virus resistant to Tamiflu (7/3/09)

                        Commentary

                        Surveillance Flaws Drive Silent Spread of Tamiflu Resistant H1N1

                        Recombinomics Commentary 15:18
                        July 3, 2009


                        The virus was isolated from the specimen taken from a 16-year-old girl coming from San Francisco. She was intercepted by Port Health Office at the Hong Kong International Airport on June 11 upon arrival. The girl was then admitted to Queen Mary Hospital for isolation. She was tested positive to HSI but opted not to take tamiflu. She had mild symptoms and was eventually discharged upon recovery on June 18.


                        The above comments from a Hong Kong DOH press release on Tamiflu resistance in pandemic H1N1 highlight severe limitations in worldwide surveillance. Although this case was identified by routine surveillance of H1N1 positive patients in Hong Kong, it is an effort largely focused on travelers. Like countries outside of the Americas, most efforts have focused on travelers and largely ignored local community spread. The recent explosion in cases in the UK has led to a focus on the community spread there, but many other counties in Europe are reporting low numbers of confirmed pandemic H1N1 because of limited testing in the community.

                        In the US, efforts are focused on the community, but severe cases are targetted. Most states have stopped reporting and testing mild cases, so real monitoring of this group is minimal. However, the case in Hong Kong originated in San Francisco and was mild. The United States has not reported any Tamiflu resistance. The CDC has tested over 200 isolates and failed to identify H274Y.


                        This may be due in part to virus mixtures. In Denmark and Japan the H274Y was discovered in patients undergoing Tamiflu prophylactic treatment. The Tamiflu treatment would reduce wild type H1N1 and allow a minor population with H274Y to expand and be detected. Therefore, it is likely that the H274Y is spreading silently and under the radar of the sequencing efforts, which are focused on the dominant (consensus) sequence.


                        The acquisition of H274Y by pandemic H1N1 was not unexpected. H274Y has a history of jumping from one sub-clade to another, as well as jumping to multiple different backgrounds within a subclade via recombination and genetic hitchhiking. This has produced resistance that is limited to H1N1 and H274Y within H1N1. The co-circulation of human H1N1 seasonal flu with swine H1N1 in humans, has created a favorable environment for the jump of H274Y from seasonal flu to pandemic flu. Moreover, the widespread use of Tamiflu in patients infected with pandemic H1N1 will drive the rate of spread in pandemic H1N1.


                        Although countries have been placing sequences on deposit in a timely manner, there are still major deficiencies in the surveillance program, as described above. Moreover, the recent reports of Tamiflu resistance in isolates in Denmark, Japan, and Hong Kong have not lead to the release of these sequences.


                        An increase in surveillance and release of full sequences is still necessary. The pandemic H1N1 is now rapidly spreading in the southern hemisphere, which is just beginning its flu season. Sequences from fatal and mild cases are required to determine important changes in pandemic H1N1 associated with increased virulence as well as increased spread.


                        A serious comprehensive surveillance program is long overdue.


                        .
                        "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


                        • #27
                          Re: Hong Kong: Detection of human swine influenza virus resistant to Tamiflu in person from USA

                          Commentary

                          Lesson Not Learned in H1N1 Tamiflu Resistant Spread

                          Recombinomics Commentary 18:26
                          July 3, 2009

                          "Picking it up in a patient who was not treated is a cause for concern," Malik Peiris, professor of microbiology at Hong Kong University, said in an interview. "One case doesn't change the world, but if we are seeing more and more cases in patients who are not treated, then I think it would be more serious."

                          The patient, who was admitted to Queen Mary Hospital for isolation, tested positive for the new H1N1 flu strain and opted not to take Tamiflu, Hong Kong's health department said. She had mild symptoms and was discharged upon recovery on June 18.

                          "The key point is whether the strains will become dominant and then we will have a problem," he said. "At this moment, I don't think there is cause for alarm. There is certainly cause for heightened surveillance."

                          "Constant, random mutation is the survival mechanism of the microbial world," WHO Director-General Margaret Chan said in an address to a meeting on the flu pandemic in Cancun, Mexico, yesterday. "Like all influenza viruses, H1N1 has the advantage of surprise on its side."

                          Studies have shown that Tamiflu-resistant bugs develop in 0.4 percent to 4 percent of adults and children treated for seasonal influenza, Claudia Schmitt, a spokeswoman at Roche, said by phone from Basel today.

                          The above comments on the emergence of H274Y and associated oseltamivir (Tamiflu) resistance clearly show that lessons were not learned from the spread of H274Y in seasonal flu (limited to H1N1). The spread of H274Y in seasonal flu destroyed the old paradigm of influenza evolution by selection of "random mutations", but as seen above, WHO is still citing that mechanism to try to explain the emergence of H274Y in pandemic H1N1 in Denmark, Japan, Hong Kong, and San Francisco.

                          Roche is still citing old data on the emergence of resistance in Japan years ago, when children were treated with sub-optical doses. That data provided a classical example of resistance, which was linked to the sub-optimal dosing, as well as mutations in H1N1 and H3N2 at multiple locations within each sero-type. However, those changes were only viable in the presence of Tamiflu, which killed off the competing wild type strains.

                          In 2005 when resistance developed in treated patients or contacts infected with H5N1 the same assurances on lack of fitness and failure to spread were offered. The first example was a patient on a prophylactic dose because her brother was a confirmed case. She developed an infection, but responded to a therapeutic dose, even though H5N1 with H274Y as well as N296S was identified in sub-clones from the patient.

                          Although the spread of resistant H5N1 in patients was not reported, the appearance of H274Y in H1N1 in wild birds later that year was cause for concern. The wild birds in Russia were not given oseltamivir, yet H5N1 was isolated from dead birds indicating H5N1 with H274Y was evolutionarily fit, leading to transmission between birds and fatal infections.

                          Concerns of H274Y were increased the following year when it was reported in seasonal flu in China. The clade 2C (Hong Kong strain) with H274Y was found in patients who were not taking Tamiflu, again showing that evolutionarily fit could transmit to humans who were not taking Tamiflu.

                          The following season (2006/2007), H274Y jumped to another H1N1 sub-clade (clade 1 - New Caledonia strain) in the United States and United Kingdom. The multiple sub-clades within clade 1 signaled multiple introductions into patients not taking Tamiflu.

                          The following season (2007/2008), H274Y jumped again. Initial cases in the United States were in Hawaii were clade 2B (Brisbane strain), but did not spread. However, the H274Y jumped onto another clade 2B sub-clade which did spread in the United States and Europe. This sub-clade was initially reported in Norway in early 2008, but had been silently spreading throughout the fall.

                          In the summer of 2008 the H274Y in combination with HA A193T emerged, which then led to the fixing of H274Y at levels approaching 100&#37; of H1N1. The A193T, as well as several additional polymorphisms had been co-circulating on clade 2C. The acquisition of these polymorphisms, including three consecutive polymorphisms in NA signaled recombination, because the NA polymorphisms were not only consecutive, but included a synonymous change, which offered no obvious selection pressure.

                          Thus, the data was inconsistent with a "random mutation" mechanism. The key changes were co-circulating on a related sub-clade, and were appended onto a clade 2B backbone. The H274Y jumped from background to background in patients who were not taking Tamiflu. This spread of H274Y via recombination and genetic hitchhiking did not require de novo mutations. The key polymorphisms were already circulating in clade 2C, and had earlier been found in other H1N1 or H1N2 isolates.

                          The mechanism of evolution raised serious concerns when swine H1N1 acquire efficient transmission in humans. This transmission offered the opportunity of genetic exchanges between human seasonal H1N1 and swine H1N1 which was now also in humans. Dual infections would allow for H274Y jumping form seasonal flu to pandemic flu in patients infected with both viruses.

                          Thus, the detection of H274Y in Denmark this week was not a surprised. However, since the patient had been on a prophylactic dose of oseltamivir, the random mutation paradigm was used to explain the data and offer assurances that the resistance wouldn't spread. However, the appearance of H274Y in the treated patient raised concerns that H274Y was lurking in a minor sub-population that was missing in sequencing of untreated patients, and was detected only in treated patients.

                          The data from Denmark was repeated in Japan this week, when another patient being treated with a prophylactic dose of oseltamivir also gave rise to the detection of H274Y. However, the appearance of H274Y in the absence of other resistance changes raised concerns that H274Y had already been acquired via recombination and was silently spreading in association with wild type H1N1.

                          The concerns were increased by the announcement in Hong Kong at a traveler from San Francisco, who was not taking Tamiflu was harboring a resisitant sequence, which was almost certainly H274Y. The presence of resistance in a patient not taking Tamiflu indicated the pandemic H1N1 with H274Y was evolutionarily fit and not only was in Hong Kong, but was also in San Francisco, the origin of the traveler.

                          However, H274Y has not been reported in the United States, raising serious surveillance concerns. Most efforts are directed to hospitalized serious cases, and state across the country announced that they were no longer testing mild cases. However, the Hong Kong, ex-San Francisco case was mild, which may explain the lack of detection.

                          However, of greater concern is the ability of H274Y to jump from one background to another in the absence of oseltamivir selection.

                          However, statements above indicate the lesson from seasonal flu was not learned, and the old discredited random mutation explain is once again offered, along with assurances that the H274Y will not spread (even after it has been found or implied on three continents).

                          Increased surveillance will demonstrate not only that H274Y can spread, but that it has already spread, under the radar of the current surveillance system. Moreover, the reliance of the old "random mutation" paradigm will lead to more "surprises" but those who adhere to an paradigm which is inconsistent with the sequence data.

                          An increase in surveillance and sequencing will allow for more accurate products of future acquisitions, which are due to recombination and not due to de novo mutations, as repeated again and again by those who ignore the data, or quote those who ignore the data.

                          .
                          "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


                          • #28
                            Re: Hong Kong: Detection of human swine influenza virus resistant to Tamiflu in person from USA

                            Here;s data for Hawaii at Genbank. One NA sequence that was just deposited from a collection in April

                            LOCUS GQ338360 1410 bp cRNA linear VRL 01-JUL-2009
                            DEFINITION Influenza A virus (A/Hawaii/09/2009(H1N1)) segment 6 neuraminidase
                            (NA) gene, complete cds.
                            ACCESSION GQ338360
                            VERSION GQ338360.1 GI:243031419
                            DBLINK Project:37813
                            KEYWORDS .
                            SOURCE Influenza A virus (A/Hawaii/09/2009(H1N1))
                            ORGANISM Influenza A virus (A/Hawaii/09/2009(H1N1))
                            Viruses; ssRNA negative-strand viruses; Orthomyxoviridae;
                            Influenzavirus A.
                            REFERENCE 1 (bases 1 to 1410)
                            AUTHORS Garten,R.
                            TITLE Direct Submission
                            JOURNAL Submitted (01-JUL-2009) Centers for Disease Control and Prevention,
                            NCIRD/Influenza Division/VSDB, Centers for Disease Control and
                            Prevention, Atlanta, 1600 Clifton Road, N.E., Atlanta, GA 30333,
                            USA
                            COMMENT Swine influenza A (H1N1) virus isolated during human swine flu
                            outbreak of 2009. For more information, see http://www.cdc.gov/.

                            Some of the information does not have GenBank feature identifiers
                            and is being provided in the comment section.

                            ##EpifluData-START##
                            Isolate A/Hawaii/09/2009
                            Subtype H1N1
                            Segment_name NA
                            Host_gender F
                            Host_age 37
                            Passage_history C1
                            Antigen_character A/California/07/2009-LIKE (H1N1)V
                            Adamantane_resistance resistant
                            Zanamivir_resistance sensitive
                            Oseltamivir_resistance sensitive
                            Country USA
                            State/Province Hawaii state
                            Collection_day 30
                            Collection_month 4
                            Collection_year 2009
                            Isolate_note Comment: Human case of 2009 H1N1 swine
                            influenza.
                            EPI_accession EPI184367
                            Lineage swl
                            ##EpifluData-END##
                            FEATURES Location/Qualifiers
                            source 1..1410
                            /organism="Influenza A virus (A/Hawaii/09/2009(H1N1))"
                            /mol_type="viral cRNA"
                            /strain="A/Hawaii/09/2009"
                            /serotype="H1N1"
                            /host="Homo sapiens; gender F; age 37"
                            /db_xref="taxon:656491"
                            /segment="6"
                            /country="USA: Hawaii state"
                            /collection_date="30-Apr-2009"
                            gene 1..1410
                            /gene="NA"
                            CDS 1..1410
                            /gene="NA"
                            /codon_start=1
                            /product="neuraminidase"
                            /protein_id="ACS94509.1"
                            /db_xref="GI:243031420"
                            /translation="MNPNQKIITIGSVCMTIGMANLILQIGNIISIWISHS IQLGNQN
                            QIETCNQSVITYENNTWVNQTYVNISNTNFAAGQSVVSVKLAGNSSLCPV GGWAIYSK
                            DNSVRIGSKGDVFVIREPFISCSPLECRTFFLTQGALLNDKHSNGTIKDR SPYRTLMS
                            CPIGEVPSPYNSRFESVAWSASACHDGINWLTIGISGPDNGAVAVLKYNG IITDTIKS
                            WRNNILRTQESECACVNGSCFTVMTDGPSNGQASYKIFRIEKGKIVKSVE MNAPNYHY
                            EECSCYPDSSEITCVCRDNWHGSNRPWVSFNQNLEYQIGYICSGIFGDNP RPNDKTGS
                            CGPVSSNGANGVKGFSFKYGNGVWIGRTKSISSRNGFEMIWDPNGWTGTD NNFSIKQD
                            IVGINEWSGYSGSFVQHPELTGLDCIRPCFWVELIRGRPKENTIWTSGSS ISFCGVNS
                            DTVGWSWPDGAELPFTIDK"
                            ORIGIN
                            1 atgaatccaa accaaaagat aataaccatt ggttcggtct gtatgacaat tggaatggct
                            61 aacttaatat tacaaattgg aaacataatc tcaatatgga ttagccactc aattcaactt
                            121 gggaatcaaa atcagattga aacatgcaat caaagcgtca ttacttatga aaacaacact
                            181 tgggtaaatc agacatatgt taacatcagc aacaccaact ttgctgctgg acagtcagtg
                            241 gtttccgtga aattagcggg caattcctct ctctgccctg ttggtggatg ggctatatac
                            301 agtaaagaca acagtgtaag aatcggttcc aagggggatg tgtttgtcat aagggaacca
                            361 ttcatatcat gctccccctt ggaatgcaga accttcttct tgactcaagg ggccttgcta
                            421 aatgacaaac attccaatgg aaccattaaa gacaggagcc catatcgaac cctaatgagc
                            481 tgtcctattg gtgaagttcc ctctccatac aactcaagat ttgagtcagt cgcttggtca
                            541 gcaagtgctt gtcatgatgg catcaattgg ctaacaattg gaatttctgg cccagacaat
                            601 ggggcagtgg ctgtgttaaa gtacaacggc ataataacag acactatcaa gagttggaga
                            661 aacaatatat tgagaacaca agagtctgaa tgtgcatgtg taaatggttc ttgctttact
                            721 gtaatgaccg atggaccaag taatggacag gcctcataca agatcttcag aatagaaaag
                            781 ggaaagatag tcaaatcagt cgaaatgaat gcccctaatt atcactatga ggaatgctcc
                            841 tgttatcctg attctagtga aatcacatgt gtgtgcaggg ataactggca tggctcgaat
                            901 cgaccgtggg tgtctttcaa ccagaatctg gaatatcaga taggatacat atgcagtggg
                            961 attttcggag acaatccacg ccctaatgat aagacaggca gttgtggtcc agtatcgtct
                            1021 aatggagcaa atggagtaaa aggattttca ttcaaatacg gcaatggtgt ttggataggg
                            1081 agaactaaaa gcattagttc aagaaacggt tttgagatga tttgggatcc gaacggatgg
                            1141 actgggacag acaataactt ctcaataaag caagatatcg taggaataaa tgagtggtca
                            1201 ggatatagcg ggagttttgt tcagcatcca gaactaacag ggctggattg tataagacct
                            1261 tgcttctggg ttgaactaat cagagggcga cccaaagaga acacaatctg gactagcggg
                            1321 agcagcatat ccttttgtgg tgtaaacagt gacactgtgg gttggtcttg gccagacggt
                            1381 gctgagttgc catttaccat tgacaagtaa

                            </PRE></P>

                            Comment


                            • #29
                              Re: Hong Kong: Detection of human swine influenza virus resistant to Tamiflu in person from USA

                              Originally posted by niman View Post
                              <TABLE dir=ltr border=1 cellSpacing=0 cellPadding=7 width=831><TBODY><TR><TD height=0 vAlign=top width="13%">
                              98

                              </TD><TD height=0 vAlign=top width="13%">F/36
                              </TD><TD height=0 vAlign=top width="13%">Asymptomatic
                              </TD><TD height=0 vAlign=top width="13%">Returned from San Francisco with mother and
                              </TD><TD height=0 vAlign=top width="13%">Imported
                              </TD><TD height=0 vAlign=top width="13%">Singapore Airlines(flight no SQ1) Arrived on June 11
                              </TD><TD height=0 vAlign=top width="13%">Daughter (confirmed patient), mother, two sisters , a brother
                              </TD><TD height=0 vAlign=top width="13%">Ping Tin Estate

                              </TD></TR></TBODY></TABLE>
                              The above data indicates the patient with Tamiflu resistant H1N1 was ASYMPTOMATIC!

                              Comment


                              • #30
                                Re: India - H1N1 Tamiflu resistance suspected

                                USA link


                                Possible case of ?resistant? A (H1N1) virus

                                Ramya Kannan

                                Positive tests, even after treatment, suggest a mutation

                                Blood sample to be sent to National Institute of Virology

                                CHENNAI: The Indian Council of Medical Research will investigate what seems to be a case of ?resistant? A (H1N1) virus in Chennai, its Director-General V. M. Katoch said. This is the first such case reported in the country.

                                The State health authorities have been asked to send a blood sample of the infected person to the National Institute of Virology (NIV), Pune.

                                The patient, a man who had flown in from the U.S. in the third week of June, had tested positive along with his wife.

                                They were quarantined at the Communicable Diseases Hospital (CDH) here and started on a course of Tamiflu. ?This was through the Directly Observed Treatment Short-course method, which means we know he took every tablet and did not miss out on even a single dose. Missing on doses can lead to resistance, but that is not the case with this patient,? Director of Public Health S. Elango said.

                                While his wife recovered and tested negative for A (H1N1) after about 10 days, the husband continued to test positive even after the treatment was completed.

                                Though he showed no symptoms, his tests kept coming back positive, Dr. Elango said.

                                ?This is a case to be studied, definitely. The virus should not remain in his blood after the treatment. It is possible that it is a mutation of the virus. I have instructed the officials at the NIV to sequence the strain [from the samples] as soon as possible. Once we have that, we can have the alternative drugs to treat the patient,? Dr. Katoch explained.

                                He said the patient at the CDH could be treated on recommended doses of the drug ?Relenza? available in India.

                                When told that the patient was anxious to go home, Dr. Katoch categorically said that he could not be discharged as long as he continued to test positive, even if he was not symptomatic.

                                ?He is certainly a carrier and can spread the virus to members of his family, and thereby take it into the community. That should not be allowed to happen. Indigenous transmission of the virus from this person will lead to a huge public health problem,? Dr. Katoch said.

                                The issue would be sorted out as soon as the sequence was drawn up. ?That way we will also be ready for any future occurrences.?

                                Comment

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