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  • Vietnam - 7 healthy people caught Tamiflu-resistant H1N1 flu on a train

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    Published at www.nejm.org December 9, 2009 (10.1056/NEJMc0910448)


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    A Community Cluster of Oseltamivir-Resistant Cases of 2009 H1N1 Influenza

    <!-- PLUGH $RESOURCE.EXT_DOI is 10.1056/NEJMc0910448 -->
    <TABLE cellSpacing=0 cellPadding=0 width=200 align=right border=0><TBODY><TR><TD width=20></TD><TD bgColor=#336699></TD></TR></TBODY></TABLE><!-- end of outer content box1 --></TABLE><!-- end of outer content box2 --><!-- TEXT --><!-- <CENTER>A Community Cluster of Oseltamivir-Resistant Cases of 2009 H1N1 Influenza

    </CENTER> -->To the Editor: Oseltamivir-resistant infection with the 2009<SUP> </SUP>pandemic influenza A (H1N1) virus has so far been described<SUP> </SUP>only rarely and is conferred by the H275Y substitution in the<SUP> </SUP>neuraminidase enzyme.<SUP>1</SUP> Only 3 of the 32 patients with oseltamivir-resistant<SUP> </SUP>infection reported on as of this writing were not receiving<SUP> </SUP>oseltamivir when the resistant viruses were detected, and ongoing<SUP> </SUP>community transmission has not yet been shown.<SUP>1</SUP> However, the<SUP> </SUP>emergence of oseltamivir-resistant 2009 H1N1 influenza remains<SUP> </SUP>a grave concern, since widespread oseltamivir resistance has<SUP> </SUP>been observed in seasonal H1N1. This resistance was unrelated<SUP> </SUP>to selective drug pressure, and the H275Y substitution did not<SUP> </SUP>appear to reduce transmissibility or severity.<SUP>2</SUP><SUP>,</SUP><SUP>3</SUP> We report<SUP> </SUP>on a cluster of seven cases of oseltamivir-resistant 2009 H1N1<SUP> </SUP>infection in Vietnam.<SUP> </SUP>

    In July 2009, during a 42-hour journey, 10 students socialized<SUP> </SUP>together in the same train carriage. None of the students knew<SUP> </SUP>each other before the journey, none had contact with a person<SUP> </SUP>with suspected influenza in the week before the trip, none were<SUP> </SUP>symptomatic during the journey, and none were previously or<SUP> </SUP>currently receiving oseltamivir. Fever developed in four of<SUP> </SUP>the students within 12 hours after arrival and in two more students<SUP> </SUP>within 48 hours after arrival (Fig. 1 in the Supplementary Appendix,<SUP> </SUP>available with the full text of this letter at NEJM.org). An<SUP> </SUP>additional case was identified in a traveler in a different<SUP> </SUP>carriage (Patient G). Nasal swabs, throat swabs, or both from<SUP> </SUP>all seven persons were positive for 2009 H1N1 RNA when tested<SUP> </SUP>with reverse-transcriptase?polymerase-chain-reaction (RT-PCR)<SUP> </SUP>assays, and viruses were successfully cultured from specimens<SUP> </SUP>obtained from three of the persons. The H275Y substitution was<SUP> </SUP>detected retrospectively in diagnostic specimens obtained from<SUP> </SUP>all seven subjects before any oseltamivir treatment. The concentrations<SUP> </SUP>of oseltamivir carboxylate required for a 50% inhibition of<SUP> </SUP>neuraminidase activity of the isolated viruses in a fluorometric<SUP> </SUP>neuraminidase-inhibition assay were 323.6, 429.5, and 889.2<SUP> </SUP>nM; these concentrations confirmed resistance<SUP>4</SUP> (see the Supplementary Appendix).<SUP> </SUP>

    Six patients were admitted to a hospital for isolation, one<SUP> </SUP>patient was isolated at home, and all were treated with oseltamivir<SUP> </SUP>phosphate at a dose of 75 mg twice daily (Fig. 1 in the Supplementary Appendix), since resistance testing had not yet been performed.<SUP> </SUP>All patients recovered uneventfully, although one patient (Patient<SUP> </SUP>F), with the highest 50% inhibitory concentration, continued<SUP> </SUP>to test positive on RT-PCR until day 9, despite receiving oseltamivir<SUP> </SUP>from the day of the onset of illness (Fig. 1 in the Supplementary Appendix). An extensive public health investigation did not<SUP> </SUP>identify additional patients or the index patient.<SUP> </SUP>

    In this cluster, infection developed in at least 6 of the 10<SUP> </SUP>people who were probably exposed to the index patient; this<SUP> </SUP>shows that resistant 2009 H1N1 viruses are transmissible and<SUP> </SUP>can replicate and cause illness in healthy people in the absence<SUP> </SUP>of selective drug pressure. Ongoing transmission from the cluster<SUP> </SUP>was not detected, but the tracing of all contacts was not possible,<SUP> </SUP>so ongoing transmission cannot be ruled out.

    However, only three<SUP> </SUP>other resistant cases have been detected in Vietnam as of this<SUP> </SUP>writing, and all were due to selection of resistant viruses<SUP> </SUP>during treatment rather than person-to-person transmission.<SUP> </SUP>Although data are limited, it is likely that the detected levels<SUP> </SUP>of oseltamivir resistance are clinically relevant.<SUP>5</SUP> The loss<SUP> </SUP>of oseltamivir as a treatment option for severe 2009 H1N1 infection<SUP> </SUP>could have profound consequences. To minimize this risk, the<SUP> </SUP>use of oseltamivir should be restricted to prophylaxis and treatment<SUP> </SUP>in high-risk persons or the treatment of people with severe<SUP> </SUP>or deteriorating illness, antiviral stockpiles should be diversified,<SUP> </SUP>and optimal dosages and combination therapies should be urgently<SUP> </SUP>studied.

    Close monitoring and reporting of resistance to neuraminidase<SUP> </SUP>inhibitors are essential.<SUP> </SUP>
    <SUP></SUP>

    Le Quynh Mai, M.D., Ph.D.
    National Institute of Hygiene and Epidemiology<SUP> </SUP>
    Hanoi, Vietnam

    Heiman F.L. Wertheim, M.D., Ph.D. <SUP></SUP>
    Oxford University Clinical Research Unit<SUP> </SUP>
    Hanoi, Vietnam
    <SUP></SUP>
    Tran Nhu Duong, M.D., Ph.D.
    National Institute of Hygiene<SUP> </SUP>and Epidemiology<SUP> </SUP>
    Hanoi, Vietnam

    H. Rogier van Doorn, M.D., Ph.D. <SUP></SUP>
    Oxford University Clinical Research Unit<SUP> </SUP>
    Ho Chi Minh City, Vietnam
    <SUP></SUP>
    Nguyen Tran Hien, M.D., Ph.D.
    National Institute of Hygiene<SUP> </SUP>and Epidemiology<SUP> </SUP>
    Hanoi, Vietnam

    Peter Horby, M.B., B.S., F.F.P.H. <SUP></SUP>
    Oxford University Clinical Research Unit<SUP> </SUP>
    Hanoi, Vietnam
    peter.horby@gmail.com<SCRIPT type=text/javascript><!-- var u = "peter.horby", d = "gmail.com"; document.getElementById("em0").innerHTML = '<a href="mailto:' + u + '@' + d + '">' + u + '@' + d + '<\/a>'//--></SCRIPT>
    <SUP></SUP>
    for the Vietnam H1N1 Investigation Team<SUP> </SUP>
    Supported by grants from the Wellcome Trust United Kingdom (081613/Z/06/Z<SUP> </SUP>and 077078/Z/05/Z, to Drs. Wertheim, van Doorn, and Horby) and<SUP> </SUP>the South East Asia Infectious Disease Clinical Research Network<SUP> </SUP>(N01-A0-50042, to Drs. Wertheim, van Doorn, and Horby).<SUP> </SUP>
    Financial and other disclosures provided by the authors are<SUP> </SUP>available with the full text of this letter at NEJM.org.<SUP> </SUP>This letter (10.1056/NEJMc0910448) was published on December<SUP> </SUP>9, 2009, at NEJM.org.

    "Safety and security don't just happen, they are the result of collective consensus and public investment. We owe our children, the most vulnerable citizens in our society, a life free of violence and fear."
    -Nelson Mandela

  • #2
    Re: Vietnam - A Community Cluster of Oseltamivir-Resistant Cases of 2009 H1N1 Influenza

    Transmission of Tamiflu-resistant H1N1 on a Vietnamese train 'a concern':
    WHO


    By: Helen Branswell, Medical Reporter, THE CANADIAN PRESS

    9/12/2009 7:00 PM |

    TORONTO - Seven healthy people on a train from Ho Chi Minh City to Hanoi in Vietnam caught Tamiflu-resistant H1N1 flu, researchers reported Wednesday in a prominent medical journal.

    The transmission event, which occurred in July, is one of the largest clusters of cases of resistant H1N1 seen so far and the first time so many linked cases have been seen in previously healthy people who had not been on the drug.

    Surveillance since the summer has only turned up three additional drug resistant viruses, the authors note in their letter to the New England Journal of Medicine. But they say they cannot rule out the possibility of ongoing transmission of resistant pandemic H1N1.

    The event is a warning that resistant viruses can spread among healthy people and more such events may be in store, an antiviral expert with the World Health Organization said.

    "What this looks to be is ... the sort of situation we have been alert for, because it's something that we certainly don't want to see happening but need to know about if it does," Charles Penn said in an interview from Geneva.

    Penn said this event is different from two recent clusters, in which severely immunocompromised patients in hospitals in Wales and North Carolina developed and probably transmitted among themselves Tamiflu-resistant H1N1 virus. It's known that resistance develops easily in such patients.

    This, however, is a case where healthy people, who weren't taking the drug and who had no known contacts with sick people in the week before they fell ill, were infected with resistant viruses - "which is an apparent transmission of the resistant virus in a more normal community setting," Penn said.

    "This is different and it does raise the levels of concern. But it also I think reinforces the message that we do need to be constantly monitoring for this. And reporting it as quickly as it's observed."

    The scientists, from Vietnam's National Institute of Hygiene and Epidemiology and Oxford University's clinical research unit in Vietnam, reported that the event first hit the radar in early September when routine screening of H1N1 viruses turned up three with the mutation known to confer resistance to Tamiflu.

    The ensuing public health investigation uncovered a tale of a 42-hour train trip in which 10 students who didn't know each other prior to the journey socialized on the train.

    Six of the 10 became sick a day or two after arriving at their destination. Two didn't develop symptoms and public health officials were not able to trace two others.

    Interestingly, a seventh person who travelled in a different carriage on the same train and who doesn't appear to have been in contact with the students also contracted Tamiflu resistant H1N1 during the trip.

    "Ongoing transmission from the cluster was not detected, but the tracing of all contacts was not possible, so ongoing transmission (of resistant virus) cannot be ruled out," the authors wrote, adding that careful use of flu antivirals should be stressed to minimize that risk.

    Penn said to date there have been over 100 cases of Tamiflu-resistant H1N1 viruses spotted. About a third have been seen in immunocompromised patients. Of the remaining two-thirds, nearly all have been in people who took the drug to treat or prevent illness, or who had close contact with people who took the drug for one of those purposes.

    Prior to this report, he said, there have only been four cases spotted in people who hadn't taken the drug and didn't have traceable exposure to someone who had.

    The authors reported they were able to grow viruses from samples from three of the cases.

    Penn said the WHO will want to know if the viruses have been checked for other mutations that might account for the seemingly easy spread of resistant viruses. "I think we'll be in touch with the authors."

    It used to be thought that flu viruses that developed resistance to Tamiflu would be so weakened by the mutation that confers resistance that they would not be able to spread from person to person. But that belief was shattered in the winter of 2008 when Norway reported a startling rate of Tamiflu resistance in seasonal H1N1 viruses.

    Over the next year, the resistant seasonal H1N1 viruses virtually crowded out the Tamiflu-susceptible versions of the virus - a precedent public health authorities don't want to see repeated with the pandemic virus.

    "But we are expecting and we've said this, that as the pandemic spreads through this Northern Hemisphere winter and as the medicines continue to be used around the world, the number of sporadic cases is going to rise, as it has been at a steady by small rate," Penn said.

    "And then the risk of this sort of event occurring is going to increase with more virus around and those infections being treated."

    ?Addressing chronic disease is an issue of human rights ? that must be our call to arms"
    Richard Horton, Editor-in-Chief The Lancet

    ~~~~ Twitter:@GertvanderHoek ~~~ GertvanderHoek@gmail.com ~~~

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    • #3
      Re: Vietnam - 7 healthy people caught Tamiflu-resistant H1N1 flu on a train

      Also at Scientific Library with PDF: http://im.ly/d394d/

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