<TABLE cellSpacing=0 cellPadding=0 width=640 border=0><TBODY><TR vAlign=top><TD>
<!-- 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.
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.
Comment