Emergence of Oseltamivir-Resistant Pandemic H1N1 Virus during Prophylaxis (N Engl J Med., edited)
Emergence of Oseltamivir-Resistant Pandemic H1N1 Virus during Prophylaxis
<!-- PLUGH $RESOURCE.EXT_DOI is 10.1056/NEJMc0910060 -->
<!-- end of outer content box1 --> <!-- end of outer content box2 --> <!-- TEXT --> <!-- <CENTER> Emergence of Oseltamivir-Resistant Pandemic H1N1 Virus during Prophylaxis
</CENTER> -->
To the Editor:
Neuraminidase inhibitors (oseltamivir and zanamivir)<sup> </sup>are recommended for treatment of severe illness caused by the<sup> </sup>2009 pandemic influenza A (H1N1) virus, and their use has also<sup> </sup>been advocated for postexposure prophylaxis in high-risk persons.<sup>1</sup> We report the emergence of an oseltamivir-resistant virus<sup> </sup>in a familial cluster of infections with the 2009 H1N1 virus.<sup> </sup>
In a 13-year-old boy with asthma, infection with the 2009 H1N1<sup> </sup>virus developed and was confirmed by reverse-transcriptase polymerase-chain-reaction<sup> </sup>(RT-PCR) testing of a nasopharyngeal aspirate. Administration<sup> </sup>of oseltamivir (60 mg twice a day for 5 days for this boy who<sup> </sup>weighed 32 kg) was begun, and the patient was discharged home<sup> </sup>the same day. Simultaneous with treatment of the index patient,<sup> </sup>postexposure prophylaxis with oseltamivir (75 mg once a day<sup> </sup>for 10 days) was prescribed to all household contacts (the boy's<sup> </sup>59-year-old father, who had chronic obstructive pulmonary disease<sup> </sup>and was taking prednisone at a dose of 5 mg daily; 50-year-old<sup> </sup>mother; and 15-year-old and 18-year-old sisters). Approximately<sup> </sup>24 hours after oseltamivir prophylaxis was begun, influenza-like<sup> </sup>symptoms developed in the father (...). On day 8 of oseltamivir<sup> </sup>prophylaxis, the father consulted his general practitioner because<sup> </sup>of persistent cough. A nasopharyngeal aspirate collected at<sup> </sup>that time was positive for the 2009 H1N1 virus, according to<sup> </sup>RT-PCR testing and culture. The father had an uneventful clinical<sup> </sup>course, and a nasopharyngeal aspirate sampled at the end of<sup> </sup>his illness was negative for the 2009 H1N1 virus. Influenza-like<sup> </sup>symptoms did not develop in any other household contacts.
The 2009 H1N1 viral isolate collected from the index patient<sup> </sup>before oseltamivir therapy was susceptible to oseltamivir (50%<sup> </sup>inhibitory concentration, 0.27 nM) and zanamivir (50% inhibitory<sup> </sup>concentration, 0.18 nM), whereas the father's 2009 H1N1 viral<sup> </sup>isolate was resistant to oseltamivir (50% inhibitory concentration,<sup> </sup>>400 nM) but susceptible to zanamivir (50% inhibitory concentration,<sup> </sup>0.12 nM). Complete 2009 H1N1 virus genomes of the father's virus<sup> </sup>(GenBank accession number, FN434454<!-- HIGHWIRE EXLINK_ID="361:23:2296:1" VALUE="FN434454" TYPEGUESS="GEN" --> [GenBank] <!-- /HIGHWIRE -->) differed from the index<sup> </sup>patient's virus (GenBank accession number, FN434445<!-- HIGHWIRE EXLINK_ID="361:23:2296:2" VALUE="FN434445" TYPEGUESS="GEN" --> [GenBank] <!-- /HIGHWIRE -->) by only<sup> </sup>one substitution (H275Y) in the neuraminidase protein. The role<sup> </sup>of the H275Y substitution was assessed by generating recombinant<sup> </sup>neuraminidase proteins.<sup>2</sup> The mutant neuraminidase protein was<sup> </sup>more resistant to oseltamivir than was the wild-type protein<sup> </sup>by a factor of more than 400, confirming the phenotypic results.
Our results indicate that the same neuraminidase mutation (H275Y)<sup> </sup>is associated with oseltamivir resistance not only in seasonal<sup> </sup>H1N1<sup>3</sup> and avian H5N1<sup>4</sup> viruses but now also in 2009 pandemic<sup> </sup>H1N1 strains. We hypothesize that the presence of subtherapeutic<sup> </sup>levels of oseltamivir at a time when viral replication had already<sup> </sup>begun was an important factor that led to the emergence of the<sup> </sup>resistant virus in the father of our index patient. Other oseltamivir-resistant<sup> </sup>strains of 2009 H1N1 virus detected during postexposure prophylaxis<sup> </sup>have been reported to the World Health Organization.<sup>5</sup>
These observations support the need for limiting the indications<sup> </sup>for postexposure prophylaxis. It also seems reasonable to rapidly<sup> </sup>convert prophylactic (once daily) regimens to therapeutic (twice<sup> </sup>daily) regimens as soon as influenza-like symptoms develop in<sup> </sup>a patient receiving prophylactic treatment. Monitoring for the<sup> </sup>H275Y mutation during outbreaks of 2009 H1N1 virus is important<sup> </sup>in order to rapidly identify transmission events that could<sup> </sup>lead to large-scale dissemination of an oseltamivir-resistant<sup> </sup>2009 H1N1 virus, similar to what occurred with recent H1N1 virus<sup> </sup>seasonal strains.<sup>3</sup><sup> </sup>
<sup> </sup>
<sup> </sup>
Mariana Baz, M.Sc.
Yacine Abed, Ph.D. <sup> </sup>
Jesse Papenburg, M.D. <sup> </sup>
Xavier Bouhy, B.Sc. <sup> </sup>
Marie-Ève Hamelin, Ph.D.
Guy Boivin,<sup> </sup>M.D. <sup> </sup>
Centre Hospitalier Universitaire de Québec
Quebec, QC, Canada<sup> </sup>
guy.boivin@crchul.ulaval.ca<script type="text/javascript"><!-- var u = "guy.boivin", d = "crchul.ulaval.ca"; document.getElementById("em0").innerHTML = '<a href="mailto:' + u + '@' + d + '">' + u + '@' + d + '<\/a>'//--></script>
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/NEJMc0910060) was published on November<sup> </sup>11, 2009, at NEJM.org.<sup> </sup>
References
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Emergence of Oseltamivir-Resistant Pandemic H1N1 Virus during Prophylaxis
<!-- PLUGH $RESOURCE.EXT_DOI is 10.1056/NEJMc0910060 -->
<!-- end of outer content box1 --> <!-- end of outer content box2 --> <!-- TEXT --> <!-- <CENTER> Emergence of Oseltamivir-Resistant Pandemic H1N1 Virus during Prophylaxis
</CENTER> -->
To the Editor:
Neuraminidase inhibitors (oseltamivir and zanamivir)<sup> </sup>are recommended for treatment of severe illness caused by the<sup> </sup>2009 pandemic influenza A (H1N1) virus, and their use has also<sup> </sup>been advocated for postexposure prophylaxis in high-risk persons.<sup>1</sup> We report the emergence of an oseltamivir-resistant virus<sup> </sup>in a familial cluster of infections with the 2009 H1N1 virus.<sup> </sup>
In a 13-year-old boy with asthma, infection with the 2009 H1N1<sup> </sup>virus developed and was confirmed by reverse-transcriptase polymerase-chain-reaction<sup> </sup>(RT-PCR) testing of a nasopharyngeal aspirate. Administration<sup> </sup>of oseltamivir (60 mg twice a day for 5 days for this boy who<sup> </sup>weighed 32 kg) was begun, and the patient was discharged home<sup> </sup>the same day. Simultaneous with treatment of the index patient,<sup> </sup>postexposure prophylaxis with oseltamivir (75 mg once a day<sup> </sup>for 10 days) was prescribed to all household contacts (the boy's<sup> </sup>59-year-old father, who had chronic obstructive pulmonary disease<sup> </sup>and was taking prednisone at a dose of 5 mg daily; 50-year-old<sup> </sup>mother; and 15-year-old and 18-year-old sisters). Approximately<sup> </sup>24 hours after oseltamivir prophylaxis was begun, influenza-like<sup> </sup>symptoms developed in the father (...). On day 8 of oseltamivir<sup> </sup>prophylaxis, the father consulted his general practitioner because<sup> </sup>of persistent cough. A nasopharyngeal aspirate collected at<sup> </sup>that time was positive for the 2009 H1N1 virus, according to<sup> </sup>RT-PCR testing and culture. The father had an uneventful clinical<sup> </sup>course, and a nasopharyngeal aspirate sampled at the end of<sup> </sup>his illness was negative for the 2009 H1N1 virus. Influenza-like<sup> </sup>symptoms did not develop in any other household contacts.
The 2009 H1N1 viral isolate collected from the index patient<sup> </sup>before oseltamivir therapy was susceptible to oseltamivir (50%<sup> </sup>inhibitory concentration, 0.27 nM) and zanamivir (50% inhibitory<sup> </sup>concentration, 0.18 nM), whereas the father's 2009 H1N1 viral<sup> </sup>isolate was resistant to oseltamivir (50% inhibitory concentration,<sup> </sup>>400 nM) but susceptible to zanamivir (50% inhibitory concentration,<sup> </sup>0.12 nM). Complete 2009 H1N1 virus genomes of the father's virus<sup> </sup>(GenBank accession number, FN434454<!-- HIGHWIRE EXLINK_ID="361:23:2296:1" VALUE="FN434454" TYPEGUESS="GEN" --> [GenBank] <!-- /HIGHWIRE -->) differed from the index<sup> </sup>patient's virus (GenBank accession number, FN434445<!-- HIGHWIRE EXLINK_ID="361:23:2296:2" VALUE="FN434445" TYPEGUESS="GEN" --> [GenBank] <!-- /HIGHWIRE -->) by only<sup> </sup>one substitution (H275Y) in the neuraminidase protein. The role<sup> </sup>of the H275Y substitution was assessed by generating recombinant<sup> </sup>neuraminidase proteins.<sup>2</sup> The mutant neuraminidase protein was<sup> </sup>more resistant to oseltamivir than was the wild-type protein<sup> </sup>by a factor of more than 400, confirming the phenotypic results.
Our results indicate that the same neuraminidase mutation (H275Y)<sup> </sup>is associated with oseltamivir resistance not only in seasonal<sup> </sup>H1N1<sup>3</sup> and avian H5N1<sup>4</sup> viruses but now also in 2009 pandemic<sup> </sup>H1N1 strains. We hypothesize that the presence of subtherapeutic<sup> </sup>levels of oseltamivir at a time when viral replication had already<sup> </sup>begun was an important factor that led to the emergence of the<sup> </sup>resistant virus in the father of our index patient. Other oseltamivir-resistant<sup> </sup>strains of 2009 H1N1 virus detected during postexposure prophylaxis<sup> </sup>have been reported to the World Health Organization.<sup>5</sup>
These observations support the need for limiting the indications<sup> </sup>for postexposure prophylaxis. It also seems reasonable to rapidly<sup> </sup>convert prophylactic (once daily) regimens to therapeutic (twice<sup> </sup>daily) regimens as soon as influenza-like symptoms develop in<sup> </sup>a patient receiving prophylactic treatment. Monitoring for the<sup> </sup>H275Y mutation during outbreaks of 2009 H1N1 virus is important<sup> </sup>in order to rapidly identify transmission events that could<sup> </sup>lead to large-scale dissemination of an oseltamivir-resistant<sup> </sup>2009 H1N1 virus, similar to what occurred with recent H1N1 virus<sup> </sup>seasonal strains.<sup>3</sup><sup> </sup>
<sup> </sup>
<sup> </sup>
Mariana Baz, M.Sc.
Yacine Abed, Ph.D. <sup> </sup>
Jesse Papenburg, M.D. <sup> </sup>
Xavier Bouhy, B.Sc. <sup> </sup>
Marie-Ève Hamelin, Ph.D.
Guy Boivin,<sup> </sup>M.D. <sup> </sup>
Centre Hospitalier Universitaire de Québec
Quebec, QC, Canada<sup> </sup>
guy.boivin@crchul.ulaval.ca<script type="text/javascript"><!-- var u = "guy.boivin", d = "crchul.ulaval.ca"; document.getElementById("em0").innerHTML = '<a href="mailto:' + u + '@' + d + '">' + u + '@' + d + '<\/a>'//--></script>
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/NEJMc0910060) was published on November<sup> </sup>11, 2009, at NEJM.org.<sup> </sup>
References
- Updated interim recommendations for the use of antiviral medications in the treatment and prevention of influenza for the 2009-2010 season. Atlanta: Centers for Disease Control and Prevention. (Accessed November 9, 2009, at http://www.cdc.gov/h1n1flu/recommendations.htm.)<!-- HIGHWIRE ID="361:23:2296:1" --> <!-- /HIGHWIRE --><!-- null -->
- Abed Y, Goyette N, Boivin G. A reverse genetics study of resistance to neuraminidase inhibitors in an influenza A/H1N1 virus. Antivir Ther 2004;9:577-581.<!-- HIGHWIRE ID="361:23:2296:2" --> [Web of Science][Medline]<!-- /HIGHWIRE --><!-- null -->
- Dharan NJ, Gubareva LV, Meyer JJ, et al. Infections with oseltamivir-resistant influenza A(H1N1) virus in the United States. JAMA 2009;301:1034-1041.<!-- HIGHWIRE ID="361:23:2296:3" --> <nobr>[Free Full Text]</nobr><!-- /HIGHWIRE --><!-- null -->
- de Jong MD, Tran TT, Truong HK, et al. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med 2005;353:2667-2672.<!-- HIGHWIRE ID="361:23:2296:4" --> <nobr>[Free Full Text]</nobr><!-- /HIGHWIRE --><!-- null -->
- Antiviral use and the risk of drug resistance: pandemic (H1N1) 2009 briefing note 12. Geneva: World Health Organization, September 25, 2009. (Accessed November 9, 2009, at http://www.who.int/csr/disease/swine.../en/index.html.).
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