Correspondence
Emergence of Oseltamivir-Resistant Pandemic H1N1 Virus during Prophylaxis
N Engl J Med 2009; 361:2296-2297December 3, 2009
- Article
To the Editor:
Neuraminidase inhibitors (oseltamivir and zanamivir) are recommended for treatment of severe illness caused by the 2009 pandemic influenza A (H1N1) virus, and their use has also been advocated for postexposure prophylaxis in high-risk persons.1 We report the emergence of an oseltamivir-resistant virus in a familial cluster of infections with the 2009 H1N1 virus.
In a 13-year-old boy with asthma, infection with the 2009 H1N1 virus developed and was confirmed by reverse-transcriptase polymerase-chain-reaction (RT-PCR) testing of a nasopharyngeal aspirate. Administration of oseltamivir (60 mg twice a day for 5 days for this boy who weighed 32 kg) was begun, and the patient was discharged home the same day. Simultaneous with treatment of the index patient, postexposure prophylaxis with oseltamivir (75 mg once a day for 10 days) was prescribed to all household contacts (the boy's 59-year-old father, who had chronic obstructive pulmonary disease and was taking prednisone at a dose of 5 mg daily; 50-year-old mother; and 15-year-old and 18-year-old sisters). Approximately 24 hours after oseltamivir prophylaxis was begun, influenza-like symptoms developed in the father (Figure 1Figure 1
Symptoms, Antiviral Therapy, and Virologic Results in the Index Patient and His Father.). On day 8 of oseltamivir prophylaxis, the father consulted his general practitioner because of persistent cough. A nasopharyngeal aspirate collected at that time was positive for the 2009 H1N1 virus, according to RT-PCR testing and culture. The father had an uneventful clinical course, and a nasopharyngeal aspirate sampled at the end of his illness was negative for the 2009 H1N1 virus. Influenza-like symptoms did not develop in any other household contacts.The 2009 H1N1 viral isolate collected from the index patient before oseltamivir therapy was susceptible to oseltamivir (50% inhibitory concentration, 0.27 nM) and zanamivir (50% inhibitory concentration, 0.18 nM), whereas the father's 2009 H1N1 viral isolate was resistant to oseltamivir (50% inhibitory concentration, >400 nM) but susceptible to zanamivir (50% inhibitory concentration, 0.12 nM). Complete 2009 H1N1 virus genomes of the father's virus (GenBank accession number, FN434454) differed from the index patient's virus (GenBank accession number, FN434445) by only one substitution (H275Y) in the neuraminidase protein. The role of the H275Y substitution was assessed by generating recombinant neuraminidase proteins.2 The mutant neuraminidase protein was more resistant to oseltamivir than was the wild-type protein by a factor of more than 400, confirming the phenotypic results.
Our results indicate that the same neuraminidase mutation (H275Y) is associated with oseltamivir resistance not only in seasonal H1N13 and avian H5N14 viruses but now also in 2009 pandemic H1N1 strains. We hypothesize that the presence of subtherapeutic levels of oseltamivir at a time when viral replication had already begun was an important factor that led to the emergence of the resistant virus in the father of our index patient. Other oseltamivir-resistant strains of 2009 H1N1 virus detected during postexposure prophylaxis have been reported to the World Health Organization.5
These observations support the need for limiting the indications for postexposure prophylaxis. It also seems reasonable to rapidly convert prophylactic (once daily) regimens to therapeutic (twice daily) regimens as soon as influenza-like symptoms develop in a patient receiving prophylactic treatment. Monitoring for the H275Y mutation during outbreaks of 2009 H1N1 virus is important in order to rapidly identify transmission events that could lead to large-scale dissemination of an oseltamivir-resistant 2009 H1N1 virus, similar to what occurred with recent H1N1 virus seasonal strains.3
Mariana Baz, M.Sc.
Yacine Abed, Ph.D.
Jesse Papenburg, M.D.
Xavier Bouhy, B.Sc.
Marie-Ève Hamelin, Ph.D.
Guy Boivin, M.D.
Centre Hospitalier Universitaire de Québec, Quebec, QC, Canada
guy.boivin@crchul. ulaval. ca Financial and other disclosures provided by the authors are available with the full text of this letter at NEJM.org.
This letter (10.1056/NEJMc0910060) was published on November 11, 2009, at NEJM.org.
5 References1
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.)
2
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
Web of Science | Medline3
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
CrossRef | Web of Science | Medline4
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
Full Text | Web of Science | Medline5
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/swineflu/notes/h1n1_antiviral_use_20090925/en/index.html.)
- Citing Articles (47)
Citing Articles
1
Madhu Khanna, Binod Kumar, Ankit Gupta, Prashant Kumar. (2012) Pandemic Influenza A H1N1 (2009) Virus: Lessons from the Past and Implications for the Future. Indian Journal of Virology 23:1, 12-17
CrossRef2
Afroditi Kourti, Grecory Spanakos, Leda Politi, Anastasia Stavropoulou, Nicholas Spanakis, Athanassios Tsakris. (2012) Oseltamivir-resistant influenza A(H1N1) 2009 virus in Greece during the post-pandemic 2010–2011 season. International Journal of Antimicrobial Agents
CrossRef3
Jin Seo Lee, So Yeon Park, Jae Seok Kim, Ji Young You, Young-Su Ju, Joong Sik Eom. (2012) The clinical effectiveness of oseltamivir in mild cases of pandemic influenza A H1N1 2009 infection. Scandinavian Journal of Infectious Diseases1-5
CrossRef4
Avinash K Shetty, Leigh A Peek. (2012) Peramivir for the treatment of influenza. Expert Review of Anti-infective Therapy 10:2, 123-143
CrossRef5
Jianqiang Ye, Hongxia Shao, Daniel R Perez. (2012) Passive immune neutralization strategies for prevention and control of influenza A infections. Immunotherapy 4:2, 175-186
CrossRef6
Junjie Zhang, Ting Liu, Xiaomei Tong, Gang Li, Jinghua Yan, Xin Ye. (2012) Identification of novel virus inhibitors by influenza A virus specific reporter cell based screening. Antiviral Research 93:1, 48-54
CrossRef7
Olivier Ferraris, Vanessa Escuret, Maude Bouscambert, Jean-Sébastien Casalegno, Frédéric Jacquot, Hervé Raoul, Valérie Caro, Martine Valette, Bruno Lina, Michèle Ottmann. (2012) H1N1 influenza A virus neuraminidase modulates infectivity in mice. Antiviral Research
CrossRef8
Tatiana Baranovich, Robert G Webster, Elena A Govorkova. (2011) Fitness of neuraminidase inhibitor-resistant influenza A viruses. Current Opinion in Virology 1:6, 574-581
CrossRef9
Futoshi Higa, Masao Tateyama, Miyuki Tomishima, Sakiko Mukatake, Tsuyoshi Yamashiro, Tomoko Owan, Shusaku Haranaga, Jiro Fujita. (2011) Role of neuraminidase inhibitor chemoprophylaxis in controlling nosocomial influenza: an observational study. Influenza and Other Respiratory Virusesno-no
CrossRef10
James R. Smith, Craig R. Rayner, Barbara Donner, Martina Wollenhaupt, Klaus Klumpp, Regina Dutkowski. (2011) Oseltamivir in seasonal, pandemic, and avian influenza: a comprehensive review of 10-years clinical experience. Advances in Therapy 28:11, 927-959
CrossRef11
Vanessa Escuret, Olivier Ferraris, Bruno Lina. (2011) The antiviral resistance of influenza virus. Therapy 8:6, 741-762
CrossRef12
Jun Wang, Chunlong Ma, Yibing Wu, Robert A. Lamb, Lawrence H. Pinto, William F. DeGrado. (2011) Exploring Organosilane Amines as Potent Inhibitors and Structural Probes of Influenza A Virus M2 Proton Channel. Journal of the American Chemical Society 133:35, 13844-13847
CrossRef13
L. M. Thorne-Humphrey, K. B. Goralski, K. L. Slayter, T. F. Hatchette, B. L. Johnston, S. A. McNeil, . (2011) Oseltamivir pharmacokinetics in morbid obesity (OPTIMO trial). Journal of Antimicrobial Chemotherapy 66:9, 2083-2091
CrossRef14
Jun Wang, Chunlong Ma, Giacomo Fiorin, Vincenzo Carnevale, Tuo Wang, Fanghao Hu, Robert A. Lamb, Lawrence H. Pinto, Mei Hong, Michael L. Klein, William F. DeGrado. (2011) Molecular Dynamics Simulation Directed Rational Design of Inhibitors Targeting Drug-Resistant Mutants of Influenza A Virus M2. Journal of the American Chemical Society 133:32, 12834-12841
CrossRef15
Kung-Cheng Liu, Pei-Shan Lee, Shi-Yun Wang, Yih-Shyun E. Cheng, Jim-Min Fang, Chi-Huey Wong. (2011) Intramolecular ion-pair prodrugs of zanamivir and guanidino-oseltamivir. Bioorganic & Medicinal Chemistry 19:16, 4796-4802
CrossRef16
Mas Suhaila, Julian W. Tang, Hong Kai Lee, Cui Lin, Paul A. Tambyah, Hui Kim Yap, Seng Hock Quak, Evelyn S. C. Koay. (2011) Mixtures of Oseltamivir-sensitive and -resistant Pandemic Influenza A/H1N1/2009 Viruses in Immunocompromised Hospitalized Children. The Pediatric Infectious Disease Journal 30:7, 625-627
CrossRef17
Mina Nakauchi, Makoto Ujike, Masatsugu Obuchi, Emi Takashita, Ikuyo Takayama, Miho Ejima, Kunihiro Oba, Nami Konomi, Takato Odagiri, Masato Tashiro, Tsutomu Kageyama, . (2011) Rapid discrimination of oseltamivir-resistant 275Y and -susceptible 275H substitutions in the neuraminidase gene of pandemic influenza A/H1N1 2009 virus by duplex one-step RT-PCR assay. Journal of Medical Virology 83:7, 1121-1127
CrossRef18
Andrés Antón, Tomás Pumarola. (2011) Influenza in immunocompromised patients: considerations for therapy. Future Virology 6:7, 855-868
CrossRef19
Gabriele Neumann, Yoshihiro Kawaoka. (2011) The first influenza pandemic of the new millennium. Influenza and Other Respiratory Viruses 5:3, 157-166
CrossRef20
Sallene Wong, Kanti Pabbaraju, Anita Wong, Kevin Fonseca, Steven J. Drews. (2011) Development of a real-time RT-PCR assay for detection of resistance to oseltamivir in influenza A pandemic (H1N1) 2009 virus using single nucleotide polymorphism probes. Journal of Virological Methods 173:2, 259-265
CrossRef21
Yi-Mo Deng, Natalie Caldwell, Aeron Hurt, Tim Shaw, Anne Kelso, Glenys Chidlow, Simon Williams, David Smith, Ian Barr. (2011) A comparison of pyrosequencing and neuraminidase inhibition assays for the detection of oseltamivir-resistant pandemic influenza A(H1N1) 2009 viruses. Antiviral Research 90:1, 87-91
CrossRef22
Kristin A. Swedish. (2011) 2009 Pandemic Influenza A (H1N1): Diagnosis, Management, and Prevention— Lessons Learned. Current Infectious Disease Reports 13:2, 169-174
CrossRef23
L. F. Chen, N. J. M. Dailey, A. K. Rao, A. T. Fleischauer, I. Greenwald, V. M. Deyde, Z. S. Moore, D. J. Anderson, J. Duffy, L. V. Gubareva, D. J. Sexton, A. M. Fry, A. Srinivasan, C. R. Wolfe. (2011) Cluster of Oseltamivir-Resistant 2009 Pandemic Influenza A (H1N1) Virus Infections on a Hospital Ward among Immunocompromised Patients--North Carolina, 2009. Journal of Infectious Diseases 203:6, 838-846
CrossRef24
Avinash K. Shetty, Gregory A. Ross, Thomas Pranikoff, Larissa V. Gubareva, Catherine Sechrist, Derek M. Guirand, Jon Abramson, Jen-Jar Lin. (2011) Oseltamivir-resistant 2009 H1N1 influenza pneumonia during therapy in a renal transplant recipient. Pediatric Transplantationno-no
CrossRef25
D. W. Brookes, S. Miah, A. Lackenby, L. Hartgroves, W. S. Barclay. (2011) Pandemic H1N1 2009 influenza virus with the H275Y oseltamivir resistance neuraminidase mutation shows a small compromise in enzyme activity and viral fitness. Journal of Antimicrobial Chemotherapy 66:3, 466-470
CrossRef26
M. J. Memoli, A. S. Davis, K. Proudfoot, D. S. Chertow, R. J. Hrabal, T. Bristol, J. K. Taubenberger. (2011) MultiDrug-Resistant 2009 Pandemic Influenza A(H1N1) Viruses Maintain Fitness and Transmissibility in Ferrets. Journal of Infectious Diseases 203:3, 348-357
CrossRef27
E. Ghedin, J. Laplante, J. DePasse, D. E. Wentworth, R. P. Santos, M. L. Lepow, J. Porter, K. Stellrecht, X. Lin, D. Operario, S. Griesemer, A. Fitch, R. A. Halpin, T. B. Stockwell, D. J. Spiro, E. C. Holmes, K. S. George. (2011) Deep Sequencing Reveals Mixed Infection with 2009 Pandemic Influenza A (H1N1) Virus Strains and the Emergence of Oseltamivir Resistance. Journal of Infectious Diseases 203:2, 168-174
CrossRef28
Carrye Cost, Evangeline Brock, Beverley Adams-Huet, Jane D. Siegel, Monica I. Ardura. (2011) 2009 pandemic influenza a (H1N1) virus infection in pediatric oncology and hematopoietic stem cell transplantation patients. Pediatric Blood & Cancer 56:1, 127-133
CrossRef29
Kristian Thorlund, Tahany Awad, Guy Boivin, Lehana Thabane. (2011) Systematic review of influenza resistance to the neuraminidase inhibitors. BMC Infectious Diseases 11:1, 134
CrossRef30
A. Pizzorno, X. Bouhy, Y. Abed, G. Boivin. (2011) Generation and Characterization of Recombinant Pandemic Influenza A(H1N1) Viruses Resistant to Neuraminidase Inhibitors. Journal of Infectious Diseases 203:1, 25-31
CrossRef31
Chuan-jian Lu, Yi Luo, Hong Zhou, Xiao-lan Qin, Bo-jun Chen, Xue-chun Tang, Hua Deng, Zhao-hui Liang, Ai-hua Ou. (2010) A preliminary study on the medical expenditure of Chinese medicine and integrative medicine treatment for influenza a (H1N1) in the fever clinics. Chinese Journal of Integrative Medicine 16:6, 493-497
CrossRef32
Ji-Rong Yang, Yuan-Pin Huang, Yu-Cheng Lin, Chun-Hui Su, Chuan-Yi Kuo, Li-Ching Hsu, Ho-Sheng Wu, Ming-Tsan Liu. (2010) Early findings of oseltamivir-resistant pandemic (H1N1) 2009 influenza A viruses in Taiwan. Antiviral Research 88:3, 256-262
CrossRef33
Hayato Ishikawa, Takaki Suzuki, Hideo Orita, Tadafumi Uchimaru, Yujiro Hayashi. (2010) High-Yielding Synthesis of the Anti-Influenza Neuraminidase Inhibitor (−)-Oseltamivir by Two “One-Pot” Sequences. Chemistry - A European Journal 16:42, 12616-12626
CrossRef34
Gil Redelman-Sidi. (2010) Influenza in patients with hematologic disease: an ounce of prevention is worth a pound of cure. Leukemia & Lymphoma 51:11, 1954-1956
CrossRef35
Nicolas Widmer, Pascal Meylan, Anton Ivanyuk, Manel Aouri, Laurent A. Decosterd, Thierry Buclin. (2010) Oseltamivir in Seasonal, Avian H5N1 and Pandemic 2009 A/H1N1 Influenza. Clinical Pharmacokinetics 49:11, 741-765
CrossRef36
N. Komiya, Y. Gu, H. Kamiya, Y. Yahata, Y. Yasui, K. Taniguchi, N. Okabe. (2010) Household transmission of pandemic 2009 influenza A (H1N1) virus in Osaka, Japan in May 2009. Journal of Infection 61:4, 284-288
CrossRef37
C. Renaud, J. Kuypers, L. Corey. (2010) Diagnostic accuracy of an allele-specific reverse transcriptase-PCR assay targeting the H275Y oseltamivir resistant mutation in 2009 pandemic influenza A/H1N1 virus. Journal of Clinical Virology 49:1, 21-25
CrossRef38
Helena C. Maltezou. (2010) Novel (pandemic) influenza A H1N1 in healthcare facilities: Implications for prevention and control. Scandinavian Journal of Infectious Diseases 42:6-7, 412-420
CrossRef39
Marc P. Girard, John S. Tam, Olga M. Assossou, Marie Paule Kieny. (2010) The 2009 A (H1N1) influenza virus pandemic: A review. Vaccine 28:31, 4895-4902
CrossRef40
Brianne A. Couturier, Jeffrey M. Bender, Monica A. Schwarz, Andrew T. Pavia, Kimberly E. Hanson, Rosemary C. She. (2010) Oseltamivir-resistant influenza A 2009 H1N1 virus in immunocompromised patients. Influenza and Other Respiratory Viruses 4:4, 199-204
CrossRef41
Kelvin Kai-Wang To, Iris Wai-Sum Li, Ivan Fan-Ngai Hung, Vincent Chi-Chung Cheng, Kwok-Yung Yuen. (2010) Pathogenesis of pandemic H1N1 2009 influenza virus infection and the implication on management. Frontiers of Medicine in China 4:2, 147-156
CrossRef42
Susanna Esposito, Claudio G. Molteni, Carla Colombo, Cristina Daleno, Valeria Daccò, Angie Lackenby, Nicola Principi. (2010) Oseltamivir-induced resistant pandemic A/H1N1 influenza virus in a child with cystic fibrosis and Pseudomonas aeruginosa infection. Journal of Clinical Virology 48:1, 62-65
CrossRef43
Guillermo Domínguez-Cherit, Silvio A. Ñamendys-Silva, Alethse Torre, Alejandro E. Macias, Jose Angel Cordova-Villalobos. (2010) H1N1 Influenza Pandemic of 2009 Compared With Other Influenza Pandemics: Epidemiology, Diagnosis, Management, Pulmonary Complications, and Outcomes. Current Infectious Disease Reports 12:3, 204-210
CrossRef44
Arturo Huerta García, Nuria González Sánchez, Antoni Torres Martí. (2010) Influenza A (H1N1): manifestaciones clínicas e indicaciones profilácticas y terapéuticas. Archivos de Bronconeumología 46, 19-23
CrossRef45
F. Eun-Hyung Lee, John Treanor. 2010. Viral Infections. , 661-698.
CrossRef46
Yo Han Lee, Hyo Youl Kim, Hyun Soo Kim, Young Uh, Young Keun Kim, Bo Ra Kim, Ho Yeon Jung, Woo Taek Kim, Hwajung Yi. (2009) A Case of Oseltamivir-Resistant Pandemic Influenza (H1N1 2009) in a Patient with Acute Myeloid Leukemia. Infection and Chemotherapy 42:2, 107
CrossRef47
Young Kyung Yoon, Jeong Yeon Kim, Byung Chul Chun, Woo Joo Kim, Hee Jin Cheong, Dae Won Park, Min Ja Kim, Jang Wook Sohn. (2009) Effective Containment of Pandemic Influenza (H1N1 2009) Virus Outbreak in an International Residence Hall of a University by Recommended Infection Control Guidance. Infection and Chemotherapy 42:2, 99
CrossRef
