Antiviral Susceptibility of Highly Pathogenic Avian Influenza A(H5N1) Viruses Isolated from Poultry, Vietnam, 2009–2011 - Vol. 19 No. 12 - December 2013 - Emerging Infectious Disease journal - CDC
|Author or Reviewer||Contact EID||Announcements|
Volume 19, Number 12—December 2013
Antiviral Susceptibility of Highly Pathogenic Avian Influenza A(H5N1) Viruses Isolated from Poultry, Vietnam, 2009–2011
AbstractWe assessed drug susceptibilities of 125 avian influenza A(H5N1) viruses isolated from poultry in Vietnam during 2009–2011. Of 25 clade 1.1 viruses, all possessed a marker of resistance to M2 blockers amantadine and rimantadine; 24 were inhibited by neuraminidase inhibitors. One clade 1.1 virus contained the R430W neuraminidase gene and reduced inhibition by oseltamivir, zanamivir, and laninamivir 12-, 73-, and 29-fold, respectively. Three of 30 clade 2.3.4 viruses contained a I223T mutation and showed 7-fold reduced inhibition by oseltamivir. One of 70 clade 22.214.171.124 viruses had the H275Y marker of oseltamivir resistance and exhibited highly reduced inhibition by oseltamivir and peramivir; antiviral agents DAS181 and favipiravir inhibited H275Y mutant virus replication in MDCK-SIAT1 cells. Replicative fitness of the H275Y mutant virus was comparable to that of wildtype virus. These findings highlight the role of drug susceptibility monitoring of H5N1 subtype viruses circulating among birds to inform antiviral stockpiling decisions for pandemic preparedness.
Genetic and antigenic divergence of HPAI (H5N1) viruses among poultry challenges development of effective vaccines for poultry and to pandemic preparedness and development of antiviral drugs for humans. Assessment of drug susceptibility has become an integral part of subtype H5N1 virus surveillance. To assist laboratories worldwide in their surveillance and pandemic preparedness efforts, the Influenza Division of the Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA, along with other partners, developed the H5N1 Genetic Changes Inventory that includes established and potential markers of drug resistance (5). Resistance to matrix 2 (M2) protein blockers amantadine and rimantadine, caused by mutations in the M2 protein, is detected commonly in clade 1.1 (S31N) and clade 2.1.3 (V27A) H5N1 virus subtypes and sporadically in other groups (6,7). Oseltamivir, an orally administered neuraminidase (NA) inhibitor, is the most prescribed medication for the treatment of persons with influenza virus infections. Emergence of resistance to NA inhibitors among H5N1 virus subtypes, especially oseltamivir resistance among H5N1 subtypes caused by the H275Y mutation, is a constant threat (8). Assessment of susceptibility to NA inhibitors is hampered by several factors: insufficient knowledge of molecular markers of resistance, lack of harmonized approaches for testing and data analysis and, most critically, lack of established laboratory correlates of clinically relevant resistance. Taking into account these and other limitations, the current method for monitoring susceptibility to NA inhibitors is a critical element needed to evaluate pandemic risk.
In this study, we assessed drug susceptibility profiles of HPAI A(H5N1) viruses isolated from poultry specimens collected in Vietnam during 2009–2011. The antiviral drugs tested included FDA-approved medications and investigational antiviral agents. We report the detection of an oseltamivir-resistant virus with H275Y mutation from the expanding clade 126.96.36.199.
Dr Ha T. Nguyen is a Battelle research scientist on the Molecular Epidemiology Team of the Influenza Division, Centers for Disease Control and Prevention, in Atlanta, Georgia. Her research interests include influenza viruses and mechanisms of resistance to antiviral agents.
We thank our collaborators in the National Center for Veterinary Diagnostics, Hanoi, Vietnam, for their valuable contributions to this study. We also thank Ronald B. Moss and Yousuke Furuta for kindly providing investigational anti-influenza drugs DAS181 and favipiravir, respectively, and Anton Chesnokov for his excellent technical assistance.
- Wan XF, Nguyen T, Davis CT, Smith CB, Zhao ZM, Carrel M, Evolution of highly pathogenic H5N1 avian influenza viruses in Vietnam between 2001 and 2007. PLoS ONE. 2008;3:e3462.
- Dung Nguyen T, Nguyen TV, Vijaykrishna D, Webster RG, Guan Y, Malik Peiris JS, Multiple sublineages of influenza A virus (H5N1), Vietnam, 2005–2007. Emerg Infect Dis. 2008;14:632–6.
- Nguyen T, Rivailler P, Davis CT. Hoa do T, Balish A, Dang NH, et al. Evolution of highly pathogenic avian influenza (H5N1) virus populations in Vietnam between 2007 and 2010. Virology. 2012;432:405–16.
- World Health Organization. Antigenic and genetic characteristics of zoonotic influenza viruses and development of candidate vaccine viruses for pandemic preparedness. Influenza, Vaccines, Vaccine Viruses. February 2013 [cited 2013Aug 6]. http://www.who.int/influenza/vaccines/virus/characteristics_virus_vaccines/en/
- Centers for Disease Control and Prevention. H5N1 Genetic changes inventory. [cited 2013 Aug 6]. http://www.cdc.gov/flu/avianflu/h5n1/inventory.htm
- Cheung CL, Rayner JM, Smith GJ, Wang P, Naipospos TS, Zhang J, Distribution of amantadine-resistant H5N1 avian influenza variants in Asia. J Infect Dis. 2006;193:1626–9.
- Hill AW, Guralnick RP, Wilson MJ, Habib F, Janies D. Evolution of drug resistance in multiple distinct lineages of H5N1 avian influenza. Infect Genet Evol. 2009;9:169–78.
- Moscona A. Oseltamivir resistance—disabling our influenza defenses. N Engl J Med. 2005;353:2633–6.
- World Health Organization Global Influenza Surveillance Network. Manual for the laboratory diagnosis and virological surveillance of influenza. 2011 [cited 2013 Aug 6]. http://whqlibdoc.who.int/publications/2011/9789241548090_eng.pdf
- World Health Organization/ World Organisation for Animal Health/ Food and Agriculture Organization (WHO/OIE/FAO) H5N1 Evolution Working Group. Continued evolution of highly pathogenic avian influenza A (H5N1): updated nomenclature. Influenza Other Respi Viruses. 2012;6:1–5 .
- Nguyen HT, Fry AM, Gubareva LV. Neuraminidase inhibitor resistance in influenza viruses and laboratory testing methods. Antivir Ther. 2012;17:159–73.
- Deyde VM, Nguyen T, Bright RA, Balish A, Shu B, Lindstrom S, Detection of molecular markers of antiviral resistance in influenza A (H5N1) viruses using a pyrosequencing method. Antimicrob Agents Chemother. 2009;53:1039–47.
- Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV. Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays. Antimicrob Agents Chemother. 2010;54:3671–7.
- Okomo-Adhiambo M, Sleeman K, Ballenger K, Nguyen HT, Mishin VP, Sheu TG, Neuraminidase inhibitor susceptibility testing in human influenza viruses: a laboratory surveillance perspective. Viruses. 2010;2:2269–89.
- Gubareva LV, Trujillo AA, Okomo-Adhiambo M, Mishin VP, Deyde VM, Sleeman K, Comprehensive assessment of 2009 pandemic influenza A (H1N1) virus drug susceptibility in vitro. Antivir Ther. 2010;15:1151–9.
- Triana-Baltzer GB, Gubareva LV, Klimov AI, Wurtman DF, Moss RB, Hedlund M, Inhibition of neuraminidase inhibitor-resistant influenza virus by DAS181, a novel sialidase fusion protein. PLoS ONE. 2009;4:e7838.
- Klimov A, Balish A, Veguilla V, Sun H, Schiffer J, Lu X, Influenza virus titration, antigenic characterization, and serological methods for antibody detection. Methods Mol Biol. 2012;865:25–51.
- Naughtin M, Dyason JC, Mardy S, Sorn S, von Itzstein M, Buchy P. Neuraminidase inhibitor sensitivity and receptor-binding specificity of Cambodian clade 1 highly pathogenic H5N1 influenza virus. Antimicrob Agents Chemother. 2011;55:2004–10.
- World Health Organization. Meetings of the WHO working group on surveillance of influenza antiviral susceptibility– Geneva, November 2011 and June 2012. Wkly Epidemiol Rec. 2012;87:369–74 .
- Yen HL, Ilyushina NA, Salomon R, Hoffmann E, Webster RG, Govorkova EA. Neuraminidase inhibitor-resistant recombinant A/Vietnam/1203/04 (H5N1) influenza viruses retain their replication efficiency and pathogenicity in vitro and in vivo. J Virol. 2007;81:12418–26.
- de Jong MD, Tran TT, Truong HK, Vo MH, Smith GJ, Nguyen VC, Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med. 2005;353:2667–72 .
- Le QM, Kiso M, Someya K, Sakai YT, Nguyen TH, Nguyen KH, Avian flu: isolation of drug-resistant H5N1 virus. Nature. 2005;437:1108.
- McKimm-Breschkin JL, Selleck PW, Usman TB, Johnson MA. Reduced sensitivity of influenza A (H5N1) to oseltamivir. Emerg Infect Dis. 2007;13:1354–7 .
- Stoner TD, Krauss S, DuBois M, Negovetich J, Stallknecht DE, Senne DA, Antiviral susceptibility of avian and swine influenza virus of the N1 neuraminidase subtype. J Virol. 2010;84:9800–9.
- Kiso M, Ozawa M, Le MT, Imai H, Takahashi K, Kakugawa S, Effect of an asparagine-to-serine mutation at position 294 in neuraminidase on the pathogenicity of highly pathogenic H5N1 influenza A virus. J Virol. 2011;85:4667–72.
- Collins PJ, Haire LF, Lin YP, Liu J, Russell RJ, Walker PA, Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants. Nature. 2008;453:1258–61.
- Ilyushina NA, Seiler JP, Rehg JE, Webster RG, Govorkova EA. Effect of neuraminidase inhibitor-resistant mutations on pathogenicity of clade 2.2 A/Turkey/15/06 (H5N1) influenza virus in ferrets. PLoS Pathog. 2010;6:e1000933.
- Earhart KC, Elsayed NM, Saad MD, Gubareva LV, Nayel A, Deyde VM, Oseltamivir resistance mutation N294S in human influenza A(H5N1) virus in Egypt. J Infect Public Health. 2009;2:74–80.
- Amaro RE, Swift RV, Votapka L, Li WW, Walker RC, Bush RM. Mechanism of 150-cavity formation in influenza neuraminidase. Nat Commun. 2011;2:388.
- Hurt AC, Holien JK, Barr IG. In vitro generation of neuraminidase inhibitor resistance in A(H5N1) influenza viruses. Antimicrob Agents Chemother. 2009;53:4433–40.
- Nguyen HT, Fry AM, Loveless PA, Klimov AI, Gubareva LV. Recovery of a multidrug-resistant strain of pandemic influenza A 2009 (H1N1) virus carrying a dual H275Y/I223R mutation from a child after prolonged treatment with oseltamivir. Clin Infect Dis. 2010;51:983–4.
- Le MT, Wertheim HF, Nguyen HD, Taylor W, Hoang PV, Vuong CD, Influenza A H5N1 clade 2.3.4 virus with a different antiviral susceptibility profile replaced clade 1 virus in humans in northern Vietnam. PLoS ONE. 2008;3:e3339.
- Chen H, Smith GJ, Li KS, Wang J, Fan XH, Rayner JM, Establishment of multiple sublineages of H5N1 influenza virus in Asia: implications for pandemic control. Proc Natl Acad Sci U S A. 2006;103:2845–50.
- Boltz DA, Douangngeun B, Phommachanh P, Sinthasak S, Mondry R, Obert C, Emergence of H5N1 avian influenza viruses with reduced sensitivity to neuraminidase inhibitors and novel reassortants in Lao People’s Democratic Republic. J Gen Virol. 2010;91:949–59.
- Wathen MW, Barro M, Bright RA. Antivirals in seasonal and pandemic influenza-future perspectives. Influenza Other Respitory Viruses. 2013;7:76–80.
- Chan-Tack KM, Gao A, Himaya AC, Thompson EG, Singer ME, Uyeki TM, Clinical experience with intravenous zanamivir under an emergency investigational new drug program in the United States. J Infect Dis. 2013;207:196–8.
- White NJ, Webster RG, Govorkova EA, Uyeki TM. What is the optimal therapy for patients with H5N1 influenza? PLoS Med. 2009;6:e1000091.
Suggested citation for this article: Nguyen HT, Nguyen T, Mishin VP, Sleeman K, Balish A, Jones J, et al. Antiviral susceptibility of highly pathogenic avian influenza A(H5N1) viruses isolated from poultry, Vietnam, 2009–2011. Emerg Infect Dis. 2013 Dec [date cited]. http://dx.doi.org/10.3201/eid1912.130705