Influenza Drug Resistance

ABSTRACT

Influenza viruses are major human pathogens with a global distribution, accounting for more than 500,000 annual deaths worldwide and with considerable impact on the quality of life and productivity of the society. Due to the limited efficacy of vaccination, antiviral drugs constitute a complementary approach in the control and prevention of influenza infections and thus play an important role in the management of influenza outbreaks and pandemics. Currently, adamantanes and neuraminidase inhibitors (NAIs) are the only two classes of anti-influenza agents approved for clinical use. However, the worldwide emergence and high prevalence of adamantane-resistant virus variants has discouraged the use of the former drugs. NAIs have proved to be very effective against influenza A and B viruses. Nevertheless, oseltamivir-resistant strains have also been reported quite frequently, as in the case of seasonal H1N1 viruses that circulated between 2007 and 2009. Indeed, the emergence of drug-resistant virus variants is always a matter of concern because it could significantly compromise the usefulness of such intervention. This highlights the need for continuous monitoring of resistance markers, as well as the development of new anti-influenza drugs and combination therapies.

KEYWORDS

Influenza - antivirals - resistance - adamantanes - neuraminidase inhibitors - oseltamivir - zanamivir - peramivir

REFERENCES

• 1 Hayden F, Palese P. Influenza virus. In: Richman D D, Whiley R J, Hayden F G, eds. Clinical Virology. 2nd ed. Washington, DC: ASM Press; 2002: 891-920
• 2 Claas E C, de Jong J C, van Beek R, Rimmelzwaan G F, Osterhaus A D. Human influenza virus A/HongKong/156/97 (H5N1) infection.  Vaccine. 1998;  16 (9–10) 977-978
• 3 Claas E C, Osterhaus A D, van Beek R al.. Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus.  Lancet. 1998;  351 (9101) 472-477
• 4 Yuen K Y, Chan P K, Peiris M et al.. Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus.  Lancet. 1998;  351 (9101) 467-471
• 5 Koopmans M, Wilbrink B, Conyn M et al.. Transmission of H7N7 avian influenza A virus to human beings during a large outbreak in commercial poultry farms in the Netherlands.  Lancet. 2004;  363 (9409) 587-593
• 6 Peiris M, Yuen K Y, Leung C W et al.. Human infection with influenza H9N2.  Lancet. 1999;  354 (9182) 916-917
• 7 Uyeki T M, Chong Y H, Katz J M et al.. Lack of evidence for human-to-human transmission of avian influenza A (H9N2) viruses in Hong Kong, China 1999.  Emerg Infect Dis. 2002;  8 (2) 154-159
• 8 Neuzil K M, Zhu Y, Griffin M R et al.. Burden of interpandemic influenza in children younger than 5 years: a 25-year prospective study.  J Infect Dis. 2002;  185 (2) 147-152
• 9 Centers for Disease Control and Prevention (CDC) . Estimates of deaths associated with seasonal influenza—United States, 1976–2007.  MMWR Morb Mortal Wkly Rep. 2010;  59 (33) 1057-1062
• 10 World Healh Organization (WHO) .Influenza fact sheet No. 211. April 2009. http://www.who.int/mediacentre/factsheets/fs211/en/index.html Accessed February 2011
• 11 Harper S A, Bradley J S, Englund J A Expert Panel of the Infectious Diseases Society of America et al. Seasonal influenza in adults and children—diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America.  Clin Infect Dis. 2009;  48 (8) 1003-1032
• 12 Monto A S, Ohmit S E, Hornbuckle K, Pearce C L. Safety and efficacy of long-term use of rimantadine for prophylaxis of type A influenza in nursing homes.  Antimicrob Agents Chemother. 1995;  39 (10) 2224-2228
• 13 Martin K, Helenius A. Nuclear transport of influenza virus ribonucleoproteins: the viral matrix protein (M1) promotes export and inhibits import.  Cell. 1991;  67 (1) 117-130
• 14 Hay A J, Wolstenholme A J, Skehel J J, Smith M H. The molecular basis of the specific anti-influenza action of amantadine.  EMBO J. 1985;  4 (11) 3021-3024
• 15 Pielak R M, Chou J J. Flu channel drug resistance: a tale of two sites.  Protein Cell. 2010;  1 (3) 246-258
• 16 Couch R B. Prevention and treatment of influenza.  N Engl J Med. 2000;  343 (24) 1778-1787
• 17 Kawai N, Ikematsu H, Iwaki N et al.. Factors influencing the effectiveness of oseltamivir and amantadine for the treatment of influenza: a multicenter study from Japan of the 2002-2003 influenza season.  Clin Infect Dis. 2005;  40 (9) 1309-1316
• 18 Keyser L A, Karl M, Nafziger A N, Bertino Jr J S. Comparison of central nervous system adverse effects of amantadine and rimantadine used as sequential prophylaxis of influenza A in elderly nursing home patients.  Arch Intern Med. 2000;  160 (10) 1485-1488
• 19 Lynch III J P, Walsh E E. Influenza: evolving strategies in treatment and prevention.  Semin Respir Crit Care Med. 2007;  28 (2) 144-158
• 20 Klimov A I, Rocha E, Hayden F G, Shult P A, Roumillat L F, Cox N J. Prolonged shedding of amantadine-resistant influenzae A viruses by immunodeficient patients: detection by polymerase chain reaction-restriction analysis.  J Infect Dis. 1995;  172 (5) 1352-1355
• 21 Masuda H, Suzuki H, Oshitani H et al.. Incidence of amantadine-resistant influenza A viruses in sentinel surveillance sites and nursing homes in Niigata, Japan.  Microbiol Immunol. 2000;  44 (10) 833-839
• 22 Boivin G, Goyette N, Bernatchez H. Prolonged excretion of amantadine-resistant influenza a virus quasi species after cessation of antiviral therapy in an immunocompromised patient.  Clin Infect Dis. 2002;  34 (5) E23-E25
• 23 Saito R, Sakai T, Sato I et al.. Frequency of amantadine-resistant influenza A viruses during two seasons featuring cocirculation of H1N1 and H3N2.  J Clin Microbiol. 2003;  41 (5) 2164-2165
• 24 Shiraishi K, Mitamura K, Sakai-Tagawa Y, Goto H, Sugaya N, Kawaoka Y. High frequency of resistant viruses harboring different mutations in amantadine-treated children with influenza.  J Infect Dis. 2003;  188 (1) 57-61
• 25 Centers for Disease Control and Prevention (CDC) . Update: drug susceptibility of swine-origin influenza A (H1N1) viruses, April 2009.  MMWR Morb Mortal Wkly Rep. 2009;  58 (16) 433-435
• 26 Ziegler T, Hemphill M L, Ziegler M L et al.. Low incidence of rimantadine resistance in field isolates of influenza A viruses.  J Infect Dis. 1999;  180 (4) 935-939
• 27 Bright R A, Medina M J, Xu X et al.. Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern.  Lancet. 2005;  366 (9492) 1175-1181
• 28 Deyde V M, Xu X, Bright R A et al.. Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide.  J Infect Dis. 2007;  196 (2) 249-257
• 29 Cheung C L, Rayner J M, Smith G J et al.. Distribution of amantadine-resistant H5N1 avian influenza variants in Asia.  J Infect Dis. 2006;  193 (12) 1626-1629
• 30 Sweet C, Hayden F G, Jakeman K J, Grambas S, Hay A J. Virulence of rimantadine-resistant human influenza A (H3N2) viruses in ferrets.  J Infect Dis. 1991;  164 (5) 969-972
• 31 Abed Y, Goyette N, Boivin G. Generation and characterization of recombinant influenza A (H1N1) viruses harboring amantadine resistance mutations.  Antimicrob Agents Chemother. 2005;  49 (2) 556-559
• 32 Hayden F G, Belshe R B, Clover R D, Hay A J, Oakes M G, Soo W. Emergence and apparent transmission of rimantadine-resistant influenza A virus in families.  N Engl J Med. 1989;  321 (25) 1696-1702
• 33 World Health Organization (WHO) .WHO guidelines for pharmacological management of pandemic influenza A (H1N1) 2009 and other influenza viruses. February 2010. http://www.who.int/csr/resources/publications/swineflu/h1n1_guidelines_pharmaceutical_mngt.pdf Accessed March 2011
• 34 Griffin J A, Basak S, Compans R W. Effects of hexose starvation and the role of sialic acid in influenza virus release.  Virology. 1983;  125 (2) 324-334
• 35 Liu C, Eichelberger M C, Compans R W, Air G M. Influenza type A virus neuraminidase does not play a role in viral entry, replication, assembly, or budding.  J Virol. 1995;  69 (2) 1099-1106
• 36 Matrosovich M N, Matrosovich T Y, Gray T, Roberts N A, Klenk H D. Neuraminidase is important for the initiation of influenza virus infection in human airway epithelium.  J Virol. 2004;  78 (22) 12665-12667
• 37 Colman P M, Varghese J N, Laver W G. Structure of the catalytic and antigenic sites in influenza virus neuraminidase.  Nature. 1983;  303 (5912) 41-44
• 38 Baker A T, Varghese J N, Laver W G, Air G M, Colman P M. Three-dimensional structure of neuraminidase of subtype N9 from an avian influenza virus.  Proteins. 1987;  2 (2) 111-117
• 39 Burmeister W P, Ruigrok R W, Cusack S. The 2.2 A resolution crystal structure of influenza B neuraminidase and its complex with sialic acid.  EMBO J. 1992;  11 (1) 49-56
• 40 Mendel D B, Roberts N A. In-vitro and in-vivo efficacy of influenza neuraminidase inhibitors.  Curr Opin Infect Dis. 1998;  11 (6) 727-732
• 41 Sidwell R W, Smee D F. Peramivir (BCX-1812, RWJ-270201): potential new therapy for influenza.  Expert Opin Investig Drugs. 2002;  11 (6) 859-869
• 42 Ferraris O, Kessler N, Lina B. Sensitivity of influenza viruses to zanamivir and oseltamivir: a study performed on viruses circulating in France prior to the introduction of neuraminidase inhibitors in clinical practice.  Antiviral Res. 2005;  68 (1) 43-48
• 43 Boivin G, Goyette N. Susceptibility of recent Canadian influenza A and B virus isolates to different neuraminidase inhibitors.  Antiviral Res. 2002;  54 (3) 143-147
• 44 Naughtin M, Dyason J C, 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 (5) 2004-2010
• 45 Sheu T G, Deyde V M, Okomo-Adhiambo M et al.. Surveillance for neuraminidase inhibitor resistance among human influenza A and B viruses circulating worldwide from 2004 to 2008.  Antimicrob Agents Chemother. 2008;  52 (9) 3284-3292
• 46 U.S. Food and Drug Administration (FDA) .Relenza prescribing information. January 2008. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm183783.htm Accessed April 2011
• 47 U.S. Food and Drug Administration (FDA) .Tamiflu prescribing information. January 2008. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm095044.htm Accessed April 2011
• 48 Barroso L, Treanor J, Gubareva L, Hayden F G. Efficacy and tolerability of the oral neuraminidase inhibitor peramivir in experimental human influenza: randomized, controlled trials for prophylaxis and treatment.  Antivir Ther. 2005;  10 (8) 901-910
• 49 Birnkrant D, Cox E. The emergency use authorization of peramivir for treatment of 2009 H1N1 influenza.  N Engl J Med. 2009;  361 (23) 2204-2207
• 50 BioCryst Pharmaceuticals, Inc .BioCryst's partner Shionogi receives marketing and manufacturing approval for peramivir in Japan. January 13, 2010. http://investor.shareholder.com/biocryst/releasedetail.cfm?ReleaseID=437335 Accessed February 2011
• 51 Abed Y, Bourgault A M, Fenton R J et al.. Characterization of 2 influenza A(H3N2) clinical isolates with reduced susceptibility to neuraminidase inhibitors due to mutations in the hemagglutinin gene.  J Infect Dis. 2002;  186 (8) 1074-1080
• 52 McKimm-Breschkin J L. Resistance of influenza viruses to neuraminidase inhibitors—a review.  Antiviral Res. 2000;  47 (1) 1-17
• 53 Russell R J, Haire L F, Stevens D J et al.. The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design.  Nature. 2006;  443 (7107) 45-49
• 54 Kiso M, Mitamura K, Sakai-Tagawa Y et al.. Resistant influenza A viruses in children treated with oseltamivir: descriptive study.  Lancet. 2004;  364 (9436) 759-765
• 55 Ives J A, Carr J A, Mendel D B et al.. The H274Y mutation in the influenza A/H1N1 neuraminidase active site following oseltamivir phosphate treatment leave virus severely compromised both in vitro and in vivo.  Antiviral Res. 2002;  55 (2) 307-317
• 56 Tai C Y, Escarpe P A, Sidwell R W et al.. Characterization of human influenza virus variants selected in vitro in the presence of the neuraminidase inhibitor GS 4071.  Antimicrob Agents Chemother. 1998;  42 (12) 3234-3241
• 57 Baz M, Abed Y, Boivin G. Characterization of drug-resistant recombinant influenza A/H1N1 viruses selected in vitro with peramivir and zanamivir.  Antiviral Res. 2007;  74 (2) 159-162
• 58 Taylor N R, von Itzstein M. Molecular modeling studies on ligand binding to sialidase from influenza virus and the mechanism of catalysis.  J Med Chem. 1994;  37 (5) 616-624
• 59 Moscona A. Oseltamivir resistance—disabling our influenza defenses.  N Engl J Med. 2005;  353 (25) 2633-2636
• 60 Barnett J M, Cadman A, Burrell F M et al.. In vitro selection and characterisation of influenza B/Beijing/1/87 isolates with altered susceptibility to zanamivir.  Virology. 1999;  265 (2) 286-295
• 61 Baum E Z, Wagaman P C, Ly L et al.. A point mutation in influenza B neuraminidase confers resistance to peramivir and loss of slow binding.  Antiviral Res. 2003;  59 (1) 13-22
• 62 Weinstock D M, Gubareva L V, Zuccotti G. Prolonged shedding of multidrug-resistant influenza A virus in an immunocompromised patient.  N Engl J Med. 2003;  348 (9) 867-868
• 63 Le Q M, Kiso M, Someya K et al.. Avian flu: isolation of drug-resistant H5N1 virus.  Nature. 2005;  437 (7062) 1108
• 64 de Jong M D, Tran T T, Truong H K et al.. Oseltamivir resistance during treatment of influenza A (H5N1) infection.  N Engl J Med. 2005;  353 (25) 2667-2672
• 65 World Health Organization (WHO) . Update on oseltamivir-resistant pandemic A (H1N1) 2009 influenza virus: January 2010.  Wkly Epidemiol Rec. 2009;  85 (6) 37-40
• 66 Ison M G, Gubareva L V, Atmar R L, Treanor J, Hayden F G. Recovery of drug-resistant influenza virus from immunocompromised patients: a case series.  J Infect Dis. 2006;  193 (6) 760-764
• 67 Baz M, Abed Y, McDonald J, Boivin G. Characterization of multidrug-resistant influenza A/H3N2 viruses shed during 1 year by an immunocompromised child.  Clin Infect Dis. 2006;  43 (12) 1555-1561
• 68 Whitley R J, Hayden F G, Reisinger K S et al.. Oral oseltamivir treatment of influenza in children.  Pediatr Infect Dis J. 2001;  20 (2) 127-133
• 69 Carr S, Ilyushina N A, Franks J et al.. Oseltamivir-resistant influenza A and B viruses pre- and postantiviral therapy in children and young adults with cancer.  Pediatr Infect Dis J. 2011;  30 (4) 284-288
• 70 Hurt A C, Holien J K, Parker M, Kelso A, Barr I G. Zanamivir-resistant influenza viruses with a novel neuraminidase mutation.  J Virol. 2009;  83 (20) 10366-10373
• 71 Dapat C, Suzuki Y, Saito R et al.. Rare influenza A (H3N2) variants with reduced sensitivity to antiviral drugs.  Emerg Infect Dis. 2010;  16 (3) 493-496
• 72 Gubareva L V. Molecular mechanisms of influenza virus resistance to neuraminidase inhibitors.  Virus Res. 2004;  103 (1–2) 199-203
• 73 Gubareva L V, Matrosovich M N, Brenner M K, Bethell R C, Webster R G. Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus.  J Infect Dis. 1998;  178 (5) 1257-1262
• 74 Oakley A J, Barrett S, Peat T S et al.. Structural and functional basis of resistance to neuraminidase inhibitors of influenza B viruses.  J Med Chem. 2010;  53 (17) 6421-6431
• 75 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 (4) 577-581
• 76 Abed Y, Baz M, Boivin G. Impact of neuraminidase mutations conferring influenza resistance to neuraminidase inhibitors in the N1 and N2 genetic backgrounds.  Antivir Ther. 2006;  11 (8) 971-976
• 77 Pizzorno A, Bouhy X, Abed Y, Boivin G. Generation and characterization of recombinant pandemic influenza A(H1N1) viruses resistant to neuraminidase inhibitors.  J Infect Dis. 2011;  203 (1) 25-31
• 78 Yen H L, Hoffmann E, Taylor G et al.. Importance of neuraminidase active-site residues to the neuraminidase inhibitor resistance of influenza viruses.  J Virol. 2006;  80 (17) 8787-8795
• 79 Jackson D, Barclay W, Zürcher T. Characterization of recombinant influenza B viruses with key neuraminidase inhibitor resistance mutations.  J Antimicrob Chemother. 2005;  55 (2) 162-169
• 80 McKimm-Breschkin J, Trivedi T, Hampson A et al.. Neuraminidase sequence analysis and susceptibilities of influenza virus clinical isolates to zanamivir and oseltamivir.  Antimicrob Agents Chemother. 2003;  47 (7) 2264-2272
• 81 Roberts N A. Treatment of influenza with neuraminidase inhibitors: virological implications.  Philos Trans R Soc Lond B Biol Sci. 2001;  356 (1416) 1895-1897
• 82 Mungall B A, Xu X, Klimov A. Surveillance of influenza isolates for susceptibility to neuraminidase inhibitors during the 2000–2002 influenza seasons.  Virus Res. 2004;  103 (1-2) 195-197
• 83 Monto A S, McKimm-Breschkin J L, Macken C et al.. Detection of influenza viruses resistant to neuraminidase inhibitors in global surveillance during the first 3 years of their use.  Antimicrob Agents Chemother. 2006;  50 (7) 2395-2402
• 84 Ward P, Small I, Smith J, Suter P, Dutkowski R. Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic.  J Antimicrob Chemother. 2005;  55 (Suppl 1) i5-i21
• 85 Hauge S H, Dudman S, Borgen K, Lackenby A, Hungnes O. Oseltamivir-resistant influenza viruses A (H1N1), Norway, 2007–08.  Emerg Infect Dis. 2009;  15 (2) 155-162
• 86 Meijer A, Lackenby A, Hungnes O European Influenza Surveillance Scheme et al. Oseltamivir-resistant influenza virus A (H1N1), Europe, 2007-08 season.  Emerg Infect Dis. 2009;  15 (4) 552-560
• 87 Kramarz P, Monnet D, Nicoll A, Yilmaz C, Ciancio B. Use of oseltamivir in 12 European countries between 2002 and 2007—lack of association with the appearance of oseltamivir-resistant influenza A(H1N1) viruses.  Euro Surveill. 2009;  14 ((5). pii) 19112
• 88 Dharan N J, Gubareva L V, Meyer J J Oseltamivir-Resistance Working Group et al. Infections with oseltamivir-resistant influenza A(H1N1) virus in the United States.  JAMA. 2009;  301 (10) 1034-1041
• 89 Centers for Disease Control and Prevention (CDC) . Update: influenza activity—United States, September 28, 2008–April 4, 2009, and composition of the 2009-10 influenza vaccine.  MMWR Morb Mortal Wkly Rep. 2009;  58 (14) 369-374
• 90 Nguyen H T, Sheu T G, Mishin V P, Klimov A I, Gubareva L V. Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.  Antimicrob Agents Chemother. 2010;  54 (9) 3671-3677
• 91 World Health Organization (WHO) .Weekly update on oseltamivir resistance in influenza A(H1N1) 2009 viruses. April 6, 2011. http://www.who.int/csr/disease/influenza/2011_04_08_weekly_web_update_oseltamivir_resistance.pdf Accessed April 2011
• 92 Centers for Disease Control and Prevention (CDC) . Oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infection in two summer campers receiving prophylaxis—North Carolina, 2009.  MMWR Morb Mortal Wkly Rep. 2009;  58 (35) 969-972
• 93 Nguyen H T, Fry A M, Loveless P A, Klimov A I, Gubareva L V. 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 (8) 983-984
• 94 Lackenby A, Moran Gilad J, Pebody R et al.. Continued emergence and changing epidemiology of oseltamivir-resistant influenza A(H1N1)2009 virus, United Kingdom, winter 2010/11.  Euro Surveill. 2011;  16 (5) 16
• 95 Herlocher M L, Truscon R, Elias S et al.. Influenza viruses resistant to the antiviral drug oseltamivir: transmission studies in ferrets.  J Infect Dis. 2004;  190 (9) 1627-1630
• 96 Baz M, Abed Y, Simon P, Hamelin M E, Boivin G. Effect of the neuraminidase mutation H274Y conferring resistance to oseltamivir on the replicative capacity and virulence of old and recent human influenza A(H1N1) viruses.  J Infect Dis. 2010;  201 (5) 740-745
• 97 Rameix-Welti M A, Enouf V, Cuvelier F, Jeannin P, van der Werf S. Enzymatic properties of the neuraminidase of seasonal H1N1 influenza viruses provide insights for the emergence of natural resistance to oseltamivir.  PLoS Pathog. 2008;  4 (7) e1000103
• 98 Ciancio B C, Meerhoff T J, Kramarz P et al.. Oseltamivir-resistant influenza A(H1N1) viruses detected in Europe during season 2007-8 had epidemiologic and clinical characteristics similar to co-circulating susceptible A(H1N1) viruses.  Euro Surveill. 2009;  14 (46) 14
• 99 Bloom J D, Gong L I, Baltimore D. Permissive secondary mutations enable the evolution of influenza oseltamivir resistance.  Science. 2010;  328 (5983) 1272-1275
• 100 Hamelin M E, Baz M, Abed Y et al.. Oseltamivir-resistant pandemic A/H1N1 virus is as virulent as its wild-type counterpart in mice and ferrets.  PLoS Pathog. 2010;  6 (7) e1001015
• 101 Hamelin M E, Baz M, Bouhy X et al.. Reduced airborne transmission of oseltamivir-resistant pandemic A/H1N1 virus in ferrets.  Antivir Ther. 2011;  In press
• 102 Gristina G, Nardi G, Orazi D et al.. Prone positioning and intravenous zanamivir may represent effective alternatives for patients with severe ARDS virus A (H1N1) related pneumonia in hospitals with no access to ECMO.  Crit Care Res Pract. 2010;  2010 146456
• 103 Härter G, Zimmermann O, Maier L et al.. Intravenous zanamivir for patients with pneumonitis due to pandemic (H1N1) 2009 influenza virus.  Clin Infect Dis. 2010;  50 (9) 1249-1251
• 104 Dohna-Schwake C, Schweiger B, Felderhoff-Müser U et al.. Severe H1N1 infection in a pediatric liver transplant recipient treated with intravenous zanamivir: efficiency and complications.  Transplantation. 2010;  90 (2) 223-224
• 105 Busani S, Girardis M, Biagioni E, Pasetto A, Sambri V. Surfactant therapy and intravenous zanamivir in severe respiratory failure due to persistent influenza A/H1N1 2009 virus infection.  Am J Respir Crit Care Med. 2010;  182 (10) 1334
• 106 Brown A N, McSharry J J, Weng Q, Adams J R, Kulawy R, Drusano G L. Zanamivir, at 600 milligrams twice daily, inhibits oseltamivir-resistant 2009 pandemic H1N1 influenza virus in an in vitro hollow-fiber infection model system.  Antimicrob Agents Chemother. 2011;  55 (4) 1740-1746
• 107 GlaxoSmithKline .GlaxoSmithKline commences Phase III study of intravenous zanamivir for hospitalised patients with influenza. January 19, 2011. http://www.gsk.com/media/pressreleases/2011/2011_pressrelease_10015.htm Accessed April 2011
• 108 ClinicalTrials.gov .A study of intravenous zanamivir versus oral oseltamivir in adults and adolescents hospitalized with influenza. October 28, 2010. http://clinicaltrials.gov/ct2/show/NCT01231620?term=zanamivir+IV&rank=2 Accessed April 2011
• 109 Kubo S, Tomozawa T, Kakuta M, Tokumitsu A, Yamashita M. Laninamivir prodrug CS-8958, a long-acting neuraminidase inhibitor, shows superior anti-influenza virus activity after a single administration.  Antimicrob Agents Chemother. 2010;  54 (3) 1256-1264
• 110 Koyama K, Takahashi M, Oitate M et al.. CS-8958, a prodrug of the novel neuraminidase inhibitor R-125489, demonstrates a favorable long-retention profile in the mouse respiratory tract.  Antimicrob Agents Chemother. 2009;  53 (11) 4845-4851
• 111 Yamashita M, Tomozawa T, Kakuta M, Tokumitsu A, Nasu H, Kubo S. CS-8958, a prodrug of the new neuraminidase inhibitor R-125489, shows long-acting anti-influenza virus activity.  Antimicrob Agents Chemother. 2009;  53 (1) 186-192
• 112 Kubo S, Kakuta M, Yamashita M. In vitro and in vivo effects of a long-acting anti-influenza agent CS-8958 (laninamivir octanoate, Inavir) against pandemic (H1N1) 2009 influenza viruses [in Japanese].  Jpn J Antibiot. 2010;  63 (5) 337-346
• 113 Watanabe A, Chang S C, Kim M J, Chu D W, Ohashi Y. MARVEL Study Group . Long-acting neuraminidase inhibitor laninamivir octanoate versus oseltamivir for treatment of influenza: a double-blind, randomized, noninferiority clinical trial.  Clin Infect Dis. 2010;  51 (10) 1167-1175
• 114 Ishizuka H, Yoshiba S, Okabe H, Yoshihara K. Clinical pharmacokinetics of laninamivir, a novel long-acting neuraminidase inhibitor, after single and multiple inhaled doses of its prodrug, CS-8958, in healthy male volunteers.  J Clin Pharmacol. 2010;  50 (11) 1319-1329
• 115 Ishizuka H, Yoshiba S, Yoshihara K, Okabe H. Assessment of the effects of renal impairment on the pharmacokinetic profile of laninamivir, a novel neuraminidase inhibitor, after a single inhaled dose of its Prodrug, CS-8958.  J Clin Pharmacol. 2011;  51 (2) 243-251
• 116 Biota Holdings Ltd .LANI Phase III clinical trials in Asia prove successful. August 10, 2009. http://www.biota.com.au/uploaded/154/1021542_25laniphaseiiiclinicaltri.pdf Accessed February 2011
• 117 Biota Holdings Ltd .Phase III trial with CS-8958 for flu prevention underway. November 5, 2009. http://www.biota.com.au/uploaded/154/1021585_54cs8958phaseiiipreventio.pdf Accessed February 2011
• 118 Biota Holdings Ltd .Inavir^® approved for sale in Japan. September 13, 2010. http://www.biota.com.au/uploaded/154/1021695_65inavirapprovedforsalein.pdf Accessed February 2011
• 119 Hanessian S, Bayrakdarian M, Luo X. Total synthesis of A-315675: a potent inhibitor of influenza neuraminidase.  J Am Chem Soc. 2002;  124 (17) 4716-4721
• 120 Baz M, Abed Y, Nehmé B, Boivin G. Activity of the oral neuraminidase inhibitor A-322278 against the oseltamivir-resistant H274Y (A/H1N1) influenza virus mutant in mice.  Antimicrob Agents Chemother. 2009;  53 (2) 791-793
• 121 Rungrotmongkol T, Udommaneethanakit T, Frecer V, Miertus S. Combinatorial design of avian influenza neuraminidase inhibitors containing pyrrolidine core with a reduced susceptibility to viral drug resistance.  Comb Chem High Throughput Screen. 2010;  13 (3) 268-277
• 122 Balfour Jr H H. Antiviral drugs.  N Engl J Med. 1999;  340 (16) 1255-1268
• 123 Brooks M J, Sasadeusz J J, Tannock G A. Antiviral chemotherapeutic agents against respiratory viruses: where are we now and what's in the pipeline?.  Curr Opin Pulm Med. 2004;  10 (3) 197-203
• 124 Sidwell R W, Bailey K W, Wong M H, Barnard D L, Smee D F. In vitro and in vivo influenza virus-inhibitory effects of viramidine.  Antiviral Res. 2005;  68 (1) 10-17
• 125 Kiso M, Takahashi K, Sakai-Tagawa Y et al.. T-705 (favipiravir) activity against lethal H5N1 influenza A viruses.  Proc Natl Acad Sci U S A. 2010;  107 (2) 882-887
• 126 Furuta Y, Takahashi K, Fukuda Y et al.. In vitro and in vivo activities of anti-influenza virus compound T-705.  Antimicrob Agents Chemother. 2002;  46 (4) 977-981
• 127 Furuta Y, Takahashi K, Kuno-Maekawa M et al.. Mechanism of action of T-705 against influenza virus.  Antimicrob Agents Chemother. 2005;  49 (3) 981-986
• 128 Sleeman K, Mishin V P, Deyde V M, Furuta Y, Klimov A I, Gubareva L V. In vitro antiviral activity of favipiravir (T-705) against drug-resistant influenza and 2009 A(H1N1) viruses.  Antimicrob Agents Chemother. 2010;  54 (6) 2517-2524
• 129 Toyama Chemical Co., Ltd .Toyama Chemical Co., Ltd. initiates phase 2 clinical trial in the US of its anti-influenza drug candidate T-705. February 15, 2010. http://www.toyama-chemical.co.jp/eng/news/news100215e.html Accessed March 2011
• 130 Belser J A, Lu X, Szretter K J et al.. DAS181, a novel sialidase fusion protein, protects mice from lethal avian influenza H5N1 virus infection.  J Infect Dis. 2007;  196 (10) 1493-1499
• 131 Triana-Baltzer G B, Gubareva L V, Nicholls J M et al.. Novel pandemic influenza A(H1N1) viruses are potently inhibited by DAS181, a sialidase fusion protein.  PLoS ONE. 2009;  4 (11) e7788
• 132 Hedlund M, Aschenbrenner L M, Jensen K, Larson J L, Fang F. Sialidase-based anti-influenza virus therapy protects against secondary pneumococcal infection.  J Infect Dis. 2010;  201 (7) 1007-1015
• 133 Triana-Baltzer G B, Sanders R L, Hedlund M et al.. Phenotypic and genotypic characterization of influenza virus mutants selected with the sialidase fusion protein DAS181.  J Antimicrob Chemother. 2011;  66 (1) 15-28
• 134 U.S. National Institutes of Health (NIH) .Randomized, double-blind, placebo controlled phase II study to examine the effects of DAS181 in healthy adult subjects with laboratory confirmed influenza. December 18, 2009. http://clinicaltrials.gov/ct2/show/NCT01037205?term=DAS181&rank=5 Accessed April 2011
• 135 Ilyushina N A, Hoffmann E, Salomon R, Webster R G, Govorkova E A. Amantadine-oseltamivir combination therapy for H5N1 influenza virus infection in mice.  Antivir Ther. 2007;  12 (3) 363-370
• 136 Masihi K N, Schweiger B, Finsterbusch T, Hengel H. Low dose oral combination chemoprophylaxis with oseltamivir and amantadine for influenza A virus infections in mice.  J Chemother. 2007;  19 (3) 295-303
• 137 Nguyen J T, Hoopes J D, Smee D F et al.. Triple combination of oseltamivir, amantadine, and ribavirin displays synergistic activity against multiple influenza virus strains in vitro.  Antimicrob Agents Chemother. 2009;  53 (10) 4115-4126
• 138 Nguyen J T, Hoopes J D, Le M H et al.. Triple combination of amantadine, ribavirin, and oseltamivir is highly active and synergistic against drug resistant influenza virus strains in vitro.  PLoS ONE. 2010;  5 (2) e9332
• 139 Smee D F, Hurst B L, Wong M H et al.. Effects of the combination of favipiravir (T-705) and oseltamivir on influenza A virus infections in mice.  Antimicrob Agents Chemother. 2010;  54 (1) 126-133
• 140 Duval X, van der Werf S, Blanchon T Bivir Study Group et al. Efficacy of oseltamivir-zanamivir combination compared to each monotherapy for seasonal influenza: a randomized placebo-controlled trial.  PLoS Med. 2010;  7 (11) e1000362
• 141 Petersen E, Keld D B, Ellermann-Eriksen S et al.. Failure of combination oral oseltamivir and inhaled zanamivir antiviral treatment in ventilator- and ECMO-treated critically ill patients with pandemic influenza A (H1N1)v.  Scand J Infect Dis. 2011 Feb 10. [Epub ahead of print]
• 142 Cheung C Y, Poon L L, Lau A S et al.. Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease?.  Lancet. 2002;  360 (9348) 1831-1837
• 143 Peiris J S, Yu W C, Leung C W et al.. Re-emergence of fatal human influenza A subtype H5N1 disease.  Lancet. 2004;  363 (9409) 617-619
• 144 Chan M C, Cheung C Y, Chui W H et al.. Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells.  Respir Res. 2005;  6 135
• 145 Kobasa D, Jones S M, Shinya K et al.. Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus.  Nature. 2007;  445 (7125) 319-323
• 146 Ottolini M, Blanco J, Porter D, Peterson L, Curtis S, Prince G. Combination anti-inflammatory and antiviral therapy of influenza in a cotton rat model.  Pediatr Pulmonol. 2003;  36 (4) 290-294
• 147 Zheng B J, Chan K W, Lin Y P et al.. Delayed antiviral plus immunomodulator treatment still reduces mortality in mice infected by high inoculum of influenza A/H5N1 virus.  Proc Natl Acad Sci U S A. 2008;  105 (23) 8091-8096
• 148 Budd A, Alleva L, Alsharifi M et al.. Increased survival after gemfibrozil treatment of severe mouse influenza.  Antimicrob Agents Chemother. 2007;  51 (8) 2965-2968
• 149 Henter J I, Palmkvist-Kaijser K, Holzgraefe B, Bryceson Y T, Palmér K. Cytotoxic therapy for severe swine flu A/H1N1.  Lancet. 2010;  376 (9758) 2116
• 150 Quispe-Laime A M, Bracco J D, Barberio P A et al.. H1N1 influenza A virus-associated acute lung injury: response to combination oseltamivir and prolonged corticosteroid treatment.  Intensive Care Med. 2010;  36 (1) 33-41
• 151 Confalonieri M, Cifaldi R, Dreas L, Viviani M, Biolo M, Gabrielli M. Methylprednisolone infusion for life-threatening H1N1-virus infection.  Ther Adv Respir Dis. 2010;  4 (4) 233-237
• 152 Kidd I M, Down J, Nastouli E et al.. H1N1 pneumonitis treated with intravenous zanamivir.  Lancet. 2009;  374 (9694) 1036
• 153 Mishin V P, Hayden F G, Gubareva L V. Susceptibilities of antiviral-resistant influenza viruses to novel neuraminidase inhibitors.  Antimicrob Agents Chemother. 2005;  49 (11) 4515-4520
• 154 Baz M, Abed Y, Papenburg J, Bouhy X, Hamelin M E, Boivin G. Emergence of oseltamivir-resistant pandemic H1N1 virus during prophylaxis.  N Engl J Med. 2009;  361 (23) 2296-2297
• 155 Hurt A C, Holien J K, Barr I G. In vitro generation of neuraminidase inhibitor resistance in A(H5N1) influenza viruses.  Antimicrob Agents Chemother. 2009;  53 (10) 4433-4440
• 156 Carr J, Ives J, Kelly L et al.. Influenza virus carrying neuraminidase with reduced sensitivity to oseltamivir carboxylate has altered properties in vitro and is compromised for infectivity and replicative ability in vivo.  Antiviral Res. 2002;  54 (2) 79-88
• 157 Gubareva L V, Robinson M J, Bethell R C, Webster R G. Catalytic and framework mutations in the neuraminidase active site of influenza viruses that are resistant to 4-guanidino-Neu5Ac2en.  J Virol. 1997;  71 (5) 3385-3390
• 158 Abed Y, Baz M, Boivin G. A novel neuraminidase deletion mutation conferring resistance to oseltamivir in clinical influenza A/H3N2 virus.  J Infect Dis. 2009;  199 (2) 180-183
• 159 Memoli M J, Hrabal R J, Hassantoufighi A, Eichelberger M C, Taubenberger J K. Rapid selection of oseltamivir- and peramivir-resistant pandemic H1N1 virus during therapy in 2 immunocompromised hosts.  Clin Infect Dis. 2010;  50 (9) 1252-1255
• 160 Okomo-Adhiambo M, Demmler-Harrison G J, Deyde V M et al.. Detection of E119V and E119I mutations in influenza A (H3N2) viruses isolated from an immunocompromised patient: challenges in diagnosis of oseltamivir resistance.  Antimicrob Agents Chemother. 2010;  54 (5) 1834-1841