Archives of Virology

, Volume 159, Issue 6, pp 1279–1291 | Cite as

In vitro activity of favipiravir and neuraminidase inhibitor combinations against oseltamivir-sensitive and oseltamivir-resistant pandemic influenza A (H1N1) virus

  • E. Bart Tarbet
  • Almut H. Vollmer
  • Brett L. Hurst
  • Dale L. Barnard
  • Yousuke Furuta
  • Donald F. Smee
Original Article

Abstract

Few anti-influenza drugs are licensed in the United States for the prevention and therapy of influenza A and B virus infections. This shortage, coupled with continuously emerging drug resistance, as detected through a global surveillance network, seriously limits our anti-influenza armamentarium. Combination therapy appears to offer several advantages over traditional monotherapy in not only delaying development of resistance but also potentially enhancing single antiviral activity. In the present study, we evaluated the antiviral drug susceptibilities of fourteen pandemic influenza A (H1N1) virus isolates in MDCK cells. In addition, we evaluated favipiravir (T-705), an investigational drug with a broad antiviral spectrum and a unique mode of action, alone and in dual combination with the neuraminidase inhibitors (NAIs) oseltamivir, peramivir, or zanamivir, against oseltamivir-sensitive pandemic influenza A/California/07/2009 (H1N1) and oseltamivir-resistant A/Hong Kong/2369/2009 (H1N1) virus. Mean inhibitory values showed that the tested virus isolates remained sensitive to commonly used antiviral drugs, with the exception of the Hong Kong virus isolate. Drug dose-response curves confirmed complete drug resistance to oseltamivir, partial sensitivity to peramivir, and retained susceptibility to zanamivir and favipiravir against the A/Hong Kong/2369/2009 virus. Three-dimensional analysis of drug interactions using the MacSynergyTM II program indicated an overall synergistic interaction when favipiravir was combined with the NAIs against the oseltamivir-sensitive influenza virus, and an additive effect against the oseltamivir-resistant virus. Although the clinical relevance of these drug combinations remains to be evaluated, results obtained from this study support the use of combination therapy with favipiravir and NAIs for treatment of human influenza virus infections.

References

  1. 1.
    Potter CW (2001) A history of influenza. J Appl Microbiol 91(4):572–579PubMedCrossRefGoogle Scholar
  2. 2.
    Molinari NA, Ortega-Sanchez IR, Messonnier ML, Thompson WW, Wortley PM, Weintraub E, Bridges CB (2007) The annual impact of seasonal influenza in the US: measuring disease burden and costs. Vaccine 25(27):5086–5096. doi:10.1016/j.vaccine.2007.03.046 PubMedCrossRefGoogle Scholar
  3. 3.
    Collin N, de Radigues X (2009) Vaccine production capacity for seasonal and pandemic (H1N1) 2009 influenza. Vaccine 27(38):5184–5186. doi:10.1016/j.vaccine.2009.06.034 PubMedCrossRefGoogle Scholar
  4. 4.
    Govorkova EA, McCullers JA (2012) Therapeutics against influenza. Current Topics in Microbiology and Immunology. Springer, Berlin. doi:10.1007/82_2011_198
  5. 5.
    Dolin R, Reichman RC, Madore HP, Maynard R, Linton PN, Webber-Jones J (1982) A controlled trial of amantadine and rimantadine in the prophylaxis of influenza A infection. New Engl J Med 307(10):580–584. doi:10.1056/NEJM198209023071002 PubMedCrossRefGoogle Scholar
  6. 6.
    Thorlund K, Awad T, Boivin G, Thabane L (2011) Systematic review of influenza resistance to the neuraminidase inhibitors. BMC Infect Dis 11:134. doi:10.1186/1471-2334-11-134 PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Centers for Disease Control and Prevention (2011) Antiviral agents for the treatment and chemoprophylaxis of influenza—recommendations of the advisory committee on immunization practices (ACIP). MMWR Recomm Rep 60(1):1–24Google Scholar
  8. 8.
    Palese P, Tobita K, Ueda M, Compans RW (1974) Characterization of temperature sensitive influenza virus mutants defective in neuraminidase. Virology 61(2):397–410PubMedCrossRefGoogle Scholar
  9. 9.
    Matrosovich MN, Matrosovich TY, Gray T, Roberts NA, Klenk HD (2004) Neuraminidase is important for the initiation of influenza virus infection in human airway epithelium. J Virol 78(22):12665–12667. doi:10.1128/JVI.78.22.12665-1 2667.2004PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    von Itzstein M (2007) The war against influenza: discovery and development of sialidase inhibitors. Nat Rev Drug Discov 6(12):967–974CrossRefGoogle Scholar
  11. 11.
    Hayden FG, Osterhaus AD, Treanor JJ, Fleming DM, Aoki FY, Nicholson KG, Bohnen AM, Hirst HM, Keene O, Wightman K (1997) Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza virus infections. GG167 Influenza Study Group. New Engl J Med 337(13):874–880. doi:10.1056/NEJM199709253371302 PubMedCrossRefGoogle Scholar
  12. 12.
    Hayden FG, Treanor JJ, Fritz RS, Lobo M, Betts RF, Miller M, Kinnersley N, Mills RG, Ward P, Straus SE (1999) Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment. JAMA 282(13):1240–1246PubMedCrossRefGoogle Scholar
  13. 13.
    Singh S, Barghoorn J, Bagdonas A, Adler J, Treanor J, Kinnersley N, Ward P (2003) Clinical benefits with oseltamivir in treating influenza in adult populations: results of a pooled and subgroup analysis. Clin Drug Investig 23(9):561–569PubMedCrossRefGoogle Scholar
  14. 14.
    Treanor JJ, Hayden FG, Vrooman PS, Barbarash R, Bettis R, Riff D, Singh S, Kinnersley N, Ward P, Mills RG (2000) Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. JAMA 283(8):1016–1024PubMedCrossRefGoogle Scholar
  15. 15.
    Nicholson KG, Aoki FY, Osterhaus AD, Trottier S, Carewicz O, Mercier CH, Rode A, Kinnersley N, Ward P (2000) Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group. Lancet 355(9218):1845–1850PubMedCrossRefGoogle Scholar
  16. 16.
    Moss RB, Davey RT, Steigbigel RT, Fang F (2010) Targeting pandemic influenza: a primer on influenza antivirals and drug resistance. J Antimicrob Chemother 65(6):1086–1093. doi:10.1093/jac/dkq100 PubMedCrossRefGoogle Scholar
  17. 17.
    Monto AS, McKimm-Breschkin JL, Macken C, Hampson AW, Hay A, Klimov A, Tashiro M, Webster RG, Aymard M, Hayden FG, Zambon M (2006) Detection of influenza viruses resistant to neuraminidase inhibitors in global surveillance during the first 3 years of their use. Antimicrob Agents Chemother 50(7):2395–2402. doi:10.1128/AAC.01339-05 PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Lackenby A, Hungnes O, Dudman SG, Meijer A, Paget WJ, Hay AJ, Zambon MC (2008) Emergence of resistance to oseltamivir among influenza A(H1N1) viruses in Europe. Euro surveillance: bulletin europeen sur les maladies transmissibles = European communicable disease bulletin 13(5)Google Scholar
  19. 19.
    Hauge SH, Dudman S, Borgen K, Lackenby A, Hungnes O (2009) Oseltamivir-resistant influenza viruses A (H1N1), Norway, 2007-08. Emerg Infect Dis 15(2):155–162PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Meijer A, Lackenby A, Hungnes O, Lina B, van der Werf S, Schweiger B, Opp M, Paget J, van de Kassteele J, Hay A, Zambon M (2009) Oseltamivir-resistant influenza virus A (H1N1), Europe, 2007-08 season. Emerg Infect Dis 15(4):552–560. doi:10.3201/eid1504.181280 PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Ives JA, Carr JA, Mendel DB, Tai CY, Lambkin R, Kelly L, Oxford JS, Hayden FG, Roberts NA (2002) 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 55(2):307–317PubMedCrossRefGoogle Scholar
  22. 22.
    Bloom JD, Gong LI, Baltimore D (2010) Permissive secondary mutations enable the evolution of influenza oseltamivir resistance. Science 328(5983):1272–1275. doi:10.1126/science.1187816 PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Yang JR, Lin YC, Huang YP, Su CH, Lo J, Ho YL, Yao CY, Hsu LC, Wu HS, Liu MT (2011) Reassortment and mutations associated with emergence and spread of oseltamivir-resistant seasonal influenza A/H1N1 viruses in 2005-2009. PloS one 6(3):e18177. doi:10.1371/journal.pone.0018177 PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Gubareva LV, Trujillo AA, Okomo-Adhiambo M, Mishin VP, Deyde VM, Sleeman K, Nguyen HT, Sheu TG, Garten RJ, Shaw MW, Fry AM, Klimov AI (2010) Comprehensive assessment of 2009 pandemic influenza A (H1N1) virus drug susceptibility in vitro. Antiv Ther 15(8):1151–1159. doi:10.3851/IMP1678 CrossRefGoogle Scholar
  25. 25.
    Graitcer SB, Gubareva L, Kamimoto L, Doshi S, Vandermeer M, Louie J, Waters C, Moore Z, Sleeman K, Okomo-Adhiambo M, Marshall SA, St George K, Pan CY, LaPlante JM, Klimov A, Fry AM (2011) Characteristics of patients with oseltamivir-resistant pandemic (H1N1) 2009, United States. Emerg Infect Dis 17(2):255–257. doi:10.3201/eid1702.101724 PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    World Health Organization (2009) Oseltamivir-resistant pandemic (H1N1) 2009 influenza virus, October 2009. http://www.who.int/wer/2009/wer8444.pdf. Accessed Oct 2012
  27. 27.
    World Health Organization (2010) Update on oseltamivir-resistant pandemic A (H1N1) 2009 influenza virus: January 2010. http://www.who.int/wer/2010/wer8506.pdf. Accessed April 2013
  28. 28.
    Chen H, Cheung CL, Tai H, Zhao P, Chan JF, Cheng VC, Chan KH, Yuen KY (2009) Oseltamivir-resistant influenza A pandemic (H1N1) 2009 virus, Hong Kong. China. Emerg Infect Dis 15(12):1970–1972. doi:10.3201/eid1512.091057 CrossRefGoogle Scholar
  29. 29.
    Storms AD, Gubareva LV, Su S, Wheeling JT, Okomo-Adhiambo M, Pan CY, Reisdorf E, St George K, Myers R, Wotton JT, Robinson S, Leader B, Thompson M, Shannon M, Klimov A, Fry AM (2012) Oseltamivir-resistant pandemic (H1N1) 2009 virus infections, United States, 2010-11. Emerg Infect Dis 18(2):308–311. doi:10.3201/eid1802.111466 PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Hurt AC, Hardie K, Wilson NJ, Deng YM, Osbourn M, Leang SK, Lee RT, Iannello P, Gehrig N, Shaw R, Wark P, Caldwell N, Givney RC, Xue L, Maurer-Stroh S, Dwyer DE, Wang B, Smith DW, Levy A, Booy R, Dixit R, Merritt T, Kelso A, Dalton C, Durrheim D, Barr IG (2012) Characteristics of a widespread community cluster of H275Y oseltamivir-resistant A(H1N1)pdm09 influenza in Australia. J Infect Dis 206(2):148–157. doi:10.1093/infdis/jis337 PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Mai LQ, Wertheim HF, Tran ND, van Doorn HR, Nguyen TH, Horby P (2010) A community cluster of oseltamivir-resistant cases of 2009 H1N1 influenza. N Engl J Med 362(1):86–87. doi:10.1056/NEJMc0910732 CrossRefGoogle Scholar
  32. 32.
    Chen LF, Dailey NJ, Rao AK, Fleischauer AT, Greenwald I, Deyde VM, Moore ZS, Anderson DJ, Duffy J, Gubareva LV, Sexton DJ, Fry AM, Srinivasan A (2009) Wolfe CR (2011) Cluster of oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infections on a hospital ward among immunocompromised patients–North Carolina. J Infect Dis 203(6):838–846. doi:10.1093/infdis/jiq124 CrossRefGoogle Scholar
  33. 33.
    Hayden FG (1996) Combination antiviral therapy for respiratory virus infections. Antiviral Res 29(1):45–48PubMedCrossRefGoogle Scholar
  34. 34.
    Poland GA, Jacobson RM, Ovsyannikova IG (2009) Influenza virus resistance to antiviral agents: a plea for rational use. Clin Infect Dis 48(9):1254–1256. doi:10.1086/598989 PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Zuniga JM, Whiteside A, Ghaziani A, Bartlett JG (2008) A decade of HAART: the development and global impact of highly active antiretroviral therapy, 1st edn. Oxford University Press, USACrossRefGoogle Scholar
  36. 36.
    Druyts E, Thorlund K, Wu P, Kanters S, Yaya S, Cooper CL, Mills EJ (2012) Efficacy and safety of pegylated interferon alfa-2a or alfa-2b plus ribavirin for the treatment of chronic hepatitis C in children and adolescents: a systematic review and meta-analysis. Clin Infect Dis. doi:10.1093/cid/cis1031 PubMedGoogle Scholar
  37. 37.
    Hayden FG, Douglas RG Jr, Simons R (1980) Enhancement of activity against influenza viruses by combinations of antiviral agents. Antimicrob Agents Chemother 18(4):536–541PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Madren LK, Shipman C, Hayden FG (1995) In vitro inhibitory effects of combinations of anti-influenza agents. Antiviral Chem Chemother 6(2):109–113Google Scholar
  39. 39.
    Govorkova EA, Fang HB, Tan M, Webster RG (2004) Neuraminidase inhibitor-rimantadine combinations exert additive and synergistic anti-influenza virus effects in MDCK cells. Antimicrob Agents Chemother 48(12):4855–4863. doi:10.1128/AAC.48.12.4855-4863.2004 PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Nguyen JT, Hoopes JD, Smee DF, Prichard MN, Driebe EM, Engelthaler DM, Le MH, Keim PS, Spence RP, Went GT (2009) Triple combination of oseltamivir, amantadine, and ribavirin displays synergistic activity against multiple influenza virus strains in vitro. Antimicrob Agents Chemother 53(10):4115–4126. doi:10.1128/AAC.00476-09 PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Tarbet EB, Maekawa M, Furuta Y, Babu YS, Morrey JD, Smee DF (2012) Combinations of favipiravir and peramivir for the treatment of pandemic influenza A/California/04/2009 (H1N1) virus infections in mice. Antiviral Res 94(1):103–110. doi:10.1016/j.antiviral.2012.03.001 PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Wilson SZ, Knight V, Wyde PR, Drake S, Couch RB (1980) Amantadine and ribavirin aerosol treatment of influenza A and B infection in mice. Antimicrob Agents Chemother 17(4):642–648PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Ilyushina NA, Hoffmann E, Salomon R, Webster RG, Govorkova EA (2007) Amantadine-oseltamivir combination therapy for H5N1 influenza virus infection in mice. Antiviral therapy 12(3):363–370PubMedGoogle Scholar
  44. 44.
    Ilyushina NA, Hay A, Yilmaz N, Boon AC, Webster RG, Govorkova EA (2008) Oseltamivir-ribavirin combination therapy for highly pathogenic H5N1 influenza virus infection in mice. Antimicrob Agents Chemother 52(11):3889–3897. doi:10.1128/AAC.01579-07 PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Nguyen JT, Smee DF, Barnard DL, Julander JG, Gross M, de Jong MD, Went GT (2012) Efficacy of combined therapy with amantadine, oseltamivir, and ribavirin in vivo against susceptible and amantadine-resistant influenza A viruses. PloS One 7(1):e31006. doi:10.1371/journal.pone.0031006 PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Furuta Y, Takahashi K, Shiraki K, Sakamoto K, Smee DF, Barnard DL, Gowen BB, Julander JG, Morrey JD (2009) T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections. Antiviral Res 82(3):95–102. doi:10.1016/j.antiviral.2009.02.198 PubMedCrossRefGoogle Scholar
  47. 47.
    Wolrd Health Organization (2013) Recommended composition of influenza virus vaccines for use in the 2013-14 northern hemisphere influenza season. http://www.who.int/influenza/vaccines/virus/recommendations/2013_14_north/en/index.html. Accessed May 2013
  48. 48.
    Prichard MN, Shipman C Jr (1990) A three-dimensional model to analyze drug-drug interactions. Antiviral Res 14(4–5):181–205PubMedCrossRefGoogle Scholar
  49. 49.
    Smee DF, Huffman JH, Morrison AC, Barnard DL, Sidwell RW (2001) Cyclopentane neuraminidase inhibitors with potent in vitro anti-influenza virus activities. Antimicrob Agents Chemother 45(3):743–748. doi:10.1128/AAC.45.3.743-748.2001 PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Reed LJ, Muench H (1938) A simple method of estimating fifty perent endpoints. Am J Hyg 27(3):493–497Google Scholar
  51. 51.
    Bliss CI (1939) The toxicity of poisons applied jointly. Ann Appl Biol 26(3):585–615CrossRefGoogle Scholar
  52. 52.
    Prichard LE, Aseltine KR, Shipman C (1992) MacSynergyTM II - User Manual. University of Michigan. http://www.uab.edu/medicine/peds/id-faculty/mprichard
  53. 53.
    Smee DF, Hurst BL, Wong MH, Bailey KW, Tarbet EB, Morrey JD, Furuta Y (2010) Effects of the combination of favipiravir (T-705) and oseltamivir on influenza A virus infections in mice. Antimicrob Agents Chemother 54(1):126–133. doi:10.1128/AAC.00933-09 PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Sleeman K, Mishin VP, Deyde VM, Furuta Y, Klimov AI, Gubareva LV (2010) In vitro antiviral activity of favipiravir (T-705) against drug-resistant influenza and 2009 A(H1N1) viruses. Antimicrob Agents Chemother 54(6):2517–2524. doi:10.1128/AAC.01739-09 PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Tisdale M (2000) Monitoring of viral susceptibility: new challenges with the development of influenza NA inhibitors. Rev Med Virol 10(1):45–55PubMedCrossRefGoogle Scholar
  56. 56.
    Ilyushina NA, Bovin NV, Webster RG, Govorkova EA (2006) Combination chemotherapy, a potential strategy for reducing the emergence of drug-resistant influenza A variants. Antiviral Res 70(3):121–131. doi:10.1016/j.antiviral.2006.01.012 PubMedCrossRefGoogle Scholar
  57. 57.
    Hoopes JD, Driebe EM, Kelley E, Engelthaler DM, Keim PS, Perelson AS, Rong L, Went GT, Nguyen JT (2011) Triple combination antiviral drug (TCAD) composed of amantadine, oseltamivir, and ribavirin impedes the selection of drug-resistant influenza A virus. PloS One 6(12):e29778. doi:10.1371/journal.pone.0029778 PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Galegov GA, Pushkarskaya NL, Obrosovaserova NP, Zhdanov VM (1977) Combined action of ribovirin and rimantadine in experimental myxovirus infection. Experientia 33(7):905–906. doi:10.1007/Bf01951273 PubMedCrossRefGoogle Scholar
  59. 59.
    Hayden FG (1986) Combinations of antiviral agents for treatment of influenza virus infections. J Antimicrob Chemother 18 Suppl B:177–183Google Scholar
  60. 60.
    Duval X, van der Werf S, Blanchon T, Mosnier A, Bouscambert-Duchamp M, Tibi A, Enouf V, Charlois-Ou C, Vincent C, Andreoletti L, Tubach F, Lina B, Mentre F, Leport C (2010) Efficacy of oseltamivir-zanamivir combination compared to each monotherapy for seasonal influenza: a randomized placebo-controlled trial. PLoS Med 7(11):e1000362. doi:10.1371/journal.pmed.1000362 PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Furuta Y, Takahashi K, Kuno-Maekawa M, Sangawa H, Uehara S, Kozaki K, Nomura N, Egawa H, Shiraki K (2005) Mechanism of action of T-705 against influenza virus. Antimicrob Agents Chemother 49(3):981–986. doi:10.1128/AAC.49.3.981-986.2005 PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien (outside the USA) 2013

Authors and Affiliations

  • E. Bart Tarbet
    • 1
  • Almut H. Vollmer
    • 1
  • Brett L. Hurst
    • 1
  • Dale L. Barnard
    • 1
  • Yousuke Furuta
    • 2
  • Donald F. Smee
    • 1
  1. 1.Institute for Antiviral ResearchUtah State UniversityLoganUSA
  2. 2.Research LaboratoriesToyama Chemical Co., Ltd.ToyamaJapan

Personalised recommendations