Current Treatment Options in Infectious Diseases

, Volume 9, Issue 3, pp 318–332 | Cite as

Antiviral Drugs for the Treatment and Prevention of Influenza

  • Rubaiyea Farrukee
  • Aeron C. HurtEmail author
Viral Infections (N Malavige, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Viral Infections


Purpose of review

This paper provides an overview of the currently available treatment options for influenza infections. Currently, the options are limited to only one class of drugs known as the neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, laninamivir and peramivir) as there is widespread resistance against the adamantanes, an older class of antivirals. This review therefore discusses the mode of action, dosing, summary of clinical trial data and resistance within the context of NAIs. Newer antiviral therapies in late-phase clinical trials are also summarized in this review.

Recent findings

Oseltamivir is the most commonly used NAI amongst the four different types available. The most recent meta-analysis of placebo-controlled trials demonstrates that for uncomplicated seasonal influenza, oseltamivir reduces symptoms by 16–24 h, while observational studies cumulatively suggest that oseltamivir treatment reduces mortality in severely ill patients. NAIs also play an important role in the treatment and control of avian influenza infections in humans, which is a public health concern due to their high case fatality rate. The latest analysis of data suggests that early treatment with oseltamivir can be attributed to reducing mortality in patients with avian A(H5N1) infections; data regarding oseltamivir effectiveness against A(H7N9) infections is however more limited. During the 2014–2015 influenza season, the frequency of resistance to the NAIs in all circulating viruses was below 1%, but immunocompromised patients infected with influenza are often at higher risk of shedding resistant viruses due to slow viral clearance and extended treatment regimens. Favipiravir, a polymerase inhibitor, has received limited approval for use in Japan, but its use is restricted to novel viruses that are resistant to other antiviral therapies. Antivirals such as thiazolide, nitazoxanide and endonuclease inhibitor, S-033188, are currently in phase III clinical trials and other influenza antivirals are in early or mid-phase clinical trials.


This review highlights a lack of different treatment options for influenza infections. While there are four different types of NAIs, in many countries, oseltamivir is the only available option. New therapies are being rapidly developed to meet the need for a greater variety of antivirals, and as such, it is likely that over the next decade, a broader range of influenza therapeutics will become available for treatment.


Neuraminidase inhibitors Antiviral treatment Influenza Oseltamivir Zanamivir Laninamivir Peramivir Favipiravir 



The Melbourne WHO Collaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health.

Compliance with Ethical Standards

Conflict of Interest

Rubaiyea Farrukee declares that he has no conflict of interest.

Aeron C. Hurt declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Muthuri SG, Myles PR, Venkatesan S, Leonardi-Bee J, Nguyen-Van-Tam JS. Impact of neuraminidase inhibitor treatment on outcomes of public health importance during the 2009–2010 influenza A(H1N1) pandemic: a systematic review and meta-analysis in hospitalized patients. J Infect Dis. 2013;207(4):553–63.CrossRefPubMedGoogle Scholar
  2. 2.
    Centre for Disease Control and Prevention. Seasonal influenza vaccine effectiveness, 2005–2016. on 23rd Jan 2017).
  3. 3.
    Xie H, Wan X-F, Ye Z, Plant EP, Zhao Y, Xu Y, et al. H3N2 mismatch of 2014–15 northern hemisphere influenza vaccines and head-to-head comparison between human and ferret antisera derived antigenic maps. Sci Rep. 2015;5:15279. doi: 10.1038/srep15279.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Nicholson KG, Wood JM, Zambon M. Influenza. Lancet. 2003;362(9397):1733–45.CrossRefPubMedGoogle Scholar
  5. 5.
    Hayden FG, Belshe RB, Clover RD, Hay AJ, Oakes MG, Soo W. Emergence and apparent transmission of rimantadine-resistant influenza A virus in families. N Engl J Med. 1989;321(25):1696–702.CrossRefPubMedGoogle Scholar
  6. 6.
    Sweet C, Hayden FG, Jakeman KJ, Grambas S, Hay AJ. Virulence of rimantadine-resistant human influenza A (H3N2) viruses in ferrets. J Infect Dis. 1991;164(5):969–72.CrossRefPubMedGoogle Scholar
  7. 7.
    Bright RA, Medina MJ, Xu X, Perez-Oronoz G, Wallis TR, Davis XM, 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):1175–81.CrossRefPubMedGoogle Scholar
  8. 8.
    Deyde VM, Xu X, Bright RA, Shaw M, Smith CB, Zhang Y, et al. Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide. J Infect Dis. 2007;196(2):249–57.CrossRefPubMedGoogle Scholar
  9. 9.
    Dong G, Peng C, Luo J, Wang C, Han L, Wu B, et al. Adamantane-resistant influenza A viruses in the world (1902–2013): frequency and distribution of M2 gene mutations. PLoS One. 2015;10(3):e0119115.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Hurt AC, Besselaar TG, Daniels RS, Ermetal B, Fry A, Gubareva L, et al. Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2014–2015. Antivir Res. 2016;132:178–85.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Centre for Disease Control and Prevention. Influenza antiviral medications: summary for clinicians. (Accessed on 1st May 2017).
  12. 12.
    Zaraket H, Saito R. Japanese surveillance systems and treatment for influenza. Curr Treat Options Infect Dis. 2016;8(4):311–28.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    F. Hoffmann-La Roche Ltd. Media release. Roche delivers solid results in 2014. (Accessed 21st May 2017).
  14. 14.
    Von Itzstein M. The war against influenza: discovery and development of sialidase inhibitors. Nat Rev Drug Discov. 2007;6(12):967–74.CrossRefGoogle Scholar
  15. 15.
    Harper SA, Bradley JS, Englund JA, File TM, Gravenstein S, Hayden FG, 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):1003–32.CrossRefPubMedGoogle Scholar
  16. 16.
    Hanatani T, Sai K, Tohkin M, Segawa K, Antoku Y, Nakashima N, et al. Evaluation of two Japanese regulatory actions using medical information databases: a ‘Dear Doctor’ letter to restrict oseltamivir use in teenagers, and label change caution against co-administration of omeprazole with clopidogrel. J Clin Pharm Ther. 2014;39(4):361–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Chan-Tack KM, Kim C, Moruf A, Birnkrant DB. Clinical experience with intravenous zanamivir under an emergency IND program in the United States (2011–2014). Antivir Ther. 2015;20(5):561–4.CrossRefPubMedGoogle Scholar
  18. 18.
    Watanabe A, Yates PJ, Murayama M, Soutome T, Furukawa H. Evaluation of safety and efficacy of intravenous zanamivir in the treatment of hospitalized Japanese patients with influenza: an open-label, single-arm study. Antivir Ther. 2015;20(4):415–23.CrossRefPubMedGoogle Scholar
  19. 19.
    Marty FM, Vidal-Puigserver J, Clark C, Gupta SK, Merino E, Garot D, et al. Intravenous zanamivir or oral oseltamivir for hospitalised patients with influenza: an international, randomised, double-blind, double-dummy, phase 3 trial. Lancet Respir Med. 2017;5(2):135–46.CrossRefPubMedGoogle Scholar
  20. 20.
    McLaughlin MM, Skoglund EW, Ison MG. Peramivir: an intravenous neuraminidase inhibitor. Expert Opin Pharmacother. 2015;16(12):1889–900.CrossRefPubMedGoogle Scholar
  21. 21.
    Ikematsu H, Kawai N. Laninamivir octanoate: a new long-acting neuraminidase inhibitor for the treatment of influenza. Expert Rev Anti-Infect Ther. 2011;9(10):851–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Robson R, Buttimore A, Lynn K, Brewster M, Ward P. The pharmacokinetics and tolerability of oseltamivir suspension in patients on haemodialysis and continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant. 2006;21(9):2556–62.CrossRefPubMedGoogle Scholar
  23. 23.
    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):243–51.CrossRefPubMedGoogle Scholar
  24. 24.
    • Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev. 2014;10(4):CD008965. This study is the most recently published Cochrane review analysing all published and unpublished data to determine the effectiveness of oseltamivir and zanamivir treatment and prophylaxisGoogle Scholar
  25. 25.
    Nakamura Y, Sugawara T, Ohkusa Y, Taniguchi K, Miyazaki C, Momoi M et al. Life-threatening abnormal behavior incidence in 10–19 year old patients administered neuraminidase inhibitors. PloS One. 2015;10(7):e0129712. doi: 10.1371/journal.pone.0129712.
  26. 26.
    Nakamura Y, Sugawara T, Ohkusa Y, Taniguchi K, Miyazaki C, Momoi M, et al. Abnormal behavior during influenza in Japan during the last seven seasons: 2006–2007 to 2012–2013. J Infect Chemother. 2014;20(12):789–93.CrossRefPubMedGoogle Scholar
  27. 27.
    • Dobson J, Whitley RJ, Pocock S, Monto AS. Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials. Lancet. 2015;385(9979):1729–37. This study is a meta-analysis of all published and unpublished data from Roche-sponsored studies to determine the effectiveness of oseltamivir treatmentCrossRefPubMedGoogle Scholar
  28. 28.
    Hurt AC, Kelly H. Debate regarding oseltamivir use for seasonal and pandemic influenza. Emerg Infect Dis. 2016;22(6):949–55. doi: 10.3201/eid2206.151037.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Hsu J, Santesso N, Mustafa R, Brozek J, Chen YL, Hopkins JP, et al. Antivirals for treatment of influenza: a systematic review and meta-analysis of observational studies. Ann Intern Med. 2012;156(7):512–24.CrossRefPubMedGoogle Scholar
  30. 30.
    Falagas ME, Koletsi PK, Vouloumanou EK, Rafailidis PI, Kapaskelis AM, Rello J. Effectiveness and safety of neuraminidase inhibitors in reducing influenza complications: a meta-analysis of randomized controlled trials. J Antimicrob Chemother. 2010;65(7):1330–46.CrossRefPubMedGoogle Scholar
  31. 31.
    Muthuri SG, Venkatesan S, Myles PR, Leonardi-Bee J, Al Khuwaitir TS, Al Mamun A, et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir Med. 2014;2(5):395–404.CrossRefPubMedGoogle Scholar
  32. 32.
    Okoli GN, Otete HE, Beck CR, Nguyen-Van-Tam JS. Use of neuraminidase inhibitors for rapid containment of influenza: a systematic review and meta-analysis of individual and household transmission studies. PloS One. 2014;9(12).:e113633. doi: 10.1371/journal.pone.0113633
  33. 33.
    Shobugawa Y, Saito R, Sato I, Kawashima T, Dapat C, Dapat IC, et al. Clinical effectiveness of neuraminidase inhibitors—oseltamivir, zanamivir, laninamivir, and peramivir—for treatment of influenza A(H3N2) and A(H1N1)pdm09 infection: an observational study in the 2010–2011 influenza season in Japan. J Infect Chemother. 2012;18(6):858–64.CrossRefPubMedGoogle Scholar
  34. 34.
    Hikita T, Hikita H, Hikita F, Hikita N, Hikita S. Clinical effectiveness of peramivir in comparison with other neuraminidase inhibitors in pediatric influenza patients. Int J Pediatr. 2012;834181(10):22.Google Scholar
  35. 35.
    Hernandez JE, Adiga R, Armstrong R, Bazan J, Bonilla H, Bradley J, et al. Clinical experience in adults and children treated with intravenous peramivir for 2009 influenza A (H1N1) under an emergency IND program in the United States. Clin Infect Dis. 2011;52(6):695–706.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Louie JK, Yang S, Yen C, Acosta M, Schechter R, Uyeki TM. Use of intravenous peramivir for treatment of severe influenza A(H1N1)pdm09. PLoS One. 2012;7(6):29.CrossRefGoogle Scholar
  37. 37.
    Ison MG, Hui DS, Clezy K, O'Neil BJ, Flynt A, Collis PJ, et al. A clinical trial of intravenous peramivir compared with oral oseltamivir for the treatment of seasonal influenza in hospitalized adults. Antivir Ther. 2013;18(5):651–61.CrossRefPubMedGoogle Scholar
  38. 38.
    Yoo JW, Choi SH, Huh JW, Lim CM, Koh Y, Hong SB. Peramivir is as effective as oral oseltamivir in the treatment of severe seasonal influenza. J Med Virol. 2015;87(10):1649–55.CrossRefPubMedGoogle Scholar
  39. 39.
    Ison MG, Fraiz J, Heller B, Jauregui L, Mills G, O'Riordan W, et al. Intravenous peramivir for treatment of influenza in hospitalized patients. Antivir Ther. 2014;19(4):349–61.CrossRefPubMedGoogle Scholar
  40. 40.
    Kohno S, Kida H, Mizuguchi M, Hirotsu N, Ishida T, Kadota J, et al. Intravenous peramivir for treatment of influenza A and B virus infection in high-risk patients. Antimicrob Agents Chemother. 2011;55(6):2803–12.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    De Jong MD, Ison MG, Monto AS, Metev H, Clark C, O'Neil B, et al. Evaluation of intravenous peramivir for treatment of influenza in hospitalized patients. Clin Infect Dis. 2014;59(12):12.Google Scholar
  42. 42.
    Ikematsu H, Kawai N, Iwaki N, Kashiwagi S. Clinical outcome of laninamivir octanoate hydrate for influenza in the 2013–2014 Japanese season. J Infect Chemother. 2015;21(11):802–7.CrossRefPubMedGoogle Scholar
  43. 43.
    Kashiwagi S, Yoshida S, Yamaguchi H, Mitsui N, Tanigawa M, Shiosakai K, et al. Clinical efficacy of long-acting neuraminidase inhibitor laninamivir octanoate hydrate in postmarketing surveillance. J Infect Chemother. 2013;19(2):223–32.CrossRefPubMedGoogle Scholar
  44. 44.
    Kashiwagi S, Watanabe A, Ikematsu H, Uemori M, Awamura S. Long-acting neuraminidase inhibitor laninamivir octanoate as post-exposure prophylaxis for influenza. Clin Infect Dis. 2016;63(3):330–7.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Nakano T, Ishiwada N, Sumitani T, Uemori M, Isobe K. Inhaled laninamivir octanoate as prophylaxis for influenza in children. Pediatrics. 2016;138(6):2.CrossRefGoogle Scholar
  46. 46.
    Louie JK, Yang S, Samuel MC, Uyeki TM, Schechter R. Neuraminidase inhibitors for critically ill children with influenza. Pediatrics. 2013;132(6):2013–149.CrossRefGoogle Scholar
  47. 47.
    Adisasmito W, Chan PK, Lee N, Oner AF, Gasimov V, Aghayev F. Effectiveness of antiviral treatment in human influenza A(H5N1) infections: analysis of a Global Patient Registry. J Infect Dis. 2010;202:1154-1160. doi: 10.1086/656316.
  48. 48.
    Yu H, Feng Z, Uyeki TM, Liao Q, Zhou L, Feng L, et al. Risk factors for severe illness with 2009 pandemic influenza A (H1N1) virus infection in China. Clin Infect Dis. 2011;52(4):457–65.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Louie JK, Yang S, Acosta M, Yen C, Samuel MC, Schechter R, et al. Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1) pdm09. Clin Infect Dis. 2012;55(9):1198–204.CrossRefPubMedGoogle Scholar
  50. 50.
    Farrukee R, Mosse J, Hurt AC. Review of the clinical effectiveness of the neuraminidase inhibitors against influenza B viruses. Expert Rev Anti-Infect Ther. 2013;11(11):1135–45.CrossRefPubMedGoogle Scholar
  51. 51.
    Ikematsu H, Kawai N, Iwaki N, Kashiwagi S. The duration of fever and other symptoms after the initiation of laninamivir octanoate hydrate in the Japanese 2011–2012 influenza season. J Infect Chemother. 2014;20(2):81–5.CrossRefPubMedGoogle Scholar
  52. 52.
    Sheu TG, Deyde VM, Okomo-Adhiambo M, Garten RJ, Xu X, Bright RA, 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):3284–92.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    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(1):i5–i21.CrossRefPubMedGoogle Scholar
  54. 54.
    Treanor JJ, Hayden FG, Vrooman PS, Barbarash R, Bettis R, Riff D, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group. JAMA. 2000;283(8):1016–24.CrossRefPubMedGoogle Scholar
  55. 55.
    Nicholson KG, Aoki FY, Osterhaus AD, Trottier S, Carewicz O, Mercier CH, et al. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group. Lancet. 2000;355(9218):1845–50.CrossRefPubMedGoogle Scholar
  56. 56.
    Lee N, Hui DS, Zuo Z, Ngai KL, Lui GC, Wo SK, et al. A prospective intervention study on higher-dose oseltamivir treatment in adults hospitalized with influenza a and B infections. Clin Infect Dis. 2013;57(11):1511–9.CrossRefPubMedGoogle Scholar
  57. 57.
    South East Asia Infectious Disease Clinical Research Network. Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial. BMJ (Clinical Research Ed). 2013;346.:f3039. doi: 10.1136/bmj.f3039.
  58. 58.
    Li H, Cao B. Pandemic and avian influenza A viruses in humans: epidemiology, virology, clinical characteristics, and treatment strategy. Clin Chest Med. 2017;38(1):59–70.CrossRefPubMedGoogle Scholar
  59. 59.
    Gao R, Cao B, Hu Y, Feng Z, Wang D, Hu W. Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med. 2013;368:1888-1897. doi: 10.1056/NEJMoa1304459.
  60. 60.
    Li FC, Choi BC, Sly T, Pak AW. Finding the real case-fatality rate of H5N1 avian influenza. J Epidemiol Community Health. 2008;62(6):555–9.CrossRefPubMedGoogle Scholar
  61. 61.
    Food and Agriculture Organization of the United States. H7N9 situation update. (Accessed 31st May 2017).
  62. 62.
    World Health Organization. http. Cumulative number of confirmed human cases for avian influenza A(H5N1) reported to WHO, 2003–2017. :// (Accessed 31st May 2017).
  63. 63.
    Smith JR. Oseltamivir in human avian influenza infection. J Antimicrob Chemother. 2010;65(2).:ii25-ii33. doi: 10.1093/jac/dkq013.
  64. 64.
    Gao HN, Lu HZ, Cao B, Du B, Shang H, Gan JH. Clinical findings in 111 cases of influenza A (H7N9) virus infection. N Engl J Med. 2013;368:2277–2285. doi: 10.1056/NEJMoa1305584.
  65. 65.
    Zhang Y, Gao H, Liang W, Tang L, Yang Y, Wu X, et al. Efficacy of oseltamivir-peramivir combination therapy compared to oseltamivir monotherapy for influenza A (H7N9) infection: a retrospective study. BMC Infect Dis. 2016;16(1):76. doi: 10.1186/s12879-016-1383-8.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Koopmans M, Wilbrink B, Conyn M, Natrop G, van der Nat H, Vennema H, 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):587–93.CrossRefPubMedGoogle Scholar
  67. 67.
    Ferraris O, Lina B. Mutations of neuraminidase implicated in neuraminidase inhibitors resistance. J Clin Virol. 2008;41(1):13–9.CrossRefPubMedGoogle Scholar
  68. 68.
    Gubareva LV. Molecular mechanisms of influenza virus resistance to neuraminidase inhibitors. Virus Res. 2004;103(1–2):199–203.CrossRefPubMedGoogle Scholar
  69. 69.
    Whitley RJ, Boucher CA, Lina B, Nguyen-Van-Tam JS, Osterhaus A, Schutten M, et al. Global assessment of resistance to neuraminidase inhibitors, 2008–2011: the Influenza Resistance Information Study (IRIS). Clin Infect Dis. 2013;56(9):1197–205. doi: 10.1093/cid/cis1220.CrossRefPubMedGoogle Scholar
  70. 70.
    Whitley RJ, Hayden FG, Reisinger KS, Young N, Dutkowski R, Ipe D, et al. Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J. 2001;20(2):127–33.CrossRefPubMedGoogle Scholar
  71. 71.
    Tamura D, Sugaya N, Ozawa M, Takano R, Ichikawa M, Yamazaki M, et al. Frequency of drug-resistant viruses and virus shedding in pediatric influenza patients treated with neuraminidase inhibitors. Clin Infect Dis. 2011;52(4):432–7.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Van der Vries E, Stittelaar KJ, van Amerongen G, Veldhuis Kroeze EJ, de Waal L, Fraaij PL, et al. Prolonged influenza virus shedding and emergence of antiviral resistance in immunocompromised patients and ferrets. PLoS Pathog. 2013;9(5):23.Google Scholar
  73. 73.
    Ison MG, Gubareva LV, Atmar RL, Treanor J, Hayden FG. Recovery of drug-resistant influenza virus from immunocompromised patients: a case series. J Infect Dis. 2006;193(6):760–4.CrossRefPubMedGoogle Scholar
  74. 74.
    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):1555–61.CrossRefPubMedGoogle Scholar
  75. 75.
    Okomo-Adhiambo M, Demmler-Harrison GJ, Deyde VM, Sheu TG, Xu X, Klimov AI, 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):1834–41.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Ruiz-Carrascoso G, Casas I, Pozo F, Gonzalez-Vincent M, Perez-Brena P. Prolonged shedding of amantadine- and oseltamivir-resistant influenza A(H3N2) virus with dual mutations in an immunocompromised infant. Antivir Ther. 2010;15(7):1059–63.CrossRefPubMedGoogle Scholar
  77. 77.
    Piralla A, Gozalo-Marguello M, Fiorina L, Rovida F, Muzzi A, Colombo AA, et al. Different drug-resistant influenza A(H3N2) variants in two immunocompromised patients treated with oseltamivir during the 2011–2012 influenza season in Italy. J Clin Virol. 2013;58(1):132–7.CrossRefPubMedGoogle Scholar
  78. 78.
    Simon P, Holder BP, Bouhy X, Abed Y, Beauchemin CAA, Boivin G. The I222V neuraminidase mutation has a compensatory role in replication of an oseltamivir-resistant influenza virus A/H3N2 E119V mutant. J Clin Microbiol. 2011;49(2):715–7. doi: 10.1128/jcm.01732-10.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Hurt AC, Leang SK, Tiedemann K, Butler J, Mechinaud F, Kelso A, et al. Progressive emergence of an oseltamivir-resistant A(H3N2) virus over two courses of oseltamivir treatment in an immunocompromised paediatric patient. Influenza Other Respir Viruses. 2013;7(6):904–8.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Eshaghi A, Shalhoub S, Rosenfeld P, Li A, Higgins RR, Stogios PJ, et al. Multiple influenza A (H3N2) mutations conferring resistance to neuraminidase inhibitors in a bone marrow transplant recipient. Antimicrob Agents Chemother. 2014;58(12):7188–97.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Moscona A. Global transmission of oseltamivir-resistant influenza. N Engl J Med. 2009;360(10):953–6. doi: 10.1056/NEJMp0900648.CrossRefPubMedGoogle Scholar
  82. 82.
    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. Eurosurveillance. 2009;14(5).:pii: 19112.Google Scholar
  83. 83.
    Carr J, Ives J, Roberts N, Kelly L, Lambkin R, Oxford J et al., eds. Virological assessment in vitro and in vivo of an influenza H1N1 virus with a H274Y mutation in the neuraminidase gene. Antiviral research; 2000: Elsevier Science, Amsterdam.Google Scholar
  84. 84.
    Ives JAL, Carr JA, Mendel DB, Tai CY, Lambkin R, Kelly L, 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. Antivir Res. 2002;55(2):307–17.CrossRefPubMedGoogle Scholar
  85. 85.
    Bouvier NM, Lowen AC, Palese P. Oseltamivir-resistant influenza A viruses are transmitted efficiently among guinea pigs by direct contact but not by aerosol. J Virol. 2008;82(20):10052–8. doi: 10.1128/jvi.01226-08.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Collins PJ, Haire LF, Lin YP, Liu J, Russell RJ, Walker PA, et al. Structural basis for oseltamivir resistance of influenza viruses. Vaccine. 2009;27(45):6317–23.CrossRefPubMedGoogle Scholar
  87. 87.
    Rameix-Welti MA, Munier S, Le Gal S, Cuvelier F, Agou F, Enouf V, et al. Neuraminidase of 2007–2008 influenza A(H1N1) viruses shows increased affinity for sialic acids due to the D344N substitution. Antivir Ther. 2011;16(4):597–603.CrossRefPubMedGoogle Scholar
  88. 88.
    Abed Y, Pizzorno A, Bouhy X, Boivin G. Role of permissive neuraminidase mutations in influenza A/Brisbane/59/2007-like (H1N1) viruses. PLoS Pathog. 2011;7(12):8.CrossRefGoogle Scholar
  89. 89.
    Duan S, Govorkova EA, Bahl J, Zaraket H, Baranovich T, Seiler P, et al. Epistatic interactions between neuraminidase mutations facilitated the emergence of the oseltamivir-resistant H1N1 influenza viruses. Nat Commun. 2014;5:5029. doi: 10.1038/ncomms6029.
  90. 90.
    Bloom JD, Gong LI, Baltimore D. Permissive secondary mutations enable the evolution of influenza oseltamivir resistance. Science. 2010;328(5983):1272–5. doi: 10.1126/science.1187816.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Michaelis M, Doerr HW, Cinatl J Jr. An influenza A H1N1 virus revival—pandemic H1N1/09 virus. Infection. 2009;37(5):381–9.CrossRefPubMedGoogle Scholar
  92. 92.
    Hurt AC, Hardie K, Wilson NJ, Deng YM, Osbourn M, Leang SK, et al. Characteristics of a widespread community cluster of H275Y oseltamivir-resistant A(H1N1)pdm09 influenza in Australia. J Infect Dis. 2012;206(2):148–57.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Takashita E, Kiso M, Fujisaki S, Yokoyama M, Nakamura K, Shirakura M, et al. Characterization of a large cluster of influenza A(H1N1)pdm09 viruses cross-resistant to oseltamivir and peramivir during the 2013–2014 influenza season in Japan. Antimicrob Agents Chemother. 2015;59(5):2607–17.CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Garg S, Moore Z, Lee N, McKenna J, Bishop A, Fleischauer A, et al. A cluster of patients infected with I221V influenza b virus variants with reduced oseltamivir susceptibility—North Carolina and South Carolina, 2010–2011. J Infect Dis. 2013;207(6):966–73.CrossRefPubMedGoogle Scholar
  95. 95.
    Meijer A, Rebelo-de-Andrade H, Correia V, Besselaar T, Drager-Dayal R, Fry A, et al. Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2012–2013. Antivir Res. 2014;110:31–41.CrossRefPubMedGoogle Scholar
  96. 96.
    Le QM, Kiso M, Someya K, Sakai YT, Nguyen TH, Nguyen KH et al. Avian flu: isolation of drug-resistant H5N1 virus. Nature. 2005;437(7062):754.Google Scholar
  97. 97.
    De Jong MD, Tran TT, Truong HK, Vo MH, Smith GJ, Nguyen VC, et al. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med. 2005;353(25):2667–72.CrossRefPubMedGoogle Scholar
  98. 98.
    Earhart KC, Elsayed NM, Saad MD, Gubareva LV, Nayel A, Deyde VM, et al. Oseltamivir resistance mutation N294S in human influenza A(H5N1) virus in Egypt. J Infect Public Health. 2009;2(2):74–80.CrossRefPubMedGoogle Scholar
  99. 99.
    Gao R, Cao B, Hu Y, Feng Z, Wang D, Hu W, et al. Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med. 2013;368(20):1888–97.CrossRefPubMedGoogle Scholar
  100. 100.
    Hu Y, Lu S, Song Z, Wang W, Hao P, Li J. Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance. Lancet (London, England). 2013;381:2273–2279. doi: 10.1016/s0140-6736(13)61125-3.
  101. 101.
    Hai R, Schmolke M, Leyva-Grado VH, Thangavel RR, Margine I, Jaffe EL et al. Influenza A(H7N9) virus gains neuraminidase inhibitor resistance without loss of in vivo virulence or transmissibility. Nat Commun. 2013;4:2854. doi: 10.1038/ncomms3854.
  102. 102.
    Lin PH, Chao TL, Kuo SW, Wang JT, Hung CC, Lin HC, et al. Virological, serological, and antiviral studies in an imported human case of avian influenza A(H7N9) virus in Taiwan. Clin Infect Dis. 2014;58(2):242–6.CrossRefPubMedGoogle Scholar
  103. 103.
    Mok CK, Chang SC, Chen GW, Lo YL, Chen SJ, Wu HS, et al. Pyrosequencing reveals an oseltamivir-resistant marker in the quasispecies of avian influenza A (H7N9) virus. J Microbiol Immunol Infect. 2015;48(4):465–9.CrossRefPubMedGoogle Scholar
  104. 104.
    Marjuki H, Mishin VP, Chesnokov AP, De La Cruz JA, Davis CT, Villanueva JM, et al. Neuraminidase mutations conferring resistance to oseltamivir in influenza A(H7N9) viruses. J Virol. 2015;89(10):5419–26.CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    •• Iuliano AD, Jang Y, Jones J, Davis CT, Wentworth DE, Uyeki TM, et al. Increase in human infections with avian influenza A(H7N9) virus during the fifth epidemic—China, October 2016–February 2017. MMWR Morb Mortal Wkly Rep. 2017;66:254–5. doi: 10.15585/mmwr.mm6609e2. This paper updates and reports on the annual A(H7N9) epidemic in China which is a growing public health concern and the frequency of known or suspected resistance markers in all viruses analyzed to dateCrossRefPubMedGoogle Scholar
  106. 106.
    Furuta Y, Gowen BB, Takahashi K, Shiraki K, Smee DF, Barnard DL. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antivir Res. 2013;100(2) doi: 10.1016/j.antiviral.2013.09.015.
  107. 107.
    Furuta Y, Takahashi K, Fukuda Y, Kuno M, Kamiyama T, Kozaki K, et al. In vitro and in vivo activities of anti-influenza virus compound T-705. Antimicrob Agents Chemother. 2002;46(4):977–81.CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Sleeman K, Mishin VP, Deyde VM, Furuta Y, Klimov AI, Gubareva LV. In vitro antiviral activity of favipiravir (T-705) against drug-resistant influenza and 2009 A(H1N1) viruses. Antimicrob Agents Chemother. 2010;54(6):2517–24.CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Takashita E, Ejima M, Ogawa R, Fujisaki S, Neumann G, Furuta Y, et al. Antiviral susceptibility of influenza viruses isolated from patients pre- and post-administration of favipiravir. Antivir Res. 2016;132:170–7.CrossRefPubMedGoogle Scholar
  110. 110.
    FujiFIlm. The new drug application approval of “AVIGAN® Tablet 200mg” in Japan for the anti-influenza virus drug 2014. Accessed 16th May 2017.
  111. 111.
    Nagata T, Lefor AK, Hasegawa M, Ishii M. Favipiravir: a new medication for the Ebola virus disease pandemic. Disaster Med Public Health Prep. 2015;9(1):79–81.CrossRefPubMedGoogle Scholar
  112. 112.
    • Koszalka P, Tilmanis D, Hurt AC. Influenza antivirals currently in late-phase clinical trial. Influenza Other Respir Viruses. 2017;11(3):240–6. This paper provides an in-depth literature review on late-phase anti-influenza drugs, their mechanism of action, results from experimental studies and available clinical dataCrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Baranovich T, Wong SS, Armstrong J, Marjuki H, Webby RJ, Webster RG, et al. T-705 (favipiravir) induces lethal mutagenesis in influenza A H1N1 viruses in vitro. J Virol. 2013;87(7):3741–51.CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Loregian A, Mercorelli B, Nannetti G, Compagnin C, Palu G. Antiviral strategies against influenza virus: towards new therapeutic approaches. Cell Mol Life Sci. 2014;71(19):3659–83.CrossRefPubMedGoogle Scholar
  115. 115.
    Broekhuysen J, Stockis A, Lins RL, De Graeve J, Rossignol JF. Nitazoxanide: pharmacokinetics and metabolism in man. Int J Clin Pharmacol Ther. 2000;38(8):387–94.CrossRefPubMedGoogle Scholar
  116. 116.
    Rossignol JF, La Frazia S, Chiappa L, Ciucci A, Santoro MG. Thiazolides, a new class of anti-influenza molecules targeting viral hemagglutinin at the post-translational level. J Biol Chem. 2009;284(43):29798–808.CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Belardo G, La Frazia S, Cenciarelli O, Carta S, Rossignol J-F, Santoro MG, editors. Nitazoxanide, a novel potential anti-influenza drug, acting in synergism with neuraminidase inhibitors. 49th Annual Meeting of the Infectious Diseases Society of America. Boston, MA: Infectious Diseases Society of America; 2011.Google Scholar
  118. 118.
    Sleeman K, Mishin V, Guo Z, Garten R, Balish A, Fry AM, et al. Antiviral susceptibility of variant influenza A (H3N2) v viruses isolated in the United States from 2011 to 2013. Antimicrob Agents Chemother. 2014;58(4):2045–51.CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Haffizulla J, Hartman A, Hoppers M, Resnick H, Samudrala S, Ginocchio C, et al. Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial. Lancet Infect Dis. 2014;14(7):609–18.CrossRefPubMedGoogle Scholar
  120. 120.
    Belardo G, Cenciarelli O, La Frazia S, Rossignol JF, Santoro MG. Synergistic effect of nitazoxanide with neuraminidase inhibitors against influenza A viruses in vitro. Antimicrob Agents Chemother. 2015;59(2):1061–9.CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Takeki Uehara TS, Toru Ishibashi, Keiko Kawaguchi, Chisako Sato, Tadashi Ishida, Nobuo Hirotsu, Akira Watanabe. S-033188, a small molecule inhibitor of cap-dependent endonuclease of influenza A and B virus, leads to rapid and profound viral load reduction Options IX for the control of Influenza; August 24-28,2016; Chicago IL, LBO-1.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.WHO Collaborating Centre for Reference and Research on InfluenzaPeter Doherty Institute for Infection and ImmunityMelbourneAustralia
  2. 2.Department of Microbiology and ImmunologyUniversity of MelbourneParkvilleAustralia

Personalised recommendations