The use of ribavirin in influenza treatment is a matter of debate. Due to adamantine- and oseltamivir-resistant strains of the current pandemic H1N1 (pdmH1N1) influenza viruses, the demand for alternative antiviral treatments has increased. This study demonstrated the potent antiviral effects of ribavirin in a mouse model of pdmH1N1 influenza infection (A/Mexico/4108/2009). It was found that treatment with 40 mg ribavirin kg day partially protected the animals if initiated immediately upon infection. Administration of similar concentrations on subsequent days or immediate therapy with lower doses efficiently delayed disease progression. Correlation studies showed a direct relationship between low viral titres in the lung during the early stages of infection with animal survival in ribavirin-treated animals. Reduced lung pathology in animals treated with ribavirin following infection also indicated the importance of immediate treatment. This study revealed the antiviral properties of ribavirin and these results justify comprehensive clinical studies for the use of ribavirin against influenza virus in future outbreaks.


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  1. Beigel, J. & Bray, M.(2008). Current and future antiviral therapy of severe seasonal and avian influenza. Antiviral Res 78, 91–102.[CrossRef] [Google Scholar]
  2. Belser, J. A., Lu, X., Szretter, K. J., Jin, X., Aschenbrenner, L. M., Lee, A., Hawley, S., Kim, D. H., Malakhov, M. P. & other authors(2007). DAS181, a novel sialidase fusion protein, protects mice from lethal avian influenza H5N1 virus infection. J Infect Dis 196, 1493–1499.[CrossRef] [Google Scholar]
  3. Bernstein, D. I., Reuman, P. D., Sherwood, J. R., Young, E. C. & Schiff, G. M.(1988). Ribavirin small-particle-aerosol treatment of influenza B virus infection. Antimicrob Agents Chemother 32, 761–764.[CrossRef] [Google Scholar]
  4. Browne, M. J., Moss, M. Y. & Boyd, M. R.(1983). Comparative activity of amantadine and ribavirin against influenza virus in vitro: possible clinical relevance. Antimicrob Agents Chemother 23, 503–505.[CrossRef] [Google Scholar]
  5. Centers for Disease Control and Prevention(2009a). Oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infection in two summer campers receiving prophylaxis – North Carolina. MMWR Morb Mortal Wkly Rep 58, 969–972. [Google Scholar]
  6. Centers for Disease Control and Prevention(2009b). Oseltamivir-resistant novel influenza A (H1N1) virus infection in two immunosuppressed patients – Seattle, Washington. MMWR Morb Mortal Wkly Rep 58, 893–896. [Google Scholar]
  7. Chan-Tack, K. M., Murray, J. S. & Birnkrant, D. B.(2009). Use of ribavirin to treat influenza. N Engl J Med 361, 1713–1714.[CrossRef] [Google Scholar]
  8. Eggleston, M.(1987). Clinical review of ribavirin. Infect Control 8, 215–218. [Google Scholar]
  9. Garten, R. J., Davis, C. T., Russell, C. A., Shu, B., Lindstrom, S., Balish, A., Sessions, W. M., Xu, X., Skepner, E. & other authors(2009). Antigenic and genetic characteristics of swine-origin 2009 A (H1N1) influenza viruses circulating in humans. Science 325, 197–201.[CrossRef] [Google Scholar]
  10. Gilbert, B. E. & Knight, V.(1986). Biochemistry and clinical applications of ribavirin. Antimicrob Agents Chemother 30, 201–205.[CrossRef] [Google Scholar]
  11. Gilbert, B. E., Wilson, S. Z., Knight, V., Couch, R. B., Quarles, J. M., Dure, L., Hayes, N. & Willis, G.(1985). Ribavirin small-particle aerosol treatment of infections caused by influenza virus strains A/Victoria/7/83 (H1N1) and B/Texas/1/84. Antimicrob Agents Chemother 27, 309–313.[CrossRef] [Google Scholar]
  12. Graci, J. D. & Cameron, C. E.(2006). Mechanisms of action of ribavirin against distinct viruses. Rev Med Virol 16, 37–48.[CrossRef] [Google Scholar]
  13. Hayden, F.(2009). Developing new antiviral agents for influenza treatment: what does the future hold? Clin Infect Dis 48, S3–S13.[CrossRef] [Google Scholar]
  14. Huffman, J. H., Sidwell, R. W., Khare, G. P., Witkowski, J. T., Allen, L. B. & Robins, R. K.(1973).In vitro effect of 1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxamide (virazole, ICN 1229) on deoxyribonucleic acid and ribonucleic acid viruses. Antimicrob Agents Chemother 3, 235–241.[CrossRef] [Google Scholar]
  15. Ilyushina, N. A., Hay, A., Yilmaz, N., Boon, A. C., Webster, R. G. & Govorkova, E. A.(2008). Oseltamivir–ribavirin combination therapy for highly pathogenic H5N1 influenza virus infection in mice. Antimicrob Agents Chemother 52, 3889–3897.[CrossRef] [Google Scholar]
  16. Jain, S., Kamimoto, L., Bramley, A. M., Schmitz, A. M., Benoit, S. R., Louie, J., Sugerman, D. E., Druckenmiller, J. K., Ritger, K. A. & other authors(2009). Hospitalized patients with 2009 H1N1 influenza in the United States, April–June 2009. N Engl J Med 361, 1935–1944.[CrossRef] [Google Scholar]
  17. Kash, J. C., Qi, L., Dugan, V. G., Jagger, B. W., Hrabal, R. J., Memoli, M. J., Morens, D. M. & Taubenberger, J. K.(2010). Prior infection with classical swine H1N1 influenza viruses is associated with protective immunity to the 2009 pandemic H1N1 virus. Influenza Other Respi Viruses 4, 121–127.[CrossRef] [Google Scholar]
  18. Khare, G. P., Sidwell, R. W., Witkowski, J. T., Simon, L. N. & Robins, R. K.(1973). Suppression by 1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxamide (virazole, ICN 1229) of influenza virus-induced infections in mice. Antimicrob Agents Chemother 3, 517–522.[CrossRef] [Google Scholar]
  19. Knight, V., McClung, H. W., Wilson, S. Z., Waters, B. K., Quarles, J. M., Cameron, R. W., Greggs, S. E., Zerwas, J. M. & Couch, R. B.(1981). Ribavirin small-particle aerosol treatment of influenza. Lancet 2, 945–949. [Google Scholar]
  20. Maines, T. R., Jayaraman, A., Belser, J. A., Wadford, D. A., Pappas, C., Zeng, H., Gustin, K. M., Pearce, M. B., Viswanathan, K. & other authors(2009). Transmission and pathogenesis of swine-origin 2009 A(H1N1) influenza viruses in ferrets and mice. Science 325, 484–487. [Google Scholar]
  21. Martina, B. E., Haagmans, B. L., Kuiken, T., Fouchier, R. A., Rimmelzwaan, G. F., Van Amerongen, G., Peiris, J. S., Lim, W. & Osterhaus, A. D.(2003). Virology: SARS virus infection of cats and ferrets. Nature 425, 915.[CrossRef] [Google Scholar]
  22. McClung, H. W., Knight, V., Gilbert, B. E., Wilson, S. Z., Quarles, J. M. & Divine, G. W.(1983). Ribavirin aerosol treatment of influenza B virus infection. JAMA 249, 2671–2674.[CrossRef] [Google Scholar]
  23. Munster, V. J., de Wit, E., van den Brand, J. M. A., Herfst, S., Schrauwen, E. J. A., Bestebroer, T. M., van de Vijver, D., Boucher, C. A., Koopmans, M. & other authors(2009). Pathogenesis and transmission of swine-origin 2009 A(H1N1) influenza virus in ferrets. Science 325, 481–483. [Google Scholar]
  24. Reid, A. H., Fanning, T. G., Janczewski, T. A., Lourens, R. M. & Taubenberger, J. K.(2004). Novel origin of the 1918 pandemic influenza virus nucleoprotein gene. J Virol 78, 12462–12470.[CrossRef] [Google Scholar]
  25. Rodriguez, W. J., Hall, C. B., Welliver, R., Simoes, E. A., Ryan, M. E., Stutman, H., Johnson, G., Van Dyke, R., Groothuis, J. R. & Arrobio, J.(1994). Efficacy and safety of aerosolized ribavirin in young children hospitalized with influenza: a double-blind, multicenter, placebo-controlled trial. J Pediatr 125, 129–135.[CrossRef] [Google Scholar]
  26. Saldaña, N. G., Sánchez, C. C., Pérez, U. O., Lorenzo, J. C., Robles, V. P., Valencia, M. G., Cordoba, V. F. & Olguín, H. J.(2009). Double blind study of placebo and ribavirin as prophylaxis in cases of contact with varicella in children. Proc West Pharmacol Soc 52, 30–32. [Google Scholar]
  27. Selvam, P., Chandramohan, M., Hurst, B. L. & Smee, D. F.(2010). Activity of isatine-sulfadimidine derivatives against 2009 pandemic H1N1 influenza virus in cell culture. Antivir Chem Chemother 20, 143–146.[CrossRef] [Google Scholar]
  28. Sidwell, R. W., Huffman, J. H., Khare, G. P., Allen, L. B., Witkowski, J. T. & Robins, R. K.(1972). Broad-spectrum antiviral activity of Virazole: 1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxamide. Science 177, 705–706.[CrossRef] [Google Scholar]
  29. Smee, D. F., Bailey, K. W., Morrison, A. C. & Sidwell, R. W.(2002). Combination treatment of influenza A virus infections in cell culture and in mice with the cyclopentane neuraminidase inhibitor RWJ-270201 and ribavirin. Chemotherapy 48, 88–93.[CrossRef] [Google Scholar]
  30. Smee, D. F., Wong, M. H., Bailey, K. W. & Sidwell, R. W.(2006). Activities of oseltamivir and ribavirin used alone and in combination against infections in mice with recent isolates of influenza A (H1N1) and B viruses. Antivir Chem Chemother 17, 185–192.[CrossRef] [Google Scholar]
  31. Smee, D. F., Hurst, B. L., Wong, M. H., Bailey, K. W. & Morrey, J. D.(2009). Effects of double combinations of amantadine, oseltamivir, and ribavirin on influenza A (H5N1) virus infections in cell culture and in mice. Antimicrob Agents Chemother 53, 2120–2128.[CrossRef] [Google Scholar]
  32. Smee, D. F., Hurst, B. L., Wong, M. H., Bailey, K. W., Tarbet, E. B., Morrey, J. D. & Furuta, Y.(2010). Effects of the combination of favipiravir (T-705) and oseltamivir on influenza A virus infections in mice. Antimicrob Agents Chemother 54, 126–133.[CrossRef] [Google Scholar]
  33. Smith, J. R., Ariano, R. E. & Toovey, S.(2010). The use of antiviral agents for the management of severe influenza. Crit Care Med 38, e43–e51.[CrossRef] [Google Scholar]
  34. Speers, D. J., Williams, S. H., Pinder, M., Moody, H. R., Hurt, A. C. & Smith, D. W.(2010). Oseltamivir-resistant pandemic (H1N1) 2009 influenza in a severely ill patient: the first Australian case. Med J Aust 192, 166–168. [Google Scholar]
  35. Thompson, W. W., Shay, D. K., Weintraub, E., Brammer, L., Cox, N., Anderson, L. J. & Fukuda, K.(2003). Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 289, 179–186.[CrossRef] [Google Scholar]
  36. Triana-Baltzer, G. B., Gubareva, L. V., Nicholls, J. M., Pearce, M. B., Mishin, V. P., Belser, J. A., Chen, L.-M., Chan, R. W. Y., Chan, M. C. W. & other authors(2009). Novel pandemic influenza A(H1N1) viruses are potently inhibited by DAS181, a sialidase fusion protein. PLoS ONE 4, e7788.[CrossRef] [Google Scholar]
  37. Uyeki, T. M., Chong, Y. H., Katz, J. M., Lim, W., Ho, Y. Y., Wang, S. S., Tsang, T. H., Au, W. W., Chan, S. C. & other authors(2002). Lack of evidence for human-to-human transmission of avian influenza A (H9N2) viruses in Hong Kong, China 1999. Emerg Infect Dis 8, 154–159.[CrossRef] [Google Scholar]
  38. Wilson, S. Z., Gilbert, B. E., Quarles, J. M., Knight, V., McClung, H. W., Moore, R. V. & Couch, R. B.(1984). Treatment of influenza A (H1N1) virus infection with ribavirin aerosol. Antimicrob Agents Chemother 26, 200–203.[CrossRef] [Google Scholar]
  39. World Health Organization(2010). Weekly update on oseltamivir resistance to pandemic influenza A (H1N1) 2009 viruses. http://www.who.int/csr/disease/swineflu/Oseltamivirresistant20100217.pdf (accessed 17 February 2010).

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vol. , part 12, pp. 2898 - 2906

Comparison of survival data of mice infected with A/Mexico/4108/2009 with and without ribavarin treatment

Comparison of survival data of mice infected with A/Mexico/4108/2009 with administration of 40 mg ribavirin kg day at different time points post-infection

Comparison of survival data of mice infected with A/Mexico/4108/2009 and treated with various concentrations of ribavirin administered at the time of infection [Single PDF file](53 KB)

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