Resistance of Influenza a Viruses to Amantadine and Rimantadine

  • Alan J. Hay
  • Setareh Grambas
  • Michael S. Bennett
Part of the GWUMC Department of Biochemistry Annual Spring Symposia book series (GWUN)


Numerous clinical studies carried out over the years have documented the efficacy of amantadine and rimantadine in the prophylaxis and treatment of influenza A infections 1–9. Although initially licensed in 1966, the use of amantadine in both the United States and the United Kingdom has been limited. Rimantadine, more widely used in the Soviet Union in recent years3 has recently been licensed in France and awaits approval for use in the United States. The reticence to use these agents has been due to several factors, not least the extreme specificity of the drugs for influenza A viruses and the lack of any benefit against influenza B infections which are responsible for a significant proportion of recurrent disease in the human population. This has not, however, precluded the successful prophylactic use of amantadine following identification of influenza A outbreaks to limit their spread within semi-closed communities such as boarding schools and nursing homes8,9. Initial concerns regarding adverse side-effects have now largely been allayed and rimantadine which causes a lower incidence of neurological reactions1,10,11 is now generally perceived as the drug of choice.


Influenza Virus Avian Influenza Nicotinic Acetylcholine Receptor Resistant Virus Amantadine Hydrochloride 
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  1. 1.
    R. Dolin, R. C. Reichman, H. P. Madore, R. Maynard, P. N. Linton, and J. Webber-Jones, A controlled trial of amantadine and rimantadine in the prophylaxis of influenza A infection, N. Engl. J. Med. 307: 580 (1982).PubMedCrossRefGoogle Scholar
  2. 2.
    T. A. Bektimirov, R. G. Douglas Jr., R. Dolin G. J. Galasso, V.F. Krylov and J. Oxford, Current status of amantadine and rimantadine as anti-influenza A agents: Memorandum from a WHO meeting, Bull WHO 63: 52 (1985).Google Scholar
  3. 3.
    D. M. Zlydnikov, O. I. Kubar, T. P. Kovaleva and L. E. Kamforin, Study of rimantadine in the USSR: a review of the literature, Rev. Infect. Dis. 3: 408 (1981).PubMedCrossRefGoogle Scholar
  4. 4.
    R. D. Clover, S. A. Crawford, T. D. Abell, C. N. Ramsey, W. P. Glezen and R. B. Couch, Effectiveness of rimantadine prophylaxis of children within families, Am. J. Dis. Child. 140: 706 (1986).PubMedGoogle Scholar
  5. 5.
    R. L. Tominack and F. G. Hayden, Rimantadine hydrochloride and amantadine hydrochloride use in influenza A virus infections, Infect. Dis. Clin. North Am. 1: 459 (1987).PubMedGoogle Scholar
  6. 6.
    W. S. Wingfield, D. Pollack and R. R. Grunert, Therapeutic efficacy of amantadine HC1 and rimantadine HC1 in naturally occurring influenza A2 respiratory illness in man, N. Engl. J. Med. 281: 579 (1969).PubMedCrossRefGoogle Scholar
  7. 7.
    L. P. Van Voris, R. F. Betts, F. G. Hayden, W. A. Christmas and R. G. Douglas, Successful treatment of naturally occurring influenza A/USSR/77 H1N1, J. Am. Med. Assoc. 245: 1128 (1981).CrossRefGoogle Scholar
  8. 8.
    D. K. Payler, P. A. Purdham, Influenza A prophylaxis with amantadine in a boarding school, Lancet 1: 504 (1984).Google Scholar
  9. 9.
    W. L. Atkinson, N. H. Arden, P. A. Patraica et al., Amantadine prophylaxis during an institutional outbreak of type A (H1N1) influenza, Arch. Intern. Med. 146: 1751 (1986).Google Scholar
  10. 10.
    F. G. Hayden, H. E. Hoffman and D. A. Spyker, Differences in side effects of amantadine hydrochloride and rimantadine hydrochloride relate to differences in pharmacokinetics. Antimicrob. Agents Chemother. 23: 458 (1983).PubMedGoogle Scholar
  11. 11.
    P. A. Patriarca, N. A. Kater, A. P. Kendal, D. J. Bregman, J. D. Smith and R. K. Sikes, Safety of prolonged administration of rimantadine hydrochloride in the prophylaxis of influenza A virus infections in nursing homes, Antimicrob. Agents Chemother. 26: 101 (1984).Google Scholar
  12. 12.
    J. S. Oxford, I. S. Logan and C. W. Potter, In vivo selection of an influenza A2 strain resistant to amantadine, Nature (London) 226:82 (1970).Google Scholar
  13. 13.
    R. G. Webster, Y. Kawaoka, W. J. Bean, C. W. Beard and M. Brugh, Chemotherapy and vaccination: A possible strategy for the control of highly virulent influenza virus, J. Virol. 55: 173 (1985).PubMedGoogle Scholar
  14. 14.
    G. Appleyard, Amantadine-resistance as a genetic marker for influenza viruses, J. Gen. Virol. 36: 249 (1977).PubMedCrossRefGoogle Scholar
  15. 15.
    H. J. Field and S. E. Goldthorpe, Antiviral drug resistance, Trends Pharmacol. Sci. 10: 333 (1989).Google Scholar
  16. 16.
    R. B. Belshe, M. Hall-Smith, C. B. Hall, R. Betts and A. J. Hay, Genetic basis of resistance to rimantadine emerging during treatment of influenza virus infection, J. Virol. 62: 1508 (1988).PubMedGoogle Scholar
  17. 17. F. G. Hayden, R. B. Belshe, R. D. Clover, A. J. Hay, M. G. Oakes and W. Soo, Emergence and apparent transmission of rimantadine-resistant influenza A virus in families, N. Engl. J. Med. 321:1696 (1989).Google Scholar
  18. 18.
    E. E. Mast, J. P. Davis, M. W. Harmon, N. H. Arden, R. Circo and G. E. Tyszka, Emergence and possible transmission of amantadine-resistant viruses during nursing home outbreaks of influenza A (H3N2), Program and Abstracts of the 29th Interscience Conference on Antimicrobial Agents and Chemotherapy, Houston. Washington D.C.: American Society for Microbiology, 111, abstract.Google Scholar
  19. 19.
    F. Roumillat, E. Roacha, H. Regnery, D. Wells and N. Cox, Emergence of amantadine-resistant influenza A viruses in nursing homes during the 1989–1990 influenza season, Program and Abstracts of the Eighth International Congress of Virology, Berlin (1990).Google Scholar
  20. 20.
    M. D. Lubeck, J. L. Schulman and P. Palese, Susceptibility of influenza A viruses to amantadine is influenced by the gene coding for M protein, J. Virol. 28: 710 (1978).PubMedGoogle Scholar
  21. 21.
    A. J. Hay, N. T. C. Kennedy, J. J. Skehel and G. Appleyard, The matrix protein gene determines amantadine-sensitivity of influenza viruses, J. Gen. Virol. 42: 189 (1979).PubMedCrossRefGoogle Scholar
  22. 22.
    C. Scholtissek, and G. P. Faulkner, Amantadine-resistant and sensitive influenza A strains and recombinants. J. Gen. Virol. 44: 807 (1979).PubMedCrossRefGoogle Scholar
  23. 23.
    A. J. Hay and M. C. Zambon, Multiple actions of amantadine against influenza viruses, in “Antiviral drugs and interferon: The molecular basis of their activity”, Y. Becker, ed. Martinus Nijhoff Publishing, Boston, MA, 301 (1984).Google Scholar
  24. 24.
    A. J. Hay, A. J. Wolstenholme, J. J. Skehel and M. H. Smith, The molecular basis of the specific anti-influenza action of amantadine, EMBO J. 4: 3021 (1985).Google Scholar
  25. 25.
    A. J. Hay, M. C. Zambon, A. J. Wolstenholme, J. J. Skehel and M. H. Smith, Molecular basis of resistance of influenza A viruses to amantadine, J. Antimicrob. Chemother. 18 (Suppl.B): 19 (1986).PubMedGoogle Scholar
  26. 26.
    A. G. Bukrinskaya, N. E. Vorkunova and N. L. Pushkarskaya, Uncoating of a rimantadine-resistant variant of influenza virus in the presence of rimantadine, J. Gen. Virol. 60: 61 (1982).PubMedCrossRefGoogle Scholar
  27. 27.
    S. A. Wharton, A. J. Hay, R. Sugrue, J. J. Skehel, W. I. Weis and D. C. Wiley, Membrane fusion by influenza viruses and the mechanism of action of amantadine, in “Use of X-ray crystallography in the design of antiviral agents”, W. G. Laver and G. M. Air eds., Academic Press.Google Scholar
  28. 28.
    R. J. Sugrue, G. Bahadur, M. C. Zambon, M. Hall-Smith, A. R. Douglas and A. J. Hay, Specific structural alteration of the influenza haemagglutinin by amantadine, EMBO J. 9: 3469 (1990)Google Scholar
  29. 29.
    R. W. H. Ruigrok, E. M. A. Hirst and A. J. Hay, The specific inhibition of influenza A virus maturation by amantadine: an electron microscopic examination, J. Gen. Virol. 71 (1990).Google Scholar
  30. 30.
    S. L. Zebedee and R. A. Lamb, Influenza A virus M2 protein: monoclonal antibody restriction of virus growth and detection of M2 in virions, J. Virol. 62: 2762 (1988).PubMedGoogle Scholar
  31. 30.
    S. L. Zebedee and R. A. Lamb, Influenza A virus M2 protein: monoclonal antibody restriction of virus growth and detection of M2 in virions, J. Virol. 62: 2762 (1988).PubMedGoogle Scholar
  32. 32.
    J. E. Warnick, M. A. Maleque, N. Bakry, A. T. Eldefrawi and E. X. Albuquerque, Structure-activity relationships of amantadine: 1. interaction of the N-alkyl analogues with the ionic channels of the nicotinic acetylcholine receptor and electrically excitable membrane, Molec. Pharmacol. 22: 82 (1982).Google Scholar
  33. 33.
    P. Charnet, C. Labarca, R. J. Leonard, N. J. Vogelaar, L. Czyzyk, A. Gouin, N. Davidson and H. A. Lester, An open-channel blocker interacts with adjacent turns of a-helices in the nicotinic acetylcholine receptor, Neuron 4: 87 (1990).PubMedCrossRefGoogle Scholar
  34. 34.
    R. B. Belshe and A. J. Hay, Drug resistance and the mechanisms of action on influenza A virus, J. Resp. Dis. Suppl. S52 (1989).Google Scholar
  35. 35.
    C. B. Hall, R. Dolin, C. L. Gala, D. M. Markovitz, Y. Q. Zhang, P. H. Madore, R. A. Disney, W. B. Talpey, J. L. Green, A. B. Francis and M. E. Pickichero, Children with influenza A infection: treatment with rimantadine, Pediatrics 80: 275 (1987).PubMedGoogle Scholar
  36. 36.
    C. W. Beard, M. Brugh and R. G. Webster, Emergence of amantadine-resistant H5N2 avian influenza virus during a simulated layer flock treatment program, Avian Dis. 31: 533 (1987).PubMedCrossRefGoogle Scholar
  37. 37.
    W. J. Bean, S. C. Threlkeld and R. G. Webster, Biologic potential of amantadine-resistant influenza A virus in an avian model, J. Infect. Dis. 159: 1050 (1989).PubMedCrossRefGoogle Scholar
  38. 38.
    R. B. Belshe, B. Burk, F. Newman, R. L. Cerruti and I. S. Sim, Resistance of influenza A virus to amantadine and rimantadine: results of one decade of surveillance, J. Infect. Dis. 159: 430 (1989).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Alan J. Hay
    • 1
  • Setareh Grambas
    • 1
  • Michael S. Bennett
    • 1
  1. 1.National Institute for Medical ResearchMill Hill, LondonUK

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