Abstract
Antiviral agents could potentially play a major role in the initial response to pandemic influenza, particularly with the likelihood that an effective vaccine is unavailable, by reducing morbidity and mortality. The M2 inhibitors are partially effective for chemoprophylaxis of pandemic influenza and evidence from studies of interpandemic influenza indicate that the neuraminidase inhibitors would be effective in prevention. In addition to the symptom benefit observed with M2 inhibitor treatment, early therapeutic use of neuraminidase inhibitors has been shown to reduce the risk of lower respiratory complications. Clinical pharmacology and adverse drug effect profiles indicate that the neuraminidase inhibitors and rimantadine are preferable to amantadine with regard to the need for individual prescribing and tolerance monitoring. Transmission of drug-resistant virus could substantially limit the effectiveness of M2 inhibitors and the possibility exists for primary M2 inhibitor resistance in a pandemic strain. The frequency of resistance emergence is lower with neuraminidase inhibitors and mathematical modelling studies indicate that the reduced transmissibility of drug-resistant virus observed with neuraminidase inhibitor-resistant variants would lead to negligible community spread of such variants. Thus, there are antiviral drugs currently available that hold considerable promise for response to pandemic influenza before a vaccine is available, although considerable work remains in realizing this potential. Markedly increasing the quantity of available antiviral agents through mechanisms such as stockpiling, educating health care providers and the public and developing effective means of rapid distribution to those in need are essential in developing an effective response, but remain currently unresolved problems.
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- Barnett J. M., Cadman A., Gor D., Dempsey M., Walters M., Candlin A., Tisdale M., Morley P. J., Owens I. J., Fenton R. J. Zanamivir susceptibility monitoring and characterization of influenza virus clinical isolates obtained during phase II clinical efficacy studies. Antimicrob Agents Chemother. 2000 Jan;44(1):78–87. doi: 10.1128/aac.44.1.78-87.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bean W. J., Threlkeld S. C., Webster R. G. Biologic potential of amantadine-resistant influenza A virus in an avian model. J Infect Dis. 1989 Jun;159(6):1050–1056. doi: 10.1093/infdis/159.6.1050. [DOI] [PubMed] [Google Scholar]
- Boivin G., Goyette N., Hardy I., Aoki F., Wagner A., Trottier S. Rapid antiviral effect of inhaled zanamivir in the treatment of naturally occurring influenza in otherwise healthy adults. J Infect Dis. 2000 Apr 13;181(4):1471–1474. doi: 10.1086/315392. [DOI] [PubMed] [Google Scholar]
- Delamothe T., Smith R. PubMed Central: creating an Aladdin's cave of ideas. BMJ. 2001 Jan 6;322(7277):1–2. doi: 10.1136/bmj.322.7277.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Doyle W. J., Skoner D. P., Alper C. M., Allen G., Moody S. A., Seroky J. T., Hayden F. G. Effect of rimantadine treatment on clinical manifestations and otologic complications in adults experimentally infected with influenza A (H1N1) virus. J Infect Dis. 1998 May;177(5):1260–1265. doi: 10.1086/515294. [DOI] [PubMed] [Google Scholar]
- Englund J. A., Champlin R. E., Wyde P. R., Kantarjian H., Atmar R. L., Tarrand J., Yousuf H., Regnery H., Klimov A. I., Cox N. J. Common emergence of amantadine- and rimantadine-resistant influenza A viruses in symptomatic immunocompromised adults. Clin Infect Dis. 1998 Jun;26(6):1418–1424. doi: 10.1086/516358. [DOI] [PubMed] [Google Scholar]
- Galbraith A. W., Oxford J. S., Schild G. C., Potter C. W., Watson G. I. Therapeutic effect of 1-adamantanamine hydrochloride in naturally occurring influenza A 2 -Hong Kong infection. A controlled double-blind study. Lancet. 1971 Jul 17;2(7716):113–115. doi: 10.1016/s0140-6736(71)92299-9. [DOI] [PubMed] [Google Scholar]
- Galbraith A. W., Oxford J. S., Schild G. C., Watson G. I. Study of 1-adamantanamine hydrochloride used prophylactically during the Hong Kong influenza epidemic in the family environment. Bull World Health Organ. 1969;41(3):677–682. [PMC free article] [PubMed] [Google Scholar]
- Gubareva L. V., Kaiser L., Hayden F. G. Influenza virus neuraminidase inhibitors. Lancet. 2000 Mar 4;355(9206):827–835. doi: 10.1016/S0140-6736(99)11433-8. [DOI] [PubMed] [Google Scholar]
- 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 Nov;178(5):1257–1262. doi: 10.1086/314440. [DOI] [PubMed] [Google Scholar]
- Hall C. B., Dolin R., Gala C. L., Markovitz D. M., Zhang Y. Q., Madore P. H., Disney F. A., Talpey W. B., Green J. L., Francis A. B. Children with influenza A infection: treatment with rimantadine. Pediatrics. 1987 Aug;80(2):275–282. [PubMed] [Google Scholar]
- Hayden F. G. Antivirals for pandemic influenza. J Infect Dis. 1997 Aug;176 (Suppl 1):S56–S61. doi: 10.1086/514177. [DOI] [PubMed] [Google Scholar]
- 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 Dec 21;321(25):1696–1702. doi: 10.1056/NEJM198912213212502. [DOI] [PubMed] [Google Scholar]
- Hayden F. G., Gubareva L. V., Monto A. S., Klein T. C., Elliot M. J., Hammond J. M., Sharp S. J., Ossi M. J., Zanamivir Family Study Group Inhaled zanamivir for the prevention of influenza in families. Zanamivir Family Study Group. N Engl J Med. 2000 Nov 2;343(18):1282–1289. doi: 10.1056/NEJM200011023431801. [DOI] [PubMed] [Google Scholar]
- Hayden F. G., Treanor J. J., Fritz R. S., Lobo M., Betts R. F., Miller M., Kinnersley N., Mills R. G., Ward P., Straus S. E. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment. JAMA. 1999 Oct 6;282(13):1240–1246. doi: 10.1001/jama.282.13.1240. [DOI] [PubMed] [Google Scholar]
- Iwahashi J., Tsuji K., Ishibashi T., Kajiwara J., Imamura Y., Mori R., Hara K., Kashiwagi T., Ohtsu Y., Hamada N. Isolation of amantadine-resistant influenza a viruses (H3N2) from patients following administration of amantadine in Japan. J Clin Microbiol. 2001 Apr;39(4):1652–1653. doi: 10.1128/JCM.39.4.1652-1653.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kaiser L., Keene O. N., Hammond J. M., Elliott M., Hayden F. G. Impact of zanamivir on antibiotic use for respiratory events following acute influenza in adolescents and adults. Arch Intern Med. 2000 Nov 27;160(21):3234–3240. doi: 10.1001/archinte.160.21.3234. [DOI] [PubMed] [Google Scholar]
- Keyser L. A., Karl M., Nafziger A. N., Bertino J. S., Jr 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 May 22;160(10):1485–1488. doi: 10.1001/archinte.160.10.1485. [DOI] [PubMed] [Google Scholar]
- Knight V., Fedson D., Baldini J., Douglas R. G., Couch R. B. Amantadine therapy of epidemic influenza a(2) (Hong Kong). Infect Immun. 1970 Feb;1(2):200–204. doi: 10.1128/iai.1.2.200-204.1970. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McKimm-Breschkin J. L. Resistance of influenza viruses to neuraminidase inhibitors--a review. Antiviral Res. 2000 Jul;47(1):1–17. doi: 10.1016/s0166-3542(00)00103-0. [DOI] [PubMed] [Google Scholar]
- Meltzer M. I., Cox N. J., Fukuda K. The economic impact of pandemic influenza in the United States: priorities for intervention. Emerg Infect Dis. 1999 Sep-Oct;5(5):659–671. doi: 10.3201/eid0505.990507. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Monto A. S., Gunn R. A., Bandyk M. G., King C. L. Prevention of Russian influenza by amantadine. JAMA. 1979 Mar 9;241(10):1003–1007. [PubMed] [Google Scholar]
- Monto A. S., Robinson D. P., Herlocher M. L., Hinson J. M., Jr, Elliott M. J., Crisp A. Zanamivir in the prevention of influenza among healthy adults: a randomized controlled trial. JAMA. 1999 Jul 7;282(1):31–35. doi: 10.1001/jama.282.1.31. [DOI] [PubMed] [Google Scholar]
- Monto A. S., Webster A., Keene O. Randomized, placebo-controlled studies of inhaled zanamivir in the treatment of influenza A and B: pooled efficacy analysis. J Antimicrob Chemother. 1999 Nov;44 (Suppl B):23–29. doi: 10.1093/jac/44.suppl_2.23. [DOI] [PubMed] [Google Scholar]
- Nafta I., TTurcanu A. G., Braun I., Companetz W., Simionescu A., Birţ E., Florea V. Administration of amantadine for the prevention of Hong Kong influenza. Bull World Health Organ. 1970;42(3):423–427. [PMC free article] [PubMed] [Google Scholar]
- Oker-Blom N., Hovi T., Leinikki P., Palosuo T., Pettersson R., Suni J. Protection of man from natural infection with influenza A2 Hong Kong virus by amantadine: a controlled field trial. Br Med J. 1970 Sep 19;3(5724):676–678. doi: 10.1136/bmj.3.5724.676. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pettersson R. F., Hellström P. E., Penttinen K., Pyhälä R., Tokola O., Vartio T., Visakorpi R. Evaluation of amantadine in the prophylaxis of influenza A (H1N1) virus infection: a controlled field trial among young adults and high-risk patients. J Infect Dis. 1980 Sep;142(3):377–383. doi: 10.1093/infdis/142.3.377. [DOI] [PubMed] [Google Scholar]
- Quarles J. M., Couch R. B., Cate T. R., Goswick C. B. Comparison of amantadine and rimantadine for prevention of type A (Russian) influenza. Antiviral Res. 1981 Sep;1(3):149–155. doi: 10.1016/0166-3542(81)90003-6. [DOI] [PubMed] [Google Scholar]
- Schoch-Spana M. Implications of pandemic influenza for bioterrorism response. Clin Infect Dis. 2000 Nov 17;31(6):1409–1413. doi: 10.1086/317493. [DOI] [PubMed] [Google Scholar]
- Smorodintsev A. A., Karpuhin G. I., Zlydnikov D. M., Malyseva A. M., Svecova E. G., Burov S. A., Hramcova L. M., Romanov J. A., Taros L. J., Ivannikov J. G. The prophylactic effectiveness of amantadine hydrochloride in an epidemic of Hong Kong influenza in Leningrad in 1969. Bull World Health Organ. 1970;42(6):865–872. [PMC free article] [PubMed] [Google Scholar]
- Stilianakis N. I., Perelson A. S., Hayden F. G. Emergence of drug resistance during an influenza epidemic: insights from a mathematical model. J Infect Dis. 1998 Apr;177(4):863–873. doi: 10.1086/515246. [DOI] [PubMed] [Google Scholar]
- Tisdale M. Monitoring of viral susceptibility: new challenges with the development of influenza NA inhibitors. Rev Med Virol. 2000 Jan-Feb;10(1):45–55. doi: 10.1002/(sici)1099-1654(200001/02)10:1<45::aid-rmv265>3.0.co;2-r. [DOI] [PubMed] [Google Scholar]
- Treanor J. J., Hayden F. G., Vrooman P. S., Barbarash R., Bettis R., Riff D., Singh S., Kinnersley N., Ward P., Mills R. G. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group. JAMA. 2000 Feb 23;283(8):1016–1024. doi: 10.1001/jama.283.8.1016. [DOI] [PubMed] [Google Scholar]
- Van Voris L. P., Betts R. F., Hayden F. G., Christmas W. A., Douglas R. G., Jr Successful treatment of naturally occurring influenza A/USSR/77 H1N1. JAMA. 1981 Mar 20;245(11):1128–1131. doi: 10.1001/jama.245.11.1128. [DOI] [PubMed] [Google Scholar]
- Walker J. B., Hussey E. K., Treanor J. J., Montalvo A., Jr, Hayden F. G. Effects of the neuraminidase inhibitor zanamavir on otologic manifestations of experimental human influenza. J Infect Dis. 1997 Dec;176(6):1417–1422. doi: 10.1086/514136. [DOI] [PubMed] [Google Scholar]
- Welliver R., Monto A. S., Carewicz O., Schatteman E., Hassman M., Hedrick J., Jackson H. C., Huson L., Ward P., Oxford J. S. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA. 2001 Feb 14;285(6):748–754. doi: 10.1001/jama.285.6.748. [DOI] [PubMed] [Google Scholar]
- Whitley R. J., Hayden F. G., Reisinger K. S., Young N., Dutkowski R., Ipe D., Mills R. G., Ward P. Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J. 2001 Feb;20(2):127–133. doi: 10.1097/00006454-200102000-00002. [DOI] [PubMed] [Google Scholar]
- Ziegler T., Hemphill M. L., Ziegler M. L., Perez-Oronoz G., Klimov A. I., Hampson A. W., Regnery H. L., Cox N. J. Low incidence of rimantadine resistance in field isolates of influenza A viruses. J Infect Dis. 1999 Oct;180(4):935–939. doi: 10.1086/314994. [DOI] [PubMed] [Google Scholar]