Efficacy and Safety of the Neuraminidase Inhibitor Zanamivir in the Treatment of Influenzavirus Infections
Frederick G. Hayden, M.D., Albert D.M.E. Osterhaus, D.V.M., Ph.D., John J. Treanor, M.D., Douglas M. Fleming, F.R.C.G.P., Ph.D., Fred Y. Aoki, M.D., Karl G. Nicholson, M.D., Arthur M. Bohnen, M.D., Hilary M. Hirst, Oliver Keene, M.A., M.S., Kevin Wightman, B.S., for The GG167 Influenza Study Group
Background The sialic acid analogue zanamivir (GG167) is a selectiveinhibitor of influenza A and B virus neuraminidases. These viralenzymes are essential for the release of virus from infectedcells, and they may also reduce the inactivation of virus byrespiratory secretions. When administered experimentally directlyto the respiratory tract, zanamivir has potent antiviral effects.We assessed the therapeutic activity of zanamivir in adultswith acute influenza.
Methods We conducted separate randomized, double-blind studiesin 38 centers in North America and 32 centers in Europe duringthe influenza season of 1994–1995. A total of 417 adultswith influenza-like illness of <48 hours' duration were randomlyassigned to one of three treatments: 6.4 mg of zanamivir byintranasal spray plus 10 mg by inhalation, 10 mg of zanamivirby inhalation plus placebo spray, or placebo by both routes.Treatments were self-administered twice daily for five days.
Results Of 262 patients with confirmed influenzavirus infection(63 percent of all patients), the median length of time to thealleviation of all major symptoms was one day shorter (fourdays vs. five days) in the 88 patients given inhaled and intranasalzanamivir (P=0.02) and the 85 patients given inhaled zanamiviralone (P=0.05) than in the 89 patients given placebo. Amongthe infected patients who were febrile at enrollment and amongthose who began treatment within 30 hours after the onset ofsymptoms, the median time to the alleviation of major symptomswas four days in both zanamivir groups and seven days in theplacebo group (P<0.01). Viral titers of nasal washings inthe group given inhaled and intranasal zanamivir were significantlylower than those in the placebo group. The topically administeredzanamivir was well tolerated.
Conclusions In adults with influenza A or B virus infections,direct administration of a selective neuraminidase inhibitor,zanamivir, to the respiratory tract is safe and reduces symptomsif begun early.
Source Information
From the University of Virginia, Charlottesville (F.G.H.); Erasmus University, Rotterdam, the Netherlands (A.D.M.E.O., A.M.B.); University of Rochester, Rochester, N.Y. (J.J.T.); the Northfield Health Centre, Birmingham, United Kingdom (D.M.F.); University of Manitoba, Winnipeg, Canada (F.Y.A.); University of Leicester, Leicester, United Kingdom (K.G.N.); Glaxo Wellcome, Research Triangle Park, N.C. (H.M.H.); and Glaxo Wellcome, Greenford, United Kingdom (O.K., K.W.).
Address reprint requests to Dr. Hayden at Box 473, University of Virginia Health Sciences Center, Charlottesville, VA 22908.
Committee on Infectious Diseases,
(2007). Antiviral Therapy and Prophylaxis for Influenza in Children. Pediatrics
119: 852-860
[Abstract][Full Text]
Nan, X., Carubelli, I., Stamatos, N. M.
(2007). Sialidase expression in activated human T lymphocytes influences production of IFN-{gamma}. J. Leukoc. Biol.
81: 284-296
[Abstract][Full Text]
Lim, W S
(2007). Pandemic flu: clinical management of patients with an influenza-like illness during an influenza pandemic. Thorax
62: 1-46
[Full Text]
Weinstock, D. M., Zucotti, G.
(2006). Shift Shown in Influenza A Adamantane Resistance--Reply. JAMA
296: 1587-1587
[Full Text]
Roberts, S., Hollier, L. M., Sheffield, J., Laibl, V., Wendel, G. D. Jr
(2006). Cost-effectiveness of universal influenza vaccination in a pregnant population.. Obstet Gynecol
107: 1323-1329
[Abstract][Full Text]
Regoes, R. R., Bonhoeffer, S.
(2006). Emergence of drug-resistant influenza virus: population dynamical considerations.. Science
312: 389-391
[Abstract][Full Text]
Gupta, R. K., Nguyen-Van-Tam, J. S., de Jong, M. D., Hien, T. T., Farrar, J.
(2006). Oseltamivir resistance in influenza A (H5N1) infection.. NEJM
354: 1423-1424
[Full Text]
Moscona, A.
(2005). Neuraminidase inhibitors for influenza.. NEJM
353: 1363-1373
[Full Text]
Kotloff, R. M., Ahya, V. N., Crawford, S. W.
(2004). Pulmonary Complications of Solid Organ and Hematopoietic Stem Cell Transplantation. Am. J. Respir. Crit. Care Med.
170: 22-48
[Abstract][Full Text]
Thompson, C. I., Barclay, W. S., Zambon, M. C.
(2004). Changes in in vitro susceptibility of influenza A H3N2 viruses to a neuraminidase inhibitor drug during evolution in the human host. J Antimicrob Chemother
53: 759-765
[Abstract][Full Text]
Oxford, J., Balasingam, S., Lambkin, R.
(2004). A new millennium conundrum: how to use a powerful class of influenza anti-neuraminidase drugs (NAIs) in the community. J Antimicrob Chemother
53: 133-136
[Abstract][Full Text]
Boivin, G., Cote, S., Dery, P., De Serres, G., Bergeron, M. G.
(2004). Multiplex Real-Time PCR Assay for Detection of Influenza and Human Respiratory Syncytial Viruses. J. Clin. Microbiol.
42: 45-51
[Abstract][Full Text]
Rothberg, M. B., Bellantonio, S., Rose, D. N.
(2003). Management of Influenza in Adults Older than 65 Years of Age: Cost-Effectiveness of Rapid Testing and Antiviral Therapy. ANN INTERN MED
139: 321-329
[Abstract][Full Text]
Unoshima, M., Iwasaka, H., Eto, J., Takita-Sonoda, Y., Noguchi, T., Nishizono, A.
(2003). Antiviral Effects of Geranylgeranylacetone: Enhancement of MxA Expression and Phosphorylation of PKR during Influenza Virus Infection. Antimicrob. Agents Chemother.
47: 2914-2921
[Abstract][Full Text]
Heikkinen, T., Chonmaitree, T.
(2003). Importance of Respiratory Viruses in Acute Otitis Media. Clin. Microbiol. Rev.
16: 230-241
[Abstract][Full Text]
Stiver, G.
(2003). The treatment of influenza with antiviral drugs. CMAJ
168: 49-57
[Abstract][Full Text]
Aoki, F. Y., Macleod, M. D., Paggiaro, P., Carewicz, O., El Sawy, A., Wat, C., Griffiths, M., Waalberg, E., Ward, P., on behalf of the IMPACT Study Group,
(2003). Early administration of oral oseltamivir increases the benefits of influenza treatment. J Antimicrob Chemother
51: 123-129
[Abstract][Full Text]
Murrell, M., Porotto, M., Weber, T., Greengard, O., Moscona, A.
(2002). Mutations in Human Parainfluenza Virus Type 3 Hemagglutinin-Neuraminidase Causing Increased Receptor Binding Activity and Resistance to the Transition State Sialic Acid Analog 4-GU-DANA (Zanamivir). J. Virol.
77: 309-317
[Abstract][Full Text]
Heikkinen, T., Marttila, J., Salmi, A. A., Ruuskanen, O.
(2002). Nasal Swab versus Nasopharyngeal Aspirate for Isolation of Respiratory Viruses. J. Clin. Microbiol.
40: 4337-4339
[Abstract][Full Text]
Lee, P. Y., Matchar, D. B., Clements, D. A., Huber, J., Hamilton, J. D., Peterson, E. D.
(2002). Economic Analysis of Influenza Vaccination and Antiviral Treatment for Healthy Working Adults. ANN INTERN MED
137: 225-231
[Abstract][Full Text]
Poehling, K. A., Griffin, M. R., Dittus, R. S., Tang, Y.-W., Holland, K., Li, H., Edwards, K. M.
(2002). Bedside Diagnosis of Influenzavirus Infections in Hospitalized Children. Pediatrics
110: 83-88
[Abstract][Full Text]
Molla, A., Kati, W., Carrick, R., Steffy, K., Shi, Y., Montgomery, D., Gusick, N., Stoll, V. S., Stewart, K. D., Ng, T. I., Maring, C., Kempf, D. J., Kohlbrenner, W.
(2002). In Vitro Selection and Characterization of Influenza A (A/N9) Virus Variants Resistant to a Novel Neuraminidase Inhibitor, A-315675. J. Virol.
76: 5380-5386
[Abstract][Full Text]
Kati, W. M., Montgomery, D., Carrick, R., Gubareva, L., Maring, C., McDaniel, K., Steffy, K., Molla, A., Hayden, F., Kempf, D., Kohlbrenner, W.
(2002). In Vitro Characterization of A-315675, a Highly Potent Inhibitor of A and B Strain Influenza Virus Neuraminidases and Influenza Virus Replication. Antimicrob. Agents Chemother.
46: 1014-1021
[Abstract][Full Text]
Sharma, V., Dowd, M. D., Slaughter, A. J., Simon, S. D.
(2002). Effect of Rapid Diagnosis of Influenza Virus Type A on the Emergency Department Management of Febrile Infants and Toddlers. Arch Pediatr Adolesc Med
156: 41-43
[Abstract][Full Text]
Zambon, M., Hays, J., Webster, A., Newman, R., Keene, O.
(2001). Diagnosis of Influenza in the Community: Relationship of Clinical Diagnosis to Confirmed Virological, Serologic, or Molecular Detection of Influenza. Arch Intern Med
161: 2116-2122
[Abstract][Full Text]
Porotto, M., Greengard, O., Poltoratskaia, N., Horga, M.-A., Moscona, A.
(2001). Human Parainfluenza Virus Type 3 HN-Receptor Interaction: Effect of 4-Guanidino-Neu5Ac2en on a Neuraminidase-Deficient Variant. J. Virol.
75: 7481-7488
[Abstract][Full Text]
Murrell, M. T., Porotto, M., Greengard, O., Poltoratskaia, N., Moscona, A.
(2001). A Single Amino Acid Alteration in the Human Parainfluenza Virus Type 3 Hemagglutinin-Neuraminidase Glycoprotein Confers Resistance to the Inhibitory Effects of Zanamivir on Receptor Binding and Neuraminidase Activity. J. Virol.
75: 6310-6320
[Abstract][Full Text]
Stephenson, I., Nicholson, K.G.
(2001). Influenza: vaccination and treatment. Eur Respir J
17: 1282-1293
[Abstract][Full Text]
Hosking, L, Thickett, D
(2001). British Thoracic Society Winter Meeting 2000. Thorax
56: 412-414
[Full Text]
Diggory, P., Fernandez, C., Humphrey, A., Jones, V., Murphy, M.
(2001). Comparison of elderly people's technique in using two dry powder inhalers to deliver zanamivir: randomised controlled trial. BMJ
322: 577-577
[Abstract][Full Text]
Sidwell, R. W., Smee, D. F., Huffman, J. H., Barnard, D. L., Bailey, K. W., Morrey, J. D., Babu, Y. S.
(2001). In Vivo Influenza Virus-Inhibitory Effects of the Cyclopentane Neuraminidase Inhibitor RWJ-270201. Antimicrob. Agents Chemother.
45: 749-757
[Abstract][Full Text]
Boivin, G., Hardy, I., Kress, A.
(2001). Evaluation of a Rapid Optical Immunoassay for Influenza Viruses (FLU OIA Test) in Comparison with Cell Culture and Reverse Transcription-PCR. J. Clin. Microbiol.
39: 730-732
[Abstract][Full Text]
Macfarlane, J, Holmes, W, Gard, P, Macfarlane, R, Rose, D, Weston, V, Leinonen, M, Saikku, P, Myint, S
(2001). Prospective study of the incidence, aetiology and outcome of adult lower respiratory tract illness in the community. Thorax
56: 109-114
[Abstract][Full Text]
Horimoto, T., Kawaoka, Y.
(2001). Pandemic Threat Posed by Avian Influenza A Viruses. Clin. Microbiol. Rev.
14: 129-149
[Abstract][Full Text]
van Elden, L. J. R., Nijhuis, M., Schipper, P., Schuurman, R., van Loon, A. M.
(2001). Simultaneous Detection of Influenza Viruses A and B Using Real-Time Quantitative PCR. J. Clin. Microbiol.
39: 196-200
[Abstract][Full Text]
Gonzales, R., Sande, M. A.
(2000). Uncomplicated Acute Bronchitis. ANN INTERN MED
133: 981-991
[Abstract][Full Text]
Couch, R. B.
(2000). Influenza: Prospects for Control. ANN INTERN MED
133: 992-998
[Abstract][Full Text]
Couch, R. B.
(2000). Prevention and Treatment of Influenza. NEJM
343: 1778-1787
[Full Text]
Greengard, O., Poltoratskaia, N., Leikina, E., Zimmerberg, J., Moscona, A.
(2000). The Anti-Influenza Virus Agent 4-GU-DANA (Zanamivir) Inhibits Cell Fusion Mediated by Human Parainfluenza Virus and Influenza Virus HA. J. Virol.
74: 11108-11114
[Abstract][Full Text]
Kaiser, L., Keene, O. N., Hammond, J. M. J., Elliott, M., Hayden, F. G.
(2000). Impact of Zanamivir on Antibiotic Use for Respiratory Events Following Acute Influenza in Adolescents and Adults. Arch Intern Med
160: 3234-3240
[Abstract][Full Text]
Monto, A. S., Gravenstein, S., Elliott, M., Colopy, M., Schweinle, J.
(2000). Clinical Signs and Symptoms Predicting Influenza Infection. Arch Intern Med
160: 3243-3247
[Abstract][Full Text]
Hayden, F. G., Gubareva, L. V., Monto, A. S., Klein, T. C., Elliott, M. J., Hammond, J. M., Sharp, S. J., Ossi, M. J., The Zanamivir Family Study Group,
(2000). Inhaled Zanamivir for the Prevention of Influenza in Families. NEJM
343: 1282-1289
[Abstract][Full Text]
Wright, P.
(2000). Influenza in the Family. NEJM
343: 1331-1332
[Full Text]
Fouchier, R. A. M., Bestebroer, T. M., Herfst, S., Van Der Kemp, L., Rimmelzwaan, G. F., Osterhaus, A. D. M. E.
(2000). Detection of Influenza A Viruses from Different Species by PCR Amplification of Conserved Sequences in the Matrix Gene. J. Clin. Microbiol.
38: 4096-4101
[Abstract][Full Text]
KASISKE, B. L., VAZQUEZ, M. A., HARMON, W. E., BROWN, R. S., DANOVITCH, G. M., GASTON, R. S., ROTH, D., SCANDLING, J. D. JR., SINGER, G. G.
(2000). Recommendations for the Outpatient Surveillance of Renal Transplant Recipients. J. Am. Soc. Nephrol.
11: S1-S86
[Abstract][Full Text]
Peng, A. W., Milleri, S., Stein, D. S.
(2000). Direct Measurement of the Anti-Influenza Agent Zanamivir in the Respiratory Tract following Inhalation. Antimicrob. Agents Chemother.
44: 1974-1976
[Abstract][Full Text]
Nichol, K. L
(2000). Zanamivir speeds symptom relief in influenza. Evid. Based Med.
5: 80-80
[Full Text]
Nichol, K. L
(2000). Oseltamivir once or twice daily safely prevented influenza. Evid. Based Med.
5: 81-81
[Full Text]
Zalman, L. S., Brothers, M. A., Dragovich, P. S., Zhou, R., Prins, T. J., Worland, S. T., Patick, A. K.
(2000). Inhibition of Human Rhinovirus-Induced Cytokine Production by AG7088, a Human Rhinovirus 3C Protease Inhibitor. Antimicrob. Agents Chemother.
44: 1236-1241
[Abstract][Full Text]
Williamson, J. C., Pegram, P. S.
(2000). Respiratory Distress Associated with Zanamivir. NEJM
342: 661-662
[Full Text]
Solorzano, A., Zheng, H., Fodor, E., Brownlee, G. G., Palese, P., García-Sastre, A.
(2000). Reduced levels of neuraminidase of influenza A viruses correlate with attenuated phenotypes in mice. J. Gen. Virol.
81: 737-742
[Abstract][Full Text]
Noyola, D. E., Clark, B., O'Donnell, F. T., Atmar, R. L., Greer, J., Demmler, G. J.
(2000). Comparison of a New Neuraminidase Detection Assay with an Enzyme Immunoassay, Immunofluorescence, and Culture for Rapid Detection of Influenza A and B Viruses in Nasal Wash Specimens. J. Clin. Microbiol.
38: 1161-1165
[Abstract][Full Text]
Treanor, J. J., Hayden, F. G., Vrooman, P. S., Barbarash, R., Bettis, R., Riff, D., Singh, S., Kinnersley, N., Ward, P., Mills, R. G., for the US Oral Neuraminidase Study Group,
(2000). Efficacy and Safety of the Oral Neuraminidase Inhibitor Oseltamivir in Treating Acute Influenza: A Randomized Controlled Trial. JAMA
283: 1016-1024
[Abstract][Full Text]
Landry, M. L., Ferguson, D.
(2000). SimulFluor Respiratory Screen for Rapid Detection of Multiple Respiratory Viruses in Clinical Specimens by Immunofluorescence Staining. J. Clin. Microbiol.
38: 708-711
[Abstract][Full Text]
Barnett, J. M., Cadman, A., Gor, D., Dempsey, M., Walters, M., Candlin, A., Tisdale, M., Morley, P. J., Owens, I. J., Fenton, R. J., Lewis, A. P., Claas, E. C. J., Rimmelzwaan, G. F., De Groot, R., Osterhaus, A. D. M. E.
(2000). Zanamivir Susceptibility Monitoring and Characterization of Influenza Virus Clinical Isolates Obtained during Phase II Clinical Efficacy Studies. Antimicrob. Agents Chemother.
44: 78-87
[Abstract][Full Text]
Landry, M. L., Cohen, S., Ferguson, D.
(2000). Impact of Sample Type on Rapid Detection of Influenza Virus A by Cytospin-Enhanced Immunofluorescence and Membrane Enzyme-Linked Immunosorbent Assay. J. Clin. Microbiol.
38: 429-430
[Abstract][Full Text]
(1999). {blacktriangledown}Zanamivir for influenza. DTB
37: 81-84
[Abstract][Full Text]
Fenton, R. J., Morley, P. J., Owens, I. J., Gower, D., Parry, S., Crossman, L., Wong, T.
(1999). Chemoprophylaxis of Influenza A Virus Infections, with Single Doses of Zanamivir, Demonstrates that Zanamivir Is Cleared Slowly from the Respiratory Tract. Antimicrob. Agents Chemother.
43: 2642-2647
[Abstract][Full Text]
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.
(1999). Use of the Oral Neuraminidase Inhibitor Oseltamivir in Experimental Human Influenza: Randomized Controlled Trials for Prevention and Treatment. JAMA
282: 1240-1246
[Abstract][Full Text]
Basler, C. F., Garcia-Sastre, A., Palese, P.
(1999). Mutation of Neuraminidase Cysteine Residues Yields Temperature-Sensitive Influenza Viruses. J. Virol.
73: 8095-8103
[Abstract][Full Text]
Nguyen-Van-Tam, J. S
(1999). Zanamivir for influenza: a public health perspective. BMJ
319: 655-656
[Full Text]
Bartlett, J. G.
(1999). Update in Infectious Diseases. ANN INTERN MED
131: 273-280
[Full Text]
Monto, A. S., Robinson, D. P., Herlocher, M. L., Hinson, J. M. Jr, Elliott, M. J., Crisp, A.
(1999). Zanamivir in the Prevention of Influenza Among Healthy Adults: A Randomized Controlled Trial. JAMA
282: 31-35
[Abstract][Full Text]
Patriarca, P. A.
(1999). New Options for Prevention and Control of Influenza. JAMA
282: 75-77
[Full Text]
Stephenson, I., Nicholson, K. G.
(1999). Chemotherapeutic control of influenza. J Antimicrob Chemother
44: 6-10
[Full Text]
Calfee, D. P., Peng, A. W., Cass, L. M., Lobo, M., Hayden, F. G.
(1999). Safety and Efficacy of Intravenous Zanamivir in Preventing Experimental Human Influenza A Virus Infection. Antimicrob. Agents Chemother.
43: 1616-1620
[Abstract][Full Text]
Balfour, H. H.
(1999). Antiviral Drugs. NEJM
340: 1255-1268
[Full Text]
Tai, C. Y., Escarpe, P. A., Sidwell, R. W., Williams, M. A., Lew, W., Wu, H., Kim, C. U., Mendel, D. B.
(1998). Characterization of Human Influenza Virus Variants Selected In Vitro in the Presence of the Neuraminidase Inhibitor GS 4071. Antimicrob. Agents Chemother.
42: 3234-3241
[Abstract][Full Text]
Drinka, P. J., Gravenstein, S., Schilling, M., Krause, P., Miller, B. A., Shult, P.
(1998). Duration of Antiviral Prophylaxis During Nursing Home Outbreaks of Influenza A: A Comparison of 2 Protocols. Arch Intern Med
158: 2155-2159
[Abstract][Full Text]
Pillay, D., Zambon, M.
(1998). Antiviral drug resistance. BMJ
317: 660-662
[Full Text]
Mossad, S. B
(1998). Fortnightly review: Treatment of the common cold. BMJ
317: 33-36
[Full Text]
Mendel, D. B., Tai, C. Y., Escarpe, P. A., Li, W., Sidwell, R. W., Huffman, J. H., Sweet, C., Jakeman, K. J., Merson, J., Lacy, S. A., Lew, W., Williams, M. A., Zhang, L., Chen, M. S., Bischofberger, N., Kim, C. U.
(1998). Oral Administration of a Prodrug of the Influenza Virus Neuraminidase Inhibitor GS 4071 Protects Mice and Ferrets against Influenza Infection. Antimicrob. Agents Chemother.
42: 640-646
[Abstract][Full Text]
Li, W., Escarpe, P. A., Eisenberg, E. J., Cundy, K. C., Sweet, C., Jakeman, K. J., Merson, J., Lew, W., Williams, M., Zhang, L., Kim, C. U., Bischofberger, N., Chen, M. S., Mendel, D. B.
(1998). Identification of GS 4104 as an Orally Bioavailable Prodrug of the Influenza Virus Neuraminidase Inhibitor GS 4071. Antimicrob. Agents Chemother.
42: 647-653
[Abstract][Full Text]
Previous
