Efficacy and Safety of the Neuraminidase Inhibitor Zanamivir in the Treatment of Influenzavirus Infections

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Frederick G. Hayden, Albert D.M.E. Osterhaus, John J. Treanor, Douglas M. Fleming, Fred Y. Aoki, Karl G. Nicholson, Arthur M. Bohnen, Hilary M. Hirst, Oliver Keene, Kevin Wightman, for the GG167 Influenza Study Group

Abstract

Background. The sialic acid analogue zanamivir (GG167) is a selective inhibitor of influenza A and B virus neuraminidases. These viral enzymes are essential for the release of virus from infected cells, and they may also reduce the inactivation of virus by respiratory secretions. When administered experimentally directly to the respiratory tract, zanamivir has potent antiviral effects. We assessed the therapeutic activity of zanamivir in adults with acute influenza.

Methods. We conducted separate randomized, double-blind studies in 38 centers in North America and 32 centers in Europe during the influenza season of 1994-1995. A total of 417 adults with influenza-like illness of less than or equal to 48 hours' duration were randomly assigned to one of three treatments: 6.4 mg of zanamivir by intranasal spray plus 10 mg by inhalation, 10 mg of zanamivir by 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 the alleviation of all major symptoms was one day shorter (four days vs. five days) in the 88 patients given inhaled and intranasal zanamivir (P = 0.02) and the 85 patients given inhaled zanamivir alone (P = 0.05) than in the 89 patients given placebo. Among the infected patients who were febrile at enrollment and among those who began treatment within 30 hours after the onset of symptoms, the median time to the alleviation of major symptoms was four days in both zanamivir groups and seven days in the placebo group (P less than or equal to 0.01). Viral titers of nasal washings in the group given inhaled and intranasal zanamivir were significantly lower than those in the placebo group. The topically administered zanamivir 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 symptoms if begun early. (N Engl J Med 1997;337:874-80.)

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.

The members of the GG167 Influenza Study Group are listed in the Appendix.

Appendix

The following are members of the GG167 Influenza Study Group: Belgium: G. Adam, Brussels; H. Van Pottelbergh, Buizingen; M. Godefroid, Marche-on-Famenne; Finland: O. Ruuskanen and M. Makela, Turku; France: A. Simmons, Linas; J. Luciani, Coligny; J. Richir, Lille; J.A. Cozic, Nantes; M. Behar, Longpont sur Orge; Germany: R. Lehm, Stolpen; Italy: F. Pregliasco, Milano; P. Crovari, Genova; the Netherlands: A. Osterhaus, R. De Groot, A. Bohnen, P. Rothbarth, E. Claas, G. Rimmelzwaan, and J.C. van der Woude, Rotterdam; Norway: H. Hauge, Eidsvaag; I. Hercz, Hoevik; K. Innvik, Fyllingsdalen; M. Haegde Naess and O. Sand, Oslo; T. Tomassen, Trondheim; Spain: C. Jane and J.M. Bordas, Barcelona; M. Palomo, M. Alonso, and M.A. Villanueva, Madrid; Sweden: T. Sandberg, Goteberg; C. Ahlm, Umea; K. Pauksens, Uppsala; M. Glimaker, Danderyd; United Kingdom: D.M. Fleming, Birmingham; M.F. Duffy, Liverpool; D.S.A. Khan, Coppull; K. Nicholson, Leicester; Canada: F. Aoki, P. Orr, Winnipeg, Man.; B. Clecner, St. Jerome, Que.; J. Dylewski, Montreal; K. Forward, Halifax, N.S.; L.J. Miedzinski, Edmonton, Alta.; S. Walmsley, Toronto; K. Williams, Saskatoon, Sask.; D.E. Zoutman, Kingston, Ont.; United States: J. Adelglass, R.C. Andruczk, Dallas; S. Becker, Houston; S. Campbell, Tucson, Ariz.; V.A. Elinoff, Endwell, N.Y.; L.A. Fischer, West Palm Beach, Fla.; L.I. Gilderman, Pembroke Pines, Fla.; A. Graff, Fort Lauderdale, Fla.; F. Hayden and M. Lobo, Charlottesville, Va.; D. Henry, Sandy, Utah; T.M. Howard, Fort Belvoir, Va.; B. Kerzner and K.H. Williams, Baltimore; R. Kobayashi, Omaha, Nebr.; D.J. Mikolich, Providence, R.I.; J. O'Rourke and J. Rubino, Raleigh, N.C.; S.A. Pace, Fort Lewis, Wash.; L.E. Payne, Lakeland AFB, Tex.; G.L. Post, Englewood, Colo.; A. Puopolo, Milford, Mass.; J. Rhudy, Salt Lake City; G.E. Ruoff, Kalamazoo, Mich.; J. Ryder-Benz, Cedar Rapids, Iowa; J. Schoenberger, Redwood City, Calif.; H.M. Serfer, Hollywood, Fla.; B.M. Sklar, Alameda, Calif.; W. Sun, El Paso, Tex.; J. Treanor, Rochester, N.Y.; W. Whitlock, Fort Gordon, Ga.