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Antimicrobial Agents and Chemotherapy, January 2000, p. 78-87, Vol. 44, No. 1
0066-4804/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Zanamivir Susceptibility Monitoring and Characterization of Influenza Virus Clinical Isolates Obtained during Phase II Clinical Efficacy Studies

J. M. Barnett,1 A. Cadman,1 D. Gor,1 M. Dempsey,1 M. Walters,1 A. Candlin,1 M. Tisdale,1,* P. J. Morley,2 I. J. Owens,2 R. J. Fenton,2 A. P. Lewis,3 E. C. J. Claas,4 G. F. Rimmelzwaan,4 R. De Groot,5 and A. D. M. E. Osterhaus6

Clinical Virology Unit,1 Systems Biology Unit,2 and Advanced Technology and Informatics Unit,3 Glaxo Wellcome Medicines Research Centre, Stevenage, United Kingdom, and University Hospital Dijkzigt,4 Sophias Children's Hospital,5 and Erasmus University,6 Rotterdam, The Netherlands

Received 8 June 1999/Returned for modification 12 August 1999/Accepted 18 October 1999

Zanamivir is a highly selective neuraminidase (NA) inhibitor with demonstrated clinical efficacy against influenza A and B virus infections. In phase II clinical efficacy trials (NAIB2005 and NAIB2008), virological substudies showed mean reductions in virus shedding after 24 h of treatment of 1.5 to 2.0 log10 50% tissue culture infective doses compared to a placebo, with no reemergence of virus after the completion of therapy. Paired isolates (n = 41) obtained before and during therapy with zanamivir demonstrated no shifts in susceptibility to zanamivir when measured by NA assays, although for a few isolates NA activity was too low to evaluate. In plaque reduction assays in MDCK cells, the susceptibility of isolates to zanamivir was extremely variable even at baseline and did not correlate with the speed of resolution of virus shedding. Isolates with apparent limited susceptibility to zanamivir by plaque reduction proved highly susceptible in vivo in the ferret model. Further sequence analysis of paired isolates revealed no changes in the hemagglutinin and NA genes in the majority of isolates. The few changes observed were all natural variants. No amino acid changes that had previously been identified in vitro as being involved with reduced susceptibility to zanamivir were observed. These studies highlighted problems associated with monitoring susceptibility to NA inhibitors in the clinic, in that no reliable cell-based assay is available. At present the NA assay is the best available predictor of susceptibility to NA inhibitors in vivo, as measured in the validated ferret model of infection.

* Corresponding author. Mailing address: Clinical Virology Unit, Glaxo Wellcome Medicines Research Centre, Stevenage, Hertfordshire, United Kingdom. Phone: 44(0) 1438764196. Fax: 44(0) 1438764263. E-mail: smt40154{at}glaxowellcome.co.uk.

Antimicrobial Agents and Chemotherapy, January 2000, p. 78-87, Vol. 44, No. 1
0066-4804/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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