Document Detail

Virus susceptibility analyses from a phase IV clinical trial of inhaled zanamivir treatment in children infected with influenza.
MedLine Citation:
PMID:  23335741     Owner:  NLM     Status:  MEDLINE    
A zanamivir postapproval efficacy study was conducted in children (n = 279) in Japan during three influenza seasons. Pharyngeal swab specimens (n = 714) were obtained for detailed resistance analysis. From 371 cultured viruses, 3 viruses (A/H1N1) from two subjects showed reduced susceptibility to zanamivir at day 1 (before treatment), 1 had an N74S amino acid substitution (fold shift, 46), and 2 (day 1 and day 2) had a Q136K amino acid substitution (fold shifts, 292 and 301). Q136K was detected only in cultured virus and not in the swab. From the remaining 118 cultured viruses obtained during or after treatment with zanamivir, no shifts in virus susceptibility were detected. Neuraminidase (NA) population sequencing showed that viruses from 12 subjects had emergent amino acid substitutions, but 3 with susceptibility data were not zanamivir resistant. The remainder may be natural variants. Further analysis is planned. Hemagglutinin (HA) sequencing showed that viruses from 20 subjects had 9 HA amino acid substitutions that were previously implicated in resistance to neuraminidase inhibitors in in vitro assays or that were close to the receptor binding site. Their role in in vivo resistance appears to be less important but is not well understood. NA clonal sequence analysis was undertaken to determine if minority species of resistant viruses were present. A total of 1,682 clones from 90 subjects were analyzed. Single clones from 12 subjects contained amino acid substitutions close to the NA active site. It is unclear whether these single amino acid substitutions could have been amplified after drug pressure or are just chance mutations introduced during PCR.
Phillip J Yates; Nalini Mehta; Joseph Horton; Margaret Tisdale
Publication Detail:
Type:  Clinical Trial, Phase IV; Journal Article     Date:  2013-01-18
Journal Detail:
Title:  Antimicrobial agents and chemotherapy     Volume:  57     ISSN:  1098-6596     ISO Abbreviation:  Antimicrob. Agents Chemother.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-15     Completed Date:  2013-09-06     Revised Date:  2013-10-08    
Medline Journal Info:
Nlm Unique ID:  0315061     Medline TA:  Antimicrob Agents Chemother     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1677-84     Citation Subset:  IM    
GlaxoSmithKline R&D, Stevenage, United Kingdom.
Data Bank Information
Bank Name/Acc. No.:
GENBANK/KC457353;  KC460206
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MeSH Terms
Amino Acid Substitution / genetics,  physiology
Drug Resistance, Viral / genetics
Influenza, Human / drug therapy*,  virology*
Molecular Sequence Data
Neuraminidase / chemistry,  genetics*
Polymerase Chain Reaction
Viral Proteins / chemistry,  genetics*
Zanamivir / therapeutic use*
Reg. No./Substance:
0/Viral Proteins; 139110-80-8/Zanamivir; EC

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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