Evidence for Zanamivir Resistance in an Immunocompromised Child Infected with Influenza B Virus

• Published in: The Journal of infectious diseases Vol. 178; no. 5; pp. 1257 - 1262
• Main Authors: Gubareva, Larisa V., Matrosovich, Mikhail N., Brenner, Malcolm K., Bethell, Richard C., Webster, Robert G.
• Format: Journal Article
• Language: English
• Published: United States The University of Chicago Press 01-11-1998; University of Chicago Press; Oxford University Press
• Subjects: Amino Acid Substitution; Animals; Antiviral Agents - therapeutic use; Antivirals; Bone Marrow Transplantation - immunology; Cell Line; Cell membranes; Cercopithecine herpesvirus 1; Cercopithecus aethiops; Dogs; Drug Resistance, Microbial - genetics; Enzyme Inhibitors - therapeutic use; Enzyme-Linked Immunosorbent Assay; Female; Ferrets; Genetic mutation; Guanidines; Hemagglutination Inhibition Tests; Humans; Immunosuppression - adverse effects; Infant; Infections; Influenza B virus - genetics; Influenza B virus - immunology; Influenza, Human - complications; Influenza, Human - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - complications; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - immunology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - therapy; Mutation; Neuraminidase - antagonists & inhibitors; Neuraminidase - genetics; Orthomyxoviridae; Orthomyxoviridae Infections - drug therapy; Pyrans; Receptors; Receptors, Virus - drug effects; Receptors, Virus - genetics; RNA, Viral - analysis; Sequence analysis; Sialic Acids - therapeutic use; Vero Cells; Virology; Viruses; Zanamivir
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/314440

Zanamivir, a neuraminidase inhibitor, has shown promise as a drug to control influenza. During prolonged treatment with zanamivir, a mutant virus was isolated from an immunocompromised child infected with influenza B virus. A hemagglutinin mutation (198 Thr→Ile) reduced the virus affinity for receptors found on susceptible human cells. A mutation in the neuraminidase active site (152 Arg→Lys) led to a 1000-fold reduction in the enzyme sensitivity to zanamivir. When tested in ferrets, the mutant virus had less virulence than the parent; however, it had a growth preference over the parent in zanamivir-treated animals. Despite these changes, the sensitivity of the mutant virus to zanamivir assessed by a standard test in MDCK cells was unaffected. These data indicate that the current methods for monitoring resistant mutants are potentially flawed because no tissue culture system adequately reflects the receptor specificity of human respiratory tract epithelium.