Neuraminidase inhibitors for influenza B virus infection: Efficacy and resistance

Abstract

Many aspects of the biology and epidemiology of influenza B viruses are far less studied than for influenza A viruses, and one of these aspects is effectiveness and resistance to the clinically available antiviral drugs, the neuraminidase (NA) inhibitors (NAIs). Acute respiratory infections are one of the leading causes of death in children and adults, and influenza is among the few respiratory infections that can be prevented and treated by vaccination and antiviral treatment. Recent data has suggested that influenza B virus infections are of specific concern to pediatric patients because of the increased risk of severe disease. Treatment of influenza B is a challenging task for the following reasons: NAIs (e.g., oseltamivir and zanamivir) are the only FDA-approved class of antivirals available for treatment;the data suggest that oseltamivir is less effective than zanamivir in pediatric patients;zanamivir is not prescribed to patients younger than 7;influenza B viruses are less susceptible than influenza A viruses to NAIs in vitro;although the level of resistance to NAIs is low, the number of different molecular markers of resistance is higher than for influenza A viruses, and they are not well defined;the relationship between levels of NAI phenotypic resistance and known molecular markers, frequency of emergence, transmissibility, and fitness of NAI-resistant variants are not well established. This review presents current knowledge of the effectiveness of NAIs for influenza B virus and antiviral resistance in clinical, surveillance, and experimental studies.

Mycophenolic acid, an immunomodulator, has potent and broad-spectrum in vitro antiviral activity against pandemic, seasonal and avian influenza viruses affecting humans

“…Clinical studies have shown that neuraminidase inhibitors are less effective against influenza A viruses ( Burnham et al, 2013). Oseltamivir was not effective in the prophylaxis of influenza B virus infection (Burnham et al, 2013). By our cellprotection assay, we have confirmed that zanamivir has poorer antiviral activity against influenza B than A viruses.…”

“…Recent influenza B virus isolates showed reduced susceptibility to neuraminidase inhibitors due to the emergence of N294S and I221V mutation of the neuraminidase (Carr et al, 2011;Garg et al, 2013), and high-level resistance, due to I221L mutation, has been reported (Escuret et al, 2014). Clinical studies have shown that neuraminidase inhibitors are less effective against influenza A viruses ( Burnham et al, 2013). Oseltamivir was not effective in the prophylaxis of influenza B virus infection (Burnham et al, 2013).…”

Competitive Fitness of Influenza B Viruses with Neuraminidase Inhibitor-Resistant Substitutions in a Coinfection Model of the Human Airway Epithelium

“…Substitutions at these conserved residues disrupt NAI inhibition, while at least some NA sialidase activity is maintained (13,14). Occasionally, substitutions affecting NAI inhibition are identified elsewhere in the NA protein of influenza B virus; these may reduce inhibition by altering NA glycosylation (G142R and N146K) or NA tetramer stabilization (E105K) (12,15,16). The World Health Organization's (WHO's) Global Influenza Surveillance and Response System recommends monitoring influenza B viruses for 6 single amino acid substitutions in NA (R152K, D198E, D198N, I222T, N294S, and G402S) that reduce inhibition by NAIs (17).…”

“…For influenza A and B viruses, the development of NAI resistance is associated with amino acid substitutions in NA, typically at 1 of 19 highly conserved residues in or near the NA active site (11,12). These amino acids are principally responsible for the sialidase activity of the NA enzyme, as they either directly contact the terminal sialic acid (catalytic residues R118, D151, R152, R224, E276, R292, R371, and Y406; the N2 numbering is used here and throughout the text) or support the NA enzymatic binding pocket (framework residues E119, R156, W178, S179, D198, I222, E227, H274, E277, N294, and E425).…”

Replication-Competent Influenza B Reporter Viruses as Tools for Screening Antivirals and Antibodies

“…There are only two approved antivirals (oseltamivir and zanamivir) for treatment of pediatric influenza virus infections (26,27). Additionally, as with IAV, antiviral resistance is present in IBV isolates (28)(29)(30). We utilized the PB1 mNeon virus to test if we could screen for antivirals since growth evaluation based on reporter signal is the least labor-intensive method and may be ideal for rapid screens of chemical libraries.…”