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 efficacy 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: This review presents current knowledge of the efficacy of NAIs for influenza B virus and antiviral resistance in clinical, surveillance, and experimental studies.

Keywords: Antiviral drug resistance; Influenza B virus; Neuraminidase inhibitors; Oseltamivir; Peramivir; Zanamivir.

Figure 1

Frequency of laboratory-confirmed cases, influenza B virus-associated pediatric mortality, and proportion of Yamagata lineage across the Northern Hemisphere. A) Frequency of circulation of influenza B viruses during 2004-2013. Data from Centers for Disease Control and Prevention (CDC, USA), National Institute for Medical Research (NIMR, Europe), and National Institute of Infectious Diseases (NIID, Japan). B) Influenza-associated pediatric mortality in the United States (2004-2013) delineated by influenza subtype. Influenza A and B indicate co-infections. Pediatric ages: < 18 years old, data from CDC, USA. C) Proportion of influenza B strains subtyped as Yamagata lineage in the United States, Europe, and Japan. Years Yamagata lineage included in seasonal influenza vaccine: 2004-5, 2005-6, 2008-9, and 2012-13. Data from CDC, WHO, and NIID.

Figure 2

Alignment of NA proteins of N1 and N2 subtypes of influenza A viruses and influenza B viruses. Transmembrane, stalk, and head regions of NA protein are indicated by gray, yellow, or green shading, respectively. Catalytic residues are highlighted in orange (R118, D151, R152, R224, E276, R292, R371, and Y406), framework residues in teal (E119, R156, W178, S179, D198, I222, E227, H274, E277, N294, and E425). Residues associated with NAI resistance in influenza B viruses from clinical, surveillance, or experimental studies are designated with an arrow, with other supporting residues (not catalytic or framework) shown in lavender (G109, E110, S250, T325, G402, G142+N146). Strain subtype and years of use in vaccine composition (shown in parentheses): A/Perth/16/2009 (H3N2, 2010-2012); A/Victoria/361/2011 (H3N2); A/Brisbane/59/2007 (H1N1, 2008-2010); A/California/07/2009 (H1N1pdm, 2010-2013); B/Victoria/02/1987 (HA and NA genes from Victoria lineage); B/Hong Kong/330/2001 (HA and NA genes from Victoria lineage, 2002-2004); B/Yamagata/16/1988 (HA and NA genes from Yamagata lineage, 1989-1992); B/Wisconsin/01/2010 (HA and NA genes from Yamagata lineage, 2012-2013).