Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2012–2013

Abstract

Emergence of influenza viruses with reduced susceptibility to neuraminidase inhibitors (NAIs) is sporadic, often follows exposure to NAIs, but occasionally occurs in the absence of NAI pressure. The emergence and global spread in 2007/2008 of A(H1N1) influenza viruses showing clinical resistance to oseltamivir due to neuraminidase (NA) H275Y substitution, in the absence of drug pressure, warrants continued vigilance and monitoring for similar viruses. Four World Health Organization (WHO) Collaborating Centres for Reference and Research on Influenza and one WHO Collaborating Centre for the Surveillance, Epidemiology and Control of Influenza (WHO CCs) tested 11,387 viruses collected by WHO-recognized National Influenza Centres (NIC) between May 2012 and May 2013 to determine 50% inhibitory concentration (IC50) data for oseltamivir, zanamivir, peramivir and laninamivir. The data were evaluated using normalized IC50 fold-changes rather than raw IC50 data. Nearly 90% of the 11,387 viruses were from three WHO regions: Western Pacific, the Americas and Europe. Only 0.2% (n=27) showed highly reduced inhibition (HRI) against at least one of the four NAIs, usually oseltamivir, while 0.3% (n=39) showed reduced inhibition (RI). NA sequence data, available from the WHO CCs and from sequence databases (n=3661), were screened for amino acid substitutions associated with reduced NAI susceptibility. Those showing HRI were A(H1N1)pdm09 with NA H275Y (n=18), A(H3N2) with NA E119V (n=3) or NA R292K (n=1) and B/Victoria-lineage with NA H273Y (n=2); amino acid position numbering is A subtype and B type specific. Overall, approximately 99% of circulating viruses tested during the 2012-2013 period were sensitive to all four NAIs. Consequently, these drugs remain an appropriate choice for the treatment and prophylaxis of influenza virus infections.

Five years of monitoring for the emergence of oseltamivir resistance in patients with influenza A infections in the Influenza Resistance Information Study

“…This low rate of detection is consistent with the literature and recent reports from WHO, where resistance in initial samples is rarely reported 15, 17, 18, 19. This oseltamivir resistance was detected only in specimens collected during the course of antiviral treatment, and mostly in patients aged 1‐5 years.…”

“…It is known that the fitness of R292K H3N2 viruses is putatively severely impaired 22. This detection of the R292K substitution was performed by a specific snip RT‐PCR, a sensitive method that can detect down to 5% of a minority species 15. It confirmed also that in most cases, a mixed population is detected, supporting the hypothesis that impaired NA activity of 292K viruses may be trans‐complemented by the NA activity of R292 bystander viruses, as it has been reported for mutations at position 119 23.…”

“…Patients had throat or nasal swabs collected on days 1, 3 (self‐swab), 6 and 10 for real‐time reverse transcription PCR (RT‐PCR) analyses of influenza type, subtype and susceptibility to NAI. NAI susceptibility was determined according to the IC 50 values performed on the viruses by a chemiluminescent assay (NA‐Star), and the measure of the fold increase observed as compared to IC 50 values of susceptible strains, according to the common procedure 14, 15. Resistant viruses were either with a reduced inhibition (RI) or a highly reduced inhibition (HRI), depending on the fold increase as per the WHO GISRS guidelines.…”

Influenza in the US Military: An Overview

“…Increased duration for up to 10 days, or higher dose (e.g., 150 mg twice daily in adults with normal renal function) may be necessary in the case of critically ill patients with respiratory failure or among immunocompromised patients in whom prolonged viral replication may occur in the lower respiratory tract [17,18,44,52]. Oral oseltamivir treatment begun more than 2 days after illness onset may also be of some benefit [54,55]. Fortunately, resistance is low to-date (less than 1-2 percent of isolates) among the prevailing seasonal viruses in the US and worldwide [8,56].…”

Standardizing the influenza neuraminidase inhibition assay among United States public health laboratories conducting virological surveillance

“…Later, monitoring NAIsusceptibility became an integral part of virological surveillance within the WHO Global Influenza Surveillance and Response System (WHO-GISRS), where both functional (NA inhibition) and sequence-based (pyrosequencing, real time RT-PCR, Sanger) assays have been utilized to conduct drug susceptibility monitoring worldwide (Monto et al, 2006;Meijer et al, 2014). Following the FDA's approval of zanamivir and oseltamivir, CDC implemented the NI assay, first using a chemiluminescence-based (Mungall et al, 2004), then a fluorescence-based methodology (OkomoAdhiambo et al, 2013).…”