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Background Here, we genetically and antigenically analyzed influenza B viruses (IBVs) isolated in Japan during the 2017‐2018 and 2018‐2019 influenza seasons. Methods A total of 68 IBVs (61 B/Yamagata/16/88‐like [B/Yamagata]‐lineage and 7 B/Victoria/2/87‐like [B/Victoria]‐lineage) were antigenically and genetically characterized by using hemagglutination inhibition (HI) assays and phylogenetic analysis, respectively. The susceptibility of IBVs to neuraminidase (NA) inhibitors was assessed by using a fluorescence‐based NA inhibition assay. Results All 61 B/Yamagata‐lineage isolates were genetically closely related to B/Phuket/3073/2013, the vaccine strain for these two seasons. Eleven B/Yamagata‐lineage isolates tested were antigenically similar to B/Phuket/3073/2013 by the HI test. Seven B/Victoria‐lineage isolates were genetically closely related to B/Texas/02/2013, the WHO‐recommended vaccine strain for the 2017‐2018 season; however, they were antigenically distinct from B/Texas/02/2013 with an eightfold or 16‐fold difference in HI titer. Of these 7 isolates, 4 possessed a two‐amino‐acid deletion at positions 162 and 163 in hemagglutinin (HA) and the other 3 had a three‐amino‐acid deletion at positions 162‐164 in HA. Importantly, the variants with the three‐amino‐acid deletion appeared to be antigenically different from the B/Colorado/06/2017 virus with the two‐amino‐acid deletion, the vaccine strain for the 2018‐2019 season with a fourfold or eightfold difference in HI titer. One B/Yamagata‐lineage isolate carrying a G407S mutation in its NA showed a marked reduction in susceptibility to zanamivir, peramivir, and laninamivir. Conclusions These results highlight the need for continued monitoring for the prevalence of the antigenic variant with the three‐amino‐acid deletion and the variant with reduced NA inhibitor susceptibility.

Background The large consumption of neuraminidase inhibitors (NAIs) for the treatment of influenza virus infections places Japan at risk of becoming the epicenter of the global spread of NAI-resistant viruses. Objective To clarify NA amino acid mutations of epidemic influenza viruses in Japan and their related NAI resistance. Methods A total of 1791 samples, including 396 A/H1N1pdm09, 1117 A/H3N2, and 278 B isolates, were collected to determine of their 50% inhibitory concentration (IC50 ) values by NAIs (oseltamivir, zanamivir, peramivir, and laninamivir) during the Japanese seasons from 2011-2012 to 2016-2017. Then, 380 samples including 49 A/H1N1pdm09, 251 A/H3N2, and 80 B isolates were sequenced for the entire NA genes. Results Neuraminidase inhibitor-resistant A/H1N1pdm09 viruses were detected at a frequency of 1.3% (5/396 isolates) in the epidemic seasons. None of the A/H3N2 and B viruses developed resistance to any of the four NAIs during the six seasons. Only five and 13 AA mutations were detected in the NA catalytic sites of A/H1N1pdm09 and A/H3N2 viruses, respectively. No mutations were observed in the catalytic sites of B viruses. Four of the five mutations in the catalytic sites of A/H1N1pdm09 consisted of H275Y, which was related to high resistance to oseltamivir and peramivir. Most (10/13) of the catalytic site mutations in A/H3N2 were associated with MDCK-passaged induction (D151G/N). Finally, no mutations related to substantial NAI resistance were detected in the A/H3N2 and B viruses examined. Conclusion These findings suggest that the NA catalytic sites of influenza viruses are well preserved. Even in Japan, no spread of NAI-resistant viruses has been observed, and A/H1N1pdm09 viruses carrying H275Y remain limited.

Viral fitness of a laninamivir-selected influenza A/Brisbane/10/2007-like (H3N2) isolate (LRVp9) containing a 237-amino acid neuraminidase deletion and a P194L hemagglutinin mutation was evaluated in vitro and in ferrets. LRVp9 and the wild-type (WT) virus showed comparable replication kinetics in MDCK-ST6GalI cells. Cultured virus was recovered between days 2 and 5 post-infection in nasal washes (NW) from the 4 WT-infected ferrets whereas no virus was recovered from the LRVp9-infected animals. There was a ≥1 log reduction in viral RNA copies/μl of NW for LRVp9 compared to WT at most time points. The large neuraminidase deletion compromises viral infectivity in vivo.

Background The relative ability of neuraminidase inhibitors (NAIs) to reduce household influenza transmission when given to index patients is not established. Objectives To compare daily secondary infection rates (SIR) of influenza A (A/H1pdm and A/H3) and B in households of index patients treated with oseltamivir, zanamivir, laninamivir, or peramivir. Patients/methods This Japanese, single-center, prospective, observational study (UMIN-CTR: UMIN000024650) enrolled index patients with confirmed influenza who were treated with an NAI during 6 influenza seasons (2010-2016). Secondary infection patients were household members diagnosed with the same influenza subtype 1-7 days after onset in the index patient. Daily SIR was calculated using a modified Reed-Frost model. The rate of household members with secondary infection and proportion of households with any secondary infection were also calculated. Results Index patients with influenza A (n = 1146) or B (n = 661) were enrolled (~3400 total index and secondary patients). Daily SIR for all virus subtypes was highest when oseltamivir was used (eg, unadjusted estimate: type A, 1.47% vs 0.71%-1.13%; type B, 1.30% vs 0.59%-0.88%). Pairwise comparisons revealed significant differences in daily SIR between NAIs for influenza type A, type B, and subtype A/H3; for example, for type A, SIR was significantly higher with oseltamivir than with peramivir or zanamivir. The rate of household members with secondary infection and proportion of households with any secondary infection also varied between NAIs. Conclusions Neuraminidase inhibitors differed in their ability to reduce household influenza transmission; transmission was highest with oseltamivir. Physicians may consider effects on household transmission when deciding which NAI to prescribe.

Influenza viruses collected from regions of Asia, Africa and Oceania between 2009 and 2012 were tested for their susceptibility to two new neuraminidase inhibitors, peramivir and laninamivir. All viruses tested had normal laninamivir inhibition. However, 3·2% (19/599) of A(H1N1)pdm09 viruses had highly reduced peramivir inhibition (due to H275Y NA mutation) and

Background Neuraminidase (NA) inhibitors (NAIs) are currently the only antivirals effective against influenza infections due to widespread resistance to M2 inhibitors. Methods Influenza A and B viruses (n = 1079) collected worldwide between April 01, 2011, and September 30, 2011, were assessed for susceptibility to FDA-approved NAIs, oseltamivir and zanamivir, and investigational peramivir, using the fluorescent-based NA-Fluor™ Influenza Neuraminidase Assay Kit. A subset of viruses (n = 98) were tested for susceptibility to the investigational NAI, laninamivir. Results Influenza A(H1N1)pdm09 viruses (n = 326) were sensitive to all NAIs, except for two (0·6%) with H275Y (N1 numbering; H274Y in N2 numbering) substitution, which exhibited elevated IC50s for oseltamivir and peramivir, and a third with previously unreported N325K substitution, exhibiting reduced susceptibility to oseltamivir. Influenza A(H3N2) viruses (n = 407) were sensitive to all NAIs. Influenza B viruses (n = 346) were sensitive to all NAIs, except two (0·6%) with H273Y (N1 numbering; H274Y in N2 numbering) substitution, exhibiting reduced susceptibility to oseltamivir and peramivir, and one with previously unreported G140R and N144K substitutions, exhibiting reduced susceptibility to oseltamivir, zanamivir, and peramivir. All influenza A and B viruses were sensitive to laninamivir. It is unknown whether substitutions N325K, G140R, and N144K were present in the virus prior to culturing because clinical specimens were unavailable for testing. Conclusions This study summarizes NAI susceptibility of influenza viruses circulating worldwide during the 2011 Southern Hemisphere (SH) season, assessed using the NA-Fluor™ Kit. Despite low resistance to NAIs among tested influenza viruses, constant surveillance of influenza virus susceptibility to NAIs should be emphasized.

Currently, there are two commonly used classes of antiviral agents approved for the prevention of and treatment for influenza: the M2 Inhibitors (amantadine and rimantadine) and the neuraminidase inhibitors (oseltamivir, laninamivir, peramivir and zanamivir). These agents have been proven to be safe and effective alone or in combination for the treatment of uncomplicated influenza in otherwise healthy individuals. Although there are few prospective, randomized studies of these antivirals for the treatment of pregnant women, hospitalized patients, and immunocompromised patients infected with seasonal, pandemic, or avian H5N1 influenza, these agents are widely used for these indications. This article reviews the pharmacokinetics and clinical data available relative to the use of commercially available antiviral agents for the prevention of and treatment for influenza.

Close monitoring of drug susceptibility among human influenza viruses was necessitated by widespread resistance to M2 inhibitors in influenza H1N1 (pre-pandemic and 2009 pandemic) and H3N2 viruses, and of oseltamivir resistance in pre-pandemic H1N1 viruses. The FDA-approved neuraminidase (NA) inhibitors (NAIs), oseltamivir and zanamivir, as well as investigational NAIs, peramivir and laninamivir, are currently the principal treatment options for managing influenza infection. However, there are challenges associated with assessing virus susceptibility to this class of drugs. Traditional cell culture-based assays are not reliable for phenotypic testing of NAI susceptibility due to complexity in interpretation. Two types of laboratory assays are currently available for monitoring NAI susceptibility, phenotypic such as the neuraminidase inhibition (NI) assay and genotypic. The NI assay's requirement for propagated virus lengthens testing turnaround; therefore, the need for timely detection of molecular markers associated with NAI resistance (e.g., H275Y in H1N1) has spurred the development of rapid, high-throughput assays, such as real-time RT-PCR and pyrosequencing. The high sensitivity of genotypic assays allows testing of clinical specimens thus eliminating the need for virus propagation in cell culture. The NI assays are especially valuable when a novel virus emerges or a new NAI becomes available. Modifications continue to be introduced into NI assays, including optimization and data analysis criteria. The optimal assay of choice for monitoring influenza drug susceptibility varies widely depending on the needs of laboratories (e.g., surveillance purposes, clinical settings). Optimally, it is desirable to combine functional and genetic analyses of virus isolates and, when possible, the respective clinical specimens.

Background No studies of the clinical symptoms before starting therapy or of the effectiveness of neuraminidase inhibitors (NAIs) have been carried out of the 2009–2010 and 2010–2011 seasons that compare A(H1N1)pdm09 or the three circulating types of influenza virus. Methods The clinical symptoms and duration of fever (body temperature ≥37·5°C) after the first dose of an NAI (oseltamivir, zanamivir, laninamivir) were analyzed. PCR was carried out for 365 patients with A(H1N1)pdm09 in the 2009–2010 season and for 388 patients with one of the three types of influenza circulating in the 2010–2011 season. IC50 for the three NAIs was also analyzed in 51 patients in the 2010–2011 season. Results The peak body temperature was significantly higher in 2010–2011 than in 2009–2010 for patients under 20 years with A(H1N1)pdm09, and in the 2010–2011 season for children 15 years or younger with A(H1N1)pdm09 than for those with other virus types. The percentage of A(H1N1)pdm09 patients with loss of appetite or fatigue was significantly higher in 2010–2011 than in the previous season. The duration of fever was not affected by the kind of NAI or by age in multiple regression analysis. The percentage of patients afebrile at 48 hours after the first dose of NAI was significantly higher for A(H1N1)pdm09 than for A(H3N2) (laninamivir) or B (oseltamivir and laninamivir). Conclusion Although the clinical symptoms of A(H1N1)pdm09 were slightly more severe in the 2010–2011 season, the effectiveness of the NAIs remained high in comparison with 2009–2010 and with other types of seasonal influenza.

Background No studies of the clinical symptoms before starting therapy or of the effectiveness of neuraminidase inhibitors (NAIs) have been carried out of the 2009–2010 and 2010–2011 seasons that compare A(H1N1)pdm09 or the three circulating types of influenza virus. Methods The clinical symptoms and duration of fever (body temperature ≥37·5°C) after the first dose of an NAI (oseltamivir, zanamivir, laninamivir) were analyzed. PCR was carried out for 365 patients with A(H1N1)pdm09 in the 2009–2010 season and for 388 patients with one of the three types of influenza circulating in the 2010–2011 season. IC50 for the three NAIs was also analyzed in 51 patients in the 2010–2011 season. Results The peak body temperature was significantly higher in 2010–2011 than in 2009–2010 for patients under 20 years with A(H1N1)pdm09, and in the 2010–2011 season for children 15 years or younger with A(H1N1)pdm09 than for those with other virus types. The percentage of A(H1N1)pdm09 patients with loss of appetite or fatigue was significantly higher in 2010–2011 than in the previous season. The duration of fever was not affected by the kind of NAI or by age in multiple regression analysis. The percentage of patients afebrile at 48 hours after the first dose of NAI was significantly higher for A(H1N1)pdm09 than for A(H3N2) (laninamivir) or B (oseltamivir and laninamivir). Conclusion Although the clinical symptoms of A(H1N1)pdm09 were slightly more severe in the 2010–2011 season, the effectiveness of the NAIs remained high in comparison with 2009–2010 and with other types of seasonal influenza.

Please cite this paper as: Sunagawa et al. (2012) Single-dose inhaled laninamivir: registered in Japan and its potential role in control of influenza epidemics. Influenza and Other Respiratory Viruses DOI: 10.1111/j.1750-2659.2012.00351.x.

Background/Objectives Japan has the highest frequency of neuraminidase (NA) inhibitor use against influenza in the world. Therefore, Japan could be at high risk of the emergence and spread of NA inhibitor-resistant viruses. The aim of this study was to monitor the emergence of NA inhibitor-resistant viruses and the possibility of human-to-human transmission during four influenza seasons in Japan. Methods To monitor antiviral-resistant A(H1N1)pdm09 viruses, we examined viruses isolated in four seasons from the 2008–2009 season through the 2011–2012 season in Japan by allelic discrimination, NA gene sequencing, and NA inhibitor susceptibility. Results We found that 157 (1·3%) of 12 026 A(H1N1)pdm09 isolates possessed an H275Y substitution in the NA protein that confers about 400- and 140-fold decreased susceptibility to oseltamivir and peramivir, respectively, compared with 275H wild-type viruses. The detection rate of resistant viruses increased from 1·0% during the pandemic period to 2·0% during the post-pandemic period. The highest detection rate of the resistant viruses was found in patients who were 0–9 years old. Furthermore, among the cases with resistant viruses, the percentage of no known exposure to antiviral drugs increased from 16% during the pandemic period to 44% during the post-pandemic period, implying that suspected human-to-human transmission of the resistant viruses gradually increased in the post-pandemic period. Conclusions A(H1N1)pdm09 viruses resistant to oseltamivir and peramivir were sporadically detected in Japan, but they did not spread throughout the community. No viruses resistant to zanamivir and laninamivir were detected.