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Larisa V Gubareva - One of the best experts on this subject based on the ideXlab platform.
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Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2015-2016.
Antiviral research, 2017Co-Authors: Larisa V Gubareva, Terry G. Besselaar, Weijuan Huang, Vicki Gregory, Rod S. Daniels, Angie Lackenby, Patricia A. Jorquera, Sook-kwan LeangAbstract: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) assessed antiviral susceptibility of 14,330 influenza A and B viruses collected by WHO-recognized National Influenza Centres (NICs) between May 2015 and May 2016. Neuraminidase (NA) inhibition assay was used to determine 50% inhibitory concentration (IC50) data for NA inhibitors (NAIs) oseltamivir, zanamivir, Peramivir and laninamivir. Furthermore, NA sequences from 13,484 influenza viruses were retrieved from public sequence databases and screened for amino acid substitutions (AAS) associated with reduced inhibition (RI) or highly reduced inhibition (HRI) by NAIs. Of the viruses tested by WHO CCs 93% were from three WHO regions: Western Pacific, the Americas and Europe. Approximately 0.8% (n = 113) exhibited either RI or HRI by at least one of four NAIs. As in previous seasons, the most common NA AAS was H275Y in A(H1N1)pdm09 viruses, which confers HRI by oseltamivir and Peramivir. Two A(H1N1)pdm09 viruses carried a rare NA AAS, S247R, shown in this study to confer RI/HRI by the four NAIs. The overall frequency of A(H1N1)pdm09 viruses containing NA AAS associated with RI/HRI was approximately 1.8% (125/6915), which is slightly higher than in the previous 2014-15 season (0.5%). Three B/Victoria-lineage viruses contained a new AAS, NA H134N, which conferred HRI by zanamivir and laninamivir, and borderline HRI by Peramivir. A single B/Victoria-lineage virus harboured NA G104E, which was associated with HRI by all four NAIs. The overall frequency of RI/HRI phenotype among type B viruses was approximately 0.6% (43/7677), which is lower than that in the previous season. Overall, the vast majority (>99%) of the viruses tested by WHO CCs were susceptible to all four NAIs, showing normal inhibition (NI). Hence, NAIs remain the recommended antivirals for treatment of influenza virus infections. Nevertheless, our data indicate that it is prudent to continue drug susceptibility monitoring using both NAI assay and sequence analysis.
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Emergence of Multidrug-Resistant Influenza A(H1N1)pdm09 Virus Variants in an Immunocompromised Child Treated With Oseltamivir and Zanamivir
The Journal of Infectious Diseases, 2015Co-Authors: Daisuke Tamura, Margaret Okomo-adhiambo, Angela P. Campbell, Brett Loechelt, Vasiliy P. Mishin, Bernhard L Wiedermann, Roberta L. Debiasi, Larisa V GubarevaAbstract:Prolonged treatment of an immunocompromised child with oseltamivir and zanamivir for A(H1N1)pdm09 virus infection led to the emergence of viruses carrying H275Y and/or E119G in the neuraminidase (NA). When phenotypically evaluated by NA inhibition, the dual H275Y-E119G substitution caused highly reduced inhibition by 4 NA inhibitors: oseltamivir, zanamivir, Peramivir, and laninamivir.
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global update on the susceptibility of human influenza viruses to neuraminidase inhibitors 2014 2015
Antiviral Research, 2014Co-Authors: Aeron C Hurt, Terry G. Besselaar, Weijuan Huang, Rod S. Daniels, Angie Lackenby, Larisa V Gubareva, Alicia M. Fry, Burcu Ermetal, Raphael T C Lee, Sebastian MaurerstrohAbstract: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) assessed antiviral susceptibility of 14,330 influenza A and B viruses collected by WHO-recognized National Influenza Centres (NICs) between May 2015 and May 2016. Neuraminidase (NA) inhibition assay was used to determine 50% inhibitory concentration (IC50) data for NA inhibitors (NAIs) oseltamivir, zanamivir, Peramivir and laninamivir. Furthermore, NA sequences from 13,484 influenza viruses were retrieved from public sequence databases and screened for amino acid substitutions (AAS) associated with reduced inhibition (RI) or highly reduced inhibition (HRI) by NAIs. Of the viruses tested by WHO CCs 93% were from three WHO regions: Western Pacific, the Americas and Europe. Approximately 0.8% (n = 113) exhibited either RI or HRI by at least one of four NAIs. As in previous seasons, the most common NA AAS was H275Y in A(H1N1)pdm09 viruses, which confers HRI by oseltamivir and Peramivir. Two A(H1N1)pdm09 viruses carried a rare NA AAS, S247R, shown in this study to confer RI/HRI by the four NAIs. The overall frequency of A(H1N1)pdm09 viruses containing NA AAS associated with RI/HRI was approximately 1.8% (125/6915), which is slightly higher than in the previous 2014-15 season (0.5%). Three B/Victoria-lineage viruses contained a new AAS, NA H134N, which conferred HRI by zanamivir and laninamivir, and borderline HRI by Peramivir. A single B/Victoria-lineage virus harboured NA G104E, which was associated with HRI by all four NAIs. The overall frequency of RI/HRI phenotype among type B viruses was approximately 0.6% (43/7677), which is lower than that in the previous season. Overall, the vast majority (>99%) of the viruses tested by WHO CCs were susceptible to all four NAIs, showing normal inhibition (NI). Hence, NAIs remain the recommended antivirals for treatment of influenza virus infections. Nevertheless, our data indicate that it is prudent to continue drug susceptibility monitoring using both NAI assay and sequence analysis.
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Influenza B Viruses with Mutation in the Neuraminidase Active Site, North Carolina, USA, 2010–11
'Centers for Disease Control and Prevention (CDC)', 2011Co-Authors: Katrina Sleeman, Tiffany G. Sheu, Zack Moore, Susan Kilpatrick, Shikha Garg, Alicia M. Fry, Larisa V GubarevaAbstract:Oseltamivir is 1 of 2 antiviral medications available for the treatment of influenza B virus infections. We describe and characterize a cluster of influenza B viruses circulating in North Carolina with a mutation in the neuraminidase active site that may reduce susceptibility to oseltamivir and the investigational drug Peramivir but not to zanamivir
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assessment of pandemic and seasonal influenza a h1n1 virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays
Antimicrobial Agents and Chemotherapy, 2010Co-Authors: Ha T Nguyen, Vasiliy P. Mishin, Tiffany G. Sheu, Alexander Klimov, Larisa V GubarevaAbstract:The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC50s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (Peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC50s against oseltamivir and Peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC50s between the wild type and the variants, whereas the IC50s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.
Jingoro Shimada - One of the best experts on this subject based on the ideXlab platform.
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post marketing safety and effectiveness evaluation of the intravenous anti influenza neuraminidase inhibitor Peramivir ii a pediatric drug use investigation
Journal of Infection and Chemotherapy, 2014Co-Authors: Takuji Komeda, Shingo Ishii, Yumiko Itoh, Yasuyuki Ariyasu, Masaki Sanekata, Takayoshi Yoshikawa, Jingoro ShimadaAbstract:Abstract Peramivir is the only intravenous formulation among anti-influenza neuraminidase inhibitors currently available. Peramivir was approved for manufacturing and marketing in Japan in January 2010. In October 2010, an additional indication for pediatric use was approved. We conducted a pediatric drug use investigation of Peramivir from October 2010 to February 2012 and evaluated its real-world safety and effectiveness in pediatric patients. We collected the data of 1254 Peramivir-treated pediatric patients from 161 facilities across Japan and examined the safety in 1199 patients and effectiveness in 1188 patients. In total, 245 adverse events were observed with an incidence rate of 14.01% (168/1199). Of these, 115 events were adverse drug reactions (ADRs) with an incidence rate of 7.67% (92/1199). Common ADRs were diarrhea and abnormal behavior, with incidence rates of 2.50% (30/1199) and 2.25% (27/1199), respectively. Fourteen serious ADRs were observed in 12 patients (1.00%), including 5 cases each of abnormal behavior and neutrophil count decreased. While 87.0% (100 events) of ADRs occurred within 3 days after the initiation of Peramivir administration, 87.8% (101 events) resolved or improved within 7 days after onset. Multivariate analyses indicated that the presence or absence of underlying diseases/complications was significantly related to ADR incidence. With regard to effectiveness, the median time to alleviation of both influenza symptoms and fever was 3 days, including the first day of administration. Thus, this study confirms the pediatric safety of Peramivir without any concerns about effectiveness under routine clinical settings.
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phase iii randomized double blind study comparing single dose intravenous Peramivir with oral oseltamivir in patients with seasonal influenza virus infection
Antimicrobial Agents and Chemotherapy, 2011Co-Authors: Shigeru Kohno, Muh Yong Yen, Hee Jin Cheong, Nobuo Hirotsu, Tadashi Ishida, Junichi Kadota, Masashi Mizuguchi, Hiroshi Kida, Jingoro ShimadaAbstract:Antiviral medications with activity against influenza viruses are important in controlling influenza. We compared intravenous Peramivir, a potent neuraminidase inhibitor, with oseltamivir in patients with seasonal influenza virus infection. In a multinational, multicenter, double-blind, double-dummy randomized controlled study, patients aged ≥20 years with influenza A or B virus infection were randomly assigned to receive either a single intravenous infusion of Peramivir (300 or 600 mg) or oral administration of oseltamivir (75 mg twice a day [b.i.d.] for 5 days). To demonstrate the noninferiority of Peramivir in reducing the time to alleviation of influenza symptoms with hazard model analysis and a noninferiority margin of 0.170, we planned to recruit 1,050 patients in South Korea, Japan, and Taiwan. A total of 1,091 patients (364 receiving 300 mg and 362 receiving 600 mg of Peramivir; 365 receiving oseltamivir) were included in the intent-to-treat infected population. The median durations of influenza symptoms were 78.0, 81.0, and 81.8 h in the groups treated with 300 mg of Peramivir, 600 mg of Peramivir, and oseltamivir, respectively. The hazard ratios of the 300- and 600-mg-Peramivir groups compared to the oseltamivir group were 0.946 (97.5% confidence interval [CI], 0.793, 1.129) and 0.970 (97.5% CI, 0.814, 1.157), respectively. Both Peramivir groups were noninferior to the oseltamivir group (97.5% CI, <1.170). The overall incidence of adverse drug reactions was significantly lower in the 300-mg-Peramivir group, but the incidence of severe reactions in either Peramivir group was not different from that in the oseltamivir group. Thus, a single intravenous dose of Peramivir may be an alternative to a 5-day oral dose of oseltamivir for patients with seasonal influenza virus infection.
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intravenous Peramivir for treatment of influenza a and b virus infection in high risk patients
Antimicrobial Agents and Chemotherapy, 2011Co-Authors: Shigeru Kohno, Nobuo Hirotsu, Tadashi Ishida, Junichi Kadota, Masashi Mizuguchi, Hiroshi Kida, Jingoro ShimadaAbstract:Influenza virus infections are known to persist longer in patients with underlying diseases, including respiratory tract diseases, and tend to become complicated by secondary influenza-associated infections, such as pneumonia. To assess the efficacy and safety of the novel anti-influenza virus drug Peramivir in high-risk patients, we conducted a clinical trial of patients with diabetes or chronic respiratory tract diseases and patients being treated with drugs that suppress immune function. In this multicenter, uncontrolled, randomized, double-blind study, Peramivir was intravenously administered at 300 or 600 mg/day for 1 to 5 days, as needed. Efficacy was investigated in 37 patients (300 mg, n = 18 patients; 600 mg, n = 19 patients). The median durations of influenza illness were 68.6 h (90% confidence interval, 41.5 to 113.4 h) overall, 114.4 h (90% confidence interval, 40.2 to 235.3 h) in the 300-mg group, and 42.3 h (90% confidence interval, 30.0 to 82.7 h) in the 600-mg group. The hazard ratio for the 600-mg group compared to the 300-mg group was 0.497 (90% confidence interval, 0.251 to 0.984), and the duration of influenza illness was significantly shorter in the 600-mg group than in the 300-mg group. Among the 42 patients in the safety analysis set, adverse events occurred in 73.8% and adverse drug reactions in 33.3%. No adverse events were particularly problematic clinically, and all patients recovered quickly from all events. The measured blood drug concentrations showed no tendency toward accumulation. Drug accumulation with repeated doses was thus considered to be of little concern. Intravenous Peramivir appears to offer a potentially useful treatment for high-risk patients in the future.
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efficacy and safety of intravenous Peramivir for treatment of seasonal influenza virus infection
Antimicrobial Agents and Chemotherapy, 2010Co-Authors: Shigeru Kohno, Masashi Mizuguchi, Hiroshi Kida, Jingoro ShimadaAbstract:Peramivir, a sialic acid analogue, is a selective inhibitor of neuraminidases produced by influenza A and B viruses. We evaluated the efficacy and safety of a single intravenous dose of Peramivir in outpatients with uncomplicated seasonal influenza virus infection. A total of 300 previously healthy adult subjects aged 20 to 64 years with a positive influenza virus rapid antigen test were recruited within 48 h of the onset of influenza symptoms and randomized to three groups: single intravenous infusion of either 300 mg Peramivir per kg of body weight, 600 mg Peramivir, or matching placebo on study day 1. Influenza symptoms and body temperature were self-assessed for 14 days. Nasal and pharyngeal swabs were collected to determine the viral titer. The primary endpoint was the time to alleviation of symptoms. Of the 300 subjects, 296 were included in the intent-to-treat infected population (300 mg Peramivir, n = 99; 600 mg Peramivir, n = 97; and placebo, n = 100). Peramivir significantly reduced the time to alleviation of symptoms at both 300 mg (hazard ratio, 0.681) and 600 mg (hazard ratio, 0.666) compared with placebo (adjusted P value, 0.0092 for both comparisons). No serious adverse events were reported. Peramivir was well tolerated, and its adverse-event profile was similar to that of placebo. A single intravenous dose of Peramivir is effective and well tolerated in subjects with uncomplicated seasonal influenza virus infection.
Donald F Smee - One of the best experts on this subject based on the ideXlab platform.
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combinations of favipiravir and Peramivir for the treatment of pandemic influenza a california 04 2009 h1n1 virus infections in mice
Antiviral Research, 2012Co-Authors: E Tarbe, Yousuke Furuta, M Maekawa, Yarlagadda S Abu, John D Morrey, Donald F SmeeAbstract:Abstract Favipiravir, an influenza virus RNA polymerase inhibitor, and Peramivir, an influenza virus neuraminidase inhibitor, were evaluated alone and in combination against pandemic influenza A/California/04/2009 (H1N1) virus infections in mice. Infected mice were treated twice daily for 5 d starting 4 h after virus challenge. Favipiravir was 40%, 70%, and 100% protective at 20, 40, and 100 mg/kg/d. Peramivir was 30% protective at 0.5 mg/kg/d, but ineffective at lower doses when used as monotherapy. Combinations of favipiravir and Peramivir increased the numbers of survivors by 10–50% when the 0.025, 0.05, and 0.1 mg/kg/d doses of Peramivir were combined with 20 mg/kg/d favipiravir and when all doses of Peramivir were combined with 40 mg/kg/d favipiravir. Three-dimensional analysis of drug interactions using the MacSynergy method indicates strong synergy for these drug combinations. In addition, an increase in lifespan for groups of mice treated with drug combinations, compared to the most effective monotherapy group, was observed for the 0.025, 0.05, and 0.1 mg/kg/d doses of Peramivir combined with favipiravir at the 20 mg dose level. Therefore, the 20 mg/kg/d dose of favipiravir was selected for further combination studies. Increased survival was exhibited when this dose was combined with Peramivir doses of 0.1, 0.25 and 0.5 mg/kg/d (1 mg/kg/d of Peramivir alone was 100% protective in this experiment). Improved body weight relative to either compound alone was evident using 0.25, 0.5, and 1 mg/kg/d of Peramivir. Significant reductions in lung hemorrhage score and lung weight were evident on day 6 post-infection. In addition, virus titers were reduced significantly on day 4 post-infection by combination therapy containing favipiravir combined with Peramivir at 0.25 and 0.5 mg/kg/d. These data demonstrate that combinations of favipiravir and Peramivir perform better than suboptimal doses of each compound alone for the treatment of influenza virus infections in mice.
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Combinations of favipiravir and Peramivir for the treatment of pandemic influenza A/California/04/2009 (H1N1) virus infections in mice.
Antiviral Research, 2012Co-Authors: E. Bart Tarbet, Yousuke Furuta, M Maekawa, Yarlagadda S. Babu, John D Morrey, Donald F SmeeAbstract:Abstract Favipiravir, an influenza virus RNA polymerase inhibitor, and Peramivir, an influenza virus neuraminidase inhibitor, were evaluated alone and in combination against pandemic influenza A/California/04/2009 (H1N1) virus infections in mice. Infected mice were treated twice daily for 5 d starting 4 h after virus challenge. Favipiravir was 40%, 70%, and 100% protective at 20, 40, and 100 mg/kg/d. Peramivir was 30% protective at 0.5 mg/kg/d, but ineffective at lower doses when used as monotherapy. Combinations of favipiravir and Peramivir increased the numbers of survivors by 10–50% when the 0.025, 0.05, and 0.1 mg/kg/d doses of Peramivir were combined with 20 mg/kg/d favipiravir and when all doses of Peramivir were combined with 40 mg/kg/d favipiravir. Three-dimensional analysis of drug interactions using the MacSynergy method indicates strong synergy for these drug combinations. In addition, an increase in lifespan for groups of mice treated with drug combinations, compared to the most effective monotherapy group, was observed for the 0.025, 0.05, and 0.1 mg/kg/d doses of Peramivir combined with favipiravir at the 20 mg dose level. Therefore, the 20 mg/kg/d dose of favipiravir was selected for further combination studies. Increased survival was exhibited when this dose was combined with Peramivir doses of 0.1, 0.25 and 0.5 mg/kg/d (1 mg/kg/d of Peramivir alone was 100% protective in this experiment). Improved body weight relative to either compound alone was evident using 0.25, 0.5, and 1 mg/kg/d of Peramivir. Significant reductions in lung hemorrhage score and lung weight were evident on day 6 post-infection. In addition, virus titers were reduced significantly on day 4 post-infection by combination therapy containing favipiravir combined with Peramivir at 0.25 and 0.5 mg/kg/d. These data demonstrate that combinations of favipiravir and Peramivir perform better than suboptimal doses of each compound alone for the treatment of influenza virus infections in mice.
Masato Tashiro - One of the best experts on this subject based on the ideXlab platform.
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substitutions at h134 and in the 430 loop region in influenza b neuraminidases can confer reduced susceptibility to multiple neuraminidase inhibitors
Antiviral Research, 2020Co-Authors: Peter G Mohr, Masato Tashiro, Victor A Streltsov, Janelle Williams, Jennifer L MckimmbreschkinAbstract:Abstract With the introduction of the influenza specific neuraminidase inhibitors (NAIs) in 1999, there were concerns about the emergence and spread of resistant viruses in the community setting. Surveillance and testing of community isolates for their susceptibility to the NAIs was initially carried out by the Neuraminidase Inhibitor Susceptibility Network (NISN) and has subsequently been taken on by the global WHO influenza network laboratories. During the NISN surveillance, we identified two Yamagata lineage influenza B viruses with amino acid substitutions of H134Y (B/Auckland/2/2001) or W438R (B/Yokohama/12/2005) which had slightly elevated IC50 values for zanamivir and/or oseltamivir, but not sufficiently to be characterized as mild outliers at the time. As it has now been well demonstrated that mixed populations can mask the true magnitude of resistance of a mutant, we re-examined both of these isolates by plaque purification to see if the true susceptibilities were being masked due to mixed populations. Results confirmed that the B/Auckland isolate contained both wild type and H134Y mutant populations, with mutant IC50 values > 250 nM for both oseltamivir and Peramivir in the enzyme inhibition assay. The B/Yokohama isolate also contained both wild type and W438R mutant populations, the latter now demonstrating IC50 values > 400 nM for zanamivir, oseltamivir and Peramivir. In addition, plaque purification of the B/Yokohama isolate identified viruses with other single neuraminidase substitutions H134Y, H134R, H431R, or T436P. H134R and H431R viruses had IC50 values > 400 nM and >250 nM respectively against all three NAIs. All changes conferred much greater resistance to Peramivir than to zanamivir, and less to oseltamivir, and affected the kinetics of binding and dissociation of the NAIs. Most affected affinity (Km) for the MUNANA substrate, but some had decreased while others had increased affinity. Despite resistance in the enzyme assay, no reduced susceptibility was seen in plaque reduction assays in MDCK cells for any of the mutant viruses. None of these substitutions was in the active site. Modelling suggests that these substitutions affect the 150 and 430-loop regions described for influenza A NAs, suggesting they may also be important for substrate and inhibitor binding for influenza B NAs.
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a community cluster of influenza a h1n1 pdm09 virus exhibiting cross resistance to oseltamivir and Peramivir in japan november to december 2013
Eurosurveillance, 2014Co-Authors: Emi Takashita, Miho Ejima, R Itoh, M Miura, A Ohnishi, H Nishimura, Takato Odagiri, Masato TashiroAbstract:Six influenza A(H1N1)pdm09 viruses were detected in Sapporo, Japan, between November and December 2013. All six viruses possessed an H275Y substitution in the neuraminidase protein, which confers cross-resistance to oseltamivir and Peramivir. No epidemiological link among the six cases could be identified; none of them had received neuraminidase inhibitors before specimen collection. The haemagglutinin and neuraminidase genes of the six viruses were closely related to one another, suggesting clonal spread of a single resistant virus.
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characterization of neuraminidase inhibitor resistant influenza a h1n1 pdm09 viruses isolated in four seasons during pandemic and post pandemic periods in japan
Influenza and Other Respiratory Viruses, 2013Co-Authors: Emi Takashita, Masato Tashiro, Masaki Imai, Seiichiro Fujisaki, Hong Xu, Noriko Kishida, Takato OdagiriAbstract: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.
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mutations at the monomer monomer interface away from the active site of influenza b virus neuraminidase reduces susceptibility to neuraminidase inhibitor drugs
Journal of Infection and Chemotherapy, 2013Co-Authors: Seiichiro Fujisaki, Masato Tashiro, Emi Takashita, Masaki Imai, Masaru Yokoyama, Tae Taniwaki, Hong Xu, Noriko Kishida, Hironori Sato, Takato OdagiriAbstract:Amino acid changes in or near the active site of neuraminidase (NA) in influenza viruses reduce the susceptibility to NA inhibitor drugs. Here, we report the recovery of three influenza B viruses with reduced susceptibilities to NA inhibitors from human patients with no history of antiviral drug treatment. The three viruses were isolated by inoculating Madin–Darby canine kidney (MDCK) cells with respiratory specimens from the patients. NA inhibition assays demonstrated that two of the three isolates showed a highly reduced susceptibility to Peramivir and moderately reduced susceptibility to oseltamivir, zanamivir, and laninamivir. The remaining one isolate exhibited moderately reduced sensitivity to Peramivir, zanamivir, and laninamivir but was susceptible to oseltamivir. A sequence analysis of viruses propagated in MDCK cells revealed that all three isolates contained a single mutation (Q138R, P139S, or G140R) in NA not previously associated with reduced susceptibility to NA inhibitors. However, pyrosequencing analyses showed that the Q138R and G140R mutations were below a detectable level in the original clinical specimens; the P139S mutation was detected at a very low level, suggesting that the mutant viruses may be preferably selected during propagation in MDCK cells. The NA crystallographic structure showed that these mutations were located at the interface between the two monomers of the NA tetramer, away from the NA active site. In addition to amino acid substitutions around the active site of NA, these observations suggest that alterations in the monomer–monomer interface region of NA may contribute to reduced sensitivity to NA inhibitors.
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a single e105k mutation far from the active site of influenza b virus neuraminidase contributes to reduced susceptibility to multiple neuraminidase inhibitor drugs
Biochemical and Biophysical Research Communications, 2012Co-Authors: Seiichiro Fujisaki, Masato Tashiro, Emi Takashita, Masaki Imai, Masaru Yokoyama, Tae Taniwaki, Hong Xu, Noriko Kishida, Hironori Sato, Takato OdagiriAbstract:Abstract Drugs inhibiting the enzymatic activity of influenza virus neuraminidase (NA) are the cornerstone of therapy for influenza virus infection. The emergence of drug-resistant variants may limit the benefits of antiviral therapy. Here we report the recovery of an influenza B virus with reduced susceptibilities to NA inhibitors from a human patient with no history of antiviral drug treatment. The virus, designated B/Kochi/61/2011, was isolated by inoculating Madin–Darby canine kidney (MDCK) cells with respiratory specimens from the patient. NA inhibition assays demonstrated that the B/Kochi/61/2011 isolate showed a remarkable reduction in susceptibility to Peramivir. The isolate also exhibited low to moderately reduced sensitivity to oseltamivir, laninamivir, and zanamivir. A sequence analysis of viruses propagated in MDCK cells revealed that the isolate contained a mutation (E105K) not previously associated with reduced susceptibility to NA inhibitors. However, pyrosequencing analysis showed that the NA E105K mutation was below a detectable level in the original clinical specimens, suggesting that the mutant virus may be preferably selected during propagation in MDCK cells. Analysis of the three-dimensional model of E105 and K105 NAs with Peramivir suggested that the E105K mutation at the monomer–monomer interface of the NA tetramer may destabilize the tetrameric form of NA, leading to decreased susceptibility to NA inhibitors. These results have implications for understanding the mechanism of resistance against NA-inhibitor drugs.
Takato Odagiri - One of the best experts on this subject based on the ideXlab platform.
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a community cluster of influenza a h1n1 pdm09 virus exhibiting cross resistance to oseltamivir and Peramivir in japan november to december 2013
Eurosurveillance, 2014Co-Authors: Emi Takashita, Miho Ejima, R Itoh, M Miura, A Ohnishi, H Nishimura, Takato Odagiri, Masato TashiroAbstract:Six influenza A(H1N1)pdm09 viruses were detected in Sapporo, Japan, between November and December 2013. All six viruses possessed an H275Y substitution in the neuraminidase protein, which confers cross-resistance to oseltamivir and Peramivir. No epidemiological link among the six cases could be identified; none of them had received neuraminidase inhibitors before specimen collection. The haemagglutinin and neuraminidase genes of the six viruses were closely related to one another, suggesting clonal spread of a single resistant virus.
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characterization of neuraminidase inhibitor resistant influenza a h1n1 pdm09 viruses isolated in four seasons during pandemic and post pandemic periods in japan
Influenza and Other Respiratory Viruses, 2013Co-Authors: Emi Takashita, Masato Tashiro, Masaki Imai, Seiichiro Fujisaki, Hong Xu, Noriko Kishida, Takato OdagiriAbstract: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.
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mutations at the monomer monomer interface away from the active site of influenza b virus neuraminidase reduces susceptibility to neuraminidase inhibitor drugs
Journal of Infection and Chemotherapy, 2013Co-Authors: Seiichiro Fujisaki, Masato Tashiro, Emi Takashita, Masaki Imai, Masaru Yokoyama, Tae Taniwaki, Hong Xu, Noriko Kishida, Hironori Sato, Takato OdagiriAbstract:Amino acid changes in or near the active site of neuraminidase (NA) in influenza viruses reduce the susceptibility to NA inhibitor drugs. Here, we report the recovery of three influenza B viruses with reduced susceptibilities to NA inhibitors from human patients with no history of antiviral drug treatment. The three viruses were isolated by inoculating Madin–Darby canine kidney (MDCK) cells with respiratory specimens from the patients. NA inhibition assays demonstrated that two of the three isolates showed a highly reduced susceptibility to Peramivir and moderately reduced susceptibility to oseltamivir, zanamivir, and laninamivir. The remaining one isolate exhibited moderately reduced sensitivity to Peramivir, zanamivir, and laninamivir but was susceptible to oseltamivir. A sequence analysis of viruses propagated in MDCK cells revealed that all three isolates contained a single mutation (Q138R, P139S, or G140R) in NA not previously associated with reduced susceptibility to NA inhibitors. However, pyrosequencing analyses showed that the Q138R and G140R mutations were below a detectable level in the original clinical specimens; the P139S mutation was detected at a very low level, suggesting that the mutant viruses may be preferably selected during propagation in MDCK cells. The NA crystallographic structure showed that these mutations were located at the interface between the two monomers of the NA tetramer, away from the NA active site. In addition to amino acid substitutions around the active site of NA, these observations suggest that alterations in the monomer–monomer interface region of NA may contribute to reduced sensitivity to NA inhibitors.
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a single e105k mutation far from the active site of influenza b virus neuraminidase contributes to reduced susceptibility to multiple neuraminidase inhibitor drugs
Biochemical and Biophysical Research Communications, 2012Co-Authors: Seiichiro Fujisaki, Masato Tashiro, Emi Takashita, Masaki Imai, Masaru Yokoyama, Tae Taniwaki, Hong Xu, Noriko Kishida, Hironori Sato, Takato OdagiriAbstract:Abstract Drugs inhibiting the enzymatic activity of influenza virus neuraminidase (NA) are the cornerstone of therapy for influenza virus infection. The emergence of drug-resistant variants may limit the benefits of antiviral therapy. Here we report the recovery of an influenza B virus with reduced susceptibilities to NA inhibitors from a human patient with no history of antiviral drug treatment. The virus, designated B/Kochi/61/2011, was isolated by inoculating Madin–Darby canine kidney (MDCK) cells with respiratory specimens from the patient. NA inhibition assays demonstrated that the B/Kochi/61/2011 isolate showed a remarkable reduction in susceptibility to Peramivir. The isolate also exhibited low to moderately reduced sensitivity to oseltamivir, laninamivir, and zanamivir. A sequence analysis of viruses propagated in MDCK cells revealed that the isolate contained a mutation (E105K) not previously associated with reduced susceptibility to NA inhibitors. However, pyrosequencing analysis showed that the NA E105K mutation was below a detectable level in the original clinical specimens, suggesting that the mutant virus may be preferably selected during propagation in MDCK cells. Analysis of the three-dimensional model of E105 and K105 NAs with Peramivir suggested that the E105K mutation at the monomer–monomer interface of the NA tetramer may destabilize the tetrameric form of NA, leading to decreased susceptibility to NA inhibitors. These results have implications for understanding the mechanism of resistance against NA-inhibitor drugs.
