#Functional #neuraminidase #inhibitor #resistance motifs in #avian #influenza A(#H5Nx) viruses (Antiviral Res., abstract)

[Source: Antiviral Research, full page: (LINK). Abstract, edited.]

Antiviral Research | Available online 1 August 2020, 104886 | In Press, Journal Pre-proof | Research paper

Functional neuraminidase inhibitor resistance motifs in avian influenza A(H5Nx) viruses

Dagmara Bialy, Holly Shelton, The Pirbright Institute, Pirbright, United Kingdom

Received 24 March 2020, Revised 13 July 2020, Accepted 16 July 2020, Available online 1 August 2020.

DOI: https://doi.org/10.1016/j.antiviral.2020.104886

 

Highlights

  • A R292K residue change in NA reduces susceptibility to NA inhibitor drugs (NAIs) in H5N6 and H5N2 avian influenza viruses.
  • All four mutations (E119V, H274Y, R292K and N294S) reducing susceptibility to NAIs in H5N6 viruses also reduced viral NA activity.
  • Reduced susceptibility to NA inhibitors in H5N6 did not attenuate virus replication efficiency in chicken cells or eggs.
  • A reduction of the viral HA affinity for sialic acid was observed in H5N6 viruses with reduced NA activity.

 

Abstract

Neuraminidase inhibitors (NAIs) are antiviral agents recommended worldwide to treat or prevent influenza virus infections in humans. Past influenza virus pandemics seeded by zoonotic infection by avian influenza viruses (AIV) as well as the increasing number of human infections with AIV have shown the importance of having information about resistance to NAIs by avian NAs that could cross the species barrier. In this study we introduced four NAI resistance-associated mutations (N2 numbering) previously found in human infections into the NA of three current AIV subtypes of the H5Nx genotype that threaten the poultry industry and human health: highly pathogenic H5N8, H5N6 and H5N2. Using the established MUNANA assay we showed that a R292K substitution in H5N6 and H5N2 viruses significantly reduced susceptibility to three licenced NAIs: oseltamivir, zanamivir and peramivir. In contrast the mutations E119V, H274Y and N294S had more variable effects with NAI susceptibility being drug- and strain-specific. We measured the replicative fitness of NAI resistant H5N6 viruses and found that they replicated to comparable or significantly higher titres in primary chicken cells and in embryonated hens’ eggs as compared to wild type – despite the NA activity of the viral neuraminidase proteins being reduced. The R292K and N294S drug resistant H5N6 viruses had single amino acid substitutions in their haemagglutinin (HA): Y98F and A189T, respectively (H3 numbering) which reduced receptor binding properties possibly balancing the reduced NA activity seen. Our results demonstrate that the H5Nx viruses can support drug resistance mutations that confer reduced susceptibility to licenced NAIs and that these H5N6 viruses did not show diminished replicative fitness in avian cell cultures. Our results support the requirement for on-going surveillance of these strains in bird populations to include motifs associated with human drug resistance.

Keywords: Avian Influenza; H5N2; H5N6; Antivirals; Drugs Resistance; Oseltamivir; Zanamivir; Peramivir.

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Successful #Treatment With #Baloxavir Marboxil of a Patient With #Peramivir #Resistant #Influenza A / #H3N2 With a Dual E119D/R292K Substitution After Allogeneic Hematopoietic Cell #Transplantation: A Case Report (BMC Infect Dis., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

BMC Infect Dis. 2020 Jul 6;20(1):478. doi: 10.1186/s12879-020-05205-1.

Successful Treatment With Baloxavir Marboxil of a Patient With Peramivir-Resistant Influenza A/H3N2 With a Dual E119D/R292K Substitution After Allogeneic Hematopoietic Cell Transplantation: A Case Report

Naonori Harada 1, Wataru Shibata 2 3, Hideo Koh 4, Emi Takashita 5, Seiichiro Fujisaki 5, Hiroshi Okamura 1, Satoru Nanno 1, Koichi Yamada 2 3, Hirohisa Nakamae 1, Masayuki Hino 1, Hiroshi Kakeya 2 3

Affiliations: 1 Hematology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan. 2 Department of Infection Control Science, Graduate School of Medicine, Osaka City University, Osaka, Japan. 3 Research Center for Infectious Disease Sciences (RCIDS), Graduate School of Medicine, Osaka City University, Osaka, Japan. 4 Hematology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan. hide_koh@med.osaka-cu.ac.jp. 5 Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo, Japan.

PMID: 32631240 DOI: 10.1186/s12879-020-05205-1

 

Abstract

Background:

Extended use of oseltamivir in an immunocompromised host could reportedly induce neuraminidase gene mutation possibly leading to oseltamivir-resistant influenza A/H3N2 virus. To our knowledge, no report is available on the clinical course of a severely immunocompromised patient with a dual E119D/R292K neuraminidase mutated-influenza A/H3N2 during the administration of peramivir.

Case presentation:

A 49-year-old male patient was admitted for second allogeneic hematopoietic cell transplantation for active acute leukemia. The patient received 5 mg prednisolone and 75 mg cyclosporine and had severe lymphopenia (70/μL). At the time of hospitalization, the patient was diagnosed with upper tract influenza A virus infection, and oseltamivir treatment was initiated immediately. However, the patient was intolerant to oseltamivir. The following day, treatment was changed to peramivir. Despite a total period of neuraminidase-inhibitor administration of 16 days, the symptoms and viral shedding continued. Changing to baloxavir marboxil resolved the symptoms, and the influenza diagnostic test became negative. Subsequently, sequence analysis of the nasopharyngeal specimen revealed the dual E119D/R292K neuraminidase mutant influenza A/H3N2.

Conclusions:

In a highly immunocompromised host, clinicians should take care when peramivir is used for extended periods to treat influenza virus A/H3N2 infection as this could potentially leading to a dual E119D/R292K substitution in neuraminidase protein. Baloxavir marboxil may be one of the agents that can be used to treat this type of mutated influenza virus infection.

Keywords: Allogeneic hematopoietic cell transplantation; Baloxavir marboxil; Dual E119D/R292K substitution; Immunocompromised host; Influenza A/H3N2; Neuraminidase mutation; Peramivir resistance.

Keywords: Seasonal Influenza; Antivirals; Drugs Resistance; Hematology; H3N2; Cancer; Immunosuppression; Peramivir; Baloxavir.

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Characterization of #Neuraminidase #Inhibitor #Resistant #Influenza Virus Isolates From Immunocompromised Patients in the Republic of #Korea (Virol J., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Virol J. 2020 Jul 6;17(1):94. doi: 10.1186/s12985-020-01375-1.

Characterization of Neuraminidase Inhibitor-Resistant Influenza Virus Isolates From Immunocompromised Patients in the Republic of Korea

Heui Man Kim 1, Namjoo Lee 1, Mi-Seon Kim 1, Chun Kang 1, Yoon-Seok Chung 2

Affiliations: 1 Division of Viral Diseases, Center for Laboratory Control of Infectious Diseases, Korea Centers for Disease Control and Prevention, Cheongju-si, South Korea. 2 Division of Viral Diseases, Center for Laboratory Control of Infectious Diseases, Korea Centers for Disease Control and Prevention, Cheongju-si, South Korea. rollstone93@korea.kr.

PMID: 32631440 DOI: 10.1186/s12985-020-01375-1

 

Abstract

Background:

The emergence of influenza viruses resistant to anti-influenza drugs is a threat to global public health. The Korea Centers for Disease Control and Prevention operates the Korea Influenza and Respiratory Viruses Surveillance System (KINRESS) to monitor epidemics of influenza and Severe Acute Respiratory Infection (SARI) to identify mutated influenza viruses affecting drug resistance, pathogenesis, and transmission.

Methods:

Oropharyngeal swab samples were collected from KINRESS and SARI during the 2018-2019 season. The specimens confirmed influenza virus using real-time RT-PCR on inoculated MDCK cells. HA and NA sequences of the influenza viruses were analyzed for phylogeny and mutations. Neuraminidase inhibition and hemagglutination inhibition assays were utilized to characterize the isolates.

Results:

Two A(H1N1)pdm09 isolates harboring an H275Y substitution in the neuraminidase sequence were detected in patients with acute hematologic cancer. They had prolonged respiratory symptoms, with the virus present in the respiratory tract despite oseltamivir and peramivir treatment. Through the neuraminidase inhibition assay, both viruses were found to be resistant to oseltamivir and peramivir, but not to zanamivir. Although hemagglutinin and neuraminidase phylogenetic analyses suggested that the 2 A(H1N1)pdm09 isolates were not identical, their antigenicity was similar to that of the 2018-19 influenza vaccine virus.

Conclusions:

Our data indicate the utility of monitoring influenza-infected immunocompromised patients in general hospitals for the early detection of emerging neuraminidase inhibitor-resistant viruses and maintaining continuous laboratory surveillance of patients with influenza-like illness in sentinel clinics to monitor the spread of such new variants. Finally, characterization of the virus can inform the risk assessment for future epidemics and pandemics caused by drug-resistant influenza viruses.

Keywords: Drug resistance; H275Y; Immunocompromised patients; Influenza virus.

Keywords: Seasonal Influenza; H1N1pdm09; Cancer; Immunosuppression; Antivirals; Drugs Resistance; Oseltamivir; Zanamivir; Peramivir; S. Korea.

——

Efficacy of #neuraminidase #inhibitors against #H5N6 highly pathogenic #avian #influenza virus in a non-human #primate model (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Efficacy of neuraminidase inhibitors against H5N6 highly pathogenic avian influenza virus in a non-human primate model

Cong Thanh Nguyen, Saori Suzuki, Yasushi Itoh, Hirohito Ishigaki, Misako Nakayama, Kaori Hayashi, Keita Matsuno, Masatoshi Okamatsu, Yoshihiro Sakoda, Hiroshi Kida, Kazumasa Ogasawara

DOI: 10.1128/AAC.02561-19

 

ABSTRACT

Attention has been paid to H5N6 highly pathogenic avian influenza virus (HPAIV) because of its heavy burden on the poultry industry and human mortality. Since an influenza A virus carrying N6 neuraminidase (NA) has never spread in humans, the potential for H5N6 HPAIV to cause disease in humans and the efficacy of antiviral drugs against the virus need to be urgently assessed. We used non-human primates to elucidate the pathogenesis of H5N6 HPAIV as well as to determine the efficacy of antiviral drugs against the virus. H5N6 HPAIV infection led to high fever in cynomolgus macaques. The lung injury caused by the virus was severe with diffuse alveolar damage and neutrophil infiltration. In addition, an increase in IFN-α showed an inverse correlation with virus titers during the infection process. Oseltamivir was effective for reducing H5N6 HPAIV propagation, and continuous treatment with peramivir reduced virus propagation and severity of symptoms in the early stage. This study also showed the pathologically severe lung injury states in the cynomolgus macaques infected with H5N6 HPAIV, even in those that received early antiviral drug treatments, indicating the need for close monitoring and the need for further studies on the virus pathogenicity and new antiviral therapies.

Copyright © 2020 American Society for Microbiology. All Rights Reserved.

Keywords: Avian Influenza; H5N6; Antivirals; Oseltamivir; Peramivir; Animal models.

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#Global #Update on the Susceptibilities of #Human #Influenza Viruses to #NAIs and the #Baloxavir, 2017-2018 (Antiviral Res., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Antiviral Res, 104718 2020 Jan 28 [Online ahead of print]

Global Update on the Susceptibilities of Human Influenza Viruses to Neuraminidase Inhibitors and the Cap-Dependent Endonuclease Inhibitor Baloxavir, 2017-2018

Emi Takashita 1, Rod S Daniels 2, Seiichiro Fujisaki 3, Vicki Gregory 2, Larisa V Gubareva 4, Weiijuan Huang 5, Aeron C Hurt 6, Angie Lackenby 7, Ha T Nguyen 4, Dmitriy Pereyaslov 8, Merryn Roe 6, Magdi Samaan 9, Kanta Subbarao 6, Herman Tse 10, Dayan Wang 5, Hui-Ling Yen 11, Wenqing Zhang 9, Adam Meijer 12

Affiliations: 1 WHO Collaborating Centre for Reference and Research on Influenza, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashimurayama, Tokyo, 208-0011, Japan. Electronic address: emitaka@nih.go.jp. 2 WHO Collaborating Centre for Reference and Research on Influenza, The Francis Crick Institute, Worldwide Influenza Centre, 1 Midland Road, London, NW1 1AT, United Kingdom. 3 WHO Collaborating Centre for Reference and Research on Influenza, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashimurayama, Tokyo, 208-0011, Japan. 4 WHO Collaborating Centre for Surveillance, Epidemiology and Control of Influenza, Centers for Diseases Control and Prevention, 1600 Clifton RD NE, MS-G16, Atlanta, GA, 30329, USA. 5 WHO Collaborating Centre for Reference and Research on Influenza, National Institute for Viral Disease Control and Prevention, China CDC, Beijing, China. 6 WHO Collaborating Centre for Reference and Research on Influenza, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, 3000, Australia. 7 National Infection Service, Public Health England, London, NW9 5HT, United Kingdom. 8 Division of Communicable Diseases, Health Security, & Environment, World Health Organization Regional Office for Europe, UN City, Marmorvej 51, DK-2100, Copenhagen Ø, Denmark. 9 Global Influenza Programme, World Health Organization, Avenue Appia 20, 1211, Geneva 27, Switzerland. 10 Public Health Laboratory Centre, 382 Nam Cheong Street, Hong Kong SAR, China. 11 School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. 12 National Institute for Public Health and the Environment, PO Box 1, 3720, BA Bilthoven, the Netherlands.

PMID: 32004620 DOI: 10.1016/j.antiviral.2020.104718

 

Abstract

The global analysis of neuraminidase inhibitor (NAI) susceptibility of influenza viruses has been conducted since the 2012-13 period. In 2018 a novel cap-dependent endonuclease inhibitor, baloxavir, that targets polymerase acidic subunit (PA) was approved for the treatment of influenza virus infection in Japan and the United States. For this annual report, the susceptibilities of influenza viruses to NAIs and baloxavir were analyzed. A total of 15409 viruses, collected by World Health Organization (WHO) recognized National Influenza Centers and other laboratories between May 2017 and May 2018, were assessed for phenotypic NAI susceptibility by five WHO Collaborating Centers (CCs). The 50% inhibitory concentration (IC50) was determined for oseltamivir, zanamivir, peramivir and laninamivir. Reduced inhibition (RI) or highly reduced inhibition (HRI) by one or more NAIs was exhibited by 0.8% of viruses tested (n = 122). The frequency of viruses with RI or HRI has remained low since this global analysis began (2012-13: 0.6%; 2013-14: 1.9%; 2014-15: 0.5%; 2015-16: 0.8%; 2016-17: 0.2%). PA gene sequence data, available from public databases (n = 13523), were screened for amino acid substitutions associated with reduced susceptibility to baloxavir (PA E23 G/K/R, PA A36V, PA A37T, PA I38 F/M/T/L, PA E119D, PA E199G): 11 (0.08%) viruses possessed such substitutions. Five of them were included in phenotypic baloxavir susceptibility analysis by two WHO CCs and IC50 values were determined. The PA variant viruses showed 6-17-fold reduced susceptibility to baloxavir. Overall, in the 2017-18 period the frequency of circulating influenza viruses with reduced susceptibility to NAIs or baloxavir was low, but continued monitoring is important.

Keywords: Baloxavir; Influenza; Neuraminidase inhibitor; Resistance; Surveillance; Susceptibility.

Copyright © 2020. Published by Elsevier B.V.

Conflict of interest statement: Declaration of competing interest None.

Keywords: Antivirals; Drugs Resistance; Influenza A; Oseltamivir; Zanamivir; Peramivir; Laninamivir; Baloxavir.

——

The #evolution and #genetic #diversity of #avian #influenza A(#H9N2) viruses in #Cambodia, 2015 – 2016 (PLOS One, abstract)

[Source: PLOS One, full page: (LINK). Abstract, edited.]

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

The evolution and genetic diversity of avian influenza A(H9N2) viruses in Cambodia, 2015 – 2016

Annika Suttie, Songha Tok, Sokhoun Yann, Ponnarath Keo, Srey Viseth Horm, Merryn Roe, Matthew Kaye, San Sorn, Davun Holl, Sothyra Tum, Ian G. Barr, Aeron C. Hurt, Andrew R. Greenhill,  [ … ], Paul F. Horwood

___

Published: December 9, 2019 / DOI: https://doi.org/10.1371/journal.pone.0225428

 

Abstract

Low pathogenic A(H9N2) subtype avian influenza viruses (AIVs) were originally detected in Cambodian poultry in 2013, and now circulate endemically. We sequenced and characterised 64 A(H9N2) AIVs detected in Cambodian poultry (chickens and ducks) from January 2015 to May 2016. All A(H9) viruses collected in 2015 and 2016 belonged to a new BJ/94-like h9-4.2.5 sub-lineage that emerged in the region during or after 2013, and was distinct to previously detected Cambodian viruses. Overall, there was a reduction of genetic diversity of H9N2 since 2013, however two genotypes were detected in circulation, P and V, with extensive reassortment between the viruses. Phylogenetic analysis showed a close relationship between A(H9N2) AIVs detected in Cambodian and Vietnamese poultry, highlighting cross-border trade/movement of live, domestic poultry between the countries. Wild birds may also play a role in A(H9N2) transmission in the region. Some genes of the Cambodian isolates frequently clustered with zoonotic A(H7N9), A(H9N2) and A(H10N8) viruses, suggesting a common ecology. Molecular analysis showed 100% of viruses contained the hemagglutinin (HA) Q226L substitution, which favours mammalian receptor type binding. All viruses were susceptible to the neuraminidase inhibitor antivirals; however, 41% contained the matrix (M2) S31N substitution associated with resistance to adamantanes. Overall, Cambodian A(H9N2) viruses possessed factors known to increase zoonotic potential, and therefore their evolution should be continually monitored.

___

Citation: Suttie A, Tok S, Yann S, Keo P, Horm SV, Roe M, et al. (2019) The evolution and genetic diversity of avian influenza A(H9N2) viruses in Cambodia, 2015 – 2016. PLoS ONE 14(12): e0225428. https://doi.org/10.1371/journal.pone.0225428

Editor: Charles J. Russell, St. Jude Children’s Research Hospital, UNITED STATES

Received: August 28, 2019; Accepted: November 4, 2019; Published: December 9, 2019

Copyright: © 2019 Suttie et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: This publication is the result of work conducted under a cooperative agreement with the Office of the Assistant Secretary for Preparedness and Response in the U.S. Department of Health and Human Services (HHS), grant number IDSEP140020-01-00 (PH). The study was also funded, in part, by the US Agency for International Development (grant No. AID-442-G-14-00005) (PH). The Melbourne WHO Collaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health (IB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Keywords: Avian Influenza; H9N2; H7N9; H9N2; H10N8; Reassortant strain; Cambodia; Antivirals; Drugs Resistance; Amantadine; Oseltamivir; Zanamivir.

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#Diversity of A(#H5N1) clade 2.3.2.1c #avian #influenza viruses with evidence of #reassortment in #Cambodia, 2014-2016 (PLOS One, abstract)

[Source: PLOS One, full page: (LINK). Abstract, edited.]

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Diversity of A(H5N1) clade 2.3.2.1c avian influenza viruses with evidence of reassortment in Cambodia, 2014-2016

Annika Suttie,  Songha Tok, Sokhoun Yann, Ponnarath Keo, Srey Viseth Horm, Merryn Roe, Matthew Kaye, San Sorn, Davun Holl, Sothyra Tum, Philippe Buchy, Ian Barr, Aeron Hurt,  [ … ], Paul F. Horwood

___

Published: December 9, 2019 / DOI: https://doi.org/10.1371/journal.pone.0226108

 

Abstract

In Cambodia, highly pathogenic avian influenza A(H5N1) subtype viruses circulate endemically causing poultry outbreaks and zoonotic human cases. To investigate the genomic diversity and development of endemicity of the predominantly circulating clade 2.3.2.1c A(H5N1) viruses, we characterised 68 AIVs detected in poultry, the environment and from a single human A(H5N1) case from January 2014 to December 2016. Full genomes were generated for 42 A(H5N1) viruses. Phylogenetic analysis shows that five clade 2.3.2.1c genotypes, designated KH1 to KH5, were circulating in Cambodia during this period. The genotypes arose through multiple reassortment events with the neuraminidase (NA) and internal genes belonging to H5N1 clade 2.3.2.1a, clade 2.3.2.1b or A(H9N2) lineages. Phylogenies suggest that the Cambodian AIVs were derived from viruses circulating between Cambodian and Vietnamese poultry. Molecular analyses show that these viruses contained the hemagglutinin (HA) gene substitutions D94N, S133A, S155N, T156A, T188I and K189R known to increase binding to the human-type α2,6-linked sialic acid receptors. Two A(H5N1) viruses displayed the M2 gene S31N or A30T substitutions indicative of adamantane resistance, however, susceptibility testing towards neuraminidase inhibitors (oseltamivir, zanamivir, lananmivir and peramivir) of a subset of thirty clade 2.3.2.1c viruses showed susceptibility to all four drugs. This study shows that A(H5N1) viruses continue to reassort with other A(H5N1) and A(H9N2) viruses that are endemic in the region, highlighting the risk of introduction and emergence of novel A(H5N1) genotypes in Cambodia.

___

Citation: Suttie A, Tok S, Yann S, Keo P, Horm SV, Roe M, et al. (2019) Diversity of A(H5N1) clade 2.3.2.1c avian influenza viruses with evidence of reassortment in Cambodia, 2014-2016. PLoS ONE 14(12): e0226108. https://doi.org/10.1371/journal.pone.0226108

Editor: Charles J. Russell, St. Jude Children’s Research Hospital, UNITED STATES

Received: August 7, 2019; Accepted: November 18, 2019; Published: December 9, 2019

Copyright: © 2019 Suttie et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: This publication is the result of work conducted under a cooperative agreement with the Office of the Assistant Secretary for Preparedness and Response in the U.S. Department of Health and Human Services (HHS), grant number IDSEP140020-01-00. Its contents and conclusions are solely the responsibility of the authors and do not represent the official views of HHS. The study was also funded, in part, by the US Agency for International Development (grant No. AID-442-G-14-00005) and partially funded through the UK Research and Innovation Global Challenges Research Fund to The Consortium of Animal Market Networks to Assess Risk of Emerging Infectious Diseases Through Enhanced Surveillance (CANARIES; grant No. GCRFNGR3\1497). Annika Suttie is funded by an Australian Government Research Training Program Scholarship and a Faculty of Science and Technology Research Scholarship from Federation University. The Melbourne WHO Collaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health. GlaxoSmithKline Biologicals SA provided support in the form of salary for an author [PB], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ‘author contributions’ section. The authors are solely responsible for final content and interpretation.

Competing interests: GlaxoSmithKline Biologicals SA provided support in the form of salary for an author [PB]. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Keywords: Avian Influenza; H5N1; H9N2; Reassortant strains; Poultry; Human; Antivirals; Drugs Resistance; Amantadine; Oseltamivir; Zanamivir; Cambodia.

——

#Influenza A virus #hemagglutinin #mutations associated with use of #NAIs correlate with decreased inhibition by anti-influenza #antibodies (Virol J., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Virol J. 2019 Nov 29;16(1):149. doi: 10.1186/s12985-019-1258-x.

Influenza A virus hemagglutinin mutations associated with use of neuraminidase inhibitors correlate with decreased inhibition by anti-influenza antibodies.

Ilyushina NA1, Komatsu TE2, Ince WL2, Donaldson EF2, Lee N3, O’Rear JJ2, Donnelly RP3.

Author information: 1 Division of Biotechnology Review and Research II, Food and Drug Administration CDER, WO Bldg. 52/72, Room 2105, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA. natalia.ilyushina@fda.hhs.gov. 2 Division of Antiviral Products, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA. 3 Division of Biotechnology Review and Research II, Food and Drug Administration CDER, WO Bldg. 52/72, Room 2105, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.

 

Abstract

BACKGROUND:

Vaccination and the use of neuraminidase inhibitors (NAIs) are currently the front lines of defense against seasonal influenza. The activity of influenza vaccines and antivirals drugs such as the NAIs can be affected by mutations in the influenza hemagglutinin (HA) protein. Numerous HA substitutions have been identified in nonclinical NAI resistance-selection experiments as well as in clinical specimens from NAI treatment or surveillance studies. These mutations are listed in the prescribing information (package inserts) for FDA-approved NAIs, including oseltamivir, zanamivir, and peramivir.

METHODS:

NAI treatment-emergent H1 HA mutations were mapped onto the H1N1 HA1 trimeric crystal structure and most of them localized to the HA antigenic sites predicted to be important for anti-influenza immunity. Recombinant A/California/04/09 (H1N1)-like viruses carrying HA V152I, G155E, S162 N, S183P, and D222G mutations were generated. We then evaluated the impact of these mutations on the immune reactivity and replication potential of the recombinant viruses in a human respiratory epithelial cell line, Calu- 3.

RESULTS:

We found that the G155E and D222G mutations significantly increased viral titers ~ 13-fold compared to the wild-type virus. The hemagglutination and microneutralization activity of goat and ferret antisera, monoclonal antibodies, and human serum samples raised against pandemic A(H1N1)pdm09 viruses was ~ 100-fold lower against mutants carrying G155E or D222G compared to the wild-type virus.

CONCLUSIONS:

Although the mechanism by which HA mutations emerge during NAI treatment is uncertain, some NAI treatment-emergent HA mutations correlate with decreased immunity to influenza virus.

KEYWORDS: Antiviral resistance; Hemagglutinin (HA); Influenza A virus; Neuraminidase (NA); Neuraminidase inhibitors (NAI)

PMID: 31783761 DOI: 10.1186/s12985-019-1258-x

Keywords: Influenza A; Antivirals; H1N1pdm09; Oseltamivir; Zanamivir; Peramivir.

——

#Outcomes and #Adverse Effects With #Peramivir for the #Treatment of #Influenza #H1N1 in Critically Ill #Pediatric Patients (J Pediatr Pharmacol Ther., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

J Pediatr Pharmacol Ther. 2019 Nov-Dec;24(6):497-503. doi: 10.5863/1551-6776-24.6.497.

Outcomes and Adverse Effects With Peramivir for the Treatment of Influenza H1N1 in Critically Ill Pediatric Patients.

Witcher R, Tracy J, Santos L, Chopra A.

 

Abstract

OBJECTIVES:

Influenza is an environmental pathogen and infection presents as a range from asymptomatic to fulminant illness. Though treatment is supportive, antiviral agents have a role in the management of infection. Pediatric use of peramivir is largely based on reports and extrapolations of pharmacokinetic data. We seek to describe efficacy and safety of peramivir in critically ill pediatric patients.

METHODS:

This is a retrospective, institutional review board-approved chart review of all patients under 21 years of age, admitted to the PICU, and treated with peramivir for influenza H1N1 infection between January 1, 2016, and March 31, 2016, at a single-center, 12-bed PICU. The primary outcome was time to sustained resolution of fever; secondary outcomes included dose, duration, and adverse effects of peramivir therapy.

RESULTS:

Seven patients were included with median age of 3.7 years. Median time to sustained resolution of fever was 49.3 hours, median duration of mechanical ventilation was 14.2 days, median ICU LOS was 18.7 days, and hospital LOS was 24.7 days. No patients suffered mortality. Three patients experienced leukopenia, one of which experienced a concurrent neutropenia. Three patients experienced hyperglycemia, 2 experienced hypertension, 1 experienced increased aspartate aminotransferase and increased alanine aminotransferase, and 1 experienced diarrhea. All adverse events assessed were classified as possible using published adverse event causality assessments.

CONCLUSIONS:

Peramivir has been shown to be an effective therapy for the treatment of influenza H1N1 in critically ill pediatric patients. In our experience with 7 pediatric patients, peramivir was well tolerated at typical durations of therapy; however, increased vigilance is warranted during prolonged courses or in patients with reasons for altered pharmacokinetics and pharmacodynamics.

Copyright Published by the Pediatric Pharmacy Association. All rights reserved. For permissions, email: mhelms@pediatricpharmacy.org 2019.

KEYWORDS: adverse drug events; critical care; influenza; pediatric; safety

PMID: 31719811 PMCID: PMC6836703 DOI: 10.5863/1551-6776-24.6.497

Keywords: Seasonal Influenza; H1N1; Antivirals; Drugs safety; Peramivir; Pediatrics.

——

#Key #aminoacid residues of #neuraminidase involved in #influenza A virus #entry (Pathog Dis., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Pathog Dis. 2019 Nov 8. pii: ftz063. doi: 10.1093/femspd/ftz063. [Epub ahead of print]

Key amino acid residues of neuraminidase involved in influenza A virus entry.

Chen F1, Liu T1, Xu J1, Huang Y1, Liu S1, Yang J1.

Author information: 1 Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.

 

Abstract

Generally, influenza virus neuraminidase (NA) plays a critical role in the release stage of influenza virus. Recently, it has been found that NA may promote influenza virus to access the target cells. However, the mechanism remain unclear. Here, we reported that peramivir indeed possessed anti-influenza A virus (IAV) activity in the stage of viral entry. Importantly, we verified the critical residues of influenza NA involved in the viral entry. As a result, peramivir as an efficient NA inhibitor could suppress the initiation of IAV infection. Furthermore, mutational analysis showed NA might be associated with viral entry via amino acids residues R118, E119, D151, R152, W178, I222, E227, E276, R292 and R371. Our results demonstrated neuraminidase must contain the key amino acid residues can involve in IAV entry.

© FEMS 2019.

KEYWORDS: Influenza A virus; neuraminidase; neuraminidase active site; peramivir; viral entry

PMID: 31702775 DOI: 10.1093/femspd/ftz063

Keywords: Influenza A; Peramivir; Antivirals; Viral pathogenesis.

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