Treatment-Emergent Influenza Virus Polymerase Acidic Substitutions Independent of Those at I38 Associated With Reduced Baloxavir Susceptibility and Virus Rebound in Trials of Baloxavir Marboxil
Abstract Influenza viruses harboring treatment-emergent I38F/M/N/T substitutions in the polymerase acidic (PA) endonuclease exhibited reduced susceptibility to baloxavir and were associated with virus rebound and variable clinical response in clinical trials. US regulatory review of registrational t...
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| Veröffentlicht in: | The Journal of infectious diseases 2020-08, Vol.222 (6), p.957-961 |
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| creator | Ince, William L Smith, Fraser B O’Rear, Julian J Thomson, Michael |
| description | Abstract
Influenza viruses harboring treatment-emergent I38F/M/N/T substitutions in the polymerase acidic (PA) endonuclease exhibited reduced susceptibility to baloxavir and were associated with virus rebound and variable clinical response in clinical trials. US regulatory review of registrational trial data also identified treatment-emergent PA substitutions E23K in A/H1N1 viruses and E23G/K, A37T, and E199G in A/H3N2 viruses, which conferred reduced susceptibility to baloxavir, although to a lesser degree than I38F/M/N/T substitutions, and were associated with virus rebound. Although these non-I38 substitutions emerged less frequently than substitutions at I38, they represent alternate pathways to baloxavir virologic resistance and should be monitored accordingly.
In clinical trials of baloxavir marboxil, treatment-emergent PA substitutions E23G/K, A37T, and E199G conferred reduced susceptibility to baloxavir and were associated with virus rebound. These non-I38 substitutions represent alternate pathways to baloxavir virologic resistance. |
| doi_str_mv | 10.1093/infdis/jiaa164 |
| format | Article |
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Influenza viruses harboring treatment-emergent I38F/M/N/T substitutions in the polymerase acidic (PA) endonuclease exhibited reduced susceptibility to baloxavir and were associated with virus rebound and variable clinical response in clinical trials. US regulatory review of registrational trial data also identified treatment-emergent PA substitutions E23K in A/H1N1 viruses and E23G/K, A37T, and E199G in A/H3N2 viruses, which conferred reduced susceptibility to baloxavir, although to a lesser degree than I38F/M/N/T substitutions, and were associated with virus rebound. Although these non-I38 substitutions emerged less frequently than substitutions at I38, they represent alternate pathways to baloxavir virologic resistance and should be monitored accordingly.
In clinical trials of baloxavir marboxil, treatment-emergent PA substitutions E23G/K, A37T, and E199G conferred reduced susceptibility to baloxavir and were associated with virus rebound. These non-I38 substitutions represent alternate pathways to baloxavir virologic resistance.</description><identifier>ISSN: 0022-1899</identifier><identifier>EISSN: 1537-6613</identifier><identifier>DOI: 10.1093/infdis/jiaa164</identifier><identifier>PMID: 32253432</identifier><language>eng</language><publisher>US: Oxford University Press</publisher><subject>Amino Acid Substitution ; Antiviral Agents - pharmacology ; Antiviral Agents - therapeutic use ; Antiviral drugs ; Clinical trials ; Dibenzothiepins - pharmacology ; Dibenzothiepins - therapeutic use ; Drug Resistance, Viral ; Endonuclease ; Humans ; Influenza ; Influenza A virus - classification ; Influenza A virus - genetics ; Influenza B virus - classification ; Influenza B virus - genetics ; Influenza, Human - drug therapy ; Influenza, Human - virology ; Morpholines - pharmacology ; Morpholines - therapeutic use ; Mutation ; Orthomyxoviridae - classification ; Orthomyxoviridae - drug effects ; Orthomyxoviridae - enzymology ; Orthomyxoviridae - genetics ; Pyridones - pharmacology ; Pyridones - therapeutic use ; RNA-Dependent RNA Polymerase - genetics ; Treatment Outcome ; Triazines - pharmacology ; Triazines - therapeutic use ; Viral Load ; Viruses</subject><ispartof>The Journal of infectious diseases, 2020-08, Vol.222 (6), p.957-961</ispartof><rights>Published by Oxford University Press for the Infectious Diseases Society of America 2020. 2020</rights><rights>Published by Oxford University Press for the Infectious Diseases Society of America 2020.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c397t-9ec46d17310c4fcc9077db0366035f43452ac2690804f15a02c32f7767ba6c9a3</citedby><cites>FETCH-LOGICAL-c397t-9ec46d17310c4fcc9077db0366035f43452ac2690804f15a02c32f7767ba6c9a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,1578,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32253432$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ince, William L</creatorcontrib><creatorcontrib>Smith, Fraser B</creatorcontrib><creatorcontrib>O’Rear, Julian J</creatorcontrib><creatorcontrib>Thomson, Michael</creatorcontrib><title>Treatment-Emergent Influenza Virus Polymerase Acidic Substitutions Independent of Those at I38 Associated With Reduced Baloxavir Susceptibility and Virus Rebound in Trials of Baloxavir Marboxil</title><title>The Journal of infectious diseases</title><addtitle>J Infect Dis</addtitle><description>Abstract
Influenza viruses harboring treatment-emergent I38F/M/N/T substitutions in the polymerase acidic (PA) endonuclease exhibited reduced susceptibility to baloxavir and were associated with virus rebound and variable clinical response in clinical trials. US regulatory review of registrational trial data also identified treatment-emergent PA substitutions E23K in A/H1N1 viruses and E23G/K, A37T, and E199G in A/H3N2 viruses, which conferred reduced susceptibility to baloxavir, although to a lesser degree than I38F/M/N/T substitutions, and were associated with virus rebound. Although these non-I38 substitutions emerged less frequently than substitutions at I38, they represent alternate pathways to baloxavir virologic resistance and should be monitored accordingly.
In clinical trials of baloxavir marboxil, treatment-emergent PA substitutions E23G/K, A37T, and E199G conferred reduced susceptibility to baloxavir and were associated with virus rebound. These non-I38 substitutions represent alternate pathways to baloxavir virologic resistance.</description><subject>Amino Acid Substitution</subject><subject>Antiviral Agents - pharmacology</subject><subject>Antiviral Agents - therapeutic use</subject><subject>Antiviral drugs</subject><subject>Clinical trials</subject><subject>Dibenzothiepins - pharmacology</subject><subject>Dibenzothiepins - therapeutic use</subject><subject>Drug Resistance, Viral</subject><subject>Endonuclease</subject><subject>Humans</subject><subject>Influenza</subject><subject>Influenza A virus - classification</subject><subject>Influenza A virus - genetics</subject><subject>Influenza B virus - classification</subject><subject>Influenza B virus - genetics</subject><subject>Influenza, Human - drug therapy</subject><subject>Influenza, Human - virology</subject><subject>Morpholines - pharmacology</subject><subject>Morpholines - therapeutic use</subject><subject>Mutation</subject><subject>Orthomyxoviridae - classification</subject><subject>Orthomyxoviridae - drug effects</subject><subject>Orthomyxoviridae - enzymology</subject><subject>Orthomyxoviridae - genetics</subject><subject>Pyridones - pharmacology</subject><subject>Pyridones - therapeutic use</subject><subject>RNA-Dependent RNA Polymerase - genetics</subject><subject>Treatment Outcome</subject><subject>Triazines - pharmacology</subject><subject>Triazines - therapeutic use</subject><subject>Viral Load</subject><subject>Viruses</subject><issn>0022-1899</issn><issn>1537-6613</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkT1vFDEQhi1ERI5AS4ksUVFs4q-1b8sjChApEVE4oFx5_UHmtLde_IFy_Dv-GY7ugDKNx6N55pniRegVJaeUdPwMJm8hnW1AayrFE7SgLVeNlJQ_RQtCGGvosuuO0fOUNoQQwaV6ho45Yy0XnC3Q73V0Om_dlJuLrYvf6wdfTn4sbvql8VeIJeGbMO7qTCeHVwYsGPy5DClDLhnClCpv3ezqU3eDx-u7UEldPXyJVykFAzo7i79BvsO3zhZTm3d6DPf6J8TqSsbNGQYYIe-wnuzh7K0bQqkdTHgdQY_pQf5_71rHIdzD-AId-Tp0Lw_1BH15f7E-_9hcffpweb66agzvVG46Z4S0VHFKjPDGdEQpOxAuJeGtF1y0TBsmO7IkwtNWE2Y480pJNWhpOs1P0Ju9d47hR3Ep95tQ4lRP9kwovqRMcFWp0z1lYkgpOt_PEbY67npK-ofE-n1i_SGxuvD6oC3D1tl_-N-IKvB2D4QyPyb7A3EypW4</recordid><startdate>20200817</startdate><enddate>20200817</enddate><creator>Ince, William L</creator><creator>Smith, Fraser B</creator><creator>O’Rear, Julian J</creator><creator>Thomson, Michael</creator><general>Oxford University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>K9.</scope><scope>NAPCQ</scope></search><sort><creationdate>20200817</creationdate><title>Treatment-Emergent Influenza Virus Polymerase Acidic Substitutions Independent of Those at I38 Associated With Reduced Baloxavir Susceptibility and Virus Rebound in Trials of Baloxavir Marboxil</title><author>Ince, William L ; Smith, Fraser B ; O’Rear, Julian J ; Thomson, Michael</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c397t-9ec46d17310c4fcc9077db0366035f43452ac2690804f15a02c32f7767ba6c9a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Amino Acid Substitution</topic><topic>Antiviral Agents - pharmacology</topic><topic>Antiviral Agents - therapeutic use</topic><topic>Antiviral drugs</topic><topic>Clinical trials</topic><topic>Dibenzothiepins - pharmacology</topic><topic>Dibenzothiepins - therapeutic use</topic><topic>Drug Resistance, Viral</topic><topic>Endonuclease</topic><topic>Humans</topic><topic>Influenza</topic><topic>Influenza A virus - classification</topic><topic>Influenza A virus - genetics</topic><topic>Influenza B virus - classification</topic><topic>Influenza B virus - genetics</topic><topic>Influenza, Human - drug therapy</topic><topic>Influenza, Human - virology</topic><topic>Morpholines - pharmacology</topic><topic>Morpholines - therapeutic use</topic><topic>Mutation</topic><topic>Orthomyxoviridae - classification</topic><topic>Orthomyxoviridae - drug effects</topic><topic>Orthomyxoviridae - enzymology</topic><topic>Orthomyxoviridae - genetics</topic><topic>Pyridones - pharmacology</topic><topic>Pyridones - therapeutic use</topic><topic>RNA-Dependent RNA Polymerase - genetics</topic><topic>Treatment Outcome</topic><topic>Triazines - pharmacology</topic><topic>Triazines - therapeutic use</topic><topic>Viral Load</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ince, William L</creatorcontrib><creatorcontrib>Smith, Fraser B</creatorcontrib><creatorcontrib>O’Rear, Julian J</creatorcontrib><creatorcontrib>Thomson, Michael</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><jtitle>The Journal of infectious diseases</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ince, William L</au><au>Smith, Fraser B</au><au>O’Rear, Julian J</au><au>Thomson, Michael</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Treatment-Emergent Influenza Virus Polymerase Acidic Substitutions Independent of Those at I38 Associated With Reduced Baloxavir Susceptibility and Virus Rebound in Trials of Baloxavir Marboxil</atitle><jtitle>The Journal of infectious diseases</jtitle><addtitle>J Infect Dis</addtitle><date>2020-08-17</date><risdate>2020</risdate><volume>222</volume><issue>6</issue><spage>957</spage><epage>961</epage><pages>957-961</pages><issn>0022-1899</issn><eissn>1537-6613</eissn><abstract>Abstract
Influenza viruses harboring treatment-emergent I38F/M/N/T substitutions in the polymerase acidic (PA) endonuclease exhibited reduced susceptibility to baloxavir and were associated with virus rebound and variable clinical response in clinical trials. US regulatory review of registrational trial data also identified treatment-emergent PA substitutions E23K in A/H1N1 viruses and E23G/K, A37T, and E199G in A/H3N2 viruses, which conferred reduced susceptibility to baloxavir, although to a lesser degree than I38F/M/N/T substitutions, and were associated with virus rebound. Although these non-I38 substitutions emerged less frequently than substitutions at I38, they represent alternate pathways to baloxavir virologic resistance and should be monitored accordingly.
In clinical trials of baloxavir marboxil, treatment-emergent PA substitutions E23G/K, A37T, and E199G conferred reduced susceptibility to baloxavir and were associated with virus rebound. These non-I38 substitutions represent alternate pathways to baloxavir virologic resistance.</abstract><cop>US</cop><pub>Oxford University Press</pub><pmid>32253432</pmid><doi>10.1093/infdis/jiaa164</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Alma/SFX Local Collection |
| subjects | Amino Acid Substitution Antiviral Agents - pharmacology Antiviral Agents - therapeutic use Antiviral drugs Clinical trials Dibenzothiepins - pharmacology Dibenzothiepins - therapeutic use Drug Resistance, Viral Endonuclease Humans Influenza Influenza A virus - classification Influenza A virus - genetics Influenza B virus - classification Influenza B virus - genetics Influenza, Human - drug therapy Influenza, Human - virology Morpholines - pharmacology Morpholines - therapeutic use Mutation Orthomyxoviridae - classification Orthomyxoviridae - drug effects Orthomyxoviridae - enzymology Orthomyxoviridae - genetics Pyridones - pharmacology Pyridones - therapeutic use RNA-Dependent RNA Polymerase - genetics Treatment Outcome Triazines - pharmacology Triazines - therapeutic use Viral Load Viruses |
| title | Treatment-Emergent Influenza Virus Polymerase Acidic Substitutions Independent of Those at I38 Associated With Reduced Baloxavir Susceptibility and Virus Rebound in Trials of Baloxavir Marboxil |
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