Emergence of telaprevir-resistant variants detected by ultra-deep sequencing after triple therapy in patients infected with HCV genotype 1
Using ultra‐deep sequencing technology, the present was designed to investigate whether the emergence of telaprevir‐resistant variants (amino acid substitutions of aa36, aa54, aa155, aa156, and aa170 positions in HCV NS3 region) after commencement of triple therapy of telaprevir/peginterferon (PEG‐I...
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| Veröffentlicht in: | Journal of medical virology 2013-06, Vol.85 (6), p.1028-1036 |
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| creator | Akuta, Norio Suzuki, Fumitaka Seko, Yuya Kawamura, Yusuke Sezaki, Hitomi Suzuki, Yoshiyuki Hosaka, Tetsuya Kobayashi, Masahiro Hara, Tasuku Kobayashi, Mariko Saitoh, Satoshi Arase, Yasuji Ikeda, Kenji Kumada, Hiromitsu |
| description | Using ultra‐deep sequencing technology, the present was designed to investigate whether the emergence of telaprevir‐resistant variants (amino acid substitutions of aa36, aa54, aa155, aa156, and aa170 positions in HCV NS3 region) after commencement of triple therapy of telaprevir/peginterferon (PEG‐IFN)/ribavirin could be predicted at baseline in previous non‐responders to dual therapy. Fourteen patients infected with HCV genotype 1 who did not respond to previous PEG‐IFN/ribavirin, received a 24‐week regimen of triple therapy, and were evaluated for appearance of telaprevir‐resistant variants (amino acid substitutions of more than 0.2% among the total coverage) by ultra‐deep sequencing. The sustained virological response rate was 28.6% (4 of 14 patients), which was significantly higher in patients with Arg70 (substitution at core aa70) and partial response (type of previous response to PEG‐IFN/ribavirin) than in other patients. Telaprevir‐resistant variants at baseline were detected in 7.1% (1 of 14 patients) by direct sequencing and in 21.4% (3 of 14 patients) by ultra‐deep sequencing. The appearance of telaprevir‐resistant variants was examined by ultra‐deep sequencing in 10 who did not show sustained virological responders. De novo variants emerged at re‐elevation of viral load, regardless of variant frequencies at baseline (one patient with very high frequency variants [T54S: 99.9%], two patients with very low frequency variants [V36A: 0.2%; and V170A: 0.4%], and seven patients of undetectable variants). It is concluded that it is difficult to predict at baseline the emergence of telaprevir‐resistant variants after commencement of triple therapy in prior non‐responders of HCV genotype 1, even with the use of ultra‐deep sequencing. J. Med. Virol. 85: 1028–1036, 2013. © 2013 Wiley Periodicals, Inc. |
| doi_str_mv | 10.1002/jmv.23579 |
| format | Article |
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Fourteen patients infected with HCV genotype 1 who did not respond to previous PEG‐IFN/ribavirin, received a 24‐week regimen of triple therapy, and were evaluated for appearance of telaprevir‐resistant variants (amino acid substitutions of more than 0.2% among the total coverage) by ultra‐deep sequencing. The sustained virological response rate was 28.6% (4 of 14 patients), which was significantly higher in patients with Arg70 (substitution at core aa70) and partial response (type of previous response to PEG‐IFN/ribavirin) than in other patients. Telaprevir‐resistant variants at baseline were detected in 7.1% (1 of 14 patients) by direct sequencing and in 21.4% (3 of 14 patients) by ultra‐deep sequencing. The appearance of telaprevir‐resistant variants was examined by ultra‐deep sequencing in 10 who did not show sustained virological responders. De novo variants emerged at re‐elevation of viral load, regardless of variant frequencies at baseline (one patient with very high frequency variants [T54S: 99.9%], two patients with very low frequency variants [V36A: 0.2%; and V170A: 0.4%], and seven patients of undetectable variants). It is concluded that it is difficult to predict at baseline the emergence of telaprevir‐resistant variants after commencement of triple therapy in prior non‐responders of HCV genotype 1, even with the use of ultra‐deep sequencing. J. Med. Virol. 85: 1028–1036, 2013. © 2013 Wiley Periodicals, Inc.</description><identifier>ISSN: 0146-6615</identifier><identifier>EISSN: 1096-9071</identifier><identifier>DOI: 10.1002/jmv.23579</identifier><identifier>PMID: 23588728</identifier><identifier>CODEN: JMVIDB</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>Adult ; Aged ; Amino Acid Substitution ; Antiviral Agents - therapeutic use ; Antiviral drugs ; Biological and medical sciences ; DNA, Viral - analysis ; DNA, Viral - genetics ; Drug resistance ; Drug Resistance, Viral - drug effects ; Drug Resistance, Viral - genetics ; Drug Therapy, Combination ; Female ; Fundamental and applied biological sciences. Psychology ; Genotype ; Genotype & phenotype ; HCV ; Hepacivirus - drug effects ; Hepacivirus - genetics ; Hepatitis ; Hepatitis C virus ; Hepatitis C, Chronic - drug therapy ; Hepatitis C, Chronic - immunology ; Hepatitis C, Chronic - virology ; High-Throughput Nucleotide Sequencing ; Human viral diseases ; Humans ; Infectious diseases ; Interferon-alpha - therapeutic use ; Male ; Medical sciences ; Microbiology ; Middle Aged ; Miscellaneous ; non-response ; Oligopeptides - therapeutic use ; Polyethylene Glycols - therapeutic use ; Recombinant Proteins - therapeutic use ; resistant variants ; Ribavirin - therapeutic use ; Sequence Analysis, DNA ; telaprevir ; Treatment Outcome ; ultra-deep sequence ; Viral diseases ; Virology</subject><ispartof>Journal of medical virology, 2013-06, Vol.85 (6), p.1028-1036</ispartof><rights>Copyright © 2013 Wiley Periodicals, Inc.</rights><rights>2014 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4549-799b9462aef852b8980ae94c04a5bf9ccd89c7ba4707e263e79a044b11de202e3</citedby><cites>FETCH-LOGICAL-c4549-799b9462aef852b8980ae94c04a5bf9ccd89c7ba4707e263e79a044b11de202e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjmv.23579$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjmv.23579$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=27286690$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23588728$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Akuta, Norio</creatorcontrib><creatorcontrib>Suzuki, Fumitaka</creatorcontrib><creatorcontrib>Seko, Yuya</creatorcontrib><creatorcontrib>Kawamura, Yusuke</creatorcontrib><creatorcontrib>Sezaki, Hitomi</creatorcontrib><creatorcontrib>Suzuki, Yoshiyuki</creatorcontrib><creatorcontrib>Hosaka, Tetsuya</creatorcontrib><creatorcontrib>Kobayashi, Masahiro</creatorcontrib><creatorcontrib>Hara, Tasuku</creatorcontrib><creatorcontrib>Kobayashi, Mariko</creatorcontrib><creatorcontrib>Saitoh, Satoshi</creatorcontrib><creatorcontrib>Arase, Yasuji</creatorcontrib><creatorcontrib>Ikeda, Kenji</creatorcontrib><creatorcontrib>Kumada, Hiromitsu</creatorcontrib><title>Emergence of telaprevir-resistant variants detected by ultra-deep sequencing after triple therapy in patients infected with HCV genotype 1</title><title>Journal of medical virology</title><addtitle>J. Med. Virol</addtitle><description>Using ultra‐deep sequencing technology, the present was designed to investigate whether the emergence of telaprevir‐resistant variants (amino acid substitutions of aa36, aa54, aa155, aa156, and aa170 positions in HCV NS3 region) after commencement of triple therapy of telaprevir/peginterferon (PEG‐IFN)/ribavirin could be predicted at baseline in previous non‐responders to dual therapy. Fourteen patients infected with HCV genotype 1 who did not respond to previous PEG‐IFN/ribavirin, received a 24‐week regimen of triple therapy, and were evaluated for appearance of telaprevir‐resistant variants (amino acid substitutions of more than 0.2% among the total coverage) by ultra‐deep sequencing. The sustained virological response rate was 28.6% (4 of 14 patients), which was significantly higher in patients with Arg70 (substitution at core aa70) and partial response (type of previous response to PEG‐IFN/ribavirin) than in other patients. Telaprevir‐resistant variants at baseline were detected in 7.1% (1 of 14 patients) by direct sequencing and in 21.4% (3 of 14 patients) by ultra‐deep sequencing. The appearance of telaprevir‐resistant variants was examined by ultra‐deep sequencing in 10 who did not show sustained virological responders. De novo variants emerged at re‐elevation of viral load, regardless of variant frequencies at baseline (one patient with very high frequency variants [T54S: 99.9%], two patients with very low frequency variants [V36A: 0.2%; and V170A: 0.4%], and seven patients of undetectable variants). It is concluded that it is difficult to predict at baseline the emergence of telaprevir‐resistant variants after commencement of triple therapy in prior non‐responders of HCV genotype 1, even with the use of ultra‐deep sequencing. J. Med. Virol. 85: 1028–1036, 2013. © 2013 Wiley Periodicals, Inc.</description><subject>Adult</subject><subject>Aged</subject><subject>Amino Acid Substitution</subject><subject>Antiviral Agents - therapeutic use</subject><subject>Antiviral drugs</subject><subject>Biological and medical sciences</subject><subject>DNA, Viral - analysis</subject><subject>DNA, Viral - genetics</subject><subject>Drug resistance</subject><subject>Drug Resistance, Viral - drug effects</subject><subject>Drug Resistance, Viral - genetics</subject><subject>Drug Therapy, Combination</subject><subject>Female</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Genotype</subject><subject>Genotype & phenotype</subject><subject>HCV</subject><subject>Hepacivirus - drug effects</subject><subject>Hepacivirus - genetics</subject><subject>Hepatitis</subject><subject>Hepatitis C virus</subject><subject>Hepatitis C, Chronic - drug therapy</subject><subject>Hepatitis C, Chronic - immunology</subject><subject>Hepatitis C, Chronic - virology</subject><subject>High-Throughput Nucleotide Sequencing</subject><subject>Human viral diseases</subject><subject>Humans</subject><subject>Infectious diseases</subject><subject>Interferon-alpha - therapeutic use</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Microbiology</subject><subject>Middle Aged</subject><subject>Miscellaneous</subject><subject>non-response</subject><subject>Oligopeptides - therapeutic use</subject><subject>Polyethylene Glycols - therapeutic use</subject><subject>Recombinant Proteins - therapeutic use</subject><subject>resistant variants</subject><subject>Ribavirin - therapeutic use</subject><subject>Sequence Analysis, DNA</subject><subject>telaprevir</subject><subject>Treatment Outcome</subject><subject>ultra-deep sequence</subject><subject>Viral diseases</subject><subject>Virology</subject><issn>0146-6615</issn><issn>1096-9071</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0ttqFTEUBuAgit1WL3wBCYigF9PmNJPksmxqq1QFDxV6EzIza9ps52SS2XVewac2dXYrCOLVuvnyr4Q_CD2l5IASwg433faA8Vzqe2hFiS4yTSS9j1aEiiIrCprvoUchbAghSjP2EO0lrJRkaoV-HnfgL6GvAA8NjtDa0cPW-cxDcCHaPuKt9S7NgGuIUEWocTnjqY3eZjXAiAN8n1KA6y-xbSJ4HL0bW8DxCrwdZ-x6PNro4CbC9c0Sce3iFT5dn-O0e4jzCJg-Rg8a2wZ4spv76Mvr48_r0-zsw8mb9dFZVolc6ExqXWpRMAuNylmptCIWtKiIsHnZ6Kqqla5kaYUkEljBQWpLhCgprYERBnwfvVxyRz-km4doOhcqaFvbwzAFQ4XgXFJO5f8pZ4oxled5os__opth8n16SArkisrUA03q1aIqP4TgoTGjd531s6HE3HRpUpfmd5fJPtslTmUH9Z28LS-BFztgQ2XbxtvUQvjjkikKTZI7XNy1a2H-90bz9t357epsOZG-APy4O2H9N1NILnPz9f2JYYW6-KQviPnIfwFik8WG</recordid><startdate>201306</startdate><enddate>201306</enddate><creator>Akuta, Norio</creator><creator>Suzuki, Fumitaka</creator><creator>Seko, Yuya</creator><creator>Kawamura, Yusuke</creator><creator>Sezaki, Hitomi</creator><creator>Suzuki, Yoshiyuki</creator><creator>Hosaka, Tetsuya</creator><creator>Kobayashi, Masahiro</creator><creator>Hara, Tasuku</creator><creator>Kobayashi, Mariko</creator><creator>Saitoh, Satoshi</creator><creator>Arase, Yasuji</creator><creator>Ikeda, Kenji</creator><creator>Kumada, Hiromitsu</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><general>Wiley</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</scope><scope>IQODW</scope><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>7QL</scope><scope>7TK</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>201306</creationdate><title>Emergence of telaprevir-resistant variants detected by ultra-deep sequencing after triple therapy in patients infected with HCV genotype 1</title><author>Akuta, Norio ; Suzuki, Fumitaka ; Seko, Yuya ; Kawamura, Yusuke ; Sezaki, Hitomi ; Suzuki, Yoshiyuki ; Hosaka, Tetsuya ; Kobayashi, Masahiro ; Hara, Tasuku ; Kobayashi, Mariko ; Saitoh, Satoshi ; Arase, Yasuji ; Ikeda, Kenji ; Kumada, Hiromitsu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4549-799b9462aef852b8980ae94c04a5bf9ccd89c7ba4707e263e79a044b11de202e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Amino Acid Substitution</topic><topic>Antiviral Agents - therapeutic use</topic><topic>Antiviral drugs</topic><topic>Biological and medical sciences</topic><topic>DNA, Viral - analysis</topic><topic>DNA, Viral - genetics</topic><topic>Drug resistance</topic><topic>Drug Resistance, Viral - drug effects</topic><topic>Drug Resistance, Viral - genetics</topic><topic>Drug Therapy, Combination</topic><topic>Female</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Genotype</topic><topic>Genotype & phenotype</topic><topic>HCV</topic><topic>Hepacivirus - drug effects</topic><topic>Hepacivirus - genetics</topic><topic>Hepatitis</topic><topic>Hepatitis C virus</topic><topic>Hepatitis C, Chronic - drug therapy</topic><topic>Hepatitis C, Chronic - immunology</topic><topic>Hepatitis C, Chronic - virology</topic><topic>High-Throughput Nucleotide Sequencing</topic><topic>Human viral diseases</topic><topic>Humans</topic><topic>Infectious diseases</topic><topic>Interferon-alpha - therapeutic use</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Microbiology</topic><topic>Middle Aged</topic><topic>Miscellaneous</topic><topic>non-response</topic><topic>Oligopeptides - therapeutic use</topic><topic>Polyethylene Glycols - therapeutic use</topic><topic>Recombinant Proteins - therapeutic use</topic><topic>resistant variants</topic><topic>Ribavirin - therapeutic use</topic><topic>Sequence Analysis, DNA</topic><topic>telaprevir</topic><topic>Treatment Outcome</topic><topic>ultra-deep sequence</topic><topic>Viral diseases</topic><topic>Virology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Akuta, Norio</creatorcontrib><creatorcontrib>Suzuki, Fumitaka</creatorcontrib><creatorcontrib>Seko, Yuya</creatorcontrib><creatorcontrib>Kawamura, Yusuke</creatorcontrib><creatorcontrib>Sezaki, Hitomi</creatorcontrib><creatorcontrib>Suzuki, Yoshiyuki</creatorcontrib><creatorcontrib>Hosaka, Tetsuya</creatorcontrib><creatorcontrib>Kobayashi, Masahiro</creatorcontrib><creatorcontrib>Hara, Tasuku</creatorcontrib><creatorcontrib>Kobayashi, Mariko</creatorcontrib><creatorcontrib>Saitoh, Satoshi</creatorcontrib><creatorcontrib>Arase, Yasuji</creatorcontrib><creatorcontrib>Ikeda, Kenji</creatorcontrib><creatorcontrib>Kumada, Hiromitsu</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medical virology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Akuta, Norio</au><au>Suzuki, Fumitaka</au><au>Seko, Yuya</au><au>Kawamura, Yusuke</au><au>Sezaki, Hitomi</au><au>Suzuki, Yoshiyuki</au><au>Hosaka, Tetsuya</au><au>Kobayashi, Masahiro</au><au>Hara, Tasuku</au><au>Kobayashi, Mariko</au><au>Saitoh, Satoshi</au><au>Arase, Yasuji</au><au>Ikeda, Kenji</au><au>Kumada, Hiromitsu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Emergence of telaprevir-resistant variants detected by ultra-deep sequencing after triple therapy in patients infected with HCV genotype 1</atitle><jtitle>Journal of medical virology</jtitle><addtitle>J. Med. Virol</addtitle><date>2013-06</date><risdate>2013</risdate><volume>85</volume><issue>6</issue><spage>1028</spage><epage>1036</epage><pages>1028-1036</pages><issn>0146-6615</issn><eissn>1096-9071</eissn><coden>JMVIDB</coden><abstract>Using ultra‐deep sequencing technology, the present was designed to investigate whether the emergence of telaprevir‐resistant variants (amino acid substitutions of aa36, aa54, aa155, aa156, and aa170 positions in HCV NS3 region) after commencement of triple therapy of telaprevir/peginterferon (PEG‐IFN)/ribavirin could be predicted at baseline in previous non‐responders to dual therapy. Fourteen patients infected with HCV genotype 1 who did not respond to previous PEG‐IFN/ribavirin, received a 24‐week regimen of triple therapy, and were evaluated for appearance of telaprevir‐resistant variants (amino acid substitutions of more than 0.2% among the total coverage) by ultra‐deep sequencing. The sustained virological response rate was 28.6% (4 of 14 patients), which was significantly higher in patients with Arg70 (substitution at core aa70) and partial response (type of previous response to PEG‐IFN/ribavirin) than in other patients. Telaprevir‐resistant variants at baseline were detected in 7.1% (1 of 14 patients) by direct sequencing and in 21.4% (3 of 14 patients) by ultra‐deep sequencing. The appearance of telaprevir‐resistant variants was examined by ultra‐deep sequencing in 10 who did not show sustained virological responders. De novo variants emerged at re‐elevation of viral load, regardless of variant frequencies at baseline (one patient with very high frequency variants [T54S: 99.9%], two patients with very low frequency variants [V36A: 0.2%; and V170A: 0.4%], and seven patients of undetectable variants). It is concluded that it is difficult to predict at baseline the emergence of telaprevir‐resistant variants after commencement of triple therapy in prior non‐responders of HCV genotype 1, even with the use of ultra‐deep sequencing. J. Med. Virol. 85: 1028–1036, 2013. © 2013 Wiley Periodicals, Inc.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>23588728</pmid><doi>10.1002/jmv.23579</doi><tpages>9</tpages></addata></record> |
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| subjects | Adult Aged Amino Acid Substitution Antiviral Agents - therapeutic use Antiviral drugs Biological and medical sciences DNA, Viral - analysis DNA, Viral - genetics Drug resistance Drug Resistance, Viral - drug effects Drug Resistance, Viral - genetics Drug Therapy, Combination Female Fundamental and applied biological sciences. Psychology Genotype Genotype & phenotype HCV Hepacivirus - drug effects Hepacivirus - genetics Hepatitis Hepatitis C virus Hepatitis C, Chronic - drug therapy Hepatitis C, Chronic - immunology Hepatitis C, Chronic - virology High-Throughput Nucleotide Sequencing Human viral diseases Humans Infectious diseases Interferon-alpha - therapeutic use Male Medical sciences Microbiology Middle Aged Miscellaneous non-response Oligopeptides - therapeutic use Polyethylene Glycols - therapeutic use Recombinant Proteins - therapeutic use resistant variants Ribavirin - therapeutic use Sequence Analysis, DNA telaprevir Treatment Outcome ultra-deep sequence Viral diseases Virology |
| title | Emergence of telaprevir-resistant variants detected by ultra-deep sequencing after triple therapy in patients infected with HCV genotype 1 |
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