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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Final Results of the Telaprevir Access Program: FibroScan Values Predict Safety and Efficacy in Hepatitis C Patients with Advanced Fibrosis or Cirrhosis</title><author><name sortKey="Lepida, Antonia" sort="Lepida, Antonia" uniqKey="Lepida A" first="Antonia" last="Lepida">Antonia Lepida</name><affiliation><nlm:aff id="aff001"><addr-line>Liver Unit, Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium</addr-line></nlm:aff></affiliation></author><author><name sortKey="Colombo, Massimo" sort="Colombo, Massimo" uniqKey="Colombo M" first="Massimo" last="Colombo">Massimo Colombo</name><affiliation><nlm:aff id="aff002"><addr-line>Department of Medicine, Division of Gastroenterology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Universita’ degli Studi di Milano, Milan, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fernandez, Inmaculada" sort="Fernandez, Inmaculada" uniqKey="Fernandez I" first="Inmaculada" last="Fernandez">Inmaculada Fernandez</name><affiliation><nlm:aff id="aff003"><addr-line>Hospital Universitario 12 de Octubre, Sección de Aparato Digestivo, Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Abdurakhmanov, Djamal" sort="Abdurakhmanov, Djamal" uniqKey="Abdurakhmanov D" first="Djamal" last="Abdurakhmanov">Djamal Abdurakhmanov</name><affiliation><nlm:aff id="aff004"><addr-line>I.M. Sechenov First Moscow State Medical University, E.M. Tareev Clinic for Nephrology, Internal and Occupational Medicine, Moscow, Russia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Abrao Ferreira, Paulo" sort="Abrao Ferreira, Paulo" uniqKey="Abrao Ferreira P" first="Paulo" last="Abrao Ferreira">Paulo Abrao Ferreira</name><affiliation><nlm:aff id="aff005"><addr-line>Outpatient Clinic to HIV and Viral Hepatitis Division of Infectious Disease, Federal University of São Paulo, São Paulo, Brazil</addr-line></nlm:aff></affiliation></author><author><name sortKey="Strasser, Simone I" sort="Strasser, Simone I" uniqKey="Strasser S" first="Simone I." last="Strasser">Simone I. Strasser</name><affiliation><nlm:aff id="aff006"><addr-line>AW Morrow Gastroenterology and Liver Center, Royal Prince Alfred hospital and University of Sydney, Sydney, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Urbanek, Petr" sort="Urbanek, Petr" uniqKey="Urbanek P" first="Petr" last="Urbanek">Petr Urbanek</name><affiliation><nlm:aff id="aff007"><addr-line>Department of Internal Medicine, First Medical Faculty, Charles University, and Central Military Hospital Prague, Prague, Czech Republic</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mangia, Alessandra" sort="Mangia, Alessandra" uniqKey="Mangia A" first="Alessandra" last="Mangia">Alessandra Mangia</name><affiliation><nlm:aff id="aff008"><addr-line>Liver Unit, IRCCS Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Calleja, Jose L" sort="Calleja, Jose L" uniqKey="Calleja J" first="José L." last="Calleja">José L. Calleja</name><affiliation><nlm:aff id="aff009"><addr-line>Gastroenterology, Hospital Universitario Puerta de Hierro, Universidad Autonoma de Madrid, CIBERehd, Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Iraqi, Wafae" sort="Iraqi, Wafae" uniqKey="Iraqi W" first="Wafae" last="Iraqi">Wafae Iraqi</name><affiliation><nlm:aff id="aff010"><addr-line>Janssen Pharmaceuticals, Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Demasi, Ralph" sort="Demasi, Ralph" uniqKey="Demasi R" first="Ralph" last="Demasi">Ralph Demasi</name><affiliation><nlm:aff id="aff011"><addr-line>Janssen Research and development, Titusville, New Jersey, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lonjon Domanec, Isabelle" sort="Lonjon Domanec, Isabelle" uniqKey="Lonjon Domanec I" first="Isabelle" last="Lonjon-Domanec">Isabelle Lonjon-Domanec</name><affiliation><nlm:aff id="aff010"><addr-line>Janssen Pharmaceuticals, Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Moreno, Christophe" sort="Moreno, Christophe" uniqKey="Moreno C" first="Christophe" last="Moreno">Christophe Moreno</name><affiliation><nlm:aff id="aff001"><addr-line>Liver Unit, Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wedemeyer, Heiner" sort="Wedemeyer, Heiner" uniqKey="Wedemeyer H" first="Heiner" last="Wedemeyer">Heiner Wedemeyer</name><affiliation><nlm:aff id="aff012"><addr-line>Medizinische Hochschule Hannover, Hannover, Germany</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26398503</idno><idno type="pmc">4580464</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580464</idno><idno type="RBID">PMC:4580464</idno><idno type="doi">10.1371/journal.pone.0138503</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000333</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000333</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Final Results of the Telaprevir Access Program: FibroScan Values Predict Safety and Efficacy in Hepatitis C Patients with Advanced Fibrosis or Cirrhosis</title><author><name sortKey="Lepida, Antonia" sort="Lepida, Antonia" uniqKey="Lepida A" first="Antonia" last="Lepida">Antonia Lepida</name><affiliation><nlm:aff id="aff001"><addr-line>Liver Unit, Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium</addr-line></nlm:aff></affiliation></author><author><name sortKey="Colombo, Massimo" sort="Colombo, Massimo" uniqKey="Colombo M" first="Massimo" last="Colombo">Massimo Colombo</name><affiliation><nlm:aff id="aff002"><addr-line>Department of Medicine, Division of Gastroenterology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Universita’ degli Studi di Milano, Milan, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fernandez, Inmaculada" sort="Fernandez, Inmaculada" uniqKey="Fernandez I" first="Inmaculada" last="Fernandez">Inmaculada Fernandez</name><affiliation><nlm:aff id="aff003"><addr-line>Hospital Universitario 12 de Octubre, Sección de Aparato Digestivo, Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Abdurakhmanov, Djamal" sort="Abdurakhmanov, Djamal" uniqKey="Abdurakhmanov D" first="Djamal" last="Abdurakhmanov">Djamal Abdurakhmanov</name><affiliation><nlm:aff id="aff004"><addr-line>I.M. Sechenov First Moscow State Medical University, E.M. Tareev Clinic for Nephrology, Internal and Occupational Medicine, Moscow, Russia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Abrao Ferreira, Paulo" sort="Abrao Ferreira, Paulo" uniqKey="Abrao Ferreira P" first="Paulo" last="Abrao Ferreira">Paulo Abrao Ferreira</name><affiliation><nlm:aff id="aff005"><addr-line>Outpatient Clinic to HIV and Viral Hepatitis Division of Infectious Disease, Federal University of São Paulo, São Paulo, Brazil</addr-line></nlm:aff></affiliation></author><author><name sortKey="Strasser, Simone I" sort="Strasser, Simone I" uniqKey="Strasser S" first="Simone I." last="Strasser">Simone I. Strasser</name><affiliation><nlm:aff id="aff006"><addr-line>AW Morrow Gastroenterology and Liver Center, Royal Prince Alfred hospital and University of Sydney, Sydney, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Urbanek, Petr" sort="Urbanek, Petr" uniqKey="Urbanek P" first="Petr" last="Urbanek">Petr Urbanek</name><affiliation><nlm:aff id="aff007"><addr-line>Department of Internal Medicine, First Medical Faculty, Charles University, and Central Military Hospital Prague, Prague, Czech Republic</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mangia, Alessandra" sort="Mangia, Alessandra" uniqKey="Mangia A" first="Alessandra" last="Mangia">Alessandra Mangia</name><affiliation><nlm:aff id="aff008"><addr-line>Liver Unit, IRCCS Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Calleja, Jose L" sort="Calleja, Jose L" uniqKey="Calleja J" first="José L." last="Calleja">José L. Calleja</name><affiliation><nlm:aff id="aff009"><addr-line>Gastroenterology, Hospital Universitario Puerta de Hierro, Universidad Autonoma de Madrid, CIBERehd, Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Iraqi, Wafae" sort="Iraqi, Wafae" uniqKey="Iraqi W" first="Wafae" last="Iraqi">Wafae Iraqi</name><affiliation><nlm:aff id="aff010"><addr-line>Janssen Pharmaceuticals, Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Demasi, Ralph" sort="Demasi, Ralph" uniqKey="Demasi R" first="Ralph" last="Demasi">Ralph Demasi</name><affiliation><nlm:aff id="aff011"><addr-line>Janssen Research and development, Titusville, New Jersey, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lonjon Domanec, Isabelle" sort="Lonjon Domanec, Isabelle" uniqKey="Lonjon Domanec I" first="Isabelle" last="Lonjon-Domanec">Isabelle Lonjon-Domanec</name><affiliation><nlm:aff id="aff010"><addr-line>Janssen Pharmaceuticals, Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Moreno, Christophe" sort="Moreno, Christophe" uniqKey="Moreno C" first="Christophe" last="Moreno">Christophe Moreno</name><affiliation><nlm:aff id="aff001"><addr-line>Liver Unit, Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wedemeyer, Heiner" sort="Wedemeyer, Heiner" uniqKey="Wedemeyer H" first="Heiner" last="Wedemeyer">Heiner Wedemeyer</name><affiliation><nlm:aff id="aff012"><addr-line>Medizinische Hochschule Hannover, Hannover, Germany</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="sec001"><title>Background</title><p>Liver stiffness determined by transient elastography is correlated with hepatic fibrosis stage and has high accuracy for detecting severe fibrosis and cirrhosis in chronic hepatitis C patients. We evaluated the clinical value of baseline FibroScan values for the prediction of safety and efficacy of telaprevir-based therapy in patients with advanced fibrosis and cirrhosis in the telaprevir Early Access Program HEP3002.</p></sec><sec id="sec002"><title>Methods</title><p>1,772 patients with HCV-1 and bridging fibrosis or cirrhosis were treated with telaprevir plus pegylated interferon-α and ribavirin (PR) for 12 weeks followed by PR alone, the total treatment duration depending on virological response and previous response type. Liver fibrosis stage was determined either by liver biopsy or by non-invasive markers. 1,282 patients (72%) had disease stage assessed by FibroScan; among those 46% were classified as Metavir F3 at baseline and 54% as F4.</p></sec><sec id="sec003"><title>Results</title><p>Overall, 1,139 patients (64%) achieved a sustained virological response (SVR) by intention-to-treat analysis. Baseline FibroScan values were tested for association with SVR and the occurrence of adverse events. By univariate analysis, higher baseline FibroScan values were predictive of lower sustained virological response rates and treatment-related anemia. By multivariate analysis, FibroScan was no longer statistically significant as an independent predictor, but higher FibroScan values were correlated with the occurrence of infections and serious adverse events.</p></sec><sec id="sec004"><title>Conclusions</title><p>FibroScan has a limited utility as a predictor of safety and efficacy in patients treated with telaprevir-based triple therapy. Nevertheless it can be used in association with other clinical and biological parameters to help determine patients who will benefit from the triple regiments.</p></sec><sec id="sec005"><title>Trial Registration</title><p>ClinicalTrials.gov <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT01508286?id=NCT01508286&rank=1">NCT01508286</ext-link></p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Rosen, Hr" uniqKey="Rosen H">HR Rosen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Verna, Ec" uniqKey="Verna E">EC Verna</name></author><author><name sortKey="Brown, Rs" uniqKey="Brown R">RS Brown</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Morgan, Tr" uniqKey="Morgan T">TR Morgan</name></author><author><name sortKey="Ghany, Mg" uniqKey="Ghany M">MG Ghany</name></author><author><name sortKey="Kim, Hy" uniqKey="Kim H">HY 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, CA USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26398503</article-id><article-id pub-id-type="pmc">4580464</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0138503</article-id><article-id pub-id-type="publisher-id">PONE-D-15-16106</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title>Final Results of the Telaprevir Access Program: FibroScan Values Predict Safety and Efficacy in Hepatitis C Patients with Advanced Fibrosis or Cirrhosis</article-title><alt-title alt-title-type="running-head">Telaprevir EAP: Fibroscan as a Predictor of Safety and Efficacy in HCV</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Lepida</surname><given-names>Antonia</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Colombo</surname><given-names>Massimo</given-names></name><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Fernandez</surname><given-names>Inmaculada</given-names></name><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Abdurakhmanov</surname><given-names>Djamal</given-names></name><xref ref-type="aff" rid="aff004"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Abrao Ferreira</surname><given-names>Paulo</given-names></name><xref ref-type="aff" rid="aff005"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Strasser</surname><given-names>Simone I.</given-names></name><xref ref-type="aff" rid="aff006"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Urbanek</surname><given-names>Petr</given-names></name><xref ref-type="aff" rid="aff007"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mangia</surname><given-names>Alessandra</given-names></name><xref ref-type="aff" rid="aff008"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Calleja</surname><given-names>José L.</given-names></name><xref ref-type="aff" rid="aff009"><sup>9</sup></xref></contrib><contrib contrib-type="author"><name><surname>Iraqi</surname><given-names>Wafae</given-names></name><xref ref-type="aff" rid="aff010"><sup>10</sup></xref></contrib><contrib contrib-type="author"><name><surname>DeMasi</surname><given-names>Ralph</given-names></name><xref ref-type="aff" rid="aff011"><sup>11</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lonjon-Domanec</surname><given-names>Isabelle</given-names></name><xref ref-type="aff" rid="aff010"><sup>10</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Moreno</surname><given-names>Christophe</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref rid="cor001" ref-type="corresp">*</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Wedemeyer</surname><given-names>Heiner</given-names></name><xref ref-type="aff" rid="aff012"><sup>12</sup></xref></contrib></contrib-group><aff id="aff001"><label>1</label><addr-line>Liver Unit, Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium</addr-line></aff><aff id="aff002"><label>2</label><addr-line>Department of Medicine, Division of Gastroenterology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Universita’ degli Studi di Milano, Milan, Italy</addr-line></aff><aff id="aff003"><label>3</label><addr-line>Hospital Universitario 12 de Octubre, Sección de Aparato Digestivo, Madrid, Spain</addr-line></aff><aff id="aff004"><label>4</label><addr-line>I.M. Sechenov First Moscow State Medical University, E.M. Tareev Clinic for Nephrology, Internal and Occupational Medicine, Moscow, Russia</addr-line></aff><aff id="aff005"><label>5</label><addr-line>Outpatient Clinic to HIV and Viral Hepatitis Division of Infectious Disease, Federal University of São Paulo, São Paulo, Brazil</addr-line></aff><aff id="aff006"><label>6</label><addr-line>AW Morrow Gastroenterology and Liver Center, Royal Prince Alfred hospital and University of Sydney, Sydney, Australia</addr-line></aff><aff id="aff007"><label>7</label><addr-line>Department of Internal Medicine, First Medical Faculty, Charles University, and Central Military Hospital Prague, Prague, Czech Republic</addr-line></aff><aff id="aff008"><label>8</label><addr-line>Liver Unit, IRCCS Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy</addr-line></aff><aff id="aff009"><label>9</label><addr-line>Gastroenterology, Hospital Universitario Puerta de Hierro, Universidad Autonoma de Madrid, CIBERehd, Madrid, Spain</addr-line></aff><aff id="aff010"><label>10</label><addr-line>Janssen Pharmaceuticals, Paris, France</addr-line></aff><aff id="aff011"><label>11</label><addr-line>Janssen Research and development, Titusville, New Jersey, United States of America</addr-line></aff><aff id="aff012"><label>12</label><addr-line>Medizinische Hochschule Hannover, Hannover, Germany</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Wong</surname><given-names>Vincent</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>The Chinese University of Hong Kong, HONG KONG</addr-line></aff><author-notes><fn fn-type="conflict" id="coi001"><p><bold>Competing Interests: </bold>The authors of this manuscript have read the journal's policy and have the following competing interests: This study was funded by Janssen Pharmaceuticals. IL-D, WI and RD are employees of Janssen. The authors also acknowledge Stephanie Gibson (Zoetic Science, an Ashfield Company, part of UDG Healthcare plc, Macclesfield, UK) for editing and co-ordination support, which was funded by Janssen Pharmaceuticals. AL: No conflicts of interest. MC: Grant and research support: BMS, Gilead Science; Advisory committees: Merck, Roche, Novartis, Bayer, BMS, Gilead Science, Tibotec, Vertex, Janssen Cilag, Achillion, Lundbeck, GSK, GenSpera, AbbVie, AlfaWasserman, Jennerex; Speaking and teaching: Tibotec, Roche, Novartis, Bayer, BMS, Gilead Science, Vertex, Merck, Janssen, Sanofi. IF: Janssen: Speakers bureau; Gilead, MSD, Roche: Speakers bureau. DA: Speaker and had grants for lectures and clinical trials from Merck, Janssen, Roche, Novartis, BMS. PAF: Speaker and Clinical Investigator to Roche, Abbvie, Janssen, BMS, Boheringer, Merck, Gilead. SIS: Speaker and advisor: Janssen, MSD, Roche, BMS, Gilead Sciences, Abbvie, Bayer, Norgine. PU: No conflicts of interest regarding the topic of manuscript. CM: Speaker or adviser for Abbvie, MSD, Janssen, Bristol-Myers Squibb and Gilead Sciences pharmaceutical companies. Research Grant from MSD, Janssen, Astellas, Gilead Sciences, Novartis and Roche pharmaceutical companies. AM: Consultant for Gilead Sciences, Abbvie, Speaker bureau for Janssen, Gilead, ROCHE, MSD, Research grant for Gilead, ROCHE, MSD. JLC: Speaker or adviser for Abbvie, MSD, Roche, Janssen, Bristol-Myers Squibb and Gilead Sciences pharmaceutical companies. A Hill: Consultant for Janssen. HW: Honoraria for consulting and/or lectures: Abbvie, Abbott, Achillion, BMS, Gilead, Janssen, MSD, Novartis, Roche, Roche Diagnostics, Siemens, Transgene. Grant support: Roche, BMS, MSD. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.</p></fn><fn fn-type="con" id="contrib001"><p>Conceived and designed the experiments: MC. Performed the experiments: AL MC IF DA PAF SIS PU AM JLC CM HW. Analyzed the data: RD. Contributed reagents/materials/analysis tools: AL MC IF DA PAF SIS PU AM JLC WI RD IL-D CM HW. Wrote the paper: AL MC IF DA PAF SIS PU AM JLC WI RD IL-D CM HW.</p></fn><corresp id="cor001">* E-mail: <email>christophe.moreno@erasme.ulb.ac.be</email></corresp></author-notes><pub-date pub-type="epub"><day>23</day><month>9</month><year>2015</year></pub-date><pub-date pub-type="collection"><year>2015</year></pub-date><volume>10</volume><issue>9</issue><elocation-id>e0138503</elocation-id><history><date date-type="received"><day>28</day><month>5</month><year>2015</year></date><date date-type="accepted"><day>29</day><month>8</month><year>2015</year></date></history><permissions><copyright-year>2015</copyright-year><copyright-holder>Lepida et al</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited</license-p></license></permissions><self-uri content-type="pdf" xlink:type="simple" xlink:href="pone.0138503.pdf"></self-uri><abstract><sec id="sec001"><title>Background</title><p>Liver stiffness determined by transient elastography is correlated with hepatic fibrosis stage and has high accuracy for detecting severe fibrosis and cirrhosis in chronic hepatitis C patients. We evaluated the clinical value of baseline FibroScan values for the prediction of safety and efficacy of telaprevir-based therapy in patients with advanced fibrosis and cirrhosis in the telaprevir Early Access Program HEP3002.</p></sec><sec id="sec002"><title>Methods</title><p>1,772 patients with HCV-1 and bridging fibrosis or cirrhosis were treated with telaprevir plus pegylated interferon-α and ribavirin (PR) for 12 weeks followed by PR alone, the total treatment duration depending on virological response and previous response type. Liver fibrosis stage was determined either by liver biopsy or by non-invasive markers. 1,282 patients (72%) had disease stage assessed by FibroScan; among those 46% were classified as Metavir F3 at baseline and 54% as F4.</p></sec><sec id="sec003"><title>Results</title><p>Overall, 1,139 patients (64%) achieved a sustained virological response (SVR) by intention-to-treat analysis. Baseline FibroScan values were tested for association with SVR and the occurrence of adverse events. By univariate analysis, higher baseline FibroScan values were predictive of lower sustained virological response rates and treatment-related anemia. By multivariate analysis, FibroScan was no longer statistically significant as an independent predictor, but higher FibroScan values were correlated with the occurrence of infections and serious adverse events.</p></sec><sec id="sec004"><title>Conclusions</title><p>FibroScan has a limited utility as a predictor of safety and efficacy in patients treated with telaprevir-based triple therapy. Nevertheless it can be used in association with other clinical and biological parameters to help determine patients who will benefit from the triple regiments.</p></sec><sec id="sec005"><title>Trial Registration</title><p>ClinicalTrials.gov <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT01508286?id=NCT01508286&rank=1">NCT01508286</ext-link></p></sec></abstract><funding-group><funding-statement>This study was funded by Janssen Pharmaceuticals. WI, RD and IL-D are employed by Janssen Pharmaceuticals. Janssen Pharmaceuticals provided support in the form of salaries for authors WI, RD and IL-D, 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 roles of these authors are articulated in the ‘author contributions’ section.</funding-statement></funding-group><counts><fig-count count="1"></fig-count><table-count count="6"></table-count><page-count count="15"></page-count></counts><custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name><meta-value>All relevant data are within the paper.</meta-value></custom-meta></custom-meta-group></article-meta><notes><title>Data Availability</title><p>All relevant data are within the paper.</p></notes></front><body><sec sec-type="intro" id="sec006"><title>Introduction</title><p>Chronic hepatitis C virus (HCV) infection is a major public health issue as it affects approximately 180 million people worldwide [<xref rid="pone.0138503.ref001" ref-type="bibr">1</xref>] and is a leading cause of cirrhosis, end stage liver disease and hepatocellular carcinoma (HCC) and one of the most common indications of liver transplantation in the Western countries [<xref rid="pone.0138503.ref001" ref-type="bibr">1</xref>, <xref rid="pone.0138503.ref002" ref-type="bibr">2</xref>]. Virus eradication arrests the progression of liver disease and diminishes the rates of liver specific and all causes of mortality [<xref rid="pone.0138503.ref003" ref-type="bibr">3</xref>–<xref rid="pone.0138503.ref005" ref-type="bibr">5</xref>].</p><p>Chronic HCV infection management has evolved over recent years from pegylated interferon-α and ribavirin (PR) to combination of direct-acting antiviral agents (DAA) with PR after approval of HCV NS3/4A serine protease inhibitors (PI), telaprevir and boceprevir [<xref rid="pone.0138503.ref001" ref-type="bibr">1</xref>]. Limited data are available on the safety and efficacy of these PIs in patients with advanced liver fibrosis or cirrhosis, as these patients were under-represented in Phase III clinical trials [<xref rid="pone.0138503.ref006" ref-type="bibr">6</xref>–<xref rid="pone.0138503.ref009" ref-type="bibr">9</xref>]. Results from post-hoc analysis of these trials showed an increased rate of serious adverse events (SAEs), poor tolerability and suboptimal rates of sustained virologic response (SVR) in patients with advanced hepatic fibrosis [<xref rid="pone.0138503.ref006" ref-type="bibr">6</xref>–<xref rid="pone.0138503.ref012" ref-type="bibr">12</xref>]. Few real-life studies evaluating safety and efficacy of triple therapy have been conducted on patients with advanced HCV-related liver disease [<xref rid="pone.0138503.ref013" ref-type="bibr">13</xref>–<xref rid="pone.0138503.ref018" ref-type="bibr">18</xref>]. Among them, the French multicenter early access program in treatment experienced patients with HCV-cirrhosis (ANRS CO20-CUPIC) [<xref rid="pone.0138503.ref014" ref-type="bibr">14</xref>] showed a high rate of severe complications and even mortality, while similar observations were made in other studies [<xref rid="pone.0138503.ref015" ref-type="bibr">15</xref>, <xref rid="pone.0138503.ref019" ref-type="bibr">19</xref>–<xref rid="pone.0138503.ref022" ref-type="bibr">22</xref>]. The Early Access Program (EAP) HEP3002 was launched in 2011 in 16 nations, giving access to treatment with telaprevir to treatment-naive and experienced patients with bridging hepatic fibrosis and compensated cirrhosis due to HCV genotype 1 infection [<xref rid="pone.0138503.ref013" ref-type="bibr">13</xref>].</p><p>Transient elastography (TE), also known as FibroScan), is a validated non-invasive method to evaluate hepatic fibrosis in patients with chronic hepatitis C viral infection [<xref rid="pone.0138503.ref023" ref-type="bibr">23</xref>, <xref rid="pone.0138503.ref024" ref-type="bibr">24</xref>] and has a high level of accuracy for detecting severe fibrosis and cirrhosis [<xref rid="pone.0138503.ref025" ref-type="bibr">25</xref>–<xref rid="pone.0138503.ref027" ref-type="bibr">27</xref>]. Furthermore, TE has a prognostic value in predicting severe portal hypertension, presence of oesophageal varices and occurrence of liver-related complications in patients with cirrhosis [<xref rid="pone.0138503.ref025" ref-type="bibr">25</xref>, <xref rid="pone.0138503.ref026" ref-type="bibr">26</xref>, <xref rid="pone.0138503.ref028" ref-type="bibr">28</xref>–<xref rid="pone.0138503.ref030" ref-type="bibr">30</xref>].</p><p>Studies of fibrosis evolution using non-invasive markers, during and after PR therapy in small cohorts of HCV-infected patients have been reported [<xref rid="pone.0138503.ref031" ref-type="bibr">31</xref>–<xref rid="pone.0138503.ref041" ref-type="bibr">41</xref>], but few studies investigated the utility of FibroScan as an SVR predictor. Among them, only two [<xref rid="pone.0138503.ref032" ref-type="bibr">32</xref>, <xref rid="pone.0138503.ref036" ref-type="bibr">36</xref>] demonstrated that TE could provide information for the prediction of virological response prior to therapy. To our knowledge, no studies have evaluated the possible association between baseline FibroScan values and the occurrence of SAEs or liver-related complications during anti-HCV treatment, and no information regarding the use of TE in therapy guidance is available.</p><p>Here, we present the final results of EAP HEP3002 trial, in which about two thirds of the patients were initially evaluated for fibrosis stage using the FibroScan technology, representing a unique opportunity to explore FibroScan potential in the everyday clinical practice. Data from the HEP3002 trial were retrospectively analyzed to determine the clinical value of baseline FibroScan values for predicting safety and efficacy of telaprevir-based triple therapy in patients with advanced fibrosis or cirrhosis.</p></sec><sec sec-type="materials|methods" id="sec007"><title>Patients and Methods</title><sec id="sec008"><title>Study design</title><p>HEP3002 is an open-label EAP of HCV genotype 1 patients with advanced hepatic fibrosis or cirrhosis treated with telaprevir-based therapy (ClinicalTrials.gov <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT01508286?id=NCT01508286&rank=1">NCT01508286</ext-link>) (<xref rid="pone.0138503.s001" ref-type="supplementary-material">S1 Protocol</xref>, <xref rid="pone.0138503.s003" ref-type="supplementary-material">S1 TREND Checklist</xref>). The program included patients from 16 centers across 181 sites in Europe, South America and Australasia and the enrolment criteria were similar to those of the REALIZE Phase III trial [<xref rid="pone.0138503.ref009" ref-type="bibr">9</xref>]. Patient recruitment and follow-up occurred between May 2011 and May 2014; the outline of the study has been described previously [<xref rid="pone.0138503.ref013" ref-type="bibr">13</xref>]. Informed written consent was obtained from each patient included in the study. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the following institutions and human research committees: Therapeutic Goods Administration, Australia; Bundesamt für Sicherheit im Gesundheitswesen, Austra; Federaal Agentschap voor Geneesmiddelen en Gezondheidsproducten, Belgium; Agência Nacional de Vigilância Sanitária, Brazil; State Institute for Drug Control, Czech Republic; Bundesinstitut für Arzneimittel und Medizinprodukte, Germany, National Organization for Medicines, Greece, L’Agenzia Italiana del Farmaco, Italy; Ministry of Health, Luxembourg; Centrale Commissie voor Mensgebonden Onderzoek, The Netherlands; Medsafe, New Zealand; National Medicines Agency, Romania; Ministry of Health and Social Development of the Russian Federation, Russia; Ministry of Health, Serbia; State Institute for Drug Control, Slovakia; Agencia Española de Medicamentos y Productos Sanitarios, Spain and Swissmedic, Switzerland.</p><p>Patients were between 18 and 70 years and had documented severe liver fibrosis [Metavir F3 or Ishak 3–4 (S 3, 4)] or cirrhosis [Metavir F4 or Ishak 5, 6 (S5, 6)] due to HCV genotype 1 infection. In order to be included, patients had to have an absolute neutrophil count >1,500/mm³, platelets >90,000/mm³ and hemoglobin >12 g/dL for women and >13 g/dL for men. Key exclusion criteria included history or other evidence of decompensated liver disease, HCC, history of alcohol abuse, infection with HCV other than genotype 1 or co-infection with hepatitis B virus or human immunodeficiency virus. Both untreated patients and patients who failed to respond to a previous treatment were included, as long as they had not previously received an HCV protease or polymerase inhibitor. During the first 12 weeks of the program, all patients received 750 mg of TVR orally every 8 hours, in combination with PR. The type (α 2a versus α 2b pegylated interferon; Copegus versus Rebetol) and doses of PR were selected according to local guidelines. After 12 weeks of combination treatment, PR alone was administered for another 12 or 36 weeks depending on the virologic response to treatment and/or previous response type; detailed description of the treatment regimens has been reported [<xref rid="pone.0138503.ref013" ref-type="bibr">13</xref>]. Patients were assessed at weeks 4 and 12 to determine whether they met the predefined stopping rules based on virologic response. If at either time point HCV RNA levels were greater than 1,000 IU/mL, all treatment was permanently discontinued.</p></sec><sec id="sec009"><title>Measures of disease severity and treatment efficacy</title><p>Hepatic fibrosis was assessed histologically or by non-invasive means. Liver specimens were obtained by percutaneous liver biopsy and fibrosis was staged using either the Metavir or the Ishak score. Patients who did not undergo a biopsy were evaluated by Fibrotest or FibroScan. The FibroScan cut-offs proposed by Castéra et al [<xref rid="pone.0138503.ref042" ref-type="bibr">42</xref>] were used to diagnose bridging fibrosis and cirrhosis. In this study the authors prospectively assessed the performance of FibroScan in HCV patients, compared to histology. The proposed cut-off values were determined from the distribution of stiffness values according to fibrosis stage for the maximum sum of sensitivity and specificity. The cut-offs for advanced fibrosis (F3 = numerous septa without cirrhosis) and cirrhosis (F4) were ≥9.5 kPa and ≥12.5 kPa respectively. The Child Pugh score system was used to define clinical status, with Child Pugh A stage indicating compensated liver disease.</p><p>The type of previous response to PR treatment was defined by standard criteria [<xref rid="pone.0138503.ref009" ref-type="bibr">9</xref>]. HCV RNA levels were measured using a range of assays at local investigational sites. The majority of sites used Roche COBAS TaqMan versions 1 or 2 with a lower limit of quantification (LLOQ) of 15–25 IU/mL and a lower limit of detection (LLOD) of 10 IU/mL, or Abbott RealTime assay with a LLOQ of 12 IU/mL and a LLOD of 10–12 IU/mL.</p></sec><sec id="sec010"><title>Safety assessments</title><p>Data on safety issues were collected during the treatment period and follow-up, including laboratory assessments, physical examinations, evaluation of vital signs and the reporting of adverse events (AEs). AEs were graded by investigators using the DAIDS criteria [<xref rid="pone.0138503.ref043" ref-type="bibr">43</xref>] except for rash, for which protocol-specific guidance for grading and management was provided. Anemia was defined as an AE according to the following guidelines: grade 1 hemoglobin values between 10.0 and 10.9 g/dL or any decrease from baseline between 2.5 and 3.4 g/dL; grade 2 hemoglobin values between 9.0 and 9.9 g/dL or any decrease of hemoglobin between 3.5 and 4.4 g/dL; grade 3 hemoglobin values between 7.0 and 8.9 g/dL or any decrease of hemoglobin ≥4.5 g/dL; and grade 4 an hemoglobin value less than 7.0 g/dL. Anemia developed during treatment was managed by reduction of ribavirin doses according to label recommendations. Use of blood transfusions, erythropoetin (EPO) or iron-based products was allowed during the trial. Telaprevir dose reduction was prohibited, and if ribavirin dose modifications or discontinuation did not result in an improvement of hemoglobin levels, telaprevir was then discontinued. The detailed methodology of the safety assessments has been formerly described [<xref rid="pone.0138503.ref013" ref-type="bibr">13</xref>].</p></sec><sec id="sec011"><title>Statistical methods</title><p>Since this program was designed to provide patients with early access to telaprevir and was not intended to evaluate a specific statistical hypothesis, all patients received open-label telaprevir in addition to PR. As such, no inferential statistical analyses were planned. Analyses were performed for descriptive purposes and were conducted using descriptive statistics to determine odds ratios along with 95% confidence intervals (CIs) by univariate and multivariate analyses.</p><p>In total, 2,034 patients were screened for the EAP, and 262 patients were excluded due to the study inclusion/exclusion criteria, withdrawal of consent or other reasons. The analysis was performed on the intent-to-treat set (N = 1,772), defined as all enrolled patients who received at least one dose of telaprevir. Patients with any major protocol deviation that plausibly affected efficacy or patients with HCV RNA under LLOQ at end-of-treatment and without any HCV RNA follow-up assessment within the week 24 follow-up visit window (and who did not relapse before) were excluded from the efficacy evaluable set.</p><p>For the analysis of safety data, FibroScan was tested for association with four adverse events: anemia (hemoglobin ≤10 g/dL), grade 1–4 infections, serious AEs and telaprevir discontinuation because of AEs. FibroScan results were divided into quartiles, and the number of events corresponding to each quartile are presented separately for the 4 endpoints.</p><p>The P values presented in these analyses were derived from the Wald Chi-square test for the univariate and multivariate predictors of SVR, the Chi-square test for the assessment of safety by Liver Stiffness Measurement and the univariate and multivariate predictors of anemia. The P values for the correlation between baseline FibroScan values and baseline laboratory parameters were derived from the Pearson Correlation Test.</p><p>Statistical analysis was performed using SAS® version 9.2 (SAS Institute Inc., Cary, NC, USA).</p></sec><sec id="sec012"><title>End points</title><p>This study evaluated the usefulness of baseline FibroScan values for predicting SVR and the occurrence of anemia and other severe adverse events in HCV genotype 1 patients with advanced fibrosis (F3) or compensated cirrhosis (F4), treated with telaprevir-based triple therapy in the EAP.</p></sec></sec><sec sec-type="results" id="sec013"><title>Results</title><sec id="sec014"><title>Patient characteristics</title><p>A total of 2,034 patients were screened and 1,772 were enrolled in the HEP3002 trial (<xref rid="pone.0138503.g001" ref-type="fig">Fig 1</xref>). Of these 1,772 patients, 1,282 (72%) had disease stage assessed by FibroScan and were included in the analyses. Among those who had liver fibrosis assessed by FibroScan 557 patients were classified as F3 (43%) at baseline and 724 (57%) as F4.</p><fig id="pone.0138503.g001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0138503.g001</object-id><label>Fig 1</label><caption><title>Patient disposition.</title><p>Showing numbers of patients screened, enrolled and treated, and with baseline FibroScan results.</p></caption><graphic xlink:href="pone.0138503.g001"></graphic></fig><p>Demographics and baseline characteristics of the ITT population are shown in <xref rid="pone.0138503.t001" ref-type="table">Table 1</xref>. Overall, the mean (SD) age of the patients was 53 (9.5) years; 1,121 patients (63%) were male and 1,741 (98%) were white. HCV genotype 1a was present in 379 patients (21%) and 1,172 (66%) had HCV RNA greater than or equal to 800,000 IU/mL at baseline. In total, 355 patients (20%) were treatment naive, 586 (33%) were prior treatment relapsers, 234 (13%) were prior partial responders, 495 (28%) were prior null responders and 49 (3%) had had a viral breakthrough. The response to prior therapy was unknown for one patient and 52 patients had had an unspecified previous non-response.</p><table-wrap id="pone.0138503.t001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0138503.t001</object-id><label>Table 1</label><caption><title>Baseline and treatment characteristics of patients in the intent-to-treat population.</title></caption><alternatives><graphic id="pone.0138503.t001g" xlink:href="pone.0138503.t001"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Characteristic<xref rid="t001fn001" ref-type="table-fn">*</xref></th><th align="center" rowspan="1" colspan="1">Bridging fibrosis (N = 813)<xref rid="t001fn002" ref-type="table-fn"><sup>†</sup></xref></th><th align="center" rowspan="1" colspan="1">Cirrhosis (N = 959)</th><th align="center" rowspan="1" colspan="1">Overall (N = 1772)</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Age year—mean (SD; range)</td><td align="center" rowspan="1" colspan="1">52 (10.1;22–73)</td><td align="center" rowspan="1" colspan="1">54 (8.8;19–75)</td><td align="center" rowspan="1" colspan="1">53 (9.5;19–75)</td></tr><tr><td align="left" rowspan="1" colspan="1">Body mass index (BMI)<xref rid="t001fn003" ref-type="table-fn"><sup>‡</sup></xref> —mean (SD)</td><td align="center" rowspan="1" colspan="1">26 (3.7)</td><td align="center" rowspan="1" colspan="1">27 (4.1)</td><td align="center" rowspan="1" colspan="1">27(4.0)</td></tr><tr><td align="left" rowspan="1" colspan="1"> BMI—range</td><td align="center" rowspan="1" colspan="1">18–42</td><td align="center" rowspan="1" colspan="1">18–47</td><td align="center" rowspan="1" colspan="1">18–47</td></tr><tr><td align="left" rowspan="1" colspan="1">Males sex—no. (%)</td><td align="center" rowspan="1" colspan="1">494 (61)</td><td align="center" rowspan="1" colspan="1">627 (65)</td><td align="center" rowspan="1" colspan="1">1121 (63)</td></tr><tr><td colspan="4" align="left" rowspan="1">Race or ethnic group—no. (%)<xref rid="t001fn004" ref-type="table-fn"><sup>§</sup></xref></td></tr><tr><td align="left" rowspan="1" colspan="1"> White</td><td align="center" rowspan="1" colspan="1">801 (99)</td><td align="center" rowspan="1" colspan="1">940 (98)</td><td align="center" rowspan="1" colspan="1">1741 (98)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Black, Asian or other</td><td align="center" rowspan="1" colspan="1">12 (1)</td><td align="center" rowspan="1" colspan="1">19 (2)</td><td align="center" rowspan="1" colspan="1">31 (2)</td></tr><tr><td colspan="4" align="left" rowspan="1">HCV-1 subtype—no. (%)</td></tr><tr><td align="left" rowspan="1" colspan="1"> 1a</td><td align="center" rowspan="1" colspan="1">173 (21)</td><td align="center" rowspan="1" colspan="1">206 (21)</td><td align="center" rowspan="1" colspan="1">379 (21)</td></tr><tr><td align="left" rowspan="1" colspan="1"> 1b</td><td align="center" rowspan="1" colspan="1">610 (75)</td><td align="center" rowspan="1" colspan="1">681 (71)</td><td align="center" rowspan="1" colspan="1">1291 (73)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Missing or unknown</td><td align="center" rowspan="1" colspan="1">30 (4)</td><td align="center" rowspan="1" colspan="1">72 (8)</td><td align="center" rowspan="1" colspan="1">102 (6)</td></tr><tr><td align="left" rowspan="1" colspan="1">HCV RNA log<sub>10</sub>—IU/mL<xref rid="t001fn005" ref-type="table-fn"><sup>¶</sup></xref></td><td align="center" rowspan="1" colspan="1">6.1±0.66</td><td align="center" rowspan="1" colspan="1">6.1±0.73</td><td align="center" rowspan="1" colspan="1">6.1±0.70</td></tr><tr><td align="left" rowspan="1" colspan="1">HCV RNA ≥800,000 IU/mL—no. (%)</td><td align="center" rowspan="1" colspan="1">545 (67)</td><td align="center" rowspan="1" colspan="1">627 (65)</td><td align="center" rowspan="1" colspan="1">1172 (66)</td></tr><tr><td align="left" rowspan="1" colspan="1">Model for End Stage Liver Disease score (range)</td><td align="center" rowspan="1" colspan="1">7.1 (6–14)</td><td align="center" rowspan="1" colspan="1">7.6 (6–20)</td><td align="center" rowspan="1" colspan="1">7.4 (6–20)</td></tr><tr><td align="left" rowspan="1" colspan="1">Liver stiffness measurement,—mean kPa (SD)</td><td align="center" rowspan="1" colspan="1">11.4 (2.82)</td><td align="center" rowspan="1" colspan="1">24.9 (12.66)</td><td align="center" rowspan="1" colspan="1">19.1 (11.78)</td></tr><tr><td align="left" rowspan="1" colspan="1">α-Fetoprotein—μg/L</td><td align="center" rowspan="1" colspan="1">8.8±11.2</td><td align="center" rowspan="1" colspan="1">16.5±25.0</td><td align="center" rowspan="1" colspan="1">13.0±20.3</td></tr><tr><td align="left" rowspan="1" colspan="1">Albumin—g/L</td><td align="center" rowspan="1" colspan="1">44.0±4.0</td><td align="center" rowspan="1" colspan="1">42.3±4.4</td><td align="center" rowspan="1" colspan="1">43.1±4.3</td></tr><tr><td align="left" rowspan="1" colspan="1">Bilirubin—μmol/L</td><td align="center" rowspan="1" colspan="1">12.7±6.4</td><td align="center" rowspan="1" colspan="1">14.7±7.1</td><td align="center" rowspan="1" colspan="1">13.7±6.8</td></tr><tr><td align="left" rowspan="1" colspan="1">Creatine—μmol/L</td><td align="center" rowspan="1" colspan="1">70.0±15.0</td><td align="center" rowspan="1" colspan="1">70.0±14.9</td><td align="center" rowspan="1" colspan="1">70.0±15.0</td></tr><tr><td align="left" rowspan="1" colspan="1">Glucose—mmol/L</td><td align="center" rowspan="1" colspan="1">5.5±1.6</td><td align="center" rowspan="1" colspan="1">5.9±2.0</td><td align="center" rowspan="1" colspan="1">5.7±1.8</td></tr><tr><td align="left" rowspan="1" colspan="1">Hemoglobin—g/L</td><td align="center" rowspan="1" colspan="1">150±13.8</td><td align="center" rowspan="1" colspan="1">149±13.3</td><td align="center" rowspan="1" colspan="1">150±13.5</td></tr><tr><td align="left" rowspan="1" colspan="1">Neutrophils–×10<sup>9</sup>/L</td><td align="center" rowspan="1" colspan="1">3.5±1.4</td><td align="center" rowspan="1" colspan="1">3.2±1.9</td><td align="center" rowspan="1" colspan="1">3.3±1.7</td></tr><tr><td align="left" rowspan="1" colspan="1">Platelets–×10<sup>9</sup>/L</td><td align="center" rowspan="1" colspan="1">190±57.9</td><td align="center" rowspan="1" colspan="1">154±54.4</td><td align="center" rowspan="1" colspan="1">171±58.9</td></tr><tr><td align="left" rowspan="1" colspan="1">Prothrombin intl. normalised ratio</td><td align="center" rowspan="1" colspan="1">1.03±0.10</td><td align="center" rowspan="1" colspan="1">1.08±0.13</td><td align="center" rowspan="1" colspan="1">1.06±0.12</td></tr><tr><td colspan="4" align="left" rowspan="1">IL28B genotype—no. (%)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Missing or unknown</td><td align="center" rowspan="1" colspan="1">627 (77)</td><td align="center" rowspan="1" colspan="1">729 (76)</td><td align="center" rowspan="1" colspan="1">1356 (77)</td></tr><tr><td align="left" rowspan="1" colspan="1"> CC</td><td align="center" rowspan="1" colspan="1">23 (3)</td><td align="center" rowspan="1" colspan="1">54 (6)</td><td align="center" rowspan="1" colspan="1">77 (4)</td></tr><tr><td align="left" rowspan="1" colspan="1"> CT</td><td align="center" rowspan="1" colspan="1">127 (16)</td><td align="center" rowspan="1" colspan="1">129 (13)</td><td align="center" rowspan="1" colspan="1">256 (14)</td></tr><tr><td align="left" rowspan="1" colspan="1"> TT</td><td align="center" rowspan="1" colspan="1">36 (4)</td><td align="center" rowspan="1" colspan="1">47 (5)</td><td align="center" rowspan="1" colspan="1">83 (5)</td></tr><tr><td colspan="4" align="left" rowspan="1">Previous type of response—no. (%)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Total non-responders<xref rid="t001fn006" ref-type="table-fn"><sup>††</sup></xref></td><td align="center" rowspan="1" colspan="1">322 (40)</td><td align="center" rowspan="1" colspan="1">459 (48)</td><td align="center" rowspan="1" colspan="1">781 (44)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Prior null responder</td><td align="center" rowspan="1" colspan="1">198 (24)</td><td align="center" rowspan="1" colspan="1">297 (31)</td><td align="center" rowspan="1" colspan="1">495 (28)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Prior partial responder</td><td align="center" rowspan="1" colspan="1">103 (13)</td><td align="center" rowspan="1" colspan="1">131 (14)</td><td align="center" rowspan="1" colspan="1">234 (13)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Relapsers</td><td align="center" rowspan="1" colspan="1">288 (35)</td><td align="center" rowspan="1" colspan="1">298 (31)</td><td align="center" rowspan="1" colspan="1">586 (33)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Treatment naive</td><td align="center" rowspan="1" colspan="1">176 (22)</td><td align="center" rowspan="1" colspan="1">179 (19)</td><td align="center" rowspan="1" colspan="1">355 (20)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Viral breakthrough</td><td align="center" rowspan="1" colspan="1">26 (3)</td><td align="center" rowspan="1" colspan="1">23 (3)</td><td align="center" rowspan="1" colspan="1">49 (3)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Unknown</td><td align="center" rowspan="1" colspan="1">1 (0)</td><td align="center" rowspan="1" colspan="1">0 (0)</td><td align="center" rowspan="1" colspan="1">1 (0)</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t001fn001"><p>* Values are means±SD unless otherwise indicated. Percentages may not total 100 because of rounding.</p></fn><fn id="t001fn002"><p><sup>†</sup> Includes six F0–F2 patients.</p></fn><fn id="t001fn003"><p><sup>‡</sup> BMI is the weight in kilograms divided by the square of the height in meters.</p></fn><fn id="t001fn004"><p><sup>§</sup> Race or ethnic group was self-reported. Patients of any race could also identify themselves as Hispanic.</p></fn><fn id="t001fn005"><p><sup>¶</sup> Log<sub>10</sub> values for HCV RNA are means±SE.</p></fn><fn id="t001fn006"><p><sup>††</sup> Includes prior null responders, prior partial responders and non-responders-unspecified.</p></fn></table-wrap-foot></table-wrap><p>Mean MELD score was 7.4 (1.4). In patients who had had liver fibrosis assessment by means of FibroScan, mean FibroScan result was 19.1 kPa. <italic>IL28B</italic> genotyping results were missing in the majority of patients. Of the 416 patients who had <italic>IL28B</italic> genotyping results, 77 (19%) had the <italic>IL28B</italic> genotype CC. The CT and TT genotypes were seen in 256 (62%) and 83 (20%) patients, respectively.</p></sec><sec id="sec015"><title>Virologic response and correlation between FibroScan and SVR</title><p>In the ITT population, SVR24 was achieved by 70% (568/807) of patients with bridging fibrosis and 59% (566/959) of patients with cirrhosis (<xref rid="pone.0138503.t002" ref-type="table">Table 2</xref>). In total, 78% (760/973) of patients who achieved eRVR went onto achieve SVR (<xref rid="pone.0138503.t002" ref-type="table">Table 2</xref>).</p><table-wrap id="pone.0138503.t002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0138503.t002</object-id><label>Table 2</label><caption><title>Efficacy outcome for each subgroup of patients with respect to fibrosis stage and to extended rapid virologic response (eRVR) in the intent-to-treat population.</title></caption><alternatives><graphic id="pone.0138503.t002g" xlink:href="pone.0138503.t002"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">n (%)</th><th align="left" rowspan="1" colspan="1">Bridging fibrosis (N = 813<xref rid="t002fn001" ref-type="table-fn"><sup>†</sup></xref>)</th><th align="left" rowspan="1" colspan="1">Cirrhosis (N = 959)</th><th align="left" rowspan="1" colspan="1">Overall (N = 1772)</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">SVR</td><td align="left" rowspan="1" colspan="1">573 (70)</td><td align="left" rowspan="1" colspan="1">566 (59)</td><td align="left" rowspan="1" colspan="1">1139 (64)</td></tr><tr><td align="left" rowspan="1" colspan="1">Virologic failure</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Relapse</td><td align="left" rowspan="1" colspan="1">69 (9)</td><td align="left" rowspan="1" colspan="1">125 (13)</td><td align="left" rowspan="1" colspan="1">194 (11)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Viral breakthrough</td><td align="left" rowspan="1" colspan="1">79 (10)</td><td align="left" rowspan="1" colspan="1">138 (14)</td><td align="left" rowspan="1" colspan="1">217 (12)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Met a stopping rule</td><td align="left" rowspan="1" colspan="1">27 (3)</td><td align="left" rowspan="1" colspan="1">27 (3)</td><td align="left" rowspan="1" colspan="1">53 (3)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Other</td><td align="left" rowspan="1" colspan="1">1 (<1)</td><td align="left" rowspan="1" colspan="1">3 (<1)</td><td align="left" rowspan="1" colspan="1">4 (<1)</td></tr><tr><td align="left" rowspan="1" colspan="1"> n/N (%)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"> SVR in all patients who achieved eRVR,</td><td align="left" rowspan="1" colspan="1">394/468 (84)</td><td align="left" rowspan="1" colspan="1">366/505 (72)</td><td align="left" rowspan="1" colspan="1">760/973 (78)</td></tr><tr><td align="left" rowspan="1" colspan="1"> SVR in patients who did not achieve eRVR</td><td align="left" rowspan="1" colspan="1">179/345 (52)</td><td align="left" rowspan="1" colspan="1">200/454 (44)</td><td align="left" rowspan="1" colspan="1">379/799 (47)</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t002fn001"><p><sup>†</sup> Includes six F0–F2 patients.</p></fn></table-wrap-foot></table-wrap><p>The percentage of treatment-naive patients who achieved SVR was 74% whereas, among treatment-experienced patients, 78% of treatment relapsers, 60% of partial responders, 44% of null responders achieved a cure (<xref rid="pone.0138503.s002" ref-type="supplementary-material">S1 Table</xref>).</p><p>Multiple parameters were tested for their association with SVR (<xref rid="pone.0138503.t003" ref-type="table">Table 3</xref>). By univariate analysis, higher baseline FibroScan values, analyzed as a continuous log<sub>10</sub> transformed variable, were predictive of lower SVR rates (Odds Ratio = 0.58, 95% CI = 0.46–0.74, p<0.0001). Other parameters significantly associated with a lower chance of SVR were HCV genotype 1a (p = 0.0003), baseline log<sub>10</sub> alfa fetoprotein (p<0.0001), baseline log<sub>10</sub> platelets (p<0.0001) and prior null response (p<0.0001). HCV genotype 1b, previous relapse or previous partial response were not predictive of SVR.</p><table-wrap id="pone.0138503.t003" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0138503.t003</object-id><label>Table 3</label><caption><title>Univariate and multivariate predictors of SVR.</title></caption><alternatives><graphic id="pone.0138503.t003g" xlink:href="pone.0138503.t003"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1"></th><th colspan="3" align="left" rowspan="1">Univariate analysis</th><th colspan="3" align="left" rowspan="1">Multivariate analysis</th></tr><tr><th align="left" rowspan="1" colspan="1">Factor</th><th align="left" rowspan="1" colspan="1">OR</th><th align="left" rowspan="1" colspan="1">95% CI</th><th align="left" rowspan="1" colspan="1">P value</th><th align="left" rowspan="1" colspan="1">OR</th><th align="left" rowspan="1" colspan="1">95% CI</th><th align="left" rowspan="1" colspan="1">P value</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">α-Fetoprotein (log<sub>10</sub> μg/L)</td><td align="char" char="." rowspan="1" colspan="1">0.20</td><td align="left" rowspan="1" colspan="1">0.15–0.28</td><td align="char" char="." rowspan="1" colspan="1"><0.0001</td><td align="char" char="." rowspan="1" colspan="1">0.28</td><td align="left" rowspan="1" colspan="1">0.19–0.39</td><td align="char" char="." rowspan="1" colspan="1"><0.0001</td></tr><tr><td align="left" rowspan="1" colspan="1">Prior null response</td><td align="char" char="." rowspan="1" colspan="1">0.29</td><td align="left" rowspan="1" colspan="1">0.22–0.37</td><td align="char" char="." rowspan="1" colspan="1"><0.0001</td><td align="char" char="." rowspan="1" colspan="1">0.34</td><td align="left" rowspan="1" colspan="1">0.26–0.44</td><td align="char" char="." rowspan="1" colspan="1"><0.0001</td></tr><tr><td align="left" rowspan="1" colspan="1">Liver stiffness measurement >18 kPa</td><td align="char" char="." rowspan="1" colspan="1">0.58</td><td align="left" rowspan="1" colspan="1">0.46–0.74</td><td align="char" char="." rowspan="1" colspan="1"><0.0001</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">Genotype subtype 1a</td><td align="char" char="." rowspan="1" colspan="1">0.60</td><td align="left" rowspan="1" colspan="1">0.45–0.79</td><td align="char" char="." rowspan="1" colspan="1">0.0003</td><td align="char" char="." rowspan="1" colspan="1">0.60</td><td align="left" rowspan="1" colspan="1">0.44–0.82</td><td align="char" char="." rowspan="1" colspan="1">0.0012</td></tr><tr><td align="left" rowspan="1" colspan="1">Age ≤65 years</td><td align="char" char="." rowspan="1" colspan="1">0.80</td><td align="left" rowspan="1" colspan="1">0.51–1.24</td><td align="char" char="." rowspan="1" colspan="1">0.3114</td><td align="char" char="." rowspan="1" colspan="1">0.60</td><td align="left" rowspan="1" colspan="1">0.37–0.98</td><td align="char" char="." rowspan="1" colspan="1">0.0407</td></tr><tr><td align="left" rowspan="1" colspan="1">HCV RNA ≥800,000 UI/mL</td><td align="char" char="." rowspan="1" colspan="1">0.83</td><td align="left" rowspan="1" colspan="1">0.64–1.07</td><td align="char" char="." rowspan="1" colspan="1">0.1515</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">BMI (log<sub>10</sub> kg/m<sup>2</sup>)</td><td align="char" char="." rowspan="1" colspan="1">1.00</td><td align="left" rowspan="1" colspan="1">0.97–1.03</td><td align="char" char="." rowspan="1" colspan="1">0.9176</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">Hemoglobin (log<sub>10</sub> g/L)</td><td align="char" char="." rowspan="1" colspan="1">1.01</td><td align="left" rowspan="1" colspan="1">1.00–1.02</td><td align="char" char="." rowspan="1" colspan="1">0.0889</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">Initial dose of ribavirin</td><td align="char" char="." rowspan="1" colspan="1">1.04</td><td align="left" rowspan="1" colspan="1">0.98–1.11</td><td align="char" char="." rowspan="1" colspan="1">0.1905</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">Male sex</td><td align="char" char="." rowspan="1" colspan="1">1.14</td><td align="left" rowspan="1" colspan="1">0.90–1.46</td><td align="char" char="." rowspan="1" colspan="1">0.2808</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">PEG-IFN alfa 2a</td><td align="char" char="." rowspan="1" colspan="1">1.21</td><td align="left" rowspan="1" colspan="1">0.85–1.72</td><td align="char" char="." rowspan="1" colspan="1">0.2952</td><td align="char" char="." rowspan="1" colspan="1">1.46</td><td align="left" rowspan="1" colspan="1">1.00–2.14</td><td align="char" char="." rowspan="1" colspan="1">0.0522</td></tr><tr><td align="left" rowspan="1" colspan="1">Platelets (log<sub>10</sub> n/L)</td><td align="char" char="." rowspan="1" colspan="1">10.1</td><td align="left" rowspan="1" colspan="1">4.41–23.1</td><td align="char" char="." rowspan="1" colspan="1"><0.0001</td><td align="char" char="." rowspan="1" colspan="1">2.69</td><td align="left" rowspan="1" colspan="1">1.06–6.84</td><td align="char" char="." rowspan="1" colspan="1">0.0373</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t003fn001"><p>All variables analysed in the univariate analysis were included in the initial multivariate model. Variables only remained in both models if they reached a significance level of the Wald chi-squared of 0.1 in the multivariate model. This analysis consisted of 1189 observations.</p></fn></table-wrap-foot></table-wrap><p>Multivariate analysis identified the following three independent predictors of lower SVR rates: genotype 1a (p = 0.0012), alfa fetoprotein (p<0.0001), log<sub>10</sub> platelets (p = 0.0373), age (p = 0.0407) and prior null response (<0.0001). FibroScan was no longer statistically significant as an independent SVR predictor.</p></sec><sec id="sec016"><title>Correlation between FibroScan and baseline laboratory parameters</title><p>FibroScan scores were tested for correlations with baseline laboratory parameters: platelets count, alfa fetoprotein, albumin, bilirubin and international normalized ratio (INR). All of the laboratory parameters tested were correlated with FibroScan, but the correlations were quite weak (correlation coefficients <0.4). More precisely, higher FibroScan score correlated with lower platelets and albumin and higher alfa fetoprotein, bilirubin and INR with a p value <0.0001 for each comparison.</p></sec><sec id="sec017"><title>Safety</title><p>AEs observed in this study were consistent with telaprevir-based therapy known side effects, namely anemia (observed in 56% of patients), rash (30%), and pruritus (16%). As previously described, the most common serious side effect was, by far, anemia (26%). Overall, 12% of patients discontinued due to AEs, 4% due to rash and 3% due to anemia (<xref rid="pone.0138503.t004" ref-type="table">Table 4</xref>).</p><table-wrap id="pone.0138503.t004" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0138503.t004</object-id><label>Table 4</label><caption><title>Reasons for discontinuation of telaprevir and incidence of the most common AEs and Grade 3–4 AEs during the telaprevir phase in the intent-to-treat population.</title></caption><alternatives><graphic id="pone.0138503.t004g" xlink:href="pone.0138503.t004"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">n (%)</th><th align="left" rowspan="1" colspan="1">Patients with bridging fibrosis<xref rid="t004fn001" ref-type="table-fn">*</xref>(N = 813)</th><th align="left" rowspan="1" colspan="1">Patients with cirrhosis (N = 959)</th><th align="left" rowspan="1" colspan="1">All patients(N = 1772)</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Patients with at least one AE†</td><td align="left" rowspan="1" colspan="1">662 (81)</td><td align="left" rowspan="1" colspan="1">804 (84)</td><td align="left" rowspan="1" colspan="1">1466 (83)</td></tr><tr><td align="left" rowspan="1" colspan="1">Anaemia<xref rid="t004fn003" ref-type="table-fn">‡</xref></td><td align="left" rowspan="1" colspan="1">435 (54)</td><td align="left" rowspan="1" colspan="1">562 (59)</td><td align="left" rowspan="1" colspan="1">997 (56)</td></tr><tr><td align="left" rowspan="1" colspan="1">Rash<xref rid="t004fn003" ref-type="table-fn">‡</xref></td><td align="left" rowspan="1" colspan="1">230 (28)</td><td align="left" rowspan="1" colspan="1">305 (32)</td><td align="left" rowspan="1" colspan="1">535 (30)</td></tr><tr><td align="left" rowspan="1" colspan="1">Pruritus<xref rid="t004fn003" ref-type="table-fn">‡</xref></td><td align="left" rowspan="1" colspan="1">114 (14)</td><td align="left" rowspan="1" colspan="1">163 (17)</td><td align="left" rowspan="1" colspan="1">277 (16)</td></tr><tr><td align="left" rowspan="1" colspan="1">Asthenia</td><td align="left" rowspan="1" colspan="1">74 (9)</td><td align="left" rowspan="1" colspan="1">80 (8)</td><td align="left" rowspan="1" colspan="1">154 (9)</td></tr><tr><td align="left" rowspan="1" colspan="1">Nausea</td><td align="left" rowspan="1" colspan="1">62 (8)</td><td align="left" rowspan="1" colspan="1">85 (9)</td><td align="left" rowspan="1" colspan="1">147 (8)</td></tr><tr><td align="left" rowspan="1" colspan="1">Thrombocytopenia</td><td align="left" rowspan="1" colspan="1">38 (5)</td><td align="left" rowspan="1" colspan="1">92 (10)</td><td align="left" rowspan="1" colspan="1">130 (7)</td></tr><tr><td align="left" rowspan="1" colspan="1">Anal Pruritus</td><td align="left" rowspan="1" colspan="1">36 (4)</td><td align="left" rowspan="1" colspan="1">64 (7)</td><td align="left" rowspan="1" colspan="1">100 (6)</td></tr><tr><td align="left" rowspan="1" colspan="1">Patients with at least one Grade 3 or 4 AE<xref rid="t004fn004" ref-type="table-fn">§</xref></td><td align="left" rowspan="1" colspan="1">274 (34)</td><td align="left" rowspan="1" colspan="1">344 (36)</td><td align="left" rowspan="1" colspan="1">618 (35)</td></tr><tr><td align="left" rowspan="1" colspan="1">Anaemia</td><td align="left" rowspan="1" colspan="1">203 (25)</td><td align="left" rowspan="1" colspan="1">253 (26)</td><td align="left" rowspan="1" colspan="1">456 (26)</td></tr><tr><td align="left" rowspan="1" colspan="1">Rash</td><td align="left" rowspan="1" colspan="1">26 (3)</td><td align="left" rowspan="1" colspan="1">27 (3)</td><td align="left" rowspan="1" colspan="1">53 (3)</td></tr><tr><td align="left" rowspan="1" colspan="1">Asthenia</td><td align="left" rowspan="1" colspan="1">15 (2)</td><td align="left" rowspan="1" colspan="1">17 (2)</td><td align="left" rowspan="1" colspan="1">32 (2)</td></tr><tr><td align="left" rowspan="1" colspan="1">Thrombocytopenia</td><td align="left" rowspan="1" colspan="1">4 (<1)</td><td align="left" rowspan="1" colspan="1">25 (3)</td><td align="left" rowspan="1" colspan="1">29 (2)</td></tr><tr><td align="left" rowspan="1" colspan="1">Hemoglobin Decreased</td><td align="left" rowspan="1" colspan="1">9 (1)</td><td align="left" rowspan="1" colspan="1">9 (<1)</td><td align="left" rowspan="1" colspan="1">18 (1)</td></tr><tr><td align="left" rowspan="1" colspan="1">Neutropenia</td><td align="left" rowspan="1" colspan="1">5 (<1)</td><td align="left" rowspan="1" colspan="1">12 (1)</td><td align="left" rowspan="1" colspan="1">17 (1)</td></tr><tr><td align="left" rowspan="1" colspan="1">Reason for discontinuation<xref rid="t004fn005" ref-type="table-fn">¶</xref></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Any AE</td><td align="left" rowspan="1" colspan="1">91 (11)</td><td align="left" rowspan="1" colspan="1">130 (14)</td><td align="left" rowspan="1" colspan="1">221 (12)</td></tr><tr><td align="left" rowspan="1" colspan="1">Rash</td><td align="left" rowspan="1" colspan="1">32 (4)</td><td align="left" rowspan="1" colspan="1">36 (4)</td><td align="left" rowspan="1" colspan="1">68 (4)</td></tr><tr><td align="left" rowspan="1" colspan="1">Anaemia</td><td align="left" rowspan="1" colspan="1">17 (2)</td><td align="left" rowspan="1" colspan="1">33 (3)</td><td align="left" rowspan="1" colspan="1">50 (3)</td></tr><tr><td align="left" rowspan="1" colspan="1">Asthenia</td><td align="left" rowspan="1" colspan="1">8 (1)</td><td align="left" rowspan="1" colspan="1">10 (1)</td><td align="left" rowspan="1" colspan="1">18 (1)</td></tr><tr><td align="left" rowspan="1" colspan="1">Vomiting</td><td align="left" rowspan="1" colspan="1">8 (1)</td><td align="left" rowspan="1" colspan="1">10 (1)</td><td align="left" rowspan="1" colspan="1">18 (1)</td></tr><tr><td align="left" rowspan="1" colspan="1">Nausea</td><td align="left" rowspan="1" colspan="1">7 (<1)</td><td align="left" rowspan="1" colspan="1">10 (1)</td><td align="left" rowspan="1" colspan="1">17 (1)</td></tr><tr><td align="left" rowspan="1" colspan="1">Pruritus</td><td align="left" rowspan="1" colspan="1">3 (<1)</td><td align="left" rowspan="1" colspan="1">11 (1)</td><td align="left" rowspan="1" colspan="1">14 (<1)</td></tr><tr><td align="left" rowspan="1" colspan="1">Abdominal Pain</td><td align="left" rowspan="1" colspan="1">1 (<1)</td><td align="left" rowspan="1" colspan="1">8 (<1)</td><td align="left" rowspan="1" colspan="1">9 (<1)</td></tr><tr><td align="left" rowspan="1" colspan="1">Infections</td><td align="left" rowspan="1" colspan="1">1 (<1)</td><td align="left" rowspan="1" colspan="1">5 (<1)</td><td align="left" rowspan="1" colspan="1">6 (<1)</td></tr><tr><td align="left" rowspan="1" colspan="1">Investigations</td><td align="left" rowspan="1" colspan="1">3 (<1)</td><td align="left" rowspan="1" colspan="1">3 (<1)</td><td align="left" rowspan="1" colspan="1">6 (<1)</td></tr><tr><td align="left" rowspan="1" colspan="1">Fatigue</td><td align="left" rowspan="1" colspan="1">3 (<1)</td><td align="left" rowspan="1" colspan="1">2 (<1)</td><td align="left" rowspan="1" colspan="1">5 (<1)</td></tr><tr><td align="left" rowspan="1" colspan="1">Pyrexia</td><td align="left" rowspan="1" colspan="1">2 (<1)</td><td align="left" rowspan="1" colspan="1">3 (<1)</td><td align="left" rowspan="1" colspan="1">5 (<1)</td></tr><tr><td align="left" rowspan="1" colspan="1">Thrombocytopenia</td><td align="left" rowspan="1" colspan="1">1 (<1)</td><td align="left" rowspan="1" colspan="1">4 (<1)</td><td align="left" rowspan="1" colspan="1">5 (<1)</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t004fn001"><p>* Includes six F0–F2 patients.</p></fn><fn id="t004fn002"><p><sup>†</sup> Listed are drug-related AEs that occurred in at least 5% of the overall population during the telaprevir phase.</p></fn><fn id="t004fn003"><p><sup>‡</sup> Included in this category are all related events that were described with a variety of descriptive terms.</p></fn><fn id="t004fn004"><p><sup>§</sup> Listed are grade 3–4 drug-related AEs that occurred in at least 1% of the overall population during the telaprevir phase.</p></fn><fn id="t004fn005"><p><sup>¶</sup> Listed are discontinuations that occurred in at least 5 patients. These figures are the number of patients who discontinued telaprevir; patients may have continued treatment with pegylated interferon plus ribavirin.</p></fn><fn id="t004fn006"><p>AE, adverse event.</p></fn></table-wrap-foot></table-wrap><p>The statistical analysis showed that higher FibroScan values were significantly correlated with anemia (p = 0.0365), occurrence of grade 1–4 infections (p = 0.0472) and SAEs (p<0.0001) but not with telaprevir discontinuation due to AEs (p = 0.0602) (<xref rid="pone.0138503.t005" ref-type="table">Table 5</xref>).</p><table-wrap id="pone.0138503.t005" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0138503.t005</object-id><label>Table 5</label><caption><title>Safety based on Liver Stiffness Measurement in patients with baseline FibroScan values.</title></caption><alternatives><graphic id="pone.0138503.t005g" xlink:href="pone.0138503.t005"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1"></th><th colspan="4" align="left" rowspan="1">Liver Stiffness Measurement (kPa)</th><th align="left" rowspan="1" colspan="1">P value</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">n/N (%)</td><td align="left" rowspan="1" colspan="1"><bold>≤11.3</bold></td><td align="left" rowspan="1" colspan="1"><bold>11.4–14.6</bold></td><td align="left" rowspan="1" colspan="1"><bold>14.7–21.9</bold></td><td align="left" rowspan="1" colspan="1"><bold>>21.9</bold></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Anemia (<10 g/dL)</td><td align="left" rowspan="1" colspan="1">140/321 (44)</td><td align="left" rowspan="1" colspan="1">132/296 (45)</td><td align="left" rowspan="1" colspan="1">164/315 (52)</td><td align="left" rowspan="1" colspan="1">161/306 (53)</td><td align="char" char="." rowspan="1" colspan="1">0.0365</td></tr><tr><td align="left" rowspan="1" colspan="1">Grade 1–4 infections</td><td align="left" rowspan="1" colspan="1">6/334 (2)</td><td align="left" rowspan="1" colspan="1">7/307 (2)</td><td align="left" rowspan="1" colspan="1">13/322 (4)</td><td align="left" rowspan="1" colspan="1">17/318 (5)</td><td align="char" char="." rowspan="1" colspan="1">0.0472</td></tr><tr><td align="left" rowspan="1" colspan="1">SAEs</td><td align="left" rowspan="1" colspan="1">26/334 (8)</td><td align="left" rowspan="1" colspan="1">19/307 (6)</td><td align="left" rowspan="1" colspan="1">47/322 (15)</td><td align="left" rowspan="1" colspan="1">53/318 (17)</td><td align="char" char="." rowspan="1" colspan="1"><0.0001</td></tr><tr><td align="left" rowspan="1" colspan="1">Telaprevir discontinuation due to AE</td><td align="left" rowspan="1" colspan="1">35/334 (10)</td><td align="left" rowspan="1" colspan="1">34/307 (11)</td><td align="left" rowspan="1" colspan="1">54/322 (17)</td><td align="left" rowspan="1" colspan="1">46/318 (14)</td><td align="char" char="." rowspan="1" colspan="1">0.0602</td></tr></tbody></table></alternatives></table-wrap></sec><sec id="sec018"><title>FibroScan and the risk of anemia</title><p>Multiple parameters were tested for their association with anemia, defined as hemoglobin ≤10 g/dL and severe anemia defined as hemoglobin ≤8.5 g/dL (<xref rid="pone.0138503.t006" ref-type="table">Table 6</xref>). In univariate analysis of anemia, among other parameters, the baseline FibroScan score was predictive of telaprevir-based treatment-related anemia (p = 0.0072). By multivariate stepwise logistic-regression analysis, independent predictors were older age (p<0.0001), female sex (p<0.0001), lower baseline hemoglobin (p<0.0001), and ribavirin dosing (p<0.0001), while FibroScan was no longer statistically significant.</p><table-wrap id="pone.0138503.t006" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0138503.t006</object-id><label>Table 6</label><caption><title>Univariate and multivariate predictors of anemia.</title></caption><alternatives><graphic id="pone.0138503.t006g" xlink:href="pone.0138503.t006"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1"></th><th colspan="3" align="left" rowspan="1">Univariate analysis</th><th colspan="3" align="left" rowspan="1">Multivariate analysis</th></tr><tr><th align="left" rowspan="1" colspan="1">Factor</th><th align="left" rowspan="1" colspan="1">OR</th><th align="left" rowspan="1" colspan="1">95% CI</th><th align="left" rowspan="1" colspan="1">P value</th><th align="left" rowspan="1" colspan="1">OR</th><th align="left" rowspan="1" colspan="1">95% CI</th><th align="left" rowspan="1" colspan="1">P value</th></tr></thead><tbody><tr><td colspan="7" align="left" rowspan="1"><bold>Predictors of anemia (hemoglobin <10 g/dL)</bold><xref rid="t006fn001" ref-type="table-fn">*</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Male sex</td><td align="char" char="." rowspan="1" colspan="1">0.22</td><td align="left" rowspan="1" colspan="1">0.18–0.27</td><td align="char" char="." rowspan="1" colspan="1"><0.0001</td><td align="char" char="." rowspan="1" colspan="1">0.59</td><td align="left" rowspan="1" colspan="1">0.45–0.76</td><td align="char" char="." rowspan="1" colspan="1"><0.0001</td></tr><tr><td align="left" rowspan="1" colspan="1">Platelets (log<sub>10</sub> n/L)</td><td align="char" char="." rowspan="1" colspan="1">0.25</td><td align="left" rowspan="1" colspan="1">0.13–0.48</td><td align="char" char="." rowspan="1" colspan="1"><0.0001</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">PEG-IFN alfa 2a</td><td align="char" char="." rowspan="1" colspan="1">0.77</td><td align="left" rowspan="1" colspan="1">0.58–1.01</td><td align="char" char="." rowspan="1" colspan="1">0.0572</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">Hemoglobin (log<sub>10</sub> g/L)</td><td align="char" char="." rowspan="1" colspan="1">0.92</td><td align="left" rowspan="1" colspan="1">0.91–0.93</td><td align="char" char="." rowspan="1" colspan="1"><0.0001</td><td align="char" char="." rowspan="1" colspan="1">0.94</td><td align="left" rowspan="1" colspan="1">0.93–0.95</td><td align="char" char="." rowspan="1" colspan="1"><0.0001</td></tr><tr><td align="left" rowspan="1" colspan="1">BMI (log<sub>10</sub> kg/m<sup>2</sup>)</td><td align="char" char="." rowspan="1" colspan="1">0.96</td><td align="left" rowspan="1" colspan="1">0.94–0.98</td><td align="char" char="." rowspan="1" colspan="1">0.0006</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">HCV RNA ≥800,000 UI/mL</td><td align="char" char="." rowspan="1" colspan="1">1.07</td><td align="left" rowspan="1" colspan="1">0.87–1.31</td><td align="char" char="." rowspan="1" colspan="1">0.5114</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">Prior null response</td><td align="char" char="." rowspan="1" colspan="1">1.11</td><td align="left" rowspan="1" colspan="1">0.90–1.37</td><td align="char" char="." rowspan="1" colspan="1">0.3416</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">Genotype subtype 1a</td><td align="char" char="." rowspan="1" colspan="1">1.21</td><td align="left" rowspan="1" colspan="1">1.08–1.36</td><td align="char" char="." rowspan="1" colspan="1">0.0011</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">Initial dose of ribavirin mg/kg</td><td align="char" char="." rowspan="1" colspan="1">1.26</td><td align="left" rowspan="1" colspan="1">1.19–1.33</td><td align="char" char="." rowspan="1" colspan="1"><0.0001</td><td align="char" char="." rowspan="1" colspan="1">1.15</td><td align="left" rowspan="1" colspan="1">1.08–1.22</td><td align="char" char="." rowspan="1" colspan="1"><0.0001</td></tr><tr><td align="left" rowspan="1" colspan="1">α-Fetoprotein (log<sub>10</sub> μg/L)</td><td align="char" char="." rowspan="1" colspan="1">1.75</td><td align="left" rowspan="1" colspan="1">1.38–2.21</td><td align="char" char="." rowspan="1" colspan="1"><0.0001</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">Liver stiffness measurement (log<sub>10</sub> kPa)</td><td align="char" char="." rowspan="1" colspan="1">2.03</td><td align="left" rowspan="1" colspan="1">1.21–3.40</td><td align="char" char="." rowspan="1" colspan="1">0.0072</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">Age >65 years</td><td align="char" char="." rowspan="1" colspan="1">3.27</td><td align="left" rowspan="1" colspan="1">2.20–4.87</td><td align="char" char="." rowspan="1" colspan="1"><0.0001</td><td align="char" char="." rowspan="1" colspan="1">2.62</td><td align="left" rowspan="1" colspan="1">1.70–4.03</td><td align="char" char="." rowspan="1" colspan="1"><0.0001</td></tr><tr><td colspan="7" align="left" rowspan="1"><bold>Predictors of severe anemia (hemoglobin <8.5 g/dL)</bold><xref rid="t006fn001" ref-type="table-fn">*</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Platelets (log<sub>10</sub> n/L)</td><td align="char" char="." rowspan="1" colspan="1">0.21</td><td align="left" rowspan="1" colspan="1">0.09–0.48</td><td align="char" char="." rowspan="1" colspan="1">0.0002</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">Male sex</td><td align="char" char="." rowspan="1" colspan="1">0.31</td><td align="left" rowspan="1" colspan="1">0.24–0.41</td><td align="char" char="." rowspan="1" colspan="1"><0.0001</td><td align="char" char="." rowspan="1" colspan="1">0.70</td><td align="left" rowspan="1" colspan="1">0.51–0.95</td><td align="char" char="." rowspan="1" colspan="1">0.0224</td></tr><tr><td align="left" rowspan="1" colspan="1">Prior null response</td><td align="char" char="." rowspan="1" colspan="1">0.82</td><td align="left" rowspan="1" colspan="1">0.61–1.08</td><td align="char" char="." rowspan="1" colspan="1">0.1604</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">HCV RNA ≥800,000 UI/mL</td><td align="char" char="." rowspan="1" colspan="1">0.86</td><td align="left" rowspan="1" colspan="1">0.66–1.11</td><td align="left" rowspan="1" colspan="1">0.2423</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">PEG-IFN alfa 2a</td><td align="char" char="." rowspan="1" colspan="1">0.93</td><td align="left" rowspan="1" colspan="1">0.65–1.32</td><td align="char" char="." rowspan="1" colspan="1">0.6739</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">Hemoglobin (log<sub>10</sub> g/L)</td><td align="char" char="." rowspan="1" colspan="1">0.95</td><td align="left" rowspan="1" colspan="1">0.94–0.96</td><td align="char" char="." rowspan="1" colspan="1"><0.0001</td><td align="char" char="." rowspan="1" colspan="1">0.96</td><td align="left" rowspan="1" colspan="1">0.94–0.97</td><td align="char" char="." rowspan="1" colspan="1"><0.0001</td></tr><tr><td align="left" rowspan="1" colspan="1">BMI (log<sub>10</sub> kg/m<sup>2</sup>)</td><td align="char" char="." rowspan="1" colspan="1">0.97</td><td align="left" rowspan="1" colspan="1">0.94–1.00</td><td align="char" char="." rowspan="1" colspan="1">0.0424</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">Genotype subtype 1a</td><td align="char" char="." rowspan="1" colspan="1">1.20</td><td align="left" rowspan="1" colspan="1">1.02–1.41</td><td align="char" char="." rowspan="1" colspan="1">0.0237</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">Initial dose of ribavirin mg/kg</td><td align="char" char="." rowspan="1" colspan="1">1.22</td><td align="left" rowspan="1" colspan="1">1.14–1.30</td><td align="char" char="." rowspan="1" colspan="1"><0.0001</td><td align="char" char="." rowspan="1" colspan="1">1.12</td><td align="left" rowspan="1" colspan="1">1.04–1.20</td><td align="char" char="." rowspan="1" colspan="1">0.0020</td></tr><tr><td align="left" rowspan="1" colspan="1">α-Fetoprotein (log<sub>10</sub> μg/L)</td><td align="char" char="." rowspan="1" colspan="1">1.92</td><td align="left" rowspan="1" colspan="1">1.43–2.59</td><td align="char" char="." rowspan="1" colspan="1"><0.0001</td><td align="char" char="." rowspan="1" colspan="1">1.67</td><td align="left" rowspan="1" colspan="1">1.22–2.27</td><td align="char" char="." rowspan="1" colspan="1">0.0012</td></tr><tr><td align="left" rowspan="1" colspan="1">Liver stiffness measurement (log<sub>10</sub> kPa)</td><td align="char" char="." rowspan="1" colspan="1">2.54</td><td align="left" rowspan="1" colspan="1">1.32–4.87</td><td align="char" char="." rowspan="1" colspan="1">0.0051</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1">Age >65 years</td><td align="char" char="." rowspan="1" colspan="1">2.81</td><td align="left" rowspan="1" colspan="1">1.93–4.09</td><td align="char" char="." rowspan="1" colspan="1"><0.0001</td><td align="char" char="." rowspan="1" colspan="1">2.25</td><td align="left" rowspan="1" colspan="1">1.51–3.37</td><td align="char" char="." rowspan="1" colspan="1"><0.0001</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t006fn001"><p>* N>1700 except for assessment of liver stiffness measurement (N = 1240) and α-Fetoprotein (N = 1679)</p></fn><fn id="t006fn002"><p>This analysis consisted of 1671 observations.</p></fn></table-wrap-foot></table-wrap><p>In univariate analysis of severe anemia, among other parameters, the baseline FibroScan score was predictive of telaprevir-based treatment related anemia (p = 0.0051). By multivariate stepwise logistic-regression analysis, independent predictors were older age (p<0.0001), lower baseline hemoglobin (p<0.0001), ribavirin dosing (p = 0.0020), alfa fetoprotein (p = 0.0012), and female sex (p = 0.0224).</p></sec></sec><sec sec-type="conclusions" id="sec019"><title>Discussion</title><p>In this paper we present the final results of the international telaprevir EAP. Of the 1,772 patients with either bridging fibrosis or cirrhosis resulting from HCV genotype 1 infection who were treated with telaprevir-based triple therapy, a percentage of 64% achieved SVR. These results are similar to the ones of an interim analysis of the study, published recently by Colombo et al [<xref rid="pone.0138503.ref044" ref-type="bibr">44</xref>].</p><p>Further analyzing the data from this large, multicenter study, we evaluated the clinical interest of FibroScan baseline values in the prediction of efficacy and safety of telaprevir-based triple therapy in patients with HCV genotype 1-related, advanced liver disease. The studied population represents the 72% of the patients included in the HEP3002 EAP and who were initially evaluated for the fibrosis stage with FibroScan. Our cohort included both treatment-naive and -experienced patients with bridging hepatic fibrosis and compensated cirrhosis, a population with priority to treatment but poorly represented in clinical trials. The present study suggests that the baseline FibroScan value is a predictor of efficacy and safety of telaprevir-based treatment. Higher baseline FibroScan measurements are correlated with lower SVR rates and higher incidence of anemia in univariate analyses. In multivariate analyses this correlation is not strong enough to be considered significant and was overshadowed by other more accurate clinical and biologic independent predictors. Additionally, higher baseline FibroScan values were correlated with the occurrence of infections and SAEs.</p><p>To our knowledge, there are only 2 previous studies validating the predictive power of FibroScan for long-term antiviral treatment response [<xref rid="pone.0138503.ref032" ref-type="bibr">32</xref>, <xref rid="pone.0138503.ref036" ref-type="bibr">36</xref>]. Patel et al evaluated the diagnostic utility of baseline FibroScan in 214 treatment-naive patients infected by genotype 1 to 3 of HCV in whom liver fibrosis was staged by a percutaneous liver biopsy and classified by Metavir (F0–F4) and who underwent treatment with interferon and ribavirin. These authors demonstrated lower baseline FibroScan scores in patients who achieved an SVR than in those who failed therapy, indicating that FibroScan could provide useful adjunctive information for the prediction of virologic response prior to IFN-based therapy for chronic HCV. The second study by Stasi et al evaluated 74 treatment naive, genotype 1 to 4 chronic HCV patients at various fibrosis stages, who were treated with PR. Patients with pretreatment FibroScan values >12 kPa that are predictive of advanced fibrosis in HCV patients, had a significantly lower response to antiviral therapy suggesting that FibroScan could be used for pretreatment patient stratification to optimize patient selection to antiviral therapy. Along this line was a smaller French study where baseline FibroScan was tested for the prediction of SVR to triple therapy with either boceprevir or telaprevir in 125 HCV genotype 1-infected patients with advanced fibrosis or cirrhosis, who were previously unsuccessfully treated with PR [<xref rid="pone.0138503.ref045" ref-type="bibr">45</xref>]. In that study, a pre-treatment FibroScan cut-off of 21.3 kPa was discriminant for the occurrence of SVR. Other smaller studies, however, have failed to demonstrate similar association between pretreatment FibroScan results and a likelihood to respond to interferon based regimens [<xref rid="pone.0138503.ref031" ref-type="bibr">31</xref>, <xref rid="pone.0138503.ref033" ref-type="bibr">33</xref>–<xref rid="pone.0138503.ref035" ref-type="bibr">35</xref>]. As far as safety is concerned, to our knowledge, there are no clinical trials evaluating pretreatment FibroScan to predict occurrence of treatment related AEs.</p><p>In this sub-analysis of the EAP HEP3002 cohort, we showed the existence of a correlation between the baseline FibroScan results and the safety and efficacy of the telaprevir-based triple therapy in more than 1,000 patients treated in field practice. The strength of our study (apart from the relevant sample size and the use of a potent anti HCV regimen) was also the exclusive inclusion of both treatment-naive and treatment-experienced patients with advanced liver disease. This is in fact a most difficult-to-treat population in the everyday clinical practice, as advanced hepatic fibrosis in chronic HCV infection represents a prioritization criterion for therapy but also a tolerability and safety issue in patients exposed to triple therapy [<xref rid="pone.0138503.ref006" ref-type="bibr">6</xref>, <xref rid="pone.0138503.ref007" ref-type="bibr">7</xref>, <xref rid="pone.0138503.ref024" ref-type="bibr">24</xref>, <xref rid="pone.0138503.ref046" ref-type="bibr">46</xref>].</p><p>FibroScan has gained popularity in HCV field since it has been extensively validated for the diagnosis of disease severity [<xref rid="pone.0138503.ref023" ref-type="bibr">23</xref>, <xref rid="pone.0138503.ref024" ref-type="bibr">24</xref>, <xref rid="pone.0138503.ref035" ref-type="bibr">35</xref>, <xref rid="pone.0138503.ref047" ref-type="bibr">47</xref>–<xref rid="pone.0138503.ref053" ref-type="bibr">53</xref>] and prediction of liver related mortality [<xref rid="pone.0138503.ref029" ref-type="bibr">29</xref>, <xref rid="pone.0138503.ref030" ref-type="bibr">30</xref>, <xref rid="pone.0138503.ref052" ref-type="bibr">52</xref>–<xref rid="pone.0138503.ref055" ref-type="bibr">55</xref>]. Despite the rapid evolution in the field of HCV treatment, PIs in association with PR remain a standard of care in accurately selected genotype 1-infected patients in countries where all oral anti-HCV regimens are not available or are restricted for money constraints. However, since triple therapy requires expertise to prevent AEs in fragile patient populations like cirrhotics, in real life practice the disposing of reliable markers to predict safety and efficacy through the selection of ideal patients to treat is crucial. In our study, higher pre-treatment FibroScan scores correlated with a higher risk of anemia in univariate analysis and with a lower chance of SVR to telaprevir-based triple therapy. The latter, however, was independently predicted by genotype 1b, elevated alfa fetoprotein and prior null response. On the other hand, anemia, was independently predicted by older age, female sex, low baseline hemoglobin, higher weight-based ribavirin dosing and high baseline HCV RNA.</p><p>The EAP study as every real-life study has some limitations. Six patients with a baseline FibroScan <9.5 kPa, were considered protocol violations, and therefore were excluded from the analyses. The FibroScan cut-offs used for advanced fibrosis and cirrhosis were based on a previous study [<xref rid="pone.0138503.ref042" ref-type="bibr">42</xref>], but its performance for the assessment of fibrosis in previously treated HCV patients has not been investigated. Moreover, we could not review all FibroScan protocols of the participating centers but we only captured the elastography result without the companion reliability results (i.e. IQR) and success rates of each exam. In the overall EAP cohort, 12% of patients experienced SAEs that ultimately led to telaprevir discontinuation, a relatively low number compared to the 40% of SAEs in the CUPIC trial, further confirming the exclusion in the EAP study of high-risk patients with poorly compensated liver and bone marrow that were instead enrolled in the French study [<xref rid="pone.0138503.ref014" ref-type="bibr">14</xref>].</p><p>In conclusion, while FibroScan on its own was able to predict both efficacy and safety of triple therapy in patients with advanced fibrosis, in the frame of overall clinical assessment of HCV patients it is overshadowed as a predictor of safety and efficacy of telaprevir-based triple therapy by other clinical and biological parameters.</p></sec><sec sec-type="supplementary-material" id="sec020"><title>Supporting Information</title><supplementary-material content-type="local-data" id="pone.0138503.s001"><label>S1 Protocol</label><caption><title>Clinical Trial Protocol.</title><p>(PDF)</p></caption><media xlink:href="pone.0138503.s001.pdf"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pone.0138503.s002"><label>S1 Table</label><caption><title>Efficacy outcome for each subgroup of patients with respect to previous PR treatment and to extended rapid virologic response (eRVR) in the intent-to-treat population.</title><p>(DOCX)</p></caption><media xlink:href="pone.0138503.s002.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pone.0138503.s003"><label>S1 TREND Checklist</label><caption><title>TREND Checklist.</title><p>(DOCX)</p></caption><media xlink:href="pone.0138503.s003.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material></sec></body><back><ack><p>We thank all investigators; the nurses and patients who were involved in this study; Valérie Philippon, Ph.D. for her assistance in the preparation of the manuscript and Christopher Liu for his contributions. 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