Hepatitis C viral evolution in genotype 1 treatment-naïve and treatment-experienced patients receiving telaprevir-based therapy in clinical trials.
<h4>Background</h4>In patients with genotype 1 chronic hepatitis C infection, telaprevir (TVR) in combination with peginterferon and ribavirin (PR) significantly increased sustained virologic response (SVR) rates compared with PR alone. However, genotypic changes could be observed in TVR...
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2012
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oai:doaj.org-article:1dbcfc20320f40f0bb077dc356b2c9f42021-11-18T07:22:28ZHepatitis C viral evolution in genotype 1 treatment-naïve and treatment-experienced patients receiving telaprevir-based therapy in clinical trials.1932-620310.1371/journal.pone.0034372https://doaj.org/article/1dbcfc20320f40f0bb077dc356b2c9f42012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22511937/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>In patients with genotype 1 chronic hepatitis C infection, telaprevir (TVR) in combination with peginterferon and ribavirin (PR) significantly increased sustained virologic response (SVR) rates compared with PR alone. However, genotypic changes could be observed in TVR-treated patients who did not achieve an SVR.<h4>Methods</h4>Population sequence analysis of the NS3•4A region was performed in patients who did not achieve SVR with TVR-based treatment.<h4>Results</h4>Resistant variants were observed after treatment with a telaprevir-based regimen in 12% of treatment-naïve patients (ADVANCE; T12PR arm), 6% of prior relapsers, 24% of prior partial responders, and 51% of prior null responder patients (REALIZE, T12PR48 arms). NS3 protease variants V36M, R155K, and V36M+R155K emerged frequently in patients with genotype 1a and V36A, T54A, and A156S/T in patients with genotype 1b. Lower-level resistance to telaprevir was conferred by V36A/M, T54A/S, R155K/T, and A156S variants; and higher-level resistance to telaprevir was conferred by A156T and V36M+R155K variants. Virologic failure during telaprevir treatment was more common in patients with genotype 1a and in prior PR nonresponder patients and was associated with higher-level telaprevir-resistant variants. Relapse was usually associated with wild-type or lower-level resistant variants. After treatment, viral populations were wild-type with a median time of 10 months for genotype 1a and 3 weeks for genotype 1b patients.<h4>Conclusions</h4>A consistent, subtype-dependent resistance profile was observed in patients who did not achieve an SVR with telaprevir-based treatment. The primary role of TVR is to inhibit wild-type virus and variants with lower-levels of resistance to telaprevir. The complementary role of PR is to clear any remaining telaprevir-resistant variants, especially higher-level telaprevir-resistant variants. Resistant variants are detectable in most patients who fail to achieve SVR, but their levels decline over time after treatment.Tara L KiefferSandra De MeyerDoug J BartelsJames C SullivanEileen Z ZhangAnn TiggesInge DierynckJoan SpanksJennifer DorrianMin JiangBambang AdiwijayaAnne GhysMaria BeumontRobert S KauffmanNathalie AddaIra M JacobsonKenneth E ShermanStefan ZeuzemAnn D KwongGaston PicchioPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 4, p e34372 (2012) |
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Medicine R Science Q Tara L Kieffer Sandra De Meyer Doug J Bartels James C Sullivan Eileen Z Zhang Ann Tigges Inge Dierynck Joan Spanks Jennifer Dorrian Min Jiang Bambang Adiwijaya Anne Ghys Maria Beumont Robert S Kauffman Nathalie Adda Ira M Jacobson Kenneth E Sherman Stefan Zeuzem Ann D Kwong Gaston Picchio Hepatitis C viral evolution in genotype 1 treatment-naïve and treatment-experienced patients receiving telaprevir-based therapy in clinical trials. |
| description |
<h4>Background</h4>In patients with genotype 1 chronic hepatitis C infection, telaprevir (TVR) in combination with peginterferon and ribavirin (PR) significantly increased sustained virologic response (SVR) rates compared with PR alone. However, genotypic changes could be observed in TVR-treated patients who did not achieve an SVR.<h4>Methods</h4>Population sequence analysis of the NS3•4A region was performed in patients who did not achieve SVR with TVR-based treatment.<h4>Results</h4>Resistant variants were observed after treatment with a telaprevir-based regimen in 12% of treatment-naïve patients (ADVANCE; T12PR arm), 6% of prior relapsers, 24% of prior partial responders, and 51% of prior null responder patients (REALIZE, T12PR48 arms). NS3 protease variants V36M, R155K, and V36M+R155K emerged frequently in patients with genotype 1a and V36A, T54A, and A156S/T in patients with genotype 1b. Lower-level resistance to telaprevir was conferred by V36A/M, T54A/S, R155K/T, and A156S variants; and higher-level resistance to telaprevir was conferred by A156T and V36M+R155K variants. Virologic failure during telaprevir treatment was more common in patients with genotype 1a and in prior PR nonresponder patients and was associated with higher-level telaprevir-resistant variants. Relapse was usually associated with wild-type or lower-level resistant variants. After treatment, viral populations were wild-type with a median time of 10 months for genotype 1a and 3 weeks for genotype 1b patients.<h4>Conclusions</h4>A consistent, subtype-dependent resistance profile was observed in patients who did not achieve an SVR with telaprevir-based treatment. The primary role of TVR is to inhibit wild-type virus and variants with lower-levels of resistance to telaprevir. The complementary role of PR is to clear any remaining telaprevir-resistant variants, especially higher-level telaprevir-resistant variants. Resistant variants are detectable in most patients who fail to achieve SVR, but their levels decline over time after treatment. |
| format |
article |
| author |
Tara L Kieffer Sandra De Meyer Doug J Bartels James C Sullivan Eileen Z Zhang Ann Tigges Inge Dierynck Joan Spanks Jennifer Dorrian Min Jiang Bambang Adiwijaya Anne Ghys Maria Beumont Robert S Kauffman Nathalie Adda Ira M Jacobson Kenneth E Sherman Stefan Zeuzem Ann D Kwong Gaston Picchio |
| author_facet |
Tara L Kieffer Sandra De Meyer Doug J Bartels James C Sullivan Eileen Z Zhang Ann Tigges Inge Dierynck Joan Spanks Jennifer Dorrian Min Jiang Bambang Adiwijaya Anne Ghys Maria Beumont Robert S Kauffman Nathalie Adda Ira M Jacobson Kenneth E Sherman Stefan Zeuzem Ann D Kwong Gaston Picchio |
| author_sort |
Tara L Kieffer |
| title |
Hepatitis C viral evolution in genotype 1 treatment-naïve and treatment-experienced patients receiving telaprevir-based therapy in clinical trials. |
| title_short |
Hepatitis C viral evolution in genotype 1 treatment-naïve and treatment-experienced patients receiving telaprevir-based therapy in clinical trials. |
| title_full |
Hepatitis C viral evolution in genotype 1 treatment-naïve and treatment-experienced patients receiving telaprevir-based therapy in clinical trials. |
| title_fullStr |
Hepatitis C viral evolution in genotype 1 treatment-naïve and treatment-experienced patients receiving telaprevir-based therapy in clinical trials. |
| title_full_unstemmed |
Hepatitis C viral evolution in genotype 1 treatment-naïve and treatment-experienced patients receiving telaprevir-based therapy in clinical trials. |
| title_sort |
hepatitis c viral evolution in genotype 1 treatment-naïve and treatment-experienced patients receiving telaprevir-based therapy in clinical trials. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/1dbcfc20320f40f0bb077dc356b2c9f4 |
| work_keys_str_mv |
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