Hepatitis C viral evolution in genotype 1 treatment-naïve and treatment-experienced patients receiving telaprevir-based therapy in clinical trials
BACKGROUND: 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.
METHODS: Population sequence analysis of the NS3•4A region was performed in patients who did not achieve SVR with TVR-based treatment.
RESULTS: 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.
CONCLUSIONS: 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2012 |
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| Erschienen: |
2012 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:7 |
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| Enthalten in: |
PloS one - 7(2012), 4 vom: 01., Seite e34372 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kieffer, Tara L [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 28.12.2012 Date Revised 18.03.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1371/journal.pone.0034372 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM217090907 |
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| 100 | 1 | |a Kieffer, Tara L |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Hepatitis C viral evolution in genotype 1 treatment-naïve and treatment-experienced patients receiving telaprevir-based therapy in clinical trials |
| 264 | 1 | |c 2012 | |
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| 500 | |a Date Completed 28.12.2012 | ||
| 500 | |a Date Revised 18.03.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a BACKGROUND: 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 | ||
| 520 | |a METHODS: Population sequence analysis of the NS3•4A region was performed in patients who did not achieve SVR with TVR-based treatment | ||
| 520 | |a RESULTS: 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 | ||
| 520 | |a CONCLUSIONS: 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
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| 650 | 7 | |a Oligopeptides |2 NLM | |
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| 650 | 7 | |a Polyethylene Glycols |2 NLM | |
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| 700 | 1 | |a Bartels, Doug J |e verfasserin |4 aut | |
| 700 | 1 | |a Sullivan, James C |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Eileen Z |e verfasserin |4 aut | |
| 700 | 1 | |a Tigges, Ann |e verfasserin |4 aut | |
| 700 | 1 | |a Dierynck, Inge |e verfasserin |4 aut | |
| 700 | 1 | |a Spanks, Joan |e verfasserin |4 aut | |
| 700 | 1 | |a Dorrian, Jennifer |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Min |e verfasserin |4 aut | |
| 700 | 1 | |a Adiwijaya, Bambang |e verfasserin |4 aut | |
| 700 | 1 | |a Ghys, Anne |e verfasserin |4 aut | |
| 700 | 1 | |a Beumont, Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Kauffman, Robert S |e verfasserin |4 aut | |
| 700 | 1 | |a Adda, Nathalie |e verfasserin |4 aut | |
| 700 | 1 | |a Jacobson, Ira M |e verfasserin |4 aut | |
| 700 | 1 | |a Sherman, Kenneth E |e verfasserin |4 aut | |
| 700 | 1 | |a Zeuzem, Stefan |e verfasserin |4 aut | |
| 700 | 1 | |a Kwong, Ann D |e verfasserin |4 aut | |
| 700 | 1 | |a Picchio, Gaston |e verfasserin |4 aut | |
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