TY  - JOUR
A1  - Kieffer, Tara L.
A1  - De Meyer, Sandra
A1  - Bartels, Doug J.
A1  - Sullivan, James C.
A1  - Zhang, Eileen Z.
A1  - Tigges, Ann
A1  - Dierynck, Inge
A1  - Spanks, Joan
A1  - Dorrian, Jennifer
A1  - Jiang, Min
A1  - Adiwijaya, Bambang
A1  - Ghys, Anne
A1  - Beumont, Maria
A1  - Kauffman, Robert S.
A1  - Adda, Nathalie
A1  - Jacobson, Ira M.
A1  - Sherman, Kenneth E.
A1  - Zeuzem, Stefan
A1  - Kwong, Ann D.
A1  - Picchio, Gaston
T1  - Hepatitis C viral evolution in genotype 1 treatment-naïve and treatment-experienced patients receiving telaprevir-based therapy in clinical trials
T2  - PLoS One
N2  - 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.
Y1  - 2012
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/24292
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-242929
SN  - 1932-6203
VL  - 7
IS  - (4):e34372
SP  - 1
EP  - 12
PB  - PLoS
CY  - Lawrence, Kan.
ER  -