Hepatitis C viral evolution in genotype 1 treatment-naïve and treatment-experienced patients receiving telaprevir-based therapy in clinical trials.

Abstract

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.

• Authors: 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
• Journal: PloS one (PLoS One) Vol. 7 Issue 4 Pg. e34372 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22511937 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antiviral Agents
• Oligopeptides
• Recombinant Proteins
• Polyethylene Glycols
• Ribavirin
• telaprevir
• Interferons

Topics

• Antiviral Agents (administration & dosage, therapeutic use)
• Clinical Trials, Phase II as Topic
• Clinical Trials, Phase III as Topic
• Drug Resistance, Viral (genetics)
• Drug Therapy, Combination
• Evolution, Molecular
• Genotype
• Hepacivirus (genetics)
• Hepatitis C, Chronic (drug therapy, virology)
• Humans
• Interferons (administration & dosage, therapeutic use)
• Oligopeptides (administration & dosage, therapeutic use)
• Polyethylene Glycols (administration & dosage, therapeutic use)
• Recombinant Proteins (administration & dosage, therapeutic use)
• Ribavirin (administration & dosage, therapeutic use)
• Treatment Outcome