Emergence of resistance-associated variants after failed triple therapy with vaniprevir in treatment-experienced non-cirrhotic patients with hepatitis C-genotype 1 infection: a population and clonal analysis.

Abstract

BACKGROUND:

Vaniprevir with P/R improved SVR rates over P/R alone in treatment-experienced patients with chronic HCV-genotype 1 infection, but treatment failure presents therapeutic challenges. We identified RAVs from non-cirrhotic patients failing to achieve SVR on vaniprevir-containing regimens from a dose/duration-ranging trial of triple-combination therapy.

METHODS:

Using population analysis, resistance sequencing was performed on all baseline samples and on samples at virologic failure in the vaniprevir arms. Longitudinal clonal analyses were performed on viral isolates from six vaniprevir recipients experiencing breakthrough viremia.

RESULTS:

Baseline RAVs were detected in two patients subsequently experiencing virologic failure. At virologic failure, the majority of RAVs had substitutions at R155, A156, or D168. Clonal analyses identified novel double/triple variants emerging with continuing vaniprevir dosing.

CONCLUSIONS:

RAVs were predominantly observed at R155, A156, and/or D168 during virologic failure on vaniprevir/P/R. Double/triple RAVs were identified in patients remaining viremic on triple therapy, suggesting evolution of resistance under selective pressure.

• Authors: Richard J O Barnard, Carolyn M McHale, William Newhard, Carol A Cheney, Donald J Graham, Amy L Himmelberger, Julie Strizki, Peggy M T Hwang, Amber A Rivera, Jacqueline D Reeves, David Nickle, Mark J Dinubile, Daria J Hazuda, Niloufar Mobashery
• Journal: Virology (Virology) Vol. 443 Issue 2 Pg. 278-84 (Sep 01 2013) ISSN: 1096-0341 [Electronic] United States
• PMID: 23763767 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Antiviral Agents
• Cyclopropanes
• Indoles
• Isoindoles
• Lactams, Macrocyclic
• RNA, Viral
• Sulfonamides
• Polyethylene Glycols
• Ribavirin
• Proline
• vaniprevir
• Peptide Hydrolases
• Leucine

Topics

• Adolescent
• Adult
• Aged
• Amino Acid Substitution
• Antiviral Agents (administration & dosage, pharmacology, therapeutic use)
• Cyclopropanes
• Double-Blind Method
• Drug Resistance, Viral (genetics)
• Drug Therapy, Combination
• Female
• Genetic Variation
• Genotype
• Hepacivirus (classification, drug effects, genetics)
• Hepatitis C, Chronic (drug therapy, virology)
• Humans
• Indoles (administration & dosage, pharmacology, therapeutic use)
• Isoindoles
• Lactams, Macrocyclic
• Leucine (analogs & derivatives)
• Male
• Middle Aged
• Peptide Hydrolases (genetics)
• Polyethylene Glycols (administration & dosage, pharmacology, therapeutic use)
• Proline (analogs & derivatives)
• RNA, Viral (genetics)
• Ribavirin (administration & dosage, pharmacology, therapeutic use)
• Sulfonamides
• Treatment Failure
• Treatment Outcome
• Viremia (drug therapy, virology)
• Young Adult