Ultradeep sequencing study of chronic hepatitis C virus genotype 1 infection in patients treated with daclatasvir, peginterferon, and ribavirin.

Abstract

Direct-acting antivirals (DAAs) are either part of the current standard of care or are in advanced clinical development for the treatment of patients chronically infected with hepatitis C virus (HCV) genotype 1, but concern exists with respect to the patients who fail these regimens with emergent drug-resistant variants. In the present study, ultradeep sequencing was performed to analyze resistance to daclatasvir (DCV), which is a highly selective nonstructural protein 5A (NS5A) inhibitor. Eight patients with HCV genotype 1b, who were either treatment naive or prior nonresponders to pegylated interferon plus ribavirin (Rebetol; Schering-Plough) (PEG-IFN/RBV) therapy, were treated with DCV combined with PEG-IFN alpha-2b (Pegintron; Schering-Plough, Kenilworth, NJ) and RBV. To identify the cause of viral breakthrough, the preexistence and emergence of DCV-resistant variants at NS5A amino acids were analyzed by ultradeep sequencing. Sustained virological response (SVR) was achieved in 6 of 8 patients (75%), with viral breakthrough occurring in the other 2 patients (25%). DCV-resistant variant Y93H preexisted as a minor population at higher frequencies (0.1% to 0.5%) in patients who achieved SVR. In patients with viral breakthrough, DCV-resistant variant mixtures emerged at NS5A-31 over time that persisted posttreatment with Y93H. Although enrichment of DCV-resistant variants was detected, the preexistence of a minor population of the variant did not appear to be associated with virologic response in patients treated with DCV/PEG-IFN/RBV. Ultradeep sequencing results shed light on the complexity of DCV-resistant quasispecies emerging over time, suggesting that multiple resistance pathways are possible within a patient who does not rapidly respond to a DCV-containing regimen. (This study has been registered at ClinicalTrials.gov under registration no. NCT01016912.).

• Authors: Eisuke Murakami, Michio Imamura, C Nelson Hayes, Hiromi Abe, Nobuhiko Hiraga, Yoji Honda, Atsushi Ono, Keiichi Kosaka, Tomokazu Kawaoka, Masataka Tsuge, Hiroshi Aikata, Shoichi Takahashi, Daiki Miki, Hidenori Ochi, Hirotaka Matsui, Akinori Kanai, Toshiya Inaba, Fiona McPhee, Kazuaki Chayama
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 58 Issue 4 Pg. 2105-12 ( 2014) ISSN: 1098-6596 [Electronic] United States
• PMID: 24468783 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Carbamates
• Imidazoles
• Interferon alpha-2
• Interferon-alpha
• Pyrrolidines
• Recombinant Proteins
• Polyethylene Glycols
• Ribavirin
• peginterferon alfa-2b
• Valine
• daclatasvir

Topics

• Adult
• Aged
• Antiviral Agents (therapeutic use)
• Carbamates
• Drug Therapy, Combination
• Female
• Genotype
• Hepacivirus (drug effects, genetics)
• Hepatitis C, Chronic (drug therapy, virology)
• Humans
• Imidazoles (therapeutic use)
• Interferon alpha-2
• Interferon-alpha (therapeutic use)
• Male
• Middle Aged
• Polyethylene Glycols (therapeutic use)
• Pyrrolidines
• Recombinant Proteins (therapeutic use)
• Ribavirin (therapeutic use)
• Valine (analogs & derivatives)