title: Telaprevir-based treatment effects on hepatitis C virus in liver and blood.
abstract: Understanding hepatitis C virus (HCV) replication has been limited by access to serial samples of liver, the primary site of viral replication. Our understanding of how HCV replicates and develops drug-resistant variants in the liver is limited. We studied 15 patients chronically infected with genotype 1 HCV treated with telaprevir (TVR)/pegylated-interferon alpha/ribavirin. Hepatic fine needle aspiration was performed before treatment and at hour 10, days 4 and 15, and week 8 after initiation of antiviral therapy. We measured viral kinetics, resistance patterns, TVR concentrations, and host transcription profiles. All patients completed all protocol-defined procedures that were generally well tolerated. First-phase HCV decline (baseline/treatment day 4) was significantly slower in liver than in plasma (slope plasma: -0.29; liver, -0.009; P < 0.001), whereas second-phase decline (posttreatment days 4-15) did not differ between the two body compartments (-0.11 and -0.15, respectively; P = 0.1). TVR-resistant variants were detected in plasma, but not in liver (where only wild-type virus was detected). Based upon nonstructural protein 3 sequence analysis, no compartmentalization of viral populations was observed between plasma and liver compartments. Gene expression profiling revealed strong tissue-specific expression signatures. Human intrahepatic TVR concentration, measured for the first time, was lower, compared to plasma, on a gram per milliliter basis. We found moderate heterogeneity between HCV RNA levels from different intrahepatic sites, indicating differences in hepatic microenvironments.
  
  
  CONCLUSIONS
  These data support an integrated model for HCV replication wherein the host hepatic milieu and innate immunity control the level of viral replication, and the early antiviral response observed in the plasma is predominantly driven by inhibition of hepatic high-level HCV replication sites.
authors.affiliation: Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY; Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, State University of New York at Buffalo, Buffalo, NY.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Talal
authors.forename: Rositsa B
authors.initials: RB
authors.lastname: Dimova
authors.forename: Eileen Z
authors.initials: EZ
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
authors.forename: Marina S
authors.initials: MS
authors.lastname: Penney
authors.forename: James C
authors.initials: JC
authors.lastname: Sullivan
authors.forename: Martyn C
authors.initials: MC
authors.lastname: Botfield
authors.forename: Ananthsrinivas
authors.initials: A
authors.lastname: Chakilam
authors.forename: Rishikesh
authors.initials: R
authors.lastname: Sawant
authors.forename: Christine M
authors.initials: CM
authors.lastname: Cervini
authors.forename: Marija
authors.initials: M
authors.lastname: Zeremski
authors.forename: Ira M
authors.initials: IM
authors.lastname: Jacobson
authors.forename: Ann D
authors.initials: AD
authors.lastname: Kwong
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D044963:Biopsy, Fine-Needle; D024882:Drug Resistance, Viral; D005260:Female; D015870:Gene Expression; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000821:virology*; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009842:Oligopeptides / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010802:Phylogeny; D012367:RNA, Viral / Q000097:blood*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D009842:Oligopeptides; D012367:RNA, Viral; C486464:telaprevir