title: Comprehensive analysis for viral elements and interleukin-28B polymorphisms in response to pegylated interferon plus ribavirin therapy in hepatitis C virus 1B infection.
abstract: To comprehensively characterize the contribution of virological factors as well as interleukin-28B (IL28B) single-nucleotide polymorphisms (SNPs) in determining treatment responses in pegylated-interferon plus ribavirin (Peg-IFN/RBV) therapy for chronic hepatitis C virus (HCV)-1b infection, we undertook a retrospective cohort analysis for the pretreatment dominant complete HCV open reading frame (ORF) amino-acid (aa) sequence study in 103 consecutive HCV-1b Japanese patients. The dominant HCV sequences classified by the response were subjected to systematic sliding-window comparison analysis to characterize response-specific viral sequences, along with IL28B SNP analyses (rs8099917). In each comparison of the patients between with and without rapid viral response (RVR), nonearly viral response (nEVR), sustained virological response (SVR), or relapse, the following regions were extracted as most significantly associated with the different responses respectively: nonstructural protein 5A (NS5A) aa.2224-2248 (P = 1.2E-07); core aa.70 (P = 4E-04); NS5A aa.2340-2382 (P = 7.0E-08); and NS5A aa.2360-2377 (P = 1.1E-05). Those NS5A regions nearly coincided with the interferon (IFN) sensitivity-determining region (NS5A aa.2209-2248) and the IFN/RBV resistance-determining region (NS5A aa.2339-2379). In a multivariate analysis, the IL28B SNP (odds ratio [OR] = 16.8; P = 0.009) and NS5A aa.2340-2382 (OR = 13.8; P = 0.0003) were extracted as the two most-significant independent variables contributing to the final outcome.
  
  
  CONCLUSIONS
  In Peg-IFN/RBV therapy, polymorphisms in IL28B, NS5A aa.2224-2248, core aa.70, and, most important, NS5A aa.2340-2382 have a tremendous influence on treatment response in association with viral kinetics, resulting in significantly different outcomes in chronic HCV-1b infection.
authors.affiliation: Department of Advanced Medicine for Liver Diseases, University of Yamanashi, Yamanashi, Japan. maekawa@yamanashi.ac.jp
authors.forename: Shinya
authors.initials: S
authors.lastname: Maekawa
authors.forename: Minoru
authors.initials: M
authors.lastname: Sakamoto
authors.forename: Mika
authors.initials: M
authors.lastname: Miura
authors.forename: Makoto
authors.initials: M
authors.lastname: Kadokura
authors.forename: Ryota
authors.initials: R
authors.lastname: Sueki
authors.forename: Kazuki
authors.initials: K
authors.lastname: Komase
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shindo
authors.forename: Nobutoshi
authors.initials: N
authors.lastname: Komatsu
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Shindo
authors.forename: Asuka
authors.initials: A
authors.lastname: Kanayama
authors.forename: Takako
authors.initials: T
authors.lastname: Ohmori
authors.forename: Fumitake
authors.initials: F
authors.lastname: Amemiya
authors.forename: Shinichi
authors.initials: S
authors.lastname: Takano
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nakayama
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Kitamura
authors.forename: Taisuke
authors.initials: T
authors.lastname: Inoue
authors.forename: Shunichi
authors.initials: S
authors.lastname: Okada
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Enomoto
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000998:Antiviral Agents / Q000627:therapeutic use*; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D007372:Interferons / Q000627:therapeutic use; D007378:Interleukins / Q000235:genetics*; D007564:Japan; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D016366:Open Reading Frames; D011092:Polyethylene Glycols / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D012008:Recurrence; D012189:Retrospective Studies; D012254:Ribavirin / Q000627:therapeutic use; D016896:Treatment Outcome; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D000095022:Interferon Lambda; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D007372:Interferons; D007378:Interleukins; D011092:Polyethylene Glycols; D012254:Ribavirin; D017361:Viral Nonstructural Proteins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase