title: An intrahepatic transcriptional signature of enhanced immune activity predicts response to peginterferon in chronic hepatitis B.
abstract: OBJECTIVE
  Differences in intrahepatic gene expression patterns may be associated with therapy response in peginterferon-treated chronic hepatitis B (CHB) patients.
  
  
  METHODS
  We employed gene expression profiling in baseline liver biopsies of 40 CHB patients (19 HBeAg-positive; 21 HBeAg-negative) treated with peginterferon and adefovir for 48 weeks, and compared expression patterns of combined responders (HBeAg loss, HBV-DNA <2000 IU/ml, alanine aminotransferase normalization after 1 year of treatment-free follow-up) with non-responders. Genes identified by transcriptome analysis in 15 biopsies were confirmed in 25 additional biopsies by RT-qPCR.
  
  
  RESULTS
  Transcriptome analysis demonstrated significant differences in expression of 41 genes between responders and non-responders. In responders, pathway analysis showed specific upregulation of genes related to the immune response, including chemotaxis and antigen processing and presentation. Genes upregulated in responders exhibited strongest similarity with a set of genes induced in livers of chimpanzees with acute Hepatitis B infection. Differential expression was confirmed for eight selected genes. A 2-gene subset (HLA-DPB1, SERPIN-E1) was found to predict response most accurately. Incorporation of these genes in a multivariable model with HBeAg status, HBV genotype and baseline HBsAg level correctly classified 90% of all patients, in which HLA-DPB1 and SERPIN-E1 were independent predictors of response.
  
  
  CONCLUSIONS
  We identified an intrahepatic transcriptional signature associated with enhanced immune activation which predicts therapy response. These novel associations could lead to better understanding of responsiveness to peginterferon in CHB patients, and may assist in selecting possible responders to interferon-based treatment.
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center (AMC), University of Amsterdam (UvA), Amsterdam, The Netherlands.|Department of Experimental Immunology, AMC, Amsterdam, The Netherlands.
authors.forename: Louis
authors.identifier: http://orcid.org/0000-0002-3371-7492
authors.initials: L
authors.lastname: Jansen
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center (AMC), University of Amsterdam (UvA), Amsterdam, The Netherlands.|Department of Experimental Immunology, AMC, Amsterdam, The Netherlands.
authors.forename: Annikki
authors.initials: A
authors.lastname: de Niet
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Zuzanna
authors.initials: Z
authors.lastname: Makowska
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Dill
authors.affiliation: Department of Experimental Immunology, AMC, Amsterdam, The Netherlands.
authors.forename: Karel A
authors.initials: KA
authors.lastname: van Dort
authors.affiliation: Department of Pathology, Bronovo Hospital, The Hague, The Netherlands.
authors.forename: Valeska
authors.initials: V
authors.lastname: Terpstra
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center (AMC), University of Amsterdam (UvA), Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Bart Takkenberg
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.|Liver Clinic, Toronto Western and General Hospital University Health Network, Toronto, Canada.
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Markus H
authors.initials: MH
authors.lastname: Heim
authors.affiliation: Department of Experimental Immunology, AMC, Amsterdam, The Netherlands.
authors.forename: Neeltje A
authors.initials: NA
authors.lastname: Kootstra
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center (AMC), University of Amsterdam (UvA), Amsterdam, The Netherlands.|Department of Experimental Immunology, AMC, Amsterdam, The Netherlands.
authors.forename: Hendrik W
authors.initials: HW
authors.lastname: Reesink
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D001706:Biopsy; D016009:Chi-Square Distribution; D004359:Drug Therapy, Combination; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D005819:Genetic Markers; D019694:Hepatitis B, Chronic / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000821:virology; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020411:Oligonucleotide Array Sequence Analysis; D063065:Organophosphonates / Q000627:therapeutic use; D018579:Patient Selection; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D057285:Precision Medicine; D011237:Predictive Value of Tests; D011994:Recombinant Proteins / Q000627:therapeutic use; D015203:Reproducibility of Results; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D005819:Genetic Markers; D016898:Interferon-alpha; D063065:Organophosphonates; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D000225:Adenine; C100416:peginterferon alfa-2a; C106812:adefovir dipivoxil
keywords: adefovir; chronic hepatitis B; combined response; gene expression; liver biopsy; microarray; peginterferon alfa-2a; response marker