title: Intrahepatic IP-10 mRNA and plasma IP-10 levels as response marker for HBeAg-positive chronic hepatitis B patients treated with peginterferon and adefovir.
abstract: Interferon-y-inducible protein-10 (IP-10), also called CXCL10, is produced by different types of cells such as monocytes, neutrophils and hepatocytes. IP-10 functions as an inflammatory cytokine, which after binding to its receptor CXCR3, expressed on T-lymphocytes, leads to immune activation. We aimed to establish if IP-10 expression in liver tissue and in plasma of chronic hepatitis B (CHB) patients correlated with each other and further to investigate if IP-10 levels before and during therapy with peginterferon and adefovir could predict treatment outcome in CHB patients.
  
  
  
  A total of 86 CHB patients (41 HBeAg-positive and 45 HBeAg-negative) received combination therapy of peginterferon and adefovir for 48 weeks. Combined Response (CR) (HBeAg-negativity, HBV-DNA ≤ 2000 IU/mL, ALT normalization) and non-response (NR) were assessed at Week 72. Plasma IP-10 levels were measured at baseline and during treatment at Day 3 (D3) and Week 1 (W1). Pre-treatment liver biopsies from 40 of 86 patients were obtained and stored in liquid nitrogen for the analysis of intrahepatic IP-10 mRNA expression.
  
  
  
  CR was achieved in 14/41 HBeAg-positive and 17/45 HBeAg-negative patients. Mean baseline plasma IP-10 levels were significantly higher in HBeAg-positive patients with CR than NR (3.20 vs 3.00 log pg/mL p = 0.03); but not in HBeAg-negative patients. Baseline IP-10 levels correlated with ALT-levels in HBeAg-positive and -negative patients (both p < 0.001), and with a decline of HBsAg-levels of ≥0.5 log IU/mL at Week 12 in HBeAg-positive patients (p = 0.001). Plasma IP-10 levels were associated with intrahepatic IP-10 mRNA expression, however, more strongly in HBeAg-positive (R = 0.79, p < 0.001) than in HBeAg-negative patients (R = 0.53, p = 0.011). IP-10 levels only correlated with HAI-scores in HBeAg-positive patients (R = 0.40 p = 0.025). Mean plasma IP-10 levels of both HBeAg-positive and -negative patients increased significantly at D3 compared to baseline (+0.30 log pg/mL p = 0.003), to then decline subsequently at W1 to a level still significantly higher than baseline (+0.14 log pg/mL p < 0.001). The increase of IP-10 was significantly higher in HBeAg-positive patients with NR than in those with CR (+0.35 versus +0.11 log pg/mL p = 0.003).
  
  
  
  Baseline plasma IP-10 levels and IP-10 mRNA expression in the liver are correlated with each other, suggesting that plasma IP-10 reflects intrahepatic immune activation. Higher IP-10 levels at baseline seem to be associated with CR in HBeAg-positive patients treated with peginterferon and adefovir, but not in HBeAg-negative patients.
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, The Netherlands. Electronic address: s.b.willemse@amc.uva.nl.
authors.forename: S B
authors.initials: SB
authors.lastname: Willemse
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Jansen
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: de Niet
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, The Netherlands; Department of Experimental Immunology, Academic Medical Center, The Netherlands.
authors.forename: M J
authors.initials: MJ
authors.lastname: Sinnige
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, The Netherlands.
authors.forename: R B
authors.initials: RB
authors.lastname: Takkenberg
authors.affiliation: Department of Pathology, Academic Medical Center, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Verheij
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, The Netherlands.
authors.forename: N A
authors.initials: NA
authors.lastname: Kootstra
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, The Netherlands.
authors.forename: H W
authors.initials: HW
authors.lastname: Reesink
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000998:Antiviral Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis / Q000097:blood; D001706:Biopsy; D054357:Chemokine CXCL10 / Q000097:blood* / Q000235:genetics*; D004279:DNA, Viral / Q000097:blood; D004359:Drug Therapy, Combination; D005260:Female; D006513:Hepatitis B e Antigens / Q000097:blood; D019694:Hepatitis B, Chronic / Q000188:drug therapy / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D008099:Liver / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011446:Prospective Studies; D012333:RNA, Messenger; D011994:Recombinant Proteins / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D004279:DNA, Viral; D006513:Hepatitis B e Antigens; D016898:Interferon-alpha; D063065:Organophosphonates; D012333:RNA, Messenger; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C053001:adefovir; D000410:Alanine Transaminase; D000225:Adenine; C100416:peginterferon alfa-2a
keywords: Adefovir; Combination therapy; HBV; Interferon-gamma-inducible protein-10 (IP-10); Intrahepatic IP-10 mRNA expression; Peginterferon