title: Anti-HDV IgM as a marker of disease activity in hepatitis delta.
abstract: BACKGROUND
  Hepatitis delta frequently leads to liver cirrhosis and hepatic decompensation. As treatment options are limited, there is a need for biomarkers to determine disease activity and to predict the risk of disease progression. We hypothesized that anti-HDV IgM could represent such a marker.
  
  
  METHODS
  Samples of 120 HDV-infected patients recruited in an international multicenter treatment trial (HIDIT-2) were studied. Anti-HDV IgM testing was performed using ETI-DELTA-IGMK-2-assay (DiaSorin). In addition, fifty cytokines, chemokines and angiogenetic factors were measured using multiplex technology (Bio-Plex System). A second independent cohort of 78 patients was studied for the development of liver-related clinical endpoints (decompensation, HCC, liver transplantation or death; median follow up of 3.0 years, range 0.6-12).
  
  
  RESULTS
  Anti-HDV IgM serum levels were negative in 18 (15%), low (OD<0.5) in 76 (63%), and high in 26 (22%) patients of the HIDIT-2 cohort. Anti-HDV IgM were significantly associated with histological inflammatory (p<0.01) and biochemical disease activity (ALT, AST p<0.01). HDV replication was independent from anti-HDV IgM, however, low HBV-DNA levels were observed in groups with higher anti-HDV IgM levels (p<0.01). While high IP-10 (CXCL10) levels were seen in greater groups of anti-HDV IgM levels, various other antiviral cytokines were negatively associated with anti-HDV IgM. Associations between anti-HDV IgM and ALT, AST, HBV-DNA were confirmed in the independent cohort. Clinical endpoints occurred in 26 anti-HDV IgM positive patients (39%) but in only one anti-HDV IgM negative individual (9%; p = 0.05).
  
  
  CONCLUSIONS
  Serum anti-HDV IgM is a robust, easy-to-apply and relatively cheap marker to determine disease activity in hepatitis delta which has prognostic implications. High anti-HDV IgM levels may indicate an activated interferon system but exhausted antiviral immunity.
authors: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors: Anika
authors: A
authors: Wranke
authors: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany.
authors: Benjamin
authors: B
authors: Heidrich
authors: Institute for Biometry, Hannover Medical School, Hannover, Germany.
authors: Stefanie
authors: S
authors: Ernst
authors: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors: Beatriz
authors: B
authors: Calle Serrano
authors: Institutul de Boli Infectioase, Bucharest, Romania.
authors: Florin Alexandru
authors: FA
authors: Caruntu
authors: Spitalul Clinic de Boli Infectioase, Timisoara, Romania.
authors: Manuela Gabriela
authors: MG
authors: Curescu
authors: Dicle University Medical Faculty, Diyarbakir, Turkey.
authors: Kendal
authors: K
authors: Yalcin
authors: Uludağ University Medical Faculty, Bursa, Turkey.
authors: Selim
authors: S
authors: Gürel
authors: Johann Wolfgang Goethe University Medical Center, Frankfurt/Main, Germany.
authors: Stefan
authors: S
authors: Zeuzem
authors: Heinrich Heine University, Düsseldorf, Germany.
authors: Andreas
authors: A
authors: Erhardt
authors: University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors: Stefan
authors: S
authors: Lüth
authors: Athens University School of Medicine, Athens, Greece.
authors: George V
authors: GV
authors: Papatheodoridis
authors: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors: Birgit
authors: B
authors: Bremer
authors: Medical University of Vienna, Vienna, Austria.
authors: Judith
authors: J
authors: Stift
authors: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors: Jan
authors: J
authors: Grabowski
authors: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors: Janina
authors: J
authors: Kirschner
authors: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors: Kerstin
authors: K
authors: Port
authors: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors: Markus
authors: M
authors: Cornberg
authors: Institute of Transplant Immunology, IFB-Tx, Hannover Medical School, Hannover, Germany.
authors: Christine S
authors: CS
authors: Falk
authors: HepNet Study-House, Hannover, Germany.
authors: Hans-Peter
authors: HP
authors: Dienes
authors: HepNet Study-House, Hannover, Germany.
authors: Svenja
authors: S
authors: Hardtke
authors: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; HepNet Study-House, Hannover, Germany; Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany.
authors: Michael P
authors: MP
authors: Manns
authors: Ankara University Medical Faculty, Ankara, Turkey.
authors: Cihan
authors: C
authors: Yurdaydin
authors: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; HepNet Study-House, Hannover, Germany; Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Partner Side HepNet Study-House, Hannover, Germany.
authors: Heiner
authors: H
authors: Wedemeyer
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D060085:Coinfection; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006508:Hepatitis Antibodies / Q000097:blood / Q000276:immunology*; D019694:Hepatitis B, Chronic; D003699:Hepatitis D / Q000175:diagnosis* / Q000276:immunology* / Q000401:mortality / Q000821:virology; D019701:Hepatitis D, Chronic / Q000175:diagnosis / Q000276:immunology / Q000821:virology; D003698:Hepatitis Delta Virus / Q000276:immunology*; D006801:Humans; D007075:Immunoglobulin M / Q000097:blood / Q000276:immunology*; D008099:Liver / Q000276:immunology / Q000473:pathology / Q000821:virology; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D063868:Patient Outcome Assessment; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; D016207:Cytokines; D006508:Hepatitis Antibodies; D007075:Immunoglobulin M