title: Circulating programmed death-1 as a marker for sustained high hepatitis B viral load and risk of hepatocellular carcinoma.
abstract: OBJECTIVE
  Recent evidence indicates a crucial role of the immunoinhibitory receptor programmed death-1 (PD-1) in enforcing T-cell dysfunction during chronic viral infection and cancer. We assessed the impact of circulating soluble PD-1 (sPD-1) levels on long-term dynamics of hepatitis B virus (HBV) load and hepatocellular carcinoma (HCC) risk.
  
  
  METHODS
  In a case-cohort study on longitudinal analysis of viral load within a cohort of 2903 men chronically infected with HBV, followed up from baseline (1989-1992) through 2010, we determined sPD-1 levels in baseline plasma with enzyme-linked immunosorbent assay from 126 men who subsequently developed HCC and 1155 men who did not develop HCC. To evaluate whether patients' characteristics involved the use of sPD-1 as a biomarker, sPD-1 was also tested in 614 newly-diagnosed patients with HBV-related HCC recruited from a multicenter study for comparison with the 1155 noncases in the case-cohort study.
  
  
  RESULTS
  Plasma quartile levels of sPD-1 were positively associated with HCC risk for men in the case-cohort analysis (vs. quartile 1: adjusted odds ratios [95% confidence intervals] for quartile 2-quartile 4 were 1.51 [0.75-3.03], 2.15 [1.12-4.13], and 2.29 [1.20-4.38], respectively), and in the case-control study regardless of age-of-onset and clinical stage. Furthermore, we found longitudinal effect of elevated sPD-1 levels to maintain higher viral load for 4 or more years, with greater and more prolonged effect among HBV genotype C- vs. non-C-infected participants. High levels of viral load and sPD-1 (vs. absence of both) was associated with a 6.29-fold increase in risk of HCC, and combining both conditions with HBV genotype C yielded an odds ratio of 30.47 with significant additive interaction (relative excess risk due to interaction: 27.08 [95% confidence interval = 8.76-45.41]).
  
  
  CONCLUSIONS
  Our data suggest plasma sPD-1 as an important immune-related marker for assessment of HBV activity and HCC risk.
authors.affiliation: Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
authors.forename: Hsiang-Yun
authors.initials: HY
authors.lastname: Cheng
authors.affiliation: Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
authors.forename: Pei-Jen
authors.initials: PJ
authors.lastname: Kang
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Chuang
authors.affiliation: Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
authors.forename: Meng-Chin
authors.initials: MC
authors.lastname: Jan
authors.affiliation: Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
authors.forename: Chih-Feng
authors.initials: CF
authors.lastname: Wu
authors.affiliation: Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan.
authors.forename: Chih-Lin
authors.initials: CL
authors.lastname: Lin
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Chun-Jen
authors.initials: CJ
authors.lastname: Liu
authors.affiliation: Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.
authors.forename: Yun-Fan
authors.initials: YF
authors.lastname: Liaw
authors.affiliation: Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.
authors.forename: Shi-Ming
authors.initials: SM
authors.lastname: Lin
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Pei-Jer
authors.initials: PJ
authors.lastname: Chen
authors.affiliation: Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Cheng Hsin General Hospital, Taipei, Taiwan.
authors.forename: Shou-Dong
authors.initials: SD
authors.lastname: Lee
authors.affiliation: Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
authors.forename: Ming-Whei
authors.initials: MW
authors.lastname: Yu
mesh_terms: D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000209:etiology / Q000821:virology*; D016022:Case-Control Studies; D015331:Cohort Studies; D006515:Hepatitis B virus / Q000302:isolation & purification* / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000150:complications* / Q000175:diagnosis; D006801:Humans; D008113:Liver Neoplasms / Q000097:blood / Q000209:etiology / Q000821:virology*; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000097:blood*; D012307:Risk Factors; D019562:Viral Load
chemical_list: C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor