title: Mediation Analysis of Hepatitis B and C in Relation to Hepatocellular Carcinoma Risk.
abstract: BACKGROUND
  Hepatitis B and C viruses are well-established risk factors for hepatocellular carcinoma (HCC) but their coordinated etiologic mechanism remains unclear. We aimed to assess the mediation effect of the two viruses on HCC risk.
  
  
  METHODS
  We conducted a prospective cohort study in Taiwan (R.E.V.E.A.L.-Hepatitis B Virus study), which included 3,851 participants seropositive for hepatitis B surface antigen and 278 incident HCC cases. Serum samples at enrollment or follow-up were tested for seromarkers and viral load of hepatitis B (HBV) and C (HCV). Mediation analyses for HCC risk were performed using Cox proportional hazards and linear regression models.
  
  
  RESULTS
  Among participants with chronic hepatitis B, the direct effect of anti-HCV serostatus (positive vs. negative) independent of HBV viral load was associated with increased risk of HCC with a hazard ratio (HR) of 2.5 (95% confidence interval [CI] = 1.7, 3.6), and the indirect effect mediated through suppressing HBV viral load decreased the HCC risk with an HR of 0.75 (95% CI = 0.67, 0.84). Opposite effects led to an attenuated marginal effect with an HR of 1.7 (95% CI = 1.2, 2.5). For an increase in HCV viral load from 800 to 404,000 IU/ml (minimum to median viral level), the HRs were 1.6 (95% CI = 1.2, 2.0) for the direct effect, 0.78 (95% CI = 0.72, 0.85) for the indirect effect, and 1.1 (95% CI = 0.89, 1.5) for the marginal effect.
  
  
  CONCLUSIONS
  The results support a suppressive effect of HCV on HCC risk mediated through HBV viral load and an adverse direct effect.
authors.affiliation: From the Departments of aEpidemiology, bBiostatistics, Brown University, Providence, RI; cGenomics Research Center, Academia Sinica, Taipei, Taiwan; and dInstitute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yen-Tsung
authors.initials: YT
authors.lastname: Huang
authors.forename: Hwai-I
authors.initials: HI
authors.lastname: Yang
authors.forename: Jessica
authors.initials: J
authors.lastname: Liu
authors.forename: Mei-Hsuan
authors.initials: MH
authors.lastname: Lee
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Freeman
authors.forename: Chien-Jen
authors.initials: CJ
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000821:virology*; D060085:Coinfection / Q000150:complications* / Q000821:virology; D005260:Female; D005500:Follow-Up Studies; D006509:Hepatitis B / Q000150:complications* / Q000821:virology; D006526:Hepatitis C / Q000150:complications* / Q000821:virology; D006801:Humans; D016014:Linear Models; D008113:Liver Neoplasms / Q000821:virology*; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D013624:Taiwan; D019562:Viral Load