A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma

Int J Cancer. 1998 Jan 30;75(3):347-54. doi: 10.1002/(sici)1097-0215(19980130)75:3<347::aid-ijc4>3.0.co;2-2.


The aim of the study was to assess whether co-infection by hepatitis-B virus (HBV) and hepatitis-C virus (HCV) is associated with a higher risk of developing hepatocellular carcinoma (HCC) than each infection alone. A meta-analysis of data published up to June 1997 was performed. HBsAg and anti-HCV antibodies or HCV RNA (anti-HCV/HCV RNA) were considered as serological markers of current HBV and HCV infection respectively. A total of 32 case-control studies were suitable for a quantitative overview. The summary odds ratios (OR) were 13.7 for HBsAg positivity and 11.5 for anti-HCV/HCV RNA positivity. The OR for anti-HCV was lower among studies using second- or third-generation anti-HCV or HCV RNA (OR, 8.2) with respect to studies with first-generation anti-HCV test (OR, 19.1). When combining data from the studies with second- or third-generation anti-HCV or HCV RNA, the OR for HBsAg positivity and anti-HCV/HCV RNA negativity was 22.5 (95% confidence interval (CI), 19.5-26.0), the OR for anti-HCV/HCV RNA positivity and HBsAg negativity was 17.3 (95% CI, 13.9-21.6), and the OR for both markers positivity was 165 (95% CI: 81.2-374, based on 191 cases and 8 controls exposed). A synergism was found between HBV and HCV infections, the OR for co-infection being greater than the sum and lower than the product of those for each infection alone. The interaction was therefore negative according to the multiplicative model, providing epidemiological evidence both of an independent effect and of interference between the 2 viruses in the carcinogenic process.

Publication types

  • Meta-Analysis

MeSH terms

  • Adult
  • Carcinoma, Hepatocellular / epidemiology*
  • Carcinoma, Hepatocellular / virology*
  • Case-Control Studies
  • Female
  • Hepacivirus* / genetics
  • Hepatitis B / complications*
  • Hepatitis B / epidemiology*
  • Hepatitis B Surface Antigens / analysis
  • Hepatitis B virus* / genetics
  • Hepatitis C / complications*
  • Hepatitis C / epidemiology*
  • Humans
  • Liver Neoplasms / epidemiology*
  • Liver Neoplasms / virology*
  • Male
  • Middle Aged
  • Polymerase Chain Reaction
  • RNA, Messenger / analysis
  • Risk Factors


  • Hepatitis B Surface Antigens
  • RNA, Messenger