Chronic hepatitis D and hepatocellular carcinoma: A systematic review and meta-analysis of observational studies

J Hepatol. 2020 Sep;73(3):533-539. doi: 10.1016/j.jhep.2020.02.030. Epub 2020 Mar 6.


Background & aims: Chronic hepatitis D (CHD) is the most severe form of chronic viral hepatitis but its role in the development of hepatocellular carcinoma (HCC) remains debated. We conducted a systematic review and meta-analysis of epidemiological studies to examine whether CHD is associated with an increased risk of HCC.

Methods: We searched PubMed, Embase and Web of Science, as well as study references and conference proceedings. We considered cohort and case-control studies allowing the calculation of effect estimates for the association between CHD (exposure) and HCC (outcome) in comparison to chronic hepatitis B. Data extraction and quality evaluation (using the Newcastle-Ottawa scale) were performed independently by 2 authors. Data were pooled using random-effects models.

Results: Ninety-three studies (68 case-control studies including 22,862 patients and 25 cohort studies including 75,427 patients) were included. Twelve studies accounted for confounders, in either study design or analysis (10 of which were cohorts), and 11 cohorts were prospective. The overall analysis showed a significantly increased risk of HCC in patients with CHD, despite substantial study heterogeneity (pooled odds ratio 1.28; 95% CI 1.05-1.57; I2 = 67.0%). The association was particularly strong in the absence of heterogeneity for prospective cohort studies (pooled odds ratio 2.77; 95% CI 1.79-4.28; I2 = 0%), and studies with HIV-infected patients (pooled odds ratio 7.13; 95% CI 2.83-17.92; I2 = 0%).

Conclusions: We found a significantly higher risk of HCC in patients with CHD. Although further studies are needed to definitively exclude a potential bias due to antiviral treatments, our findings highlight the rationale for improved screening of hepatitis D virus infection in patients with chronic hepatitis B, and the urgent need for novel and effective antiviral therapies.

Lay summary: Hepatitis D virus (HDV) is a defective pathogen requiring hepatitis B virus (HBV) to complete its life cycle. Chronic hepatitis D is the most severe form of chronic viral hepatitis, increasing the risk of cirrhosis, liver decompensation and death compared to HBV monoinfection. However, the association between HDV infection and increased risk of hepatocellular carcinoma is debated. We conducted a systematic review and found that patients with HDV infection had a significantly higher risk of developing hepatocellular carcinoma than those with HBV monoinfection.

Keywords: Antivirals; Coinfection; HCC; Hepatitis B virus; Hepatitis D virus.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma, Hepatocellular / diagnosis
  • Carcinoma, Hepatocellular / virology*
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Coinfection / complications*
  • Coinfection / virology
  • Female
  • Hepatitis B virus*
  • Hepatitis B, Chronic / complications*
  • Hepatitis B, Chronic / virology
  • Hepatitis D, Chronic / complications*
  • Hepatitis D, Chronic / virology
  • Hepatitis Delta Virus*
  • Humans
  • Infant
  • Liver Neoplasms / diagnosis
  • Liver Neoplasms / virology*
  • Male
  • Middle Aged
  • Observational Studies as Topic
  • Prospective Studies
  • Risk Factors
  • Young Adult