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

  • Author Footnotes
    † Current affiliation: Department of Infectious Diseases, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France.
    Dulce Alfaiate
    Footnotes
    † Current affiliation: Department of Infectious Diseases, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France.
    Affiliations
    Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
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  • Sophie Clément
    Affiliations
    Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland
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  • Diana Gomes
    Affiliations
    Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
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  • Author Footnotes
    ‡ Equal contribution.
    Nicolas Goossens
    Footnotes
    ‡ Equal contribution.
    Affiliations
    Division of Gastroenterology and Hepatology, Geneva University Hospitals, Geneva, Switzerland
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  • Author Footnotes
    ‡ Equal contribution.
    Francesco Negro
    Correspondence
    Corresponding author. Address: Divisions of Gastroenterology and Hepatology and Clinical Pathology, Geneva University Hospitals, 4 Rue Gabrielle-Perret-Gentil, 1211 Geneva 14, Switzerland. Tel.: +41 22 3729355; fax: +41 22 3729366.
    Footnotes
    ‡ Equal contribution.
    Affiliations
    Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland

    Division of Gastroenterology and Hepatology, Geneva University Hospitals, Geneva, Switzerland
    Search for articles by this author
  • Author Footnotes
    † Current affiliation: Department of Infectious Diseases, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France.
    ‡ Equal contribution.
Published:March 06, 2020DOI:https://doi.org/10.1016/j.jhep.2020.02.030

      Highlights

      • HDV infection is associated with an increased risk of HCC in HBV-infected patients.
      • The association is stronger in high quality and/or prospective cohort studies.
      • The association between HDV and HCC is stronger in the setting of HIV coinfection.

      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.

      Graphical abstract

      Keywords

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      Linked Article

      • Cirrhotic controls in a pooled analysis of hepatitis D and hepatocellular carcinoma
        Journal of HepatologyVol. 73Issue 6
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          The role of HDV infection in hepatocarcinogenesis remains a topic of debate and HDV is currently considered “not classifiable as to its carcinogenicity to humans” by the International Agency for Research on Cancer.1 Relatively few HBV carriers are coinfected with HDV,2 therefore, single studies on HDV and hepatocellular carcinoma (HCC) are often underpowered to assess this association.3 In such situations, a meta-analysis or pooled analysis may be useful. A meta-analysis combines weighted association estimates (e.g.
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      • Reply to: “Cirrhotic controls in a pooled analysis of hepatitis D and hepatocellular carcinoma”
        Journal of HepatologyVol. 73Issue 6
        • Preview
          We appreciate Argirion et al.'s interest on our paper. We agree that the overall odds ratio of 1.28 underestimates the real impact of HDV superinfection on oncogenesis. We would like to point out, however, that this figure is the consequence of including a great deal of studies of weak quality. When the data quality is assured by a robust study design – such as in prospective cohort studies – the OR is significantly increased, suggesting that HDV may indeed be a potent carcinogen.
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