Risk of Hepatocellular Carcinoma in Hepatitis B and D Virus Co-infected Patients

A Systematic Review and Meta-analysis of Longitudinal Studies

Habiba Kamal; Romina Fornes; Johanna Simin; Per Stål; Ann-Sofi Duberg; Nele Brusselaers; Soo Aleman


J Viral Hepat. 2021;28(10):1431-1442. 

In This Article

Abstract and Introduction


Hepatitis D virus (HDV) infection causes a severe chronic viral hepatitis with accelerated development of liver cirrhosis and decompensation, but whether it further increases the risk of hepatocellular carcinoma (HCC) is unclear. We performed a comprehensive systematic review of the published literature and meta-analysis to assess the risk of HCC in HDV and hepatitis B virus (HBV) co-infected, compared to HBV mono-infected patients. The study was conducted per a priori defined protocol, including only longitudinal studies, thus excluding cross-sectional studies. Random-effects models were used to determine aggregate effect sizes (ES) with 95% confidence intervals (CI). Meta-regression was used to examine the associations among study level characteristics. Twelve cohort studies comprising a total of 6099 HBV/HDV co-infected and 57,620 chronic HBV mono-infected patients were analysed. The overall pooled ES showed that HBV/HDV co-infected patients were at 2-fold increased risk of HCC compared to HBV mono-infected patients (ES = 2.12, 95% CI 1.14–3.95, I 2 = 72%, N = 12). A six-fold significant increased risk of HCC was noted among HIV/HBV/HDV triple-infected, compared to HIV/HBV co-infected patients. The magnitude of ES did not differ significantly after adjustment for study design and quality, publication year and follow-up duration in univariable meta-regression analysis. This systematic review and meta-analysis shows that infection with HDV is associated with a 2-fold higher risk of HCC development compared to HBV mono-infection. HCC surveillance strategies taking this increased risk into account, and new treatment options against HDV, are warranted.


Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer-related death.[1] Chronic viral hepatitis B, C and D are the strongest risk factors, present in 80–90% of all HCC cases worldwide.[1] The prognosis is poor, with a 1 year survival of approximately 50%, while five year survival is less than 20%, highlighting the need for surveillance of HCC in high-risk groups.[1]

Hepatitis D virus (HDV) is a defective RNA virus that requires hepatitis B virus (HBV) for replication and infectivity in the human hepatocytes.[2] The prevalence of HDV infection is of debate, with estimates ranging from 10–15 million up to 60 million in two recent meta-analysis.[3,4] The endemic areas include Central and West Africa, Central and Northern Asia, Mediterranean/East European countries, Middle East, Amazon basin in South America and Western Pacific islands.[3] A decrease in the prevalence of HDV was observed in the 1990s in Europe; however, this decline was halted as a consequence of increased migration from endemic regions.[5] Although the least common among viral hepatitis, HDV superinfection in chronic HBV carriers causes the most severe disease course. It is often described as leading to accelerated progression to cirrhosis and consequential risks for end-stage liver disease including liver transplantation.[6–9] Presently, the World Health Organization (WHO) has not classified HDV as a carcinogenic agent to humans, as HBV and HCV have been classified.[10]

The increased risk of HCC in HBV mono-infected patients has become well-established.[11] However, whether HDV infection is associated with further risk increase for HCC development remains controversial with divergent results among studies.[9,12–16] Many previous studies may have been hampered by sub-optimal design, power limitations and several have been descriptive, limiting the possibility to draw valid causal association.[17–19] In addition, we identified that several cross-sectional studies were often misclassified as case-control or cohort studies, which may systematically bias the results. A recently published meta-analysis of 93 studies (68 case-control and 25 cohort studies), suggested an increased risk of HCC in HBV/HDV co-infected patients.[20] However, 72% (67/93) of the included studies were cross-sectional in design, misclassified as case-control or cohort studies.[20] (Table S1). In cross-sectional studies, the direction of causality cannot be ascertained, making it difficult to draw definite conclusions. We, therefore, performed this comprehensive systematic review and meta-analysis assessing the risks of HCC in HBV/HDV co-infected compared to HBV mono-infected patients, including only longitudinal studies that allow us to include the temporality in the evaluation of HDV as a risk factor for HCC development.