Role of hepatitis D virus infection in development of hepatocellular carcinoma among chronic hepatitis B patients treated with nucleotide/nucleoside analogues

Abstract

Hepatitis D virus (HDV) infection increases the risk of hepatocellular carcinoma (HCC) in the natural course of chronic hepatitis B (CHB) patients. Its role in patients treated with nucleotide/nucleoside analogues (NAs) is unclear. We aimed to study the role of hepatitis D in the development of HCC in CHB patients treated with NAs. Altogether, 1349 CHB patients treated with NAs were tested for anti-HDV antibody and RNA. The incidence and risk factors of HCC development were analyzed. Rates of anti-HDV and HDV RNA positivity were 2.3% and 1.0%, respectively. The annual incidence of HCC was 1.4 per 100 person-years after a follow-up period of over 5409.5 person-years. The strongest factor association with HCC development was liver cirrhosis (hazard ratio [HR]/95% confidence interval [CI] 9.98/5.11–19.46, P < 0.001), followed by HDV RNA positivity (HR/ CI 5.73/1.35–24.29, P = 0.02), age > 50 years old (HR/CI 3.64/2.03–6.54, P < 0.001), male gender (HR/CI 2.69/1.29–5.60, P: 0.01), and body mass index (BMI, HR/CI 1.11/1.03–1.18, P = 0.004). The 5-year cumulative incidence of HCC was 7.3% for patients with HDV RNA negativity compared to that of 22.2% for patients with HDV RNA positivity (P = 0.01). In the subgroup of cirrhotic patients, the factors associated with HCC development were HDV RNA positivity (HR/CI 4.45/1.04–19.09, P = 0.04) and BMI (HR/CI 1.11/1.03–1.19, P = 0.01). HDV viremia played a crucial role in HCC development in CHB patients who underwent NA therapy.

Molecular epidemiology and clinical characteristics of hepatitis D virus infection in Canada

“… 36 A study of Taiwanese chronic hepatitis B patients treated with NA showed that HDV viraemia contributed significantly to the development of HCC, with a 5-year cumulative incidence of 22.2% compared with HDV RNA-negative patients (7.3%, p = 0.01). 37 In the present study, upon stratification by RNA positivity, cirrhosis, elevated ALT, AST, and TE indicating greater than stage 2 fibrosis, were significantly associated with HDV viraemia. The significant association between HDV viraemia and increased ALT levels has also been described in both univariate and multivariate analyses in a cross-sectional study of over 1,500 patients from 15 countries.…”

Hepatocellular Carcinoma in Chronic Viral Hepatitis: Where Do We Stand?

“…Regarding risk factors, cirrhosis, HDV-RNA positivity, age > 50 years old, male gender, and BMI are independently predictive of HCC development in patients with CHB treated with NAs. Interestingly, in the subgroup of those with cirrhosis, HDV-RNA positivity remains independently predictive of HCC [ 88 ].…”

Beyond the Usual Suspects: Hepatitis E Virus and Its Implications in Hepatocellular Carcinoma

“…Previous studies on hepatotropic viruses including HBV, HCV and HDV have frequently shown the significance of viral infection in HCC development [ 6 , 34 , 35 ]. Whether HEV has a similar function in hepatocarcinogenesis remains controversial, but several epidemiological and clinical studies imply a potential role of HEV in the HCC pathogenesis.…”

“…Indeed, 78% of all HCC cases are attributable to HBV (53%) or HCV (25%) infection alone [ 4 ]. Current research also suggests hepatitis D virus (HDV) plays a crucial role in HCC formation [ 5 , 6 ].…”