Quantitative analysis of intrahepatic hepatitis B (HBV) DNA and cccDNA and their impact on survival posthepatectomy in HBV-associated hepatocellular carcinoma (HCC) patients.

Abstract

e14583 Background: Little is known about the prognostic significance of total intrahepatic HBV DNA (ihHBV DNA) and cccDNA, a stable episome that accumulates in the nuclei and serves as the template for viral replication. This study aims to quantitate ihHBV DNA and cccDNA in the non-neoplastic liver and to assess their impact on prognosis in HBV-HCC patients. Methods: 111 patients, many on HBV antivirals, who underwent liver resection for HBV-HCC from 1991 to 2008 were assessed by real time PCR for ihHBV DNA, cccDNA, and albumin. Liver fibrosis and necroinflammation was assessed using the modified Ishak method. Independent variables associated with survival were analyzed using multivariate Cox regression model, with a median follow up for survivors of 52 months. Results: Serum HBV DNA was detectable in only 42% of patients, but 106 patients (95%) had detectable ihHBV DNA (median: 0.018copy/hepatocyte); and 89 patients (80%) had detectable cccDNA (0.00058 copy/hepatocyte). Median cccDNA/ihHBV DNA ratio was 0.019. ihHBV DNA correlated with histologic activity index (p = 0.04) and serum ALT (p = 0.004). Patients in the lowest quartile of cccDNA/ihHBV DNA ratio (<0.0032) trended towards poor overall 5-year survival by univariate analysis (p = 0.09), with higher mortality at 2 years (89% vs. 45%, p = 0.03). In multivariate analysis, AFP > 20, Ishak fibrosis stage 6 (established cirrhosis), cccDNA/ihHBV DNA < 0.0032, and large tumor diameter were independently associated with poor overall survival (Table). Conclusions: ihHBV DNA levels were associated with severity of liver necroinflammation and injury. ihHBV DNA and cccDNA levels were not associated with survival; rather, low proportion of total HBV DNA in the form of cccDNA was independently associated with poor overall survival. Thus, viral behavior at the time of liver resection influences clinical outcome for HBV-HCC patients. [Table: see text]