Evaluation of Impact of Serial Hepatitis B Virus DNA Levels on Development of Hepatocellular Carcinoma

We aimed to investigate the impact of hepatitis B virus (HBV) DNA on the development of hepatocellular carcinoma (HCC). We conducted a case/control study based on 506 chronic HBV patients followed up since 1997. Forty-one patients developed HCC, and each of them was age and gender matched with two simultaneously recruited controls without HCC. HBV DNA was measured at the initial visit, at yearly intervals, and at the last visit. Patient age at the time of HCC development was 55 ± 9 years. Forty-nine (40%) patients experienced antiviral treatment. The median time from diagnosis to the development of HCC was 17 months, and the control patients were followed for 92 months. At the trough level (defined as lowest level among all studied visits), more (27 patients; 66%) HCC patients had HBV DNA levels of >10,000 copies/ml than the controls (17 patients; 21%). The area under the receiver operating characteristic curve of the trough log HBV DNA level for HCC was 0.79 (95% confidence interval [CI], 0.69 to 0.89). Trough log HBV DNA (odds ratio, 11.4; 95% CI, 3.6 to 37.6; P < 0.0001) and liver cirrhosis (odds ratio, 11.4; 95% CI, 3.6 to 36.2; P < 0.0001) levels were independently associated with HCC after an adjustment for age, gender, antiviral treatment, and HBV genotype. The difference in the trough HBV DNA level was more obvious among untreated patients (5.7 ± 1.4 log copies/ml in HCC patients versus 3.2 ± 1.3 log copies/ml in control patients; P < 0.0001) than among those who had received antiviral treatment (3.0 ± 1.4 log copies/ml in HCC patients versus 2.5 ± 0.9 log copies/ml in control patients; P = 0.38). A high trough HBV DNA level was associated with a higher risk of HCC. Whether antiviral treatment could prevent HCC was uncertain.Chronic hepatitis B virus (HBV) infection is the commonest cause of hepatocellular carcinoma (HCC) in Southeast Asia (8). In addition to the host factors, including an older age and male gender, viral factors such as being positive for HBV e antigen (HBeAg) and having high HBV DNA levels, genotype C HBV (particularly subgenotype Ce), and basal core promoter mutations have been suggested to associate with a higher risk of HCC (7, 9, 10, 11, 14, 28). In several cohort studies in Taiwan, China, and Hong Kong, a single high HBV DNA level higher than 4 log to 4.5 log copies/ml was associated with an increased HCC risk in the subsequent 10 years (7, 9, 10, 11). In addition, patients who had persistently high HBV DNA levels at the last follow-up visit also had an increased risk of developing HCC (10). In all previous studies, there was no information on the HBV DNA levels during the years between the first and last follow-up visits. As HBV DNA levels tend to fluctuate, particularly in HBeAg-negative patients, an assessment at a single time point cannot accurately reflect the severity of liver disease (6, 12, 13).In recently published management guidelines, antiviral treatment is recommended in patients with liver cirrhosis when the HBV DNA level is higher than 4 log copies/ml (15, 21, 23). This recommendation was based primarily on a multicentered, placebo-controlled trial among Asian chronic HBV patients who suffered from severe liver fibrosis (20). In this study, lamivudine treatment was demonstrated to reduce the risk of liver-related complications in 3 years. However, the benefit of prevention of HCC development among lamivudine-treated patients became dubious after excluding patients who developed HCC within the first year. In an Italian series, HBV DNA suppression by lamivudine and adefovir could not prevent the development of HCC among patients with decompensated liver cirrhosis (18).In this study, we aimed to investigate the impact of changes in HBV DNA on the development of HCC, either in the natural course of disease or as a result of antiviral treatment. To address this question, we studied the HBV DNA levels at different time intervals of follow-up among a cohort of chronic HBV patients before the development of HCC compared to those of simultaneously recruited controls.