Hepatitis B e antigen predicts delayed reduction of HBV DNA without viral breakthrough with adefovir dipivoxil and lamivudine: a 5-year study of patients with hepatitis B with lamivudine resistance.

To clarify the factors associated with delayed reduction of HBV DNA during combination treatment with adefovir dipivoxil (ADV) and lamivudine (LAM) for patients with LAM-resistant hepatitis B virus (HBV), factors including patient characteristics, viral mutations, and drug metabolism were investigated during a 5-year observation period. Delayed reduction of HBV DNA was defined as delayed viral response of detectable HBV DNA after 3 years of combination therapy. Of 67 consecutive patients, 47 attained undetectable HBV DNA after 3 years of combination therapy, and the mean therapeutic duration was 5 years (range: 3.0-8.4 years). The patients with delayed viral response had high levels of HBV DNA and HBe antigen, while those with negative or low levels of HBe antigen were also negative for HBV DNA, even if they had high levels of HBV DNA. In the multivariate analysis with the proportional hazards model, a high baseline level of HBe antigen was negatively associated with viral decline to an undetectable level (P = 0.013). A higher baseline of HBe antigen corresponded to a lower annual decline in HBV DNA (R = -0.38, P = 0.004). No patients showed ADV-resistant mutations in the HBV reverse transcriptase region. Trough concentrations of LAM and ADV showed no clear associations with viral response. HBe antigen levels at the initiation of therapy, and reductions in these levels during therapy are predictive of the therapeutic response to combination therapy with ADV and LAM for patients with LAM-resistant HBV.

Prognostic model for hepatocellular carcinoma with time-dependent factors.

The purpose of this study was to build a prognostic model of hepatocellular carcinoma (HCC) using time-dependent covariates to re-evaluate the prognosis at any stage of the disease. The subjects were consecutive HCC patients who were treated at our institute between 1995 and 2007. We constructed time-fixed and time-dependent prognostic models with a training group (n=336) and compared the prognostic abilities between conventional Cancer of the Liver Italian Program (CLIP) scores, Japan Integrated Staging (JIS) scores, an Okuda classification, and our prognostic models in the testing group (n=227) with the c-index. The time-dependent prognostic model consisted of main tumor size, tumor number, portal vein invasion, distant metastasis, alpha-fetoprotein, des-gamma-carboxy prothrombin (DCP), bilirubin, and albumin and the weighted scores were set for each factor depending on the hazard ratio for the prognosis. The prognostic index was determined by summing the scores. The c-index values for the CLIP scores, JIS scores, Okuda classification, and our time-dependent model were 0.741, 0.727, 0.609, and 0.870, respectively. These results indicate that our time-dependent model can estimate the prognosis of HCC more precisely than traditional time-fixed models and can be used to re-predict the prognosis of HCC.

Time-dependent analysis of predisposing factors for the recurrence of hepatocellular carcinoma.

BACKGROUND/AIM: There are many reports dealing with the risk factors for hepatocellular carcinoma (HCC) recurrence. However, in most of these reported studies, factors were analysed only at the initial treatment stage, and the predisposing factors for the recurrence during follow-up have not been well studied. The aim of this study is to evaluate the predisposing factors after treatments. METHODS: Two hundred and seventy-one consecutive HCC patients curatively treated between January 1994 and March 2004 were followed up and analysed. The recurrence rate was estimated by the Kaplan- Meier method and the predisposing factors were evaluated by time-fixed Cox regression analysis and by time-dependent covariate analysis using multiple parameters. RESULTS: The mean follow-up period was 4.86 years and recurrence was observed in 169 patients (62.4%). The recurrence rates were 27.9, 65.1 and 84.3% at 1, 3 and 5 years respectively. Among the variables determined before treatment, predisposing factors for recurrence were low serum albumin [< or =3.5 g/dl, hazard ratio (HR)=1.47, 95% confidence interval (CI)=1.07-2.01] and multiple tumour number (HR=2.04, 95% CI=1.46-2.84) by time-fixed multivariate analysis. In the time-dependent analysis, six variables with 12 013 plots were examined. The multivariate analysis revealed that high des- gamma-carboxy prothrombin (DCP > or =40 mAU/ml, HR=2.33, 95% CI=1.61-3.39), high alpha-fetoprotein (AFP > or =100 ng/ml, HR=2.01, 95% CI=1.3-3.35) and high alanine aminotransferase (ALT > or = 40 IU/L, HR= 1.52, 95% CI=1.1-2.1) were significant predisposing factors for recurrence. CONCLUSION: Predisposing factors for the recurrence of HCC after treatment are different from those before treatments and special cautions are required when AFP, DCP or ALT is high during follow-up.

Surveillance of hepatocellular carcinoma in patients with hepatitis C virus infection may improve patient survival.

BACKGROUND: The benefit of surveillance of hepatocellular carcinoma (HCC) for patients with hepatitis C virus (HCV) infection, in terms of long-term survival, has not yet been established. METHODS: A total of 384 consecutive anti-HCV-positive HCC patients admitted to our hospital between January 1991 and October 2003 were enrolled. Patients were categorized into two groups, a surveillance group (182 patients) and a non-surveillance group (202 patients), according to tumor detection in a surveillance program based on periodical examination via ultrasound sonography and alpha fetoprotein determination at 6-month intervals, and their survival rates were compared. RESULTS: Although there were no significant differences in age and Child-Pugh classes between the two groups, the surveillance group exhibited a smaller tumor size (19 vs. 35 mm) and a higher incidence of single HCC (67% vs. 46%), compared with the non-surveillance group (each, P < 0.001). The cumulative survival rate in the surveillance group was higher than that in the non-surveillance group (5 years survival, 46% vs. 32%, P < 0.001). When the survival after correction of the lead-time bias in the surveillance group was analyzed according to the Child-Pugh classification, the surveillance program was found to have had a favorable outcome in Child-Pugh class A patients, but not in Child-Pugh class B/C patients. CONCLUSIONS: HCC surveillance for patients with HCV infection can lead to discovery of tumors at an early stage, especially in Child-Pugh class A, resulting in a favorable outcome.