Tsung-i Hu

Reactivation of hepatitis B virus following rituximab-based regimens: a serious complication in both HBsAg-positive and HBsAg-negative patients

Hepatitis B virus (HBV) reactivation is a well-known complication of lymphoma treatment in the pre-rituximab era. This complication has not been as well studied, however, since monoclonal anti-CD20 antibody became the standard regimen for B cell lymphoma. In this retrospective study, 115 B cell lymphoma patients who received rituximab-containing therapy were analyzed. Of 15 hepatitis B surface antigen (HBsAg)-positive patients, five received lamivudine prophylaxis and did not develop HBV-related hepatitis during lymphoma treatment. Eight of ten HBV carriers without lamivudine prophylaxis experienced HBV-related hepatitis, including one fatal hepatic failure. Four (4.2%) of 95 HBsAg-negative patients developed de novo HBV-related hepatitis and two died of fulminant hepatitis. In conclusion, rituximab-based therapy may cause serious HBV-related complications and even death in both HBsAg-positive and HBsAg-negative patients.

The efficacy of treatment schedules according to Barcelona Clinic Liver Cancer staging for hepatocellular carcinoma – Survival analysis of 3892 patients

The Barcelona Clinic Liver Cancer (BCLC) staging offers prognostic stratification and treatment allocation for hepatocellular carcinoma (HCC). We conducted this retrospective study to assess the efficacy of different treatment options for patients with initial HCC diagnosis. Survival rate and median survival times associated with different treatment options in each stage of BCLC classification were compared using the Kaplan-Meier method and log-rank test. A total of 3892 patients were enrolled. Overall survival rates were 46.2% at 1 year and 16.6% at 5 years. The median survival times decreased from 57.7 months in very early stage to 1.6 months in terminal stage. Surgical resection offered the best survival benefit for patients in very early, early and even intermediate stages. Transarterial embolisation and conformal radiotherapy offered survival benefits for selected patients in advanced and terminal stages. In conclusion, following the treatment schedules allocated by BCLC staging had survival benefits for HCC patients.

Long‐term effect of interferon alpha‐2b plus ribavirin therapy on incidence of hepatocellular carcinoma in patients with hepatitis C virus‐related cirrhosis

Summary.  We assessed the efficacy of interferon (IFN) alpha‐2b plus ribavirin therapy in patients with hepatitis C virus (HCV)‐related cirrhosis, and elucidated the risk factors for the development of hepatocellular carcinoma (HCC) to determine whether these therapies might reduce the incidence of HCC. One hundred and thirty‐two HCV‐cirrhotic patients receiving IFN alpha‐2b (3 or 5 MU thrice weekly) and oral ribavirin (1000–1200 mg/day) for 24 or 48 weeks were analysed. Cumulative incidence of HCC was estimated by the Kaplan–Meier method. The prognostic relevance of clinical variables and HCC occurrence was evaluated by univariate analysis with the log‐rank test and by multivariate Coxs regression analysis. A total of 116 patients completed the treatment and 73 (55%) achieved a sustained virological response (SVR). Stepwise logistic regression analysis showed that nongenotype 1b (P < 0.001) and low viral load (P = 0.018) were independent variables of SVR. During a median follow‐up period of 37 (12–63) months, HCC developed in 11 patients with non‐SVR and five with SVR (P = 0.0178), whereas there was no difference between those with transient biochemical response and nonresponse (P = 0.5970). The Kaplan–Meier method also showed that old age (≥60 years) (P = 0.0034) and genotype 1b (P = 0.0104) were associated with HCC occurrence. Using Coxs regression analysis, non‐SVR (odds ratio = 3.521, P = 0.036), male (odds ratio = 6.269, P = 0.011) and old age (odds ratio = 3.076, P = 0.049) were independent significant risk factors contributing to HCC development. Our results suggest that achieving SVR by IFN alpha‐2b plus ribavirin therapy may decrease the incidence of HCC in patients with HCV‐related cirrhosis.

Clinical Significance of Hepatitis B Virus (HBV) Genotypes and Precore and Core Promoter Mutations Affecting HBV e Antigen Expression in Taiwan

ABSTRACT To assess the prevalence and clinical significance of hepatitis B virus (HBV) genotypes and precore and core promoter mutations in Taiwan, a cohort of 200 Taiwanese chronic hepatitis B patients was analyzed. The HBV genotypes and sequences of the precore and the core promoter regions were determined in 66 asymptomatic carriers and 134 patients who had liver biopsy-verified chronic hepatitis and liver cirrhosis. The HBV e-antigen (HBeAg)-negative patients had a higher frequency of mutations at core promoter nucleotides 1753 and 1773 and precore nucleotides 1846, 1896, and 1899 than HBeAg-positive patients. Among the 200 patients, the frequencies of genotype C, T1762 and A1764, C1753, T1766 and A1768, and A1896 mutations increased and the frequencies of T or G1752, T1773, G1799, and C1858 mutations decreased with advancing liver diseases. These factors were different between those with HBeAg-positive status and those with HBeAg-negative status. Based on multiple logistic regression analysis, the risk factors of liver cirrhosis for 200 patients were the presence of T1762 and A1764 mutations (odds ratio [OR] = 11.11; 95% confidence interval [CI] = 3.91 to 31.25; P < 0.001), age ≥35 years (OR = 3.42; 95% CI = 1.33 to 8.77; P = 0.011), and genotype C (OR = 2.87; 95% CI = 1.21 to 6.81; P = 0.017). Further categorical analysis found that 62.1% of patients with genotype C, T1762 and A1764 mutations and age ≥35 years had liver cirrhosis. None of the 55 patients infected with the genotype B, A1762 and G1764 wild type and age <35 years showed liver cirrhosis. In conclusion, our data suggest that pathogenic differences between HBeAg-positive and -negative patients may exist. In Taiwan, HBV genotype C and the T1762 and A1764 mutations may play a role in HBV-related liver cirrhosis, and these could serve as molecular markers for prediction of the clinical outcomes of chronic HBV patients.

Combined Mutations in Pre-S/Surface and Core Promoter/Precore Regions of Hepatitis B Virus Increase the Risk of Hepatocellular Carcinoma: A Case-Control Study

BACKGROUND We sought to investigate the role of sequence variations in pre-S/surface and basal core promoter (BCP)/precore regions of the hepatitis B virus (HBV) in hepatocellular carcinoma (HCC). METHODS The direct sequencing in pre-S/surface and BCP/precore regions of HBV was determined for 80 patients with HCC and 160 control patients with HBV infection. RESULTS Compared with control patients, patients with HCC had higher frequencies of pre-S deletions and amino acid substitutions at codon 4, 7, and 81 in pre-S1 genes; at the start codon in pre-S2 genes; and at codon 68 in surface genes. Patients also had a lower frequency of amino acid substitution at codon 2 in pre-S2 genes, compared with control patients. In BCP/precore regions, patients with HCC had higher frequencies of C or G1753, A1762/T1764, T1846, and A1899. Multivariate analysis showed that pre-S deletions, I68T surface gene, T1762/A1764, and A1899 were independent factors associated with the development of HCC. The HBV strain with a complex mutation pattern rather than a single mutation was associated with HCC, and the HCC risks increased for patients having these factors in combination. CONCLUSIONS Pre-S deletions, I68T in surface gene, T1762/A1764, and A1899 were independent risk factors for HCC. Combination of these viral mutations appeared to increase the risk of HCC.

Validation of clinical AJCC/UICC TNM staging system for hepatocellular carcinoma: analysis of 5,613 cases from a medical center in southern Taiwan.

This study was aimed to validate the 5th and 6th editions of tumor‐node‐metastasis (TNM) system for patients with hepatocellular carcinoma (HCC), and attempted to improve prognostic stratification by modifying the 6th edition according to vascular invasion and tumor size. From 1986 to 2002, a total of 5,613 HCC cases from Kaohsiung Chang Gung Memorial Hospital in southern Taiwan were enrolled. The 6th edition was modified by dividing stage I into stages IA (single tumor, ≤2cm) and IB (single tumor, >2cm), and by dividing stage II into IIA (multiple tumors, none >5cm) and IIB (tumor with segmental macro vascular invasion). The Akaike information criteria (AIC), within a Cox proportional hazard regression model were used; lower AIC value indicated a better discriminatory ability for staging system. The 1‐, 3‐, 5‐, and 7‐year overall survival rates were 45.6, 25.9, 17.9, and 13.4%, respectively. Significant differences in survival curve existed in the 5th, 6th, and modified 6th edition TNM systems. For the modified 6th edition TNM, survival differed significantly between stages IA and IB, and between stage IIA and IIB. The AIC values of 5th (72,328), 6th (72,188), modified 6th (71,991) edition TNM system were decreasing. This investigation demonstrated better prognostic stratifications for the 6th edition than the 5th edition TNM staging system. Moreover, the modified 6th edition staging system demonstrated better prognostic prediction than the former two. Pretreatment staging and simple classification of current modified 6th edition TNM staging can be applied to all HCC patients and are clinically useful.

The role of hepatitis B surface antigen quantification in predicting HBsAg loss and HBV relapse after discontinuation of lamivudine treatment.

BACKGROUND & AIMS We investigated whether the quantification of hepatitis surface antigen (HBsAg) could predict HBsAg loss or hepatitis B virus (HBV) relapse after stopping lamivudine treatment. METHODS A total of 188 naive chronic hepatitis B patients (83 HBeAg-positive, 105 HBeAg-negative patients), who were previously treated with lamivudine (treatment duration: 89.3 ± 35.9 weeks, range: 52-243 weeks) but stopped the treatment for at least 12 months were recruited. RESULTS The cumulative incidence of HBsAg loss and HBV relapse at year 6 after stopping lamivudine treatment was 24% and 65.9% respectively. Cox regression analysis revealed that lower alanine aminotransferase (ALT) at baseline, lower HBsAg levels at the end of treatment, and longer treatment duration were independent predictors for HBsAg loss, and old age, male sex and higher HBsAg levels at the end of treatment were independent predictors for post-treatment HBV relapse. At the end of treatment, the HBsAg cut-off value of 300 IU/ml could predict 55.6% (5/9) HBsAg loss in HBeAg-positive patients. In HBeAg-negative patients, the HBsAg cut-off values of 120 and 200 IU/ml could predict 79.2% (19/24) HBsAg loss and 93.3% (28/30) post-treatment sustained response respectively. Further HBsAg reduction (>0.22 log IU/ml) at month 6 after stopping treatment was an independent predictor for HBsAg loss after adjusting for HBsAg level at the end of treatment. CONCLUSIONS Serum HBsAg level at the end of treatment is a useful predictor to guide the timing of stopping lamivudine treatment in chronic hepatitis B patients.

Impact of diabetes mellitus on incidence of hepatocellular carcinoma in chronic hepatitis C patients treated with interferon‐based antiviral therapy

There is strong evidence linking chronic hepatitis C virus (HCV) infection and Type 2 diabetes mellitus (DM). Recent studies have suggested that DM is associated with increased risk of developing hepatocellular carcinoma (HCC). The aim of our cohort study was to assess whether DM influence the incidence of HCC in chronic hepatitis C patients treated with interferon (IFN)‐based antiviral therapy. A total of 1,470 chronic hepatitis C patients treated with IFN or pegylated‐IFN plus ribavirin therapy were enrolled. Of them, 253 (17%) patients had DM at entry. Evaluation of HCC incidence was performed by Kaplan–Meier method and Cox proportional hazards analysis. Patients with baseline DM were significantly older and had higher body mass index, serum transaminase levels and fibrosis scores and lower platelet counts compared to non‐DM subjects. Sustained virological response (SVR) was achieved in 160 (63%) of DM and 867 (71%) of non‐DM patients (p = 0.008). During a median follow‐up period of 4.3 years, HCC developed in 21 (8.3%) of DM and 66 (5.4%) of non‐DM patients (p = 0.017). However, DM was not an independent covariate by Cox proportional hazards analysis. In a subgroup analysis, DM (hazard ratio, 4.32; 95% confidence interval, 1.23–15.25; p = 0.023) was an independent predictor of HCC in the SVR patients without baseline cirrhosis, despite a low HCC incidence. In conclusion, DM has a selective impact on HCC development among chronic hepatitis C patients after IFN‐based therapy. DM may increase the HCC risk in chronic hepatitis C without cirrhosis after eradication of HCV.

Liver stiffness decrease after effective antiviral therapy in patients with chronic hepatitis C: Longitudinal study using FibroScan.

Aim:  The aim of the present study was to assess the changes of liver stiffness (LS) and its associated factors in patients with chronic hepatitis C virus infection (HCV) after interferon (IFN)‐based therapy.

Is the Cancer of the Liver Italian Program system an adequate weighting for survival of hepatocellular carcinoma? Evaluation of intrascore prognostic value among 36 subgroups

Background: The Cancer of the Liver Italian Program (CLIP) staging system for hepatocellular carcinoma (HCC) was subdivided into 36 subgroups. We aimed to validate the prognostic value of CLIP scoring.