Chang Wook Kim

A randomized controlled study of preemptive lamivudine in patients receiving transarterial chemo-lipiodolization.

Reactivation of hepatitis B virus (HBV) during chemotherapy is well documented. However, there are limited data on this complication in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemotherapy. The aim of this study was to evaluate the efficacy of preemptive lamivudine therapy in reducing hepatitis due to HBV reactivation in patients with HCC undergoing transarterial chemo‐lipiodolization (TACL) and to seek predictors of this event. A total of 73 consecutive HCC patients undergoing TACL using epirubicin 50 mg/m2 and cisplatin 60 mg/m2 at monthly intervals were prospectively and randomly assigned to receive lamivudine 100 mg daily from the start of TACL (preemptive group) or not (control group). During the study, 11 (29.7%) of 37 patients in the control group and 1 (2.8%) of 36 patients in the preemptive group developed hepatitis due to HBV reactivation (P = .002). In addition, there were significantly more incidences of overall hepatitis (P = .021) and severe grade of hepatitis (P = .035) in the control group. With multivariate Cox regression model, a baseline HBV DNA level of more than 104 copies/mL was the only independent predictor of hepatitis due to HBV reactivation during chemo‐lipiodolization (P = .046). In conclusion, preemptive lamivudine therapy demonstrated excellent efficacy in reducing hepatitis due to HBV reactivation and hepatic morbidity during TACL. Preemptive therapy should be considered in HCC patients with an HBV DNA level of more than 104 copies/mL. Further studies are needed to confirm the value of this approach in patients with low‐level viremia. (HEPATOLOGY 2006;43:233–240.)

HCV core protein promotes liver fibrogenesis via up-regulation of CTGF with TGF-β1

Liver cirrhosis is one of the major complications of hepatitis C virus (HCV) infection, but the mechanisms underlying HCV-related fibrogenesis are still not clear. Although the roles of HCV core protein remain poorly understood, it is supposed to play an important role in the regulation of cellular growth and hepatocarcinogenesis. The aim of this study was to examine the role of HCV core protein on the hepatic fibrogenesis. We established an in vitro co-culture system with primary hepatic stellate cell (HSC) isolated from rats, and a stable HepG2-HCV core cell line which had been transfected with HCV core gene. The expressions of fibrosis-related molecules transforming growth factor β1 (TGF-β1), transforming growth factor b receptor II (TGF β RII), α-smooth muscle actin (α-SMA) and connective tissue growth factor (CTGF) were analyzed via histological or molecular methods. In addition, the expression levels of matrix metaloprotinase-2 (MMP-2) and collagen type I (Col I) from the co-cultured media were measured by zymogram and ELISA, respectively. The expressions of α-SMA, TGF-β1, Col I, TGF β RII and MMP-2 were significantly increased in the co-culture of stable HepG2-HCV core with HSC. Moreover, the significant increases of CTGF and TGF-β1 in the HCV core-expressing cells were observed by either Northern or Western blot analysis. These results suggest that HCV core protein may contribute to the hepatic fibrogenesis via up-regulation of CTGF and TGF-β1.

Hepatitis B Virus Genotype C Prevails Among Chronic Carriers of the Virus in Korea

Hepatitis B virus (HBV) is one of the major causative agents of chronic liver diseases in Korea. HBV has been classified into 8 genotypes by a divergence of >8% in the entire genomic sequence, and have distinct geographic distributions. There are limited data on the relevance between HBV genotypes and clinical outcomes in Korea. To investigate the clinical feature relating to HBV genotype in Korea, a total 120 serum samples with HBsAg (65 from Seoul and 55 from the other city in Korea) were obtained from each 30 chronic HBV carriers with asymptomatic carrier (ASC), chronic hepatitis (CH), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). HBV genotype was determined by either enzyme-linked immunosorbent assay (ELISA) using monoclonal antibodies against genotype-specific epitopes in the preS2-region or the direct sequencing of small S gene. HBV genotypes were determined in 105 (87.5%) of 120 samples. HBV genotype C was identified in all HBV carriers with ASC, CH, LC, and HCC. Genotypes A, B, D, E, F and G were not detected in any of them. Genotype C HBV prevails predominantly among chronic carriers of the virus in Korea, irrespective of their clinical stages of liver disease and geographic origin.

Hepatitis C virus: virology and life cycle

Hepatitis C virus (HCV) is a positive sense, single-stranded RNA virus in the Flaviviridae family. It causes acute hepatitis with a high propensity for chronic infection. Chronic HCV infection can progress to severe liver disease including cirrhosis and hepatocellular carcinoma. In the last decade, our basic understanding of HCV virology and life cycle has advanced greatly with the development of HCV cell culture and replication systems. Our ability to treat HCV infection has also been improved with the combined use of interferon, ribavirin and small molecule inhibitors of the virally encoded NS3/4A protease, although better therapeutic options are needed with greater antiviral efficacy and less toxicity. In this article, we review various aspects of HCV life cycle including viral attachment, entry, fusion, viral RNA translation, posttranslational processing, HCV replication, viral assembly and release. Each of these steps provides potential targets for novel antiviral therapeutics to cure HCV infection and prevent the adverse consequences of progressive liver disease.

Simultaneous Multitarget Irradiation Using Helical Tomotherapy for Advanced Hepatocellular Carcinoma With Multiple Extrahepatic Metastases

PURPOSE The prognosis of hepatocellular carcinoma (HCC) patients with extrahepatic metastases is extremely poor. Helical tomotherapy, an image-guided, intensity-modulated radiotherapy system, can allow for simultaneous and precise targeting of multiple cancerous lesions, while sparing normal tissues. This study evaluated the feasibility and outcome of tomotherapy for advanced HCC with metastases. PATIENTS AND METHODS A total of 42 consecutive HCC patients with metastases were treated with tomotherapy using the Hi-Art system. A total of 152 intra- and extrahepatic lesions (3.5 lesions/patient) were treated simultaneously, with a dose of 51.03 Gy (range, 30-57.61) in 10 fractions. Transarterial chemolipiodolization using epirubicin (50 mg) and cisplatin (60 mg) was repeated in patients with intrahepatic HCC (mean size, 9.0 cm) after tomotherapy. RESULTS An objective response (complete response and partial response) was achieved in 45.2% of patients with intrahepatic tumors, 68.4% of patients with pulmonary lesions, 60.0% of patients with lymph node/adrenal lesions, and 66.7% of patients with soft-tissue metastases. The complete response rate for those with pulmonary and lymph node/adrenal metastases was 26.3% and 5.0%, respectively. The overall survival rate at 1 and 2 years was 50.1% and 14.9%, respectively, with a median survival of 12.3 months. The actuarial in-field tumor control rate for < or =1 year was 79.0%. No cases of Grade 4-5 acute toxicity occurred. CONCLUSION The results of this study have shown that helical tomotherapy is safe and feasible without major toxicities for the treatment of advanced HCC and results in excellent tumor control and a potential survival benefit. This approach is expected to be a useful palliative option for selected HCC patients with metastases.

Long-Term Results of Lamivudine Monotherapy in Korean Patients with HBeAg-Positive Chronic Hepatitis B: Response and Relapse Rates, and Factors Related to Durability of HBeAg Seroconversion

Objective: The aim of this study was to evaluate retrospectively the long-term effects of lamivudine in 461 Korean patients with chronic hepatitis B who were treated for more than 12 months. Methods: The annual rates of virological response and breakthrough were examined and the predictive factors for post-treatment relapse in 114 patients who achieved hepatitis B e antigen (HBeAg) loss or seroconversion after lamivudine therapy were also analyzed. Results: During follow-up, the rates of HBeAg seroconversion after 1, 2, 3, 4 and 5 years of treatment were 22.9, 33.2, 47.6, 54.2 and 58.8%, respectively, while those for virological breakthrough at 1, 2, 3 and 4 years were 8.2, 41.7, 55.7 and 64.8%, respectively. Ninety-five patients (20.6%) had HBeAg seroconversion and 19 (4.1%) showed HBeAg loss alone with disappearance of hepatitis B virus DNA in serum. Seroconversion was higher with prolonged treatment in patients who had elevated serum alanine aminotransferase. The cumulative relapse rates in the seroconversion group were 52.0 and 55.7% 1 and 2 years after treatment, respectively. Age and the duration of additional treatment were significant predictive factors for post-treatment relapse. Patients aged ≤40 who had additional treatment for >12 months after seroconversion had the lowest relapse rate (p < 0.001). Conclusions: These results suggest that additional treatment for over 12 months after HBeAg seroconversion in younger patients may produce a better long-term outcome.

Polymorphism near the IL28B gene in Korean hepatitis C virus-infected patients treated with peg-interferon plus ribavirin

BACKGROUND Single nucleotide polymorphisms (SNPs) near the IL28B gene have recently been described as predictors of antiviral therapy responses in patients with hepatitis C virus (HCV) genotype-1. OBJECTIVES The aim of this study was to investigate the association between genetic variation near the IL28B gene and treatment outcome prediction in Korean patients receiving peg-interferon (PEG-IFN) plus ribavirin therapy. STUDY DESIGN The allelic discrimination assay by Taqman real-time PCR was developed to determine genotypes of SNPs, rs12979860 and rs8099917, which were analyzed in 65 Korean patients with HCV genotype-1. RESULTS For rs12979860, the frequency of patients with sustained virological response (SVR) was 70.2% in those with the CC genotype and 25% in those with the CT genotype. Early virological response (EVR) in patients with the CC genotype (84.2%) was higher than in those with the CT genotype (25.0%). For rs8099917, patients with the TT genotype showed significantly higher in SVR and EVR than those with the TG/GG genotype (69.6% vs 33.3% and 82.1% vs 44.4%, respectively). With regards to the genotype frequency of the SNPs, the homozygous genotypes for rs12979860 (CC) or rs8099917 (TT) in Korean patients showed a significantly higher frequency as compared with other ethnicities; Caucasians, African-American, Hispanic, and Japanese. CONCLUSIONS These results demonstrate that the genotypes rs12979860 CC and rs8099917 TT were more frequently observed in Korean patients compared to other ethnicities, and suggest that the genetic characteristics of patients may be prognostic factor that predicts antiviral response to PEG-IFN therapy for chronic hepatitis C.

The impact of hepatitis B viral load on recurrence after complete necrosis in patients with hepatocellular carcinoma who receive transarterial chemolipiodolization: implications for viral suppression to reduce the risk of cancer recurrence.

Hepatocellular carcinoma (HCC) has a high tendency for recurrence after radical treatment. Apart from tumor and liver function parameters, little is known about the role of hepatitis B virus (HBV) factors in the recurrence of HCC. The objective of this study was to identify the potential relation between viral load and HCC recurrence in patients undergoing transarterial chemolipiodolization.

Association between human leukocytes antigen alleles and chronic hepatitis C virus infection in the Korean population.

Abstract: Background/Aim: Recent data have shown that the clinical outcome of hepatitis C virus (HCV) infection may be influenced by the host genetic factor. The aim of this study was to investigate whether particular human leukocytes antigen (HLA) molecules are associated with the susceptibility to HCV infection in the Korean population.

Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid–enhanced magnetic resonance imaging predicts the histological grade of hepatocellular carcinoma only in patients with child-pugh class a cirrhosis†

The aim of this study was to investigate the role of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd‐EOB‐DTPA)–enhanced magnetic resonance imaging (MRI) in predicting the histological grade of hepatocellular carcinoma (HCC) according to the hepatic function. Eighty‐one consecutive patients with 122 histologically proven HCCs who underwent Gd‐EOB‐DTPA–enhanced MRI before resection (45 HCCs in 42 patients) or transplantation (77 HCCs in 39 patients) were analyzed retrospectively. We calculated the relative enhancement ratios (RER), which is the ratio of the relative intensity of a tumor versus the surrounding parenchyma on hepatobiliary phase images to the relative intensity on unenhanced MRI scans. We then analyzed the correlation between the RER and the tumor differentiation grade in patients with various degrees of hepatic function. The degree of tumor enhancement, which included the precontrast relative intensity ratio (RIR), the postcontrast RIR, and the RER, for well‐differentiated (WD) HCCs was significantly higher than the degree of tumor enhancement for moderately differentiated and poorly differentiated (PD) HCCs (P = 0.001 and P = 0.001, respectively, for precontrast RIRs; P < 0.001 and P < 0.001, respectively, for postcontrast RIRs; and P = 0.01 and P = 0.001, respectively, for RERs). In a subgroup analysis based on liver function, the correlation between the histological grade and the enhancement ratio was demonstrated only in the group of patients with Child‐Pugh class A cirrhosis. The accuracy of postcontrast RIRs for predicting WD and PD HCCs was favorable; the areas under the receiver operating characteristic curves were 0.896 [95% confidence interval (CI) = 0.817‐0.974] and 0.769 (95% CI = 0.658‐0.879), respectively. In conclusion, the hepatobiliary phase of Gd‐EOB‐DTPA–enhanced MRI may help to predict the differentiation of HCCs, especially in HCC patients with Child‐Pugh class A cirrhosis before liver transplantation or resection. Liver Transpl, 2012.