Comparison of Efficacy between Tenofovir Disoproxil Fumarate and Entecavir in Chronic Hepatitis B Patients with High Hepatitis B Virus DNA

( Hyeki Cho ),( Hongkeun Ahn ),( Yoon Jun Kim ),( Young Chang ),( Joon Yeul Nam ),( Young Youn Cho ),( Seong Hee Kang ),( Eun Ju Cho ),( Jeong-hoon Lee ),( Su Jong Yu ),( Jung-hwan Yoon ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: High Hepatitis B Virus (HBV) DNA is associated with increased risk of cirrhosis and hepatocellular carcinoma in chronic hepatitis B patients. There are few studies comparing the efficacy of tenofovir disoproxil fumarate (TDF) and entecavir (ETV) in patients with high HBV DNA. This study aimed to evaluate the efficacy of TDF and ETV in chronic hepatitis B patients with high HBV DNA. Methods: We conducted a retrospective analysis of data from 189 consecutive chronic hepatitis B patients with high HBV DNA titers (≥10(8) IU/mL). We included nucleos(t)ide analogue (NA) treatment- naive patients or NA-experienced patients without detectable genotypic resistance. 95 patients were treated with TDF and 94 were treated with ETV. Complete virologic response (CVR) rate in two groups was analyzed by Kaplan-Meier curve analysis and Cox proportional hazards model. Results: The median duration of follow-up was 15.5 months. The median time to CVR was 12.8 and 18.0 months in TDF group and ETV group, respectively (P=0.011 by log-rank test). In multivariate analysis, TDF group had significantly higher probability of CVR (hazard ratio [HR]=1.72, 95% confidence interval [CI]=1.16-2.56; P=0.007) after adjustment for age, HBeAg status, aminotransferase and previous NA experience. The cumulative probability of HBeAg loss was not significantly different between two groups (P=0.210 by log-rank test). None of the patients had discontinued medication due to adverse reactions and GFR at each time point was significantly different in two groups (P=0.003 by linear mixed model). Conclusions: Tenofovir disoproxil fumarate is superior to entecavir in achieving complete virologic response in chronic hepatitis B patients with HBV DNA greater than 10(8) IU/mL.

Tenofovir-associated nephrotoxicity in patients with chronic hepatitis B: two cases

( Hyeki Cho ),( Yuri Cho ),( Eun Ju Cho ),( Jeong Hoon Lee ),( Su Jong Yu ),( Kook Hwan Oh ),( Kyoungbun Lee ),( Syifa Mustika ),( Jung Hwan Yoon ),( Yoon Jun Kim ) 대한간학회 2016 Clinical and Molecular Hepatology(대한간학회지) Vol.22 No.2

Tenofovir disoproxil fumarate (TDF) is effective against chronic hepatitis B (CHB) infection and its use is increasing rapidly worldwide. However, it has been established that TDF is associated with renal toxicity in human immunodeficiency virus-infected patients, while severe or symptomatic TDF-associated nephrotoxicity has rarely been reported in patients with CHB. Here we present two patients with TDF-associated nephrotoxicity who were being treated for CHB infection. The first patient was found to have clinical manifestations of proximal renal tubular dysfunction and histopathologic evidence of acute tubular necrosis at 5 months after starting TDF treatment. The second patient developed acute kidney injury at 17 days after commencing TDF, and he was found to have membranoproliferative glomerulonephritis with acute tubular injury. The renal function improved in both patients after discontinuing TDF. We discuss the risk factors for TDF-associated renal toxicity and present recommendations for monitoring renal function during TDF therapy. (Clin Mol Hepatol 2016;22:286-291)

Modified AS1411 Aptamer Suppresses Hepatocellular Carcinoma by Up-regulating Galectin-14

( Hyeki Cho ),( Yun Bin Lee ),( Yuri Cho ),( Jeong-hoon Lee ),( Dong Hyeon Lee ),( Jeong-ju Yoo ),( Young Youn Cho ),( Eun Ju Cho ),( Su Jong Yu ),( Yoon Jun Kim ),( Jong In Kim ),( Jong Hun Im ),( Ju 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: Aptamers are small synthetic oligonucleotides that bind to target proteins with high specificity and affinity. AS1411 is an aptamer that binds to the protein nucleolin, which is overexpressed in the cytoplasm and occurs on the surface of cancer cells. We investigated the therapeutic potential of aptamers in treating hepatocellular carcinoma (HCC) by evaluating anti-tumor effects and confirming the affinity and specificity of AS1411 and modified AS1411 aptamers in HCC cells. Methods: Cell growth was assessed using the MTS assay, and cell death signaling was explored by immunoblot analysis. Fluore- scence-activated cell sorting was performed to evaluate the affinity and specificity of AS1411 aptamers in SNU-761 HCC cells. We investigated the in vivo effects of the AS1411 aptamer using BALB/c nude mice in a subcutaneous xenograft model with SNU-761 cells. Results: Treatment with a modified AS1411 aptamer significantly decreased in vitro (under normoxic [P=0.035] and hypoxic [P=0.018] conditions) and in vivo (under normoxic conditions, P=0.041) HCC cell proliferation compared to control aptamers. AS1411 and control aptamers failed to control HCC cell proliferation. However, AS1411 and the modified AS1411 aptamer did not induce caspase activation. Decrease in cell growth by AS1411 or modified AS1411 was not prevented by caspase or necrosis inhibitors. In a microarray, AS1411 significantly enhanced galectin-14 expression. Suppression of HCC cell proliferation by the modified AS1411 aptamer was attenuated by galectin-14 siRNA transfection. Conclusions: The modified AS1411 aptamer suppressed HCC cell growth in vitro and in vivo by up-regulating galectin-14 expression. Modified AS1411 aptamers may have therapeutic potential as a novel targeted therapy for HCC.

Efficacy and Safety of Daclatasvir plus Asunaprevir for Hepatitis C Virus Genotype 1b Infection

( Hyeki Cho ),( Yoon Jun Kim ),( Young Chang ),( Joon Yeul Nam ),( Young Youn Cho ),( Eun Ju Cho ),( Jeong-hoon Lee ),( Su Jong Yu ),( Jung-hwan Yoon ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Introduction of all-oral therapy with direct-acting antivirals has changed the treatment strategy for hepatitis C virus (HCV) infection. We evaluated the efficacy and safety of daclatasvir (NS5A replication complex inhibitor) plus asunaprevir (NS3 protease inhibitor) in real- world HCV genotype 1b-infected Korean individuals. Methods: Patients received daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily for 24 weeks. The primary endpoint was sustained virologic response at 12 weeks after treatment (SVR12). Results: This retrospective study included 182 patients with chronic HCV genotype 1b infection. Among them, 86 patients (47.3%) were diagnosed with compensated cirrhosis, and 46 patients (25.3%) experienced previous pegylated interferon and ribavirin treatment. Daclatasvir plus asunaprevir provided SVR12 in 90.7% (n = 165) of the entire cohort. Seven of the 17 who failed to achieve SVR12 had discontinued treatment before 24 weeks due to viral breakthrough. HCV NS5A resistance-associated variants (RAVs) were confirmed in 12 of 17 patients. Adverse events leading to discontinuation occurred in 2 patients, with no death recorded. SVR12 was achieved by 87.2% (75 of 86) of patients with compensated cirrhosis and 93.8% (90 of 96) of non-cirrhosis patients; rates were similar in treatment- experienced patients (91.3%, 42 of 46) and treatment-naïve patients (90.4%, 123 of 136). Conclusions: Treatment with daclatasvir plus asunaprevir achieved high sustained virological response with few adverse events even in those with compensated cirrhosis and nonresponse/relapse to prior interferon-based therapy.

The Role of Nuclear Factor Erythroid 2-Related Factor 2 in Resistance of Hepatocellular Carcinoma to Sorafenib

( Hyeki Cho ),( Young Chang ),( Joon Yeul Nam ),( Young Youn Cho ),( Eun Ju Cho ),( Jeong-hoon Lee ),( Su Jong Yu ),( Jung-hwan Yoon ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor regulating antioxidant and detoxification enzymes, and has recently emerged as an important contributor to chemoresistance in cancer therapy. Minichromosome maintenance proteins (MCMs), essential for DNA replication, are frequently upregulated in various cancers and have also been implicated in chemoresistance. However, their roles in hepatocellular carcinoma (HCC) remains unclear, and therefore, we investigated whether Nrf2 or MCMs are participating in resistance of HCC to Sorafenib. Methods: We performed in vitro experiments using Sorafenib-sensitive and -resistant Huh-7 cell lines under either normoxic or hypoxic conditions. The nuclear translocation of Nrf2 and the expression of MCM were examined using immunoblot analyses. MTS and invasion assays were performed to evaluate the role of Nrf2 in HCC cells. The mechanism of cell death was investigated using small interfering RNA (siRNA) transfection and immunoblot analyses. Results: Sorafenib-resistant Huh-7 cells showed higher Nrf2 nuclear translocation than Sorafenib-sensitive Huh-7 cells. Knockdown of Nrf2 expression by siRNA transfection markedly attenuated the cell proliferation and hypoxia-induced invasion of Huh-7 cells. Both Nrf2 siRNA transfection and the treatment with inhibitor of TGF-β-activated kinase 1 (TAK-1), a known Nrf2 regulator, significantly improved sensitivity to Sorafenib in Sorafenib-resistant cells. However, the expression of MCM2 and MCM7 were decreased in Sorafenib-resistant Huh-7 cells, and the expression of microRNA 1296, which can regulate MCMs, was increased in Sorafenib-resistant cells, indicating that MCMs are not participating in Sorafenib resistance. Conclusions: These results implicate that Nrf2 may be involved in Sorafenib resistance in HCCs. Therefore, Nrf2 may serve as a therapeutic target for HCCs.

Incomplete Biochemical Response Increases the Risk of Hepatocellular Carcinoma in Patients with Suppressed Chronic Hepatitis B

( Hyeki Cho ),( Young Youn Cho ),( Jeong-hoon Lee ),( Young Chang ),( Joon Yeul Nam ),( Dong Ho Lee ),( Eun Ju Cho ),( Su Jong Yu ),( Yoon Jun Kim ),( Jeong Min Lee ),( Jung-hwan Yoon ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: It has been unclear whether incomplete biochemical response (BR) is related to the risk of hepatocellular carcinoma (HCC) among chronic hepatitis B (CHB) patients who achieve virologic suppression with nucleos(t)ide analogues (NAs). This study evaluated the association between BR and the risk of HCC. Methods: This retrospective study included consecutive CHB patients whose serum hepatitis B virus (HBV) DNA levels were suppressed below 2,000 IU/mL with NAs. Patients with concomitant hepatitis C infection, autoimmune hepatitis, or excessive alcohol use were excluded. Multivariable cox proportional hazards model was applied. Results: Among 826 patients, 743 patients (89.9%) had evidence of cirrhosis at the time of virologic response. Eighty-five patients (10.3%) developed HCC during the study period (median, 43.1 months). Patients with elevated ALT levels (≥40 IU/L, N=356) in spite of HBV suppression had a significantly higher risk for HCC compared with patients with low ALT levels (<40 IU/L, N=470) (adjusted hazard ratio [aHR], 1.61; 95% confidence interval [CI], 1.04-2.49; P=0.031) after adjustment for age, serum albumin, HBeAg-positivity, hypertension, and the presence of cirrhosis. Among patients who failed to achieve BR, 150 (42.1%) had sonographical fatty liver and there was significant association between BR and the presence of fatty liver (P<0.001 by chi-square test). Patients with radiological fatty liver (N=260) had a significantly higher risk for HCC compared with patients without radiologically-proven fatty liver (N=566) (aHR, 1.71; 95% CI, 1.09-2.69; P=0.019). Conclusions: Incomplete BR increases the risk of HCC in patients with CHB whose HBV is effectively suppressed by NAs and radiological fatty liver was the major cause of incomplete BR. Further study is warranted to evaluate whether the improvement of fatty liver might decrease the risk of HCC development.

Model to Predict Recurrence after Living Donor Liver Transplantation for Hepatocellular Carcinoma beyond the Milan Criteria

Yuri Cho,Jeong-Hoon Lee,Dong Hyeon Lee,Hyeki Cho,Hongkeun Ahn,Minjong Lee,Jeong-ju Yoo,Won-mook Choi,Young Youn Cho,Yun Bin Lee,Su Jong Yu,Nam-Joon Yi,Kwang-Woong Lee,Seoung Hoon Kim,Jong Man Kim,Jae- 한국간담췌외과학회 2014 한국간담췌외과학회 학술대회지 Vol.2014 No.4

복수와 간성뇌증의 치료

조혜기 ( Hyeki Cho ) 대한간학회 2023 간질환 연수강좌 Vol.2023 No.1

Lipids Induce Release of Tumor-Promoting Exosomes from Hepatocellular Carcinoma Cells

( Eun Ju Cho ),( Hyo Yeong Lee ),( Joon Yeul Nam ),( Young Chang ),( Hyeki Cho ),( Young Youn Cho ),( Jeong-hoon Lee ),( Su Jong Yu ),( Yoon Jun Kim ),( Jung-hwan Yoon ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Hypoxia enhances lipid droplets accumulation by HIF-dependent mechanism, leading to intra-tumoral fatty metamorphosis which is one of the characteristics of early-stage hepatocellular carcinoma (HCC). We investigated whether lipids and lipids-induced exosomes released from HCC cells can induce a tumor-promoting phenotype. Methods: Human HCC cell lines (Huh-7, SNU-761, and SNU-3058) were incubated with oleic acid (OA) or control vehicle. The released exosomes were isolated, quantified, and applied to HCC cells. Results: Incubation of Huh-7 and SNU-761 cells with OA increased proliferation and migration of cells in a fatty-acid binding protein 3 (FABP-3) dependent manner, whereas SNU-3058 cells did not respond to OA. Furthermore, OA upregulated FABP-3 mRNA expression in Huh-7 and SNU-761 cells, whereas its expression in SNU-3058 cells did not change. OA enhanced release of exosomes from Huh-7 and SNU-761 cells, and exosomes collected form these cells upregulated proliferation and invasion of cells. However, this was not observed in SNU-3058 cells. Exosomes released from OA-treated cells were reduced by the inhibition of rho-associated, coiled-coil-containing protein kinase 1 (ROCK1) or FABP-3. Conclusions: These findings suggest that lipids induce release of exo-somes containing unique cargoes from HCC cells in a FABP-3 dependent manner, which may induce the progression of HCC.

Long-term Nucleotide Analogue Treatment Has Higher Levels of Renal Toxicities than Does Entecavir in Patients with Chronic Hepatitis B

( Young Youn Cho ),( Young Chang ),( Joon Yeul Nam ),( Hyeki Cho ),( Eun Ju Cho ),( Jeong-hoon Lee ),( Su Jong Yu ),( Jung-hwan Yoon ),( Yoon Jun Kim ) 대한간학회 2020 Gut and Liver Vol.14 No.2

Background/Aims: Renal toxicity is a concern in patients with chronic hepatitis B taking nucleotide analogues, such as adefovir (ADV) and tenofovir disoproxil fumarate (TDF). We sought to determine the long-term renal effects of nucleotide analogue treatment versus entecavir (ETV) treatment. Methods: In this retrospective single-center study, we selected 87 patients who were treated with ADV and subsequently with TDF from June 2008 to December 2013. ETV-treated patients were matched by treatment duration. We analyzed the creatinine increase over 0.5 mg/dL, glomerular filtration rate (GFR) decrease over 25%, phosphorus decrease under 2.0 mg/dL, and dose reduction of antiviral agents. Results: The median follow-up period was 60.0 months for both groups. The incidence of liver cirrhosis was higher in the ADV-TDF group than in the ETV group (32.2% vs 74.7%, p<0.01). Creatinine increased in both groups during follow-up, but the difference was not significant (5.7% and 2.3%, p=0.44). In addition, GFR decreased more often in the ADV-TDF group than in the ETV group (31.0% and 14.9%, p=0.01). After multivariate Cox regression analysis, ADV-TDF treatment was significantly associated with a GFR decrease over 25% (hazard ratio, 2.10; 95% confidence interval, 1.08 to 4.10; p=0.03) after adjusting for the baseline GFR decrease. Conclusions: Patients taking nucleotide analogues had a significantly higher number of renal events than did those taking ETV. Clinicians should be aware of the development of renal toxicity in this patient population. Further long-term studies are warranted.