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.

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.

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 Severity of COVID-19 in Patients with Nonalcoholic Fatty Liver Disease in Korea

( Hyeki Park ),( Hyun Joe ) 한국보건행정학회 2021 보건행정학회지 Vol.31 No.4

Background: Early identification of patients who are highly likely to develop severe illness among confirmed cases of coronavirus disease 19 (COVID-19) can be expected to lead to effective treatment. This study therefore aimed to determine whether the presence of nonalcoholic fatty liver disease (NAFLD) has an impact on the exacerbation of COVID-19 symptoms. Methods: The study used the Korean National Health Insurance claim data for treatment of COVID-19 patients in 2020. NAFLD includes nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). The outcome variables used were hospitalization and the use of medical devices. Hospitalization was defined by a length of stay exceeding one day and the use of medical devices was defined as one or more uses of a ventilator or extracorporeal membrane oxygenation. Multivariable logistic regression analysis was performed to determine if there was a difference in the hospitalization and use of medical devices of COVID-19 patients depending on the presence of NAFLD. Results: The odds ratio of hospitalization was 1.059, indicating slightly higher odds of hospitalization for patients with NAFL or NASH compared to those without the conditions, but it was not statistically significant (0.969-1.156). On the other hand, the odds ratio of use of medical devices was high at 1.667 and was statistically significant (1.111-2.501). Conclusion: The study results found NAFLD to be a risk factor that can exacerbate symptoms in COVID-19 patients. Accordingly, it is necessary to identify NAFLD patients through preemptive screening and provide them with appropriate treatments.

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)

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.

코로나19 유행에 따른 보건소 진료량 변화분석

박혜기 ( Hyeki Park ),양유선 ( Yu Seon Yang ) 대한보건협회 2021 대한보건연구 Vol.47 No.3

연구목적 : 한국은 코로나19 유행기간 동안 보건소의 건강증진사업과 진료서비스를 긴급히 축소하고 의료진을 방역 업무에 배치하였다. 이 연구는 코로나19 대응이 보건소의 진료제공에 미치는 영향을 평가하고자 하였다. 연구방법 : 2018년 12월부터 2020년 8월(85주)까지 국민건강보험과 의료급여 청구 자료를 사용하였다. 코로나19 유행 전, 확산기, 회복기의 세 단계를 기준으로 단적절 시계열 분석을 시행하였으며, 지역별 차이를 확인하기 위한 시도별 하위 그룹 분석 또한 수행되었다. 주요결과 : 코로나19의 발생(β: -64,448, P value <0.0001)과 확산(β: -7,346, P value: 0.0003)이 보건소 이용량을 감소시키는 것으로 나타났다. 진료량은 사회적 거리두기를 완화한 시점에(β: 27,650, P value: 0.0176) 증가했으며, 이후에도 점차 증가했다(β: 8,507, P value <0.0001). 결론 : 코로나19 유행에 따라 보건소에서 의료 서비스 제공량이 감소했으며, 유행이 약화 되었음에도 불구하고 완전히 회복되지 않았다. 이는 보건소의 의료제공에 공백이 존재했음을 의미하며, 보건소의 주요 이용자인 취약 계층을 위한 지원의 필요성을 시사한다. Background : In the Republic of Korea, medical personnel at the Public health centers (PHCs) were urgently deployed to the quarantine while the healthcare projects and medical treatments are scaled back during the COVID-19 pandemic. This study aimed to evaluate the impact of COVID-19 response on the number of visits at PHCs. Materials and methods : The Republic of Korean National Health Insurance and Medical Aid claims data between December 2018 and August 2020 (85 weeks) were used. Interrupted time series and segmented regression model was conducted for statistical analysis by three stages (pre-wave period, the spreading period during the wave and recovery period). Subgroup analysis was performed based on the regions. Results : The results showed that the outbreak (β: -64,448, P value < 0.0001) and the spreading (β: -7,346, P value: 0.0003) of COVID-19 decreased the number of visits. The volume increased when the social distancing was eased (β: 27,650, P value: 0.0176), and gradually increased (β 8,507, P value < 0.0001). Conclusion : In conclusion, the COVID-19 pandemic decreased the volume of healthcare services at PHCs. However, it was not fully recovered again despite the weakening of the prevalence, implying that the vacuum of healthcare has existed at PHCs. The findings suggest the importance of alternative supports for healthcare for the vulnerable, who are the main user of health centers.

복수와 간성뇌증의 치료

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

Nakagami 페이딩 채널하에서 PSK 신호의 변조 분류

오혜기(Hyeki Oh),김치환(Chihwan Kim),윤동원(Dongweon Yoon),한영열(Youngyearl Han) 대한전자공학회 1995 대한전자공학회 학술대회 Vol.1995 No.12