Antiviral-Induced HBsAg-Seroclearance Might Not Necessarily Indicate a Functional Cure of Chronic Hepatitis B and Can Be Reversed

( Minseok Albert Kim ),( Jeong-hoon Lee ),( Sungwon Chung ),( Sun Woong Kim ),( Jun Sik Yoon ),( Young Chang ),( Eun Ju Cho ),( Su Jong Yu ),( Yoon Jun Kim ),( Jung-hwan Yoon ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: The seroclearance of hepatitis B virus (HBV) surface antigen (HBsAg) is currently considered as a functional cure of chronic hepatitis B. However, there is still a lack of evidence whether the HBsAg-seroclearance is a reliable and durable indicator of HBV eradication. In this study, we aimed to evaluate the reliability and durability of NA-induced HBsAg-seroclearance. Methods: Among 1,100 patients with chronic hepatitis B, 33 patients who achieved HBsAg-seroclearance with NA treatment between January 2010 and December 2017 at a single referral center were analyzed retrospectively. HBsAg was examined using ELISA kit (ARCHITECT HBsAg Qualitative II; Abbott, Wiesbaden, Germany) and < 1.17 S/Co (~0.02 IU/mL) was defined as a negativity. Results: The median age at NA-induced HBsAg-seroclearance was 59.8 (range, 22.4-74.6) years and median NA treatment duration before seroclearance was 76.1 (range, 11.3-193.5) months. At the time of HBsAg-seroclearance, all patients had undetectable serum HBV DNA (< 20 IU/mL). Among them, 22 patients (66.7%) stopped NAs after HBsAg-seroclearance (the NA-off group) and the remaining 11 patients (33.3%) maintained NAs for median 23.5 (range, 5.0-49.8) months (the NA-maintenance group) after HBsAg-seroclearance. During follow-up period (median, 35.0 months; range, 4.7-89.9), two patients (one in the NA-off group and one in the NA-maintenance group) experienced HBsAg-seroreversion although their serum HBV DNA were not detectable. Of the two patents, a patient who are in the NA-maintenance group developed HBsAg-seroreversion at 19 months after HBsAg-seroclearance and again experienced HBsAg-re-seroclearance 17 months later. Interestingly, both patients experiencing HBsAg-seroreversion had hepatocellular carcinoma. Conclusions: A single time negative-conversion of HBsAg might not be a reliable and durable indicator of HBV eradication since there were a few cases of detectable HBV DNA and HBsAg-seroreversion. Thus, repeated evaluation of both HBsAg and HBV DNA might be necessary to confirm the functional cure of chronic hepatitis B undergoing antiviral treatment.

Yttrium-90 Radioembolization Might Have Better Efficacy in Overall Survival in Patients with Hepatocellular Carcinoma Compared with Conventional Chemoembolization: A Propensity Score-Matched Study

( Minseok Albert Kim ),( Heejoon Jang ),( Hyunwoo Oh ),( Joon Yeul Nam ),( Yun Bin Lee ),( Eun Ju Cho ),( Jeong-hoon Lee ),( Su Jong Yu ),( Jung-hwan Yoon ),( Hyo-cheol Kim ),( Jin Wook Chung ),( Yoon 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: Locoregional therapies, such as yttrium-90 (Y-90) radioembolization (RE) and conventional chemoembolization (CE) can effectively control localized hepatocellular carcinoma (HCC) in patients who are not amenable to curative resection. However, it has not yet been fully established which modality is more effective. The aim of this study was to compare effectiveness of RE and CE as the first treatment of HCC. Methods: We retrospectively reviewed data of patients who received RE or CE as the first treatment of HCC at Seoul National University Hospital from March 2012 to December 2017. A propensity score matching was performed to reduce selection bias. Overall survival (OS), progression-free survival (PFS), and intrahepatic PFS were compared. Results: A total of 138 patients who were initially treated with RE (n=54) or CE (n=84) was included in this study and baseline characteristics was well-balanced between the two groups. Of 138 patients, median age was 59 and median follow-up period was 22.5 months. RE showed better overall survival than CE (hazard ratio [HR]=0.30, 95% confidence interval [CI]=0.10- 0.90, log-rank P=0.02) and tended toward better intrahepatic PFS than CE (HR=0.52, 95% CI=0.25-1.09, log-rank P=0.08). However, progression-free survival was not significantly different between the two groups (HR=0.67, 95% CI=0.39-1.16, log-rank P=0.15). In multivariable analysis, RE was an independent prognositc factor for overall survival (adjusted HR=0.31, 95% CI=0.11-0.92, P=0.04). Conclusions: RE might be more effective as the initial treatment than CE in patients with HCC.

Effectiveness of nivolumab versus regorafenib in hepatocellular carcinoma patients who failed sorafenib treatment

Cheol-Hyung Lee,Yun Bin Lee,Minseok Albert Kim,Heejoon Jang,Hyunwoo Oh,Sun Woong Kim,Eun Ju Cho,Kyung-Hun Lee,Jeong-Hoon Lee,Su Jong Yu,Jung-Hwan Yoon,Tae-You Kim,Yoon Jun Kim 대한간학회 2020 Clinical and Molecular Hepatology(대한간학회지) Vol.26 No.3

Background/Aims: Several treatment options are currently available for patients with hepatocellular carcinoma (HCC) failing previous sorafenib treatment. We aimed to compare the effectiveness of regorafenib and nivolumab in these patients. Methods: Consecutive HCC patients who received regorafenib or nivolumab after failure of sorafenib treatment were included. Primary endpoint was overall survival (OS) and secondary endpoints were time to progression, tumor response rate, and adverse events. Inverse probability of treatment weighting (IPTW) using the propensity score was conducted to reduce treatment selection bias. Results: Among 150 study patients, 102 patients received regorafenib and 48 patients received nivolumab. Median OS was 6.9 (95% confidence interval [CI], 3.0–10.8) months for regorafenib and 5.9 (95% CI, 3.7–8.1) months for nivolumab (P=0.77 by log-rank test). In multivariable analysis, nivolumab was associated with prolonged OS (vs. regorafenib: adjusted hazard ratio [aHR], 0.54; 95% CI, 0.30–0.96; P=0.04). Time to progression was not significantly different between groups (nivolumab vs. regorafenib: aHR, 0.82; 95% CI, 0.51–1.30; P=0.48). HRs were maintained after IPTW. Objective response rates were 5.9% and 16.7% in patients treated with regorafenib and nivolumab, respectively (P=0.04). Conclusions: After sorafenib failure, the use of nivolumab may be associated with improved OS and better objective response rate as compared to using regorafenib.

Characterization of Cirrhotic Cardiomyopathy Using Cardiac Magnetic Resonance Imaging: A Prospective Study

( Yun Bin Lee ),( Hyue Mee Kim ),( Sung Won Chung ),( Minseok Albert Kim ),( Sun Woong Kim ),( Jun Sik Yoon ),( Hyo Young Lee ),( Young Chang ),( Eun Ju Cho ),( Su Jong Yu ),( Yoon Jun Kim ),( Jung- H 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Liver cirrhosis is known to decrease the cardiac performance. However, it is unclear whether this change is related to the change in myocardial muscle itself, or is a secondary functional phenomenon. In this study, we aimed to characterize myocardial tissue using cardiovascular magnetic resonance (CMR) imaging in cirrhotic patients. Methods: Thirty-five patients with cirrhosis who were listed for liver transplantation and 20 normal healthy controls were prospectively enrolled. All included subjects underwent conventional echocardiography, speckle-tracking echocardiography, and CMR imaging with T1 mapping and late gadolinium enhancement. Native T1 and extracellular volume (ECV) were measured for assessing myocardial fibrosis. Echocardiography and CMR imaging were performed at just before and 1 year after liver transplantation. Results: Both echocardiography and CMR imaging demonstrated hyperdynamic left ventricular (LV) function in cirrhotic patients. There were no significant differences in LV size, LV wall thickness, LV mass index, E/A ratio, and deceleration time between cirrhotic patients and non-cirrhotic healthy controls (all P>0.1). However, cirrhotic patients showed significantly higher values of native T1 (1230.1±79.0 vs 1173.3±34.7, P=0.001) (Table 1 and Figure 1A) and ECV (31.4±4.9 vs 25.4±1.9, P<0.001) (Table 1 and Figure 1B) compared to non-cirrhotic controls. Specifically, ECV had a significant correlation with Child-Pugh class (26.2±3.4 in Child class A or B vs 33.2±4.3 in Child class C; P=0.001). At 1 year after liver transplantation, native T1 (from 1224.0±55.7 to 1155.8±77.0, P=0.010) and ECV (from 30.9±3.6 to 25.2±2.6, P<0.001) values significantly decreased, but there was no difference in other parameters regarding LV function and LV size. Conclusions: Decreased cardiac performance in cirrhotic patients may result from myocardial change reflected by the increase in native T1 and ECV values, which was normalized after liver transplantation. Native T1 and ECV values of CMR imaging could be more straightforward diagnostic indices for cirrhotic cardiomyopathy.

Comparison of Overall Survival between Surgical Resection and Radiofrequency Ablation for Early Hepatitis B-Related Hepatocellular Carcinoma after Adjusting Antiviral Treatment

( Moonhaeng Hur ),( Jeong-Hoon Lee ),( Ju Yeon Kim ),( Ji Hoon Hong ),( Min Kyung Park ),( Hee Jin Cho ),( Ji Hye Kim ),( Minseok Albert Kim ),( Joon Yeul Nam ),( Yun Bin Lee ),( Eun Ju Cho ),( Su Jon 대한간학회 2021 춘·추계 학술대회 (KASL) Vol.2021 No.1

Fibrates Significantly Increase the Biochemical Response and Reduce the Risk of Cirrhosis Development in UD-CA-Refractory Primary Biliary Cholangitis Patients

( Sung Won Chung ),( Jeong-hoon Lee ),( Minseok Albert Kim ),( Sun Woong Kim ),( Young Chang ),( Hyo Young Lee ),( Joon Sik Yoon ),( Yun Bin Lee ),( Eun Ju Cho ),( Su Jong Yu ),( Yoon Jun Kim ),( Jung 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Ursodeoxycholic acid (UDCA) is the only treatment which can modify the clinical course of primary biliary cholangitis (PBC) and there have been few treatment options for UDCA-refractory PBC. Several studies reported that fibrates effectively reduce serum alkaline phosphatase (ALP) levels in UDCA-refractory PBC, but their long-term effects remain unclear. The aim of this study was to evaluate the effect of fibrates on clinical outcomes in UDCA-refractory PBC. Methods: This retrospective study involved consecutive patients whose ALP had not been normalized with UDCA treatment for >1 year at a tertiary referral center. The primary outcome was the rate of ALP (± gamma-glutamyltransferase [GGT]) normalization and secondary outcomes included the development of liver cirrhosis, hepatocellular carcinoma, death, and liver transplantation. Baseline characteristics were adjusted or balanced using inverse probability weighting analysis (IPW) and the Cox hazards model. Results: A total of 66 UDCA-refractory PBC patients were included: 45 patients who were treated with 13-15 mg/kg of UDCA (the UDCA group) and 21 patients who received UDCA + additional fibrate (fenofibrate 160 mg/day or bezafibrate 200 mg/day; the fibrate/UDCA group). The baseline serum levels of aspartate aminotransferase (53.8±33.5 vs 38.8±17.1 IU/L, P=0.02) and albumin (4.0±0.5 vs 4.2±0.2 g/dL, P=0.006) significantly differed between two groups. The rates of both ALP normalization (hazard ratio [HR]=7.82, 95% confidence interval [CI]=3.65-16.77, P<0.001 by log-rank test) and ALP/GGT normalization (HR=5.50, 95% CI=2.34-12.95, P<0.001) were significantly higher in the fibrate/UDCA group. At week 48, ALP was normalized in 86.3% of the fibrate/UDCA group and 17.9% of the UDCA group. Of the 36 patients who had no baseline cirrhosis (11 in the fibrate/ UDCA group and 25 in the fibrate/UDCA group), none in the fibrate/UDCA group and 9 patients (36.0%) in the UDCA group developed cirrhosis (HR=0.16, 95% CI=0.001-1.35, P=0.09) during study period. However, when baseline characteristics were balanced by IPW, the fibrate/UDCA group demonstrated a significantly lower risk of cirrhosis development (P=0.02). Neither the risk of hepatocellular carcinoma development (P=0.69) nor death or liver transplantation (P=0.16) differed significantly. Conclusions: In PBC patients who failed to achieve ALP normalization despite the appropriate dose of UDCA, additional fibrate treatment is associated with a higher probability of ALP normalization and a lower risk of cirrhosis.

Comparison of the Effects of Ultrasound Alone and Ultrasound, Computed Tomography, and Magnetic Resonance Imaging Combination on Surveillance in High-Risk Patients with Hepatocellular Carcinoma

( Heejoon Jang ),( Minkyung Park ),( Na Ryung Choi ),( Minseok Albert Kim ),( Hyunwoo Oh ),( Joon Yeul Nam ),( Yun Bin Lee ),( Eun Ju Cho ),( Jeong-hoon Lee ),( Su Jong Yu ),( Jung-hwan Yoon ),( Yoon 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: Many guidelines suggest ultrasonography at six-month intervals for patients at high risk for hepatocellular carcinoma (HCC). Nevertheless, surveillance is often performed by combining ultrasound with computed tomography (CT) and magnetic resonance imaging (MRI). This study analyzed the differences in clinical outcomes depending on whether the patients had imaging tests other than ultrasound as a surveillance test. Methods: Patients diagnosed with chronic hepatitis B or cirrhosis at Seoul National University Hospital from 2010 to 2014 were included. Patients diagnosed with other cancers or with surveillance intervals shorter or longer than 6±1 month were excluded. Patients were divided into 2 groups: those who only had ultrasound scans (USG group) and those who had a combination of ultrasound, CT, and MRI. (combination group). Propensity score matching was applied to adjust the difference in baseline characteristics between the two groups. The difference of HCC detection, liver-related mortality and all-cause mortality between the two groups was analyzed by the Cox proportional hazards model. The difference in the stages at HCC diagnosis between the two groups was compared using Fisher’s exact test. Results: From a total of 4,779 patients, we obtained a propensity score matched cohort of 794 patients. The combination group showed a higher risk of HCC detection than the USG group. (adjusted hazard ratio [aHR] 2.07; 95% confidence interval [CI] 1.21-3.54) The combination group showed more very early stages at the time of HCC diagnosis based on the Barcelona Clinic Liver Cancer staging system. (Fisher’s exact test P=0.03). Liver-related mortality (aHR 2.00; 95% CI 0.53-7.56) and all-cause mortality (aHR 1.06; 95% CI 0.49-2.26) were not significantly different between the two groups. Conclusions: Combining ultrasound, CT, and MRI as a surveillance test may detect HCC in earlier stages.

A MoRAL Score Utilizing Serum Tumor Markers Provides Refined Prognostication of Patients with Hepatocellular Carcinoma after Curative Resection: Data from 662 Con-secutive Patients

( Hyo Young Lee ),( Yun Bin Lee ),( Jeong-hoon Lee ),( Sungwon Chung ),( Minseok Albert Kim ),( Sun Woong Kim ),( Jun Sik Yoon ),( Young Chang ),( Eun Ju Cho ),( Su Jong Yu ),( Nam-joon Yi ),( Yoon Ju 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: We recently developed and validated a MoRAL score (=11 x √PIVKA + 2 x √AFP) that can predict the risk of hepatocellular carcinoma (HCC) recurrence after living-donor liver transplantation (LDLT) regardless of tumor size and number, which may reflect tumor cell biology. Patients with a low MoRAL score (≤ 314.8) showed excellent treatment outcomes after LDLT, even though they are beyond the Milan criteria. We investigated whether a MoRAL score is a predictor of HCC recurrence and mortality after curative hepatic resection. Methods: A total of 662 consecutive patients who underwent curative resection for HCC of BCLC stage 0-B between 2006 and 2013 at a single tertiary referral center were included. Primary and secondary endpoints were recurrence-free survival (RFS) and overall survival (OS), respectively. Results: During a median observation period of 68.8 months, 326 (49.2%) patients experienced tumor recurrence and 59 (8.9%) died. In multivariable analysis, high MoRAL score (>314.8) was an independent risk factor of both recurrence (adjusted hazard ratio [aHR]=1.61, 95% confidence interval [CI]=1.22-2.12, P=0.001) and death (aHR=2.62, 95% CI=1.49-4.59, P=0.001). The presence of cirrhosis was another independent prognostic factor for RFS (aHR=1.76, 95% CI=1.38-2.24, P<0.001) and OS (aHR=1.82, 95% CI=1.06- 3.14, P=0.031). When patients were stratified into four groups as low-MoRAL/no-cirrhosis, low-MoRAL/cirrhosis, high-MoRAL/ no-cirrhosis, or high-MoRAL/cirrhosis; the RFS (Figure 1A) and OS (Figure 1B) significantly differed among strata (all P<0.001). Median RFSs of the high-MoRAL/LC, the low-MoRAL/LC, and the high-MoRAL/no-LC groups were 20.4, 41.8, and 53.2 months, respectively; while the low-MoRAL/no-LC group did not reach median RFS. A MoRAL score showed significant association to hypermetabolism on positron emission tomography (P<0.001, chi-squared test for trend) and cytokeratin 19-positivity in tumor tissue (P=0.003, Pearson chi-square), which reflect aggressive tumor cell biology. Conclusions: A MoRAL score was an independent predictor of tumor recurrence and mortality after curative resection of HCC regardless of tumor size and number and reflects tumor biology. Combination of MoRAL score and the presence of cirrhosis might be utilized as an accurate prediction model.

Risk and Risk Score Performance for Hepatocellular Carcinoma Development in Patients with HBsAg Seroclearance

( Yewan Park ),( Jeong-hoon Lee ),( Dong Hyun Sinn ),( Jun Yong Park ),( Minseok Albert Kim ),( Yoon Jun Kim ),( Jung-hwan Yoon ),( Do Young Kim ),( Sang Hoon Ahn ),( Wonseok Kang ),( Geum-youn Gwak ) 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: Hepatocellular carcinoma (HCC) can develop after hepatitis B surface antigen (HBsAg) seroclearance. However, whether HCC risk differs between antiviral therapy (AVT)-induced or spontaneous seroclearance cases, and ways to identify atrisk populations remain unclear. We compared the HCC risk between AVT-induced and spontaneous cases and tested whether several HCC risk prediction models could be applied to HBsAg seroclearance patients. Methods: A retrospective cohort of 1,200 patients (median age: 56 years; 824 males; 165 with cirrhosis; 216 AVT-induced cases) who achieved HBsAg seroclearance were analyzed for the development of HCC after HBsAg seroclearance. The performance of five HCC prediction models, CU-HCC, GAG-HCC, REACH-B, PAGE-B, and modified PAGE-B, was assessed. Results: During a median of 4.8 years of follow-up (range: 0.5 - 17.8 years), HCC developed in 23 patients (1.9%). The HCC incidence rate was higher in the AVT-induced cases than in the spontaneous cases (3.9% vs. 0.9% at five years). AVT and cirrhosis were independent factors associated with HCC, with HCC incidence rates of 0.5%, 1.2%, 4.0%, and 10.5% at five years for spontaneous/no-cirrhosis, AVT-induced/no-cirrhosis, spontaneous/cirrhosis, and AVT-induced/cirrhosis patients, respectively. The area under the receiver operating curve (AUROC) for HCC development at five years was highest for CU-HCC scores (0.82). The HCC incidence was high for high CU-HCC scores (14.3% at five years) and high GAG-HCC scores (7.9% at five years), and was very low for low PAGE-B scores (0% at five years) or low modified PAGE-B scores (0% at five years). Conclusions: AVT-induced HBsAg seroclearance was associated with higher HCC risk, especially for patients with cirrhosis, indicating that they need careful monitoring for HCC risk. The HCC risk models were able to stratify the HCC risk in patients with HBsAg seroclearance.

Effectiveness of Lenvatinib versus Sorafenib for Unresectable Hepatocellular Carcinoma in Patients with Hepatic Decompensation

( Min Kyung Park ),( Yun Bin Lee ),( Hyemi Moon ),( Na Ryung Choi ),( Minseok Albert Kim ),( Heejoon Jang ),( Joon Yeul Nam ),( Eun Ju Cho ),( Jeong-hoon Lee ),( Su Jong Yu ),( Yoon Jun Kim ),( Jung-h 대한간학회 2021 춘·추계 학술대회 (KASL) Vol.2021 No.1