Publications by authors named "Kwang-Hyub Han"

544 Publications

Pharmacodynamic Biomarkers Predictive of Survival Benefit with Lenvatinib in Unresectable Hepatocellular Carcinoma: From the Phase III REFLECT Study.

Clin Cancer Res 2021 Jun 9. Epub 2021 Jun 9.

Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK.

Purpose: In REFLECT, lenvatinib demonstrated an effect on overall survival (OS) by confirmation of noninferiority to sorafenib in unresectable hepatocellular carcinoma. This analysis assessed correlations between serum or tissue biomarkers and efficacy outcomes from REFLECT.

Experimental Design: Serum biomarkers (VEGF, ANG2, FGF19, FGF21, and FGF23) were measured by ELISA. Gene expression in tumor tissues was measured by the nCounter PanCancer Pathways Panel. Pharmacodynamic changes in serum biomarker levels from baseline, and associations of clinical outcomes with baseline biomarker levels, were evaluated.

Results: Four hundred and seven patients were included in the serum analysis set (lenvatinib = 279, sorafenib = 128); 58 patients were included in the gene-expression analysis set (lenvatinib = 34, sorafenib = 24). Both treatments were associated with increases in VEGF; only lenvatinib was associated with increases in FGF19 and FGF23 at all time points. Lenvatinib-treated responders had greater increases in FGF19 and FGF23 versus nonresponders at cycle 4, day 1 (FGF19: 55.2% vs. 18.3%, = 0.014; FGF23: 48.4% vs. 16.4%, = 0.0022, respectively). Higher baseline VEGF, ANG2, and FGF21 correlated with shorter OS in both treatment groups. OS was longer for lenvatinib than sorafenib [median, 10.9 vs. 6.8 months, respectively; HR, 0.53; 95% confidence interval (CI), 0.33-0.85; interaction = 0.0397] with higher baseline FGF21. In tumor tissue biomarker analysis, VEGF/FGF-enriched groups showed improved OS with lenvatinib versus the intermediate VEGF/FGF group (HR, 0.39; 95% CI, 0.16-0.91; = 0.0253).

Conclusions: Higher baseline levels of VEGF, FGF21, and ANG2 may be prognostic for shorter OS. Higher baseline FGF21 may be predictive for longer OS with lenvatinib compared with sorafenib, but this needs confirmation.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4219DOI Listing
June 2021

Efficacy and Safety of Glecaprevir/Pibrentasvir in Korean Patients with Chronic Hepatitis C: A Pooled Analysis of Five Phase II/III Trials.

Gut Liver 2021 Jun 2. Epub 2021 Jun 2.

Department of Internal Medicine, Inje University Busan Paik Hospital, Inje University College of Medicine, Busan, Korea.

Background/aims: Glecaprevir/pibrentasvir (G/P) is the first pan-genotypic direct-acting antiviral combination therapy approved in Korea. An integrated analysis of five phase II and III trials was conducted to evaluate the efficacy and safety of G/P in Korean patients with chronic hepatitis C virus (HCV) infection.

Methods: The study analyzed pooled data on Korean patients with HCV infection enrolled in the ENDURANCE 1 and 2, SURVEYOR II part 4 and VOYAGE I and II trials, which evaluated the efficacy and safety of 8 or 12 weeks of G/P treatment. The patients were either treatment-naïve or had received sofosbuvir or interferon-based treatment. Efficacy was evaluated by assessing the rate of sustained virologic response at 12 weeks posttreatment (SVR12). Safety was evaluated by monitoring adverse events (AEs) and laboratory assessments.

Results: The analysis included 265 patients; 179 (67.5%) were HCV treatment-naïve, and most patients were either subgenotype 1B (48.7%) or 2A (44.5%). In the intention-to-treat population, 262 patients (98.9%) achieved SVR12. Three patients did not achieve SVR12: one had virologic failure and two had non-virologic failures. Most AEs were grade 1/2; eight patients (3.0%) experienced at least one grade ≥3 AE. No serious AEs related to G/P treatment were reported, and grade ≥3 hepatic laboratory abnormalities were rare (0.8%).

Conclusions: G/P therapy was highly efficacious and well tolerated in Korean patients with HCV infection, with most patients achieving SVR12. The safety profile was comparable to that observed in a pooled analysis of a global pan-genotypic population of patients with HCV infection who received G/P.
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http://dx.doi.org/10.5009/gnl20321DOI Listing
June 2021

Safety and efficacy of lenvatinib by starting dose based on body weight in patients with unresectable hepatocellular carcinoma in REFLECT.

J Gastroenterol 2021 Jun 4;56(6):570-580. Epub 2021 May 4.

Toranomon Hospital, Tokyo, Japan.

Background: REFLECT was an open-label, phase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib in patients with unresectable hepatocellular carcinoma (uHCC). Based on phase 2 study (Study 202) results, body weight-based dosing for lenvatinib was used in REFLECT to minimize dose disruptions and modifications needed to address dose-related adverse events. This post hoc analysis of REFLECT data assessed lenvatinib efficacy and safety by body weight group.

Methods: The study randomly administered lenvatinib (n = 476) or sorafenib (n = 475) to patients with untreated (no prior systemic therapy) uHCC. Lenvatinib starting-dose data were stratified by body weight: patients weighing < 60 kg received 8 mg/day; patients weighing ≥ 60 kg received 12 mg/day. Overall survival (OS), progression-free survival (PFS), objective response rate, and safety were assessed.

Results: Survival outcomes and safety profiles appeared similar between the two body-weight-based lenvatinib starting-dose groups. Median OS for patients in the < 60 kg body weight group (n = 153) was 13.4 months [95% confidence interval (CI) 10.5-15.7] compared to 13.7 months (95% CI 12.0-15.6) in the ≥ 60 kg body weight group (n = 325). In both lenvatinib groups, PFS was 7.4 months (< 60 kg group: 95% CI 5.4-9.2; ≥ 60 kg group: 95% CI 6.9-9.0). Treatment-emergent adverse events (TEAEs) required dose modifications in 43.0% in the < 60 kg body weight group and 57.5% in the ≥ 60 kg body weight group.

Conclusions: This exploratory analysis of data from REFLECT indicated that body weight-based lenvatinib dosing in patients with uHCC was successful in maintaining efficacy, with comparable rates of TEAEs and dose modifications in the two body weight groups.

Clinincal Trial: Trial registration ID: ClinicalTrials.gov # NCT01761266.
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http://dx.doi.org/10.1007/s00535-021-01785-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137475PMC
June 2021

Revised Korean Antiviral Guideline Reduces the Hepatitis B-related Hepatocellular Carcinoma Risk in Cirrhotic Patients.

J Korean Med Sci 2021 Apr 26;36(16):e105. Epub 2021 Apr 26.

Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.

Background: Since September 2015, the initiation of antiviral therapy (AVT) for patients with chronic hepatitis B (CHB)-related cirrhosis has been reimbursed according to the revised Korean Association for the Study of Liver (KASL) guideline, if the patient had hepatitis B virus DNA level ≥ 2,000 IU/L, regardless of aminotransferase or alanine aminotransferase levels. This study investigated whether the KASL guideline implementation reduced the risk of CHB-related hepatocellular carcinoma (HCC) in patients with cirrhosis in South Korea.

Methods: A total of 429 patients with CHB-related cirrhosis who initiated AVT between 2014 and 2016 were recruited. The risk of HCC development was compared between patients who initiated AVT before and after September 2015 (pre-guideline [n = 196, 45.7%] vs. post-guideline implementation [n = 233, 54.3%]).

Results: Univariate analysis showed that AVT initiation before guideline implementation, older age, male gender, and diabetes significantly predicted increased risk of HCC development (all < 0.05). Subsequent multivariate analysis showed that AVT initiation before guideline implementation (HR = 1.941), older age (HR = 5.762), male gender (HR = 2.555), and diabetes (HR = 1.568) independently predicted increased risk of HCC development (all < 0.05). Additionally, multivariate analysis showed that AVT initiation before guideline implementation (HR = 2.309), male gender (HR = 3.058), and lower platelet count (HR = 0.989) independently predicted mortality ( < 0.05). The cumulative incidences of HCC and mortality were significantly higher in patients who initiated AVT before guideline implementation than in those who initiated AVT after guideline implementation (all < 0.05, log-rank test).

Conclusion: The prognosis of patients with CHB-related cirrhosis who initiated AVT improved after guideline implementation according to the revised KASL guideline.
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http://dx.doi.org/10.3346/jkms.2021.36.e105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076846PMC
April 2021

Treatment efficacy by hepatic arterial infusion chemotherapy vs. sorafenib after liver-directed concurrent chemoradiotherapy for advanced hepatocellular carcinoma.

J Cancer Res Clin Oncol 2021 Apr 23. Epub 2021 Apr 23.

Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.

Background: We compared the clinical efficacies of hepatic arterial infusion chemotherapy (HAIC) vs. sorafenib as sequential maintenance therapy following liver-directed concurrent chemoradiotherapy (LD-CCRT) for locally advanced-stage hepatocellular carcinoma (HCC).

Methods: Patients undergoing HAIC with 5-fluorouracil and cisplatin (HAIC-maintain group, n = 151) or sorafenib (Sorafenib-maintain group, n = 37) after LD-CCRT were consecutively enrolled. The study endpoints were overall survival (OS), progression-free survival (PFS), and treatment response rates.

Results: The median OS among HAIC-maintain and Sorafenib-maintain groups were 15.9 and 24.3 months (p = 0.287), whereas the median PFS were 8.1 and 9.1 months (p = 0.651), respectively. During the planned treatments, the radiological objective response rate (54.3% vs. 64.9%; p = 0.246), and conversion rate to surgical resection or liver transplantation after successful down-staging (15.9% vs. 18.9%; p = 0.657) were comparable between the HAIC-maintain and Sorafenib-maintain groups. Similar results were found after the inverse probability of treatment weighting and propensity score-matching analyses. Regarding treatment-related adverse events, the HAIC-maintain group showed worse profiles in terms of leukopenia (all grades [p = 0.001] and grades 3 or 4 [p = 0.041]) and hypoalbuminemia (p = 0.001) than the Sorafenib-maintain group.

Conclusions: The overall clinical efficacies between the sequential treatment of HAIC vs. sorafenib after LD-CCRT were comparable for locally advanced HCC.
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http://dx.doi.org/10.1007/s00432-021-03632-4DOI Listing
April 2021

Epidemiological and Clinical History of Viral Hepatitis in Korea.

Infect Chemother 2021 Jan 26. Epub 2021 Jan 26.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

Viral hepatitis is the most important cause of acute and chronic liver disease in Korea. Particularly, hepatitis B virus (HBV) is the leading cause of liver-related mortality. Because of the nationwide vaccinations in the 1980s, hepatitis B surface antigen positive rates substantially decreased from 8% to 3%. Moreover, the introduction of potent nucleoside or nucleotide analogs led to the effective treatment of patients who had already been infected by HBV. The remaining issue has been to develop novel drugs that can cure HBV infection. Hepatitis C virus (HCV), on the other hand, is a hepatotropic virus that is parenterally transmitted. In Korea, the prevalence of HCV is estimated to be approximately 1%. Although no effective vaccine for HCV has been developed yet, highly effective and safe direct-acting antiviral therapy, which has a short treatment duration of 8-12 weeks, has made HCV eradication possible globally. Currently, the unsolved issue regarding HCV management is low disease awareness among patients and health care providers. Therefore, nationwide testing for anti-HCV would be a solution to identify patients infected with HCV but with no symptoms. Lastly, the Hepatitis A virus (HAV) is orally transmitted and results in acute hepatitis. In Korea, the young adult population is a high-risk group since this group is not vaccinated against HAV. More active vaccination and improved hygiene would be necessary to prevent HAV infection.
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http://dx.doi.org/10.3947/ic.2021.0300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032906PMC
January 2021

Continuing besifovir dipivoxil maleate versus switching from tenofovir disoproxil fumarate for treatment of chronic hepatitis B: Results of 192-week phase 3 trial.

Clin Mol Hepatol 2021 Apr 25;27(2):346-359. Epub 2021 Jan 25.

Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.

Background/aims: Besifovir dipivoxil maleate (BSV), an acyclic nucleotide phosphonate, shows potent antiviral activity against hepatitis B virus. Our previous 48-week trial revealed that BSV has comparable antiviral efficacy to tenofovir disoproxil fumarate (TDF) and better safety profiles in terms of improved renal and bone safety. This extension study evaluated the prolonged efficacy and safety of BSV in treatment-naive chronic hepatitis B patients.

Methods: Patients continued to participate in an open-label BSV study after an initial 48-week double-blind comparison of BSV and TDF treatment. The antiviral efficacy and drug safety was evaluated up to 192 weeks in two groups: patients continuing BSV treatment (BSV-BSV) and patients switching from TDF to BSV after 48 weeks (TDF-BSV).

Results: Among 197 patients receiving randomized treatments, 170 (86%) entered the open-label phase and 152 (77%) entered the 192-week extension study. Virological response rates over 192 weeks were 92.50% and 93.06% in the BSV-BSV and TDF-BSV groups, respectively (P=0.90). Hepatitis B envelop antigen seroconversion and alanine aminotransferase normalization rates were similar between the groups (P=0.75 and P=0.36, respectively). There were no drug-resistant mutations to BSV. Bone mineral density and renal function were well preserved in the BSV-BSV group, whereas these initially worsened then recovered after switching therapy in the TDF-BSV group.

Conclusion: BSV maintained potent antiviral efficacy after 192 weeks and showed no evidence of drug resistance. BSV was safe, well tolerated, and effective in patients who switched from TDF to BSV. Trial Registration Number: NCT01937806 (date: 10 Sep 2013).
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http://dx.doi.org/10.3350/cmh.2020.0307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046633PMC
April 2021

Prognostic Value of Alpha-Fetoprotein in Patients Who Achieve a Complete Response to Transarterial Chemoembolization for Hepatocellular Carcinoma.

Yonsei Med J 2021 Jan;62(1):12-20

Liver Center, Pusan National University Yangsan Hospital, Yangsan, Korea.

Purpose: Alpha-fetoprotein (AFP) is a prognostic marker for hepatocellular carcinoma (HCC). We investigated the prognostic value of AFP levels in patients who achieved complete response (CR) to transarterial chemoembolization (TACE) for HCC.

Materials And Methods: Between 2005 and 2018, 890 patients with HCC who achieved a CR to TACE were recruited. An AFP responder was defined as a patient who showed elevated levels of AFP (>10 ng/mL) during TACE, but showed normalization or a >50% reduction in AFP levels after achieving a CR.

Results: Among the recruited patients, 569 (63.9%) with naïve HCC and 321 (36.1%) with recurrent HCC after complete resection were treated. Before TACE, 305 (34.3%) patients had multiple tumors, 219 (24.6%) had a maximal tumor size >3 cm, and 22 (2.5%) had portal vein tumor thrombosis. The median AFP level after achieving a CR was 6.36 ng/mL. After a CR, 473 (53.1%) patients experienced recurrence, and 417 (46.9%) died [median progression-free survival (PFS) and overall survival (OS) of 16.3 and 62.8 months, respectively]. High AFP levels at CR (>20 ng/mL) were independently associated with a shorter PFS [hazard ratio (HR)=1.403] and OS (HR=1.284), together with tumor multiplicity at TACE (HR=1.518 and 1.666, respectively). AFP non-responders at CR (76.2%, n=359 of 471) showed a shorter PFS (median 10.5 months vs. 15.5 months, HR=1.375) and OS (median 41.4 months vs. 61.8 months, HR=1.424) than AFP responders (all =0.001).

Conclusion: High AFP levels and AFP non-responders were independently associated with poor outcomes after TACE. AFP holds clinical implications for detailed risk stratification upon achieving a CR after TACE.
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http://dx.doi.org/10.3349/ymj.2021.62.1.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820452PMC
January 2021

Appraisal of Long-Term Outcomes of Liver-Directed Concurrent Chemoradiotherapy for Hepatocellular Carcinoma with Major Portal Vein Invasion.

J Hepatocell Carcinoma 2020 17;7:403-412. Epub 2020 Dec 17.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.

Backgrounds And Aims: Molecular-targeted agents are acceptable standards to treat advanced-stage hepatocellular carcinoma (HCC), however, their therapeutic benefit, ie, sorafenib, was significantly offset in case of major vessel invasion. Liver-directed concurrent chemo-radiotherapy (LD-CCRT) provided favorable outcomes in terms of survivals and tumor shrinkage, so, we appraised its long-term therapeutic efficacy.

Patients And Methods: Advanced HCC patients with portal vein invasion (main trunk or the 1st order branch) were enrolled. During a 5-week radiotherapy course, concurrent hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil and leucovorin was administered through an implanted port on the first and last 5 days. Four weeks after LD-CCRT, a maintenance HAIC using 5-fluorouracil and cisplatin was administered every 4 weeks.

Results: Among 152 patients, the objective response rates as the best response by modified Response Evaluation Criteria In Solid Tumors were 48.0% after LD-CCRT and 55.3% during subsequent HAIC maintenance. After LD-CCRT, biological responses in alpha-fetoprotein and protein induced by the absence of vitamin K or antagonist-II levels were achieved in 46.2% and 52.6%, respectively. Sixteen patients (10.5%) underwent curative resection or liver transplantation after down-staging. Median overall survival and progression-free survival were 13.5 and 6.9 months, respectively.

Conclusion: LD-CCRT followed by maintenance HAIC yielded favorable survival outcomes in advanced HCC patients with major portal vein invasion. Through initial tumor reduction, LD-CCRT induced down-staging with subsequent curative treatment feasible in 10.5% of patients, resulting in long-term survival. Further prospective trials are warranted to confirm these results.
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http://dx.doi.org/10.2147/JHC.S276528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751588PMC
December 2020

Negligible risks of hepatocellular carcinoma during biomarker-defined immune-tolerant phase for patients with chronic hepatitis B.

Clin Mol Hepatol 2021 Apr 3;27(2):295-304. Epub 2020 Dec 3.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

Background/aims: The immune-tolerant (IT) phase of chronic hepatitis B (CHB) patients is not generally indicative of antiviral therapy (AVT). We assessed and compared the risk of hepatocellular carcinoma (HCC) during the IT-phase stringently defined by a low fibrosis-4 (FIB-4) index, compared to that in patients undergoing AVT.

Methods: Among 125 untreated patients that were hepatitis B e-antigen positive, hepatitis B virus-DNA >20,000 IU/mL, with normal alanine aminotransferase level from 2012 to 2018, those with a FIB-4 index of <1.45 were classified into the IT-group. The cumulative probability of HCC was estimated using Kaplan-Meier analysis. All patients were assessed until HCC development (intention-to-treat [ITT] analysis), whereas those suspected of experiencing CHB phase switch were assessed using the per-protocol (PP) and censored at the time of phase switch.

Results: The cumulative probability of HCC at 1-, 3-, and 5-years among the IT-group was zero, compared to AVT-treated patients with FIB-4 indices <1.45 during the same period: 0.2%, 0.6%, and 1.4%, respectively (P=0.264 for ITT and P=0.533 for PP). Among the initially screened 125 untreated patients, those with a FIB-4 index of ≥1.45 had a higher risk of HCC compared to the IT-group (P=0.005). Furthermore, among AVT-treated patients, those with a FIB-4 index of ≥1.45 had a higher risk of HCC compared to their counterpart (P<0.001).

Conclusion: The risk of HCC was negligible in the IT-group stringently defined by a low FIB-4 index. However, given that a higher HCC risk exists among untreated patients with higher FIB-4, appropriate criteria for AVT should be established.
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http://dx.doi.org/10.3350/cmh.2020.0216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046628PMC
April 2021

Efficacy and safety of ledipasvir/sofosbuvir in 5,028 Mongolian patients infected with genotype 1 hepatitis C virus: A multicenter study.

Clin Mol Hepatol 2021 01 27;27(1):125-135. Epub 2020 Nov 27.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

Background/aims: Ledipasvir/sofosbuvir (LDV/SOF) shows high efficacy and safety in patients with genotype 1-hepatitis C virus (HCV). We aimed to investigate the efficacy and safety of LDV/SOF in real-world Mongolian patients.

Methods: Between 2015 to 2019, 23 (0.5%) and 5,005 patients (99.5%) with genotype 1a and 1b HCV, respectively, were treated with a fixed-dose tablet containing 90 mg ledipasvir and 400 mg sofosbuvir for 12 weeks, and 81 patients (1.6%) with previous experience of interferon (IFN)-based treatment received additional 1,000 mg ribavirin. HCV RNA was measured at 4, 12, and 24 weeks after the first dose to determine rapid virologic response, end of treatment response (ETR), and sustained virologic response at 12 weeks after end of treatment (SVR12).

Results: Most patients (n=5,008; 99.6%) achieved ETR and SVR12 without virologic relapse. Patients with genotype 1a showed low rates of ETR and SVR12 in only 16 patients (69.6%). There was no significant difference in SVR12 rate between patients regardless of IFN experience (n=81; 1.6%), cirrhosis (n=1,151; 22.9%), HCV RNA >6×106 IU/mL (n=866; 17.2%), or liver stiffness >9.6 kPa (n=1,721; 34.2%) (100.0%, 99.3%, 99.4%, and 99.4%, respectively). No severe adverse events (AEs) were reported, and there was no dose reduction or interruption due to AE. The most common AEs were headache (n=472; 9.4%), fatigue (n=306; 6.2%), abdominal discomfort (n=295; 5.9%), and skin rash (n=141; 2.8%).

Conclusion: LDV/SOF showed high efficacy and safety for patients with genotype 1, especially 1b HCV, in Mongolia. The real-world data might be applicable to patients in other Asian-Pacific countries.
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http://dx.doi.org/10.3350/cmh.2020.0023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820214PMC
January 2021

Advanced Liver Fibrosis Predicts Unfavorable Long-Term Prognosis in First-Ever Ischemic Stroke or Transient Ischemic Attack.

Cerebrovasc Dis 2020 25;49(5):474-480. Epub 2020 Sep 25.

Department of Neurology, Yonsei University College of Medicine, Seoul, Republic of Korea,

Introduction: There are a limited number of studies investigating the relationship between the degree of liver fibrosis and the long-term prognosis, especially ischemic stroke (IS) recurrence, in first-ever IS or transient ischemic attack (TIA).

Objective: We investigated whether there are differences in the long-term all-cause and cardiovascular mortalities and IS recurrence based on the degree of liver fibrosis in first-ever IS or TIA.

Methods: This analysis included 2,504 patients with first-ever IS or TIA recruited from a prospective stroke cohort. Liver fibrosis was predicted using the fibrosis-4 (FIB-4) index, and advanced fibrosis was defined as an FIB-4 index of >3.25. Using Cox regression models, we compared the all-cause and cardiovascular mortalities and IS recurrence. As measures for the additive predictive value of the FIB-4 index for prediction of all-cause mortality, the integrated area under the receiver operating characteristic curve (iAUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were used.

Results: There were 231 (9.2%) patients with advanced fibrosis. During a median follow-up of 1.2 years, the cumulative all-cause and cardiovascular mortalities were 6.4 and 1.9%, and IS recurrence was observed in 5.3%. The advanced fibrosis was associated with an increased risk of all-cause mortality (hazard ratio [HR] = 3.98, 95% confidence interval [CI] = 2.40-6.59), cardiovascular mortality (HR = 4.48, 95% CI = 1.59-12.65), and IS recurrence (HR = 1.95, 95% CI = 1.05-3.65). Adding the FIB-4 index to the model consisting of traditional cardiovascular risk factors improved the predictive accuracy for all-cause mortality as measured using the iAUC (from 0.7594 to 0.7729) and for all-cause mortality at 1 year as measured using the NRI (38.6%) and IDI (0.037).

Conclusions: The burden of liver fibrosis is associated with unfavorable long-term prognosis, including recurrent IS, in first-ever IS or TIA.
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http://dx.doi.org/10.1159/000510436DOI Listing
November 2020

Direct-Acting Antivirals Improve Treatment Outcomes in Patients with Hepatitis C Virus-Related Hepatocellular Carcinoma Treated with Transarterial Chemoembolization: A Nationwide, Multi-center, Retrospective Cohort Study.

Dig Dis Sci 2021 Jul 28;66(7):2427-2438. Epub 2020 Aug 28.

Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.

Background And Aims: The influence of direct-acting antivirals (DAAs) on chronic hepatitis C (CHC)-related hepatocellular carcinoma (HCC) remains controversial. We investigated the effect of eradicating CHC using DAAs on treatment outcomes in patients with CHC-related HCC treated with transarterial chemoembolization (TACE).

Methods: This nationwide, multi-center, retrospective study recruited patients with CHC-related HCC treated with TACE as the first-line anti-cancer treatment, and who achieved a sustained virological response (SVR) using DAAs (DAA group) between 2006 and 2017. Patients achieving an SVR following interferon-based treatment (IFN group) and those without treatment (control group) were also recruited for comparison.

Results: A total of 425 patients were eligible for the study. Of these, 356 (83.8%), 26 (6.1%), and 43 (10.1%) were allocated to the control, IFN, and DAA groups, respectively. A multivariate analysis showed that liver cirrhosis, segmental portal vein thrombosis, and larger maximal tumor size independently predicted an increased risk of progression (all p < 0.05), whereas, the DAA group (vs. IFN and control groups) independently predicted a reduced risk of progression (hazard ratio (HR) = 0.630, 95% confidence interval 0.411-0.966, p = 0.034). The cumulative incidence rate of HCC progression in the DAA group was significantly lower than that in the IFN and control groups (p = 0.033, log-rank test). In addition, the DAA group (vs. IFN and control groups) was independently associated with a reduced risk of mortality (p = 0.042).

Conclusions: DAA treatment provided significantly prolonged progression-free survival in patients with CHC-related HCC treated with TACE compared to that in patients administered IFN or no treatment.
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http://dx.doi.org/10.1007/s10620-020-06533-7DOI Listing
July 2021

Change in the Recurrence Pattern and Predictors over Time after Complete Cure of Hepatocellular Carcinoma.

Gut Liver 2021 May;15(3):420-429

Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.

Background/aims: We investigated changes in recurrence rates and significant recurrence predictors over time after complete cure of hepatocellular carcinoma (HCC).

Methods: A total of 1,491 patients with first-time diagnosis of Barcelona Clinic Liver Cancer stage A HCC, completely cured by treatment between 2007 and 2016, were recruited from two Korean tertiary institutes.

Results: The mean age of the population (1,144 men and 347 women) was 58.6 years. Of the total population, 914 patients (61.3%) had liver cirrhosis. Nine-hundred and forty-one (63.1%) and 550 (36.9%) patients were treated with surgical resection and radiofrequency ablation (RFA), respectively. One-year cumulative incidences of HCC recurrence were 14.3%, 9.9%, and 5.1% from the time of treatment, 3 years after treatment, and 5 years after treatment, respectively. Upon multivariate analysis, multiple tumors, maximal tumor size ≥3 cm, and high Model for End-Stage Liver Disease scores were independently associated with increased HCC recurrence risk from the time of treatment and 1 and 2 years after curative treatment (all p<0.05, except for maximal tumor size ≥3 cm for recurrence 2 years after treatment). Meanwhile, liver cirrhosis and RFA were independently associated with the increased HCC recurrence risk for almost all time points (liver cirrhosis: all p<0.05; RFA: all p<0.005 except for recurrence from 5 years after treatment).

Conclusions: The recurrence rate of HCC after curative treatment gradually decreased over time. Two years after treatment, when tumor-related factors lose their prognostic implications, may be used as a cutoff to define the boundary between early and late recurrence of HCC.
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http://dx.doi.org/10.5009/gnl20101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129665PMC
May 2021

Association between liver fibrosis and appendicular skeletal muscle mass during antiviral therapy in chronic hepatitis B.

Dig Liver Dis 2020 11 6;52(11):1338-1345. Epub 2020 Aug 6.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea; Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea. Electronic address:

Background And Aims: Sarcopenia is associated with fibrotic burden in patients with chronic hepatitis B. We investigated the dynamic association between fibrosis changes and appendicular skeletal muscle mass during antiviral therapy in patients with chronic hepatitis B.

Methods: Between 2015 and 2018, chronic hepatitis B patients who received paired transient elastography to assess fibrotic burden in the liver and bioelectrical impedance analysis to assess appendicular skeletal muscle mass were recruited retrospectively. The sarcopenia index was calculated as total appendicular skeletal muscle mass/body mass index. Significant liver fibrosis was defined as a liver stiffness value≥8 kPa.

Results: In total, 223 (53.7%) received antiviral therapy, whereas 192 (46.3%) did not. Appendicular skeletal muscle mass decreased significantly in the antiviral therapy group (mean 21.16→21.00 kg, P = 0.01), but not in the non-antiviral therapy group (mean 20.77→20.64 kg, P = 0.134). In a subgroup with significant liver fibrosis, similar findings were observed (mean 20.73→20.54 kg in antiviral therapy group, P = 0.037; mean 21.39→21.07 kg in the non-antiviral therapy group, P = 0.097). Older age, male gender, higher body mass index, and higher aspartate aminotransferase were significantly associated with the increased risk of appendicular skeletal muscle mass reduction (≥5% from the baseline).

Conclusions: Appendicular skeletal muscle mass significantly decreased during antiviral therapy in patients with chronic hepatitis B patients.
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http://dx.doi.org/10.1016/j.dld.2020.07.004DOI Listing
November 2020

Liver-directed combined radiotherapy as a bridge to curative surgery in locally advanced hepatocellular carcinoma beyond the Milan criteria.

Radiother Oncol 2020 11 31;152:1-7. Epub 2020 Jul 31.

Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address:

Background And Purpose: Liver-directed combined radiotherapy (LDCRT) can provide substantial tumor control, which may be an effective bridge to curative surgery for selected patients. We aimed to investigate the outcomes of LDCRT for locally advanced hepatocellular carcinoma (LAHCC) beyond the Milan criteria.

Materials And Methods: We identified 1078 patients diagnosed with LAHCC who received LDCRT and compared the outcomes based on no surgery, conversion to surgical resection, and liver transplantation (LT). Predictive factors for conversion to curative surgery were identified using logistic regression analysis.

Results: The most frequently used LDCRT strategies were concurrent chemoradiation (CCRT) (497 patients, 46.1%) and transarterial chemoembolization (TACE) plus radiotherapy (251 patients 23.3%). After LDCRT, 96 (8.9%) and 42 patients (3.9%) received surgical resection and LT, respectively. After a median follow-up of 14.4 months, the 5-year overall survival (OS) rate was 16.5% for all patients. Conversion to curative surgery group had higher 5-year OS (surgical resection vs. LT vs. no surgery: 58.1% vs. 54.3% vs. 10.2%, p < 0.001). Patients aged < 60 years with a single tumor, no treatment history, pre-treatment Child class A, lower pre-treatment tumor marker levels, and radiologic complete or partial response (all p < 0.050) had a higher chance of conversion to surgery.

Conclusion: LDCRT could convert tumors to within the Milan criteria as a bridge to curative surgery, and improved long-term survival for the selected patients. Clinicians should consider LDCRT followed by curative surgery for young patients who are treatment-naïve and have good liver function with favorable tumor characteristics showing radiologic response to LDCRT.
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http://dx.doi.org/10.1016/j.radonc.2020.07.046DOI Listing
November 2020

A Changing Paradigm for the Treatment of Intermediate-Stage Hepatocellular Carcinoma: Asia-Pacific Primary Liver Cancer Expert Consensus Statements.

Liver Cancer 2020 Jun 13;9(3):245-260. Epub 2020 May 13.

Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.

The Asia-Pacific Primary Liver Cancer Expert (APPLE) Consensus Statement on the treatment strategy for patients with intermediate-stage hepatocellular carcinoma (HCC) was established on August 31, 2019, in Sapporo, Hokkaido during the 10th Annual APPLE Meeting. This manuscript summarizes the international consensus statements developed at APPLE 2019. Transarterial chemoembolization (TACE) is the only guideline-recommended global standard of care for intermediate-stage HCC. However, not all patients benefit from TACE because intermediate-stage HCC is a heterogeneous disease in terms of tumor burden and liver function. Ten important clinical questions regarding this stage of HCC were raised, and consensus statements were generated based on high-quality evidence. In intermediate-stage HCC, preservation of liver function is as important as achieving a high objective response (OR) because the treatment goal is to prolong overall survival. Superselective conventional TACE (cTACE) is recommended as the first choice of treatment in patients eligible for effective (curative) TACE, whereas in patients who are not eligible, systemic therapy is recommended as the first choice of treatment. TACE is not indicated as the first-line therapy in TACE-unsuitable patients. Another important statement is that TACE should not be continued in patients who develop TACE failure/refractoriness in order to preserve liver function. Targeted therapy is the recommended first-line treatment for TACE-unsuitable patients. Especially, the drug, which can have higher OR rate, is preferred. Immunotherapy, transarterial radioembolization, TACE + targeted therapy or other modalities may be considered alternative options in TACE-unsuitable patients who are not candidates for targeted therapy. Better liver function, such as albumin-bilirubin grade 1, is an important factor for maximizing the therapeutic effect of systemic therapy.
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http://dx.doi.org/10.1159/000507370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325125PMC
June 2020

High body mass index hinders fibrosis improvement in patients receiving long-term tenofovir therapy in hepatitis B virus-related cirrhosis.

J Viral Hepat 2020 11 23;27(11):1119-1126. Epub 2020 Jun 23.

Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.

Long-term suppression of hepatitis B virus with tenofovir (TDF) induces fibrosis regression, and repeated liver stiffness (LS) measurement can indicate the improvement of fibrosis. We aimed to investigate predictors for LS improvement assessed by changes in patients receiving long-term TDF therapy in chronic hepatitis B (CHB) with liver cirrhosis. CHB patients with histologically proven liver cirrhosis who received TDF as the first-line therapy from 2012 to 2015 were recruited. LS and controlled attenuation parameter (CAP) measurements were repeated at baseline and 3 years after therapy. Liver stiffness improvement was defined as a drop of LS value ≥30% from the baseline. A total of 131 patients were enrolled (mean age 51.4% and male 64.9%). After 3 years of TDF therapy, the mean LS value significantly improved (from 14.7 to 8.6 kPa, P < .001), and 96 (73.3%) patients have achieved LS improvement. Predictors associated with improvement of LS were low body mass index (BMI), HBeAg positivity, and low CAP value at baseline. In multivariate analysis, low BMI was a single factor independently associated with LS improvement (odds ratio 0.680, 95% CI 0.560-0.825, P < .001). Patients with BMI < 23.5, had a 1.96 times more chance of achieving LS improvement compared to those with BMI ≥ 23.5 (90.1% vs. 46.0%, P = .001). High BMI was a single significant factor hindering the fibrosis improvement in patients receiving long-term TDF therapy in CHB with liver cirrhosis. Life style modification and BMI reduction should be encouraged to enhance fibrosis improvement.
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http://dx.doi.org/10.1111/jvh.13345DOI Listing
November 2020

Dynamics of liver stiffness-based risk prediction model during antiviral therapy in patients with chronic hepatitis B.

Eur J Gastroenterol Hepatol 2021 Jun;33(6):885-893

Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Bundang.

Objective: The liver stiffness-based risk prediction models predict hepatocellular carcinoma (HCC) development. We investigated the influence of antiviral therapy (AVT) on liver stiffness-based risk prediction model in patients with chronic hepatitis B (CHB).

Methods: Patients with CHB who initiated AVT were retrospectively recruited from 13 referral Korean institutes. The modified risk estimation for hepatocellular carcinoma in chronic hepatitis B (mREACH-B) model was selected for the analysis.

Results: Between 2007 and 2015, 1034 patients with CHB were recruited. The mean age of the study population (639 men and 395 women) was 46.8 years. During AVT, the mREACH-B score significantly decreased from the baseline to 3 years of AVT (mean 9.21 → 7.46, P < 0.05) and was maintained until 5 years of AVT (mean 7.23, P > 0.05). The proportion of high-risk patients (mREACH-B score ≥11) was significantly reduced from the baseline to 2 years of AVT (36.4% → 16.4%, P < 0.001) and was maintained until 5 years of AVT (12.2%, P > 0.05). The mREACH-B scores at baseline and 1 year of AVT independently predicted HCC development (hazard ratio = 1.209-1.224) (all P < 0.05). The cumulative incidence rate of HCC was significantly different at 5 years of AVT among risk groups (high vs. high-intermediate vs. low-intermediate vs. low) from baseline (4.5% vs. 3.2% vs. 1.5% vs. 0.8%) and 1 year (11.8% vs. 4.6% vs. 1.8% vs. 0.6%) (all P < 0.05, log-rank tests).

Conclusions: The mREACH-B score was dynamically changed during AVT. Thus, repeated assessment of the mREACH-B score is required to predict the changing risk of HCC development in patients with CHB undergoing AVT.
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http://dx.doi.org/10.1097/MEG.0000000000001794DOI Listing
June 2021

Extremely low risk of hepatocellular carcinoma development in patients with chronic hepatitis B in immune-tolerant phase.

Aliment Pharmacol Ther 2020 07 26;52(1):196-204. Epub 2020 May 26.

Yonsei University College of Medicine, Seoul, Korea.

Background: Anti-viral therapy is not indicated for patients with chronic hepatitis B (CHB) in the immune-tolerant phase.

Aims: To investigate the cumulative incidence of phase change and hepatocellular carcinoma (HCC) and independent predictors for phase change in patients with CHB in immune-tolerant phase.

Methods: In total, 946 patients in immune-tolerant phase, defined as hepatitis B e antigen positivity, HBV-DNA >20 000 IU/mL and alanine aminotransferase (ALT) ≤40 IU/L, between 1989 and 2017 were enrolled from eight institutes.

Results: The mean age of study population (429 men and 517 women) was 36.7 years. The mean ALT and HBV-DNA levels were 24.6 IU/L and 8.50 log IU/mL, respectively. Of the study population, 476 (50.3%) patients remained in immune-tolerant phase throughout the study period (median: 63.6 months). The cumulative incidence rates of phase change and HCC at 10 years were 70.7% and 1.7%, respectively. Multivariate analyses revealed that HBV-DNA level >10  IU/mL was associated independently with a reduced risk of phase change (hazard ratio [HR] = 0.734, P = 0.008), whereas a high ALT level, above the cut-off recommended in the Korean Association for the Study of the Liver guidelines (34 IU/L for men and 30 IU/L for women), was associated independently with a greater risk of phase change (HR = 1.885, P < 0.001).

Conclusions: The criterion of HBV-DNA level > 10  IU/mL may be useful to define immune-tolerant phase. In addition, an extremely low risk of HCC development was observed in patients with CHB in immune-tolerant phase.
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http://dx.doi.org/10.1111/apt.15741DOI Listing
July 2020

Entecavir and tenofovir on renal function in patients with hepatitis B virus-related hepatocellular carcinoma.

J Viral Hepat 2020 09 28;27(9):932-940. Epub 2020 May 28.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.

The use of tenofovir disoproxil fumarate (TDF) is associated with a risk of renal dysfunction. We investigated whether TDF is associated with the deterioration of renal function in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) requiring frequent computed tomography (CT) evaluations and transarterial chemoembolization (TACE) sessions, when compared to entecavir (ETV). Between 2007 and 2017, 493 patients with HBV-related HCC were enrolled. The number of CT evaluations and TACE sessions were collected through 3 years of follow-up. The median age of the study population (373 men and 120 women; 325 with ETV and 168 with TDF) was 56.5 years. TDF was significantly associated with a serum creatinine increase (≥25% from the baseline; unadjusted hazard ratio [uHR] = 1.620) and an estimated glomerular filtration rate (eGFR) reduction (<20% from the baseline) (uHR = 1.950) (all P < .05), when compared to ETV. In addition, CT evaluations ≥4 times/year were significantly associated with a serum creatinine increase (uHR = 2.709), eGFR reduction (uHR = 3.274) and chronic kidney disease (CKD) progression (≥1 CKD stage from the baseline) (uHR = 1.980) (all P < .05). In contrast, TACE was not associated with all renal dysfunction parameters (all P > .05). After adjustment, TDF use was independently associated with the increased risk of eGFR reduction (adjusted HR [aHR] = 1.945; P = .023), whereas CT evaluation ≥4 times/year was independently associated with the increased risk of serum creatinine increase (aHR = 2.898), eGFR reduction (aHR = 3.484) and CKD progression (aHR = 1.984) (all P < .01). In conclusion, patients with HBV-related HCC treated with TDF and frequent CT evaluations should be closely monitored for the detection of associated renal dysfunction.
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http://dx.doi.org/10.1111/jvh.13313DOI Listing
September 2020

A nomogram based on liver stiffness predicts postoperative complications in patients with hepatocellular carcinoma.

J Hepatol 2020 10 30;73(4):855-862. Epub 2020 Apr 30.

Department of Medical and Surgical Sciences, General Surgery and Transplantation Unit, University of Bologna, Italy. Electronic address:

Background & Aims: Liver stiffness measurement (LSM), assessed by transient elastography (Fibroscan), has been demonstrated to predict post-hepatectomy liver failure in patients who undergo hepatic resection for hepatocellular carcinoma (HCC). However, other complications are also likely to be related to the underlying grade of liver fibrosis. Herein, we aimed to identify predictors of postoperative complications and to build and develop a novel nomogram able to identify patients at risk of developing severe complications.

Methods: Data from patients who underwent hepatectomy for HCC between 2006 and 2016 at 2 referral centres were retrospectively reviewed. All surgical complications were recorded and scored using the comprehensive complication index (CCI), ranging from 0 (uneventful course) to 100 (death). A CCI ≥26.2 was used as a threshold to define severe complications.

Results: During the study period, 471 patients underwent hepatic resection for HCC. Among them, 50 patients (10.6%) had a CCI ≥26.2. Age, model for end-stage liver disease (MELD) score and LSM values, together with serum albumin, were independent predictors of high CCI. The nomogram built on these variables was internally validated and showed good performance (optimism-corrected c-statistic = 0.751). A regression equation to predict the CCI was also established by multiple linear regression analysis: [LSM (kPa) × 0.254] + [age (years) × 0.118] + [MELD score (pt.) × 1.050] - [albumin (g/dl) × 2.395] - 3.639.

Conclusion: A novel nomogram, combining LSM values, age and liver function tests provided an excellent preoperative prediction of high CCI in patients with resectable HCC. This predictive model could be used as a reference for clinicians and surgeons to help them in clinical decision-making.

Lay Summary: Liver stiffness measurement is increasingly being used to assess the degree of liver fibrosis in patients with cirrhosis and/or chronic hepatitis. Using Fibroscan, we developed a novel nomogram to predict severe complications following liver resection for hepatocellular carcinoma, according to the new comprehensive complication index. This tool could be used as a reference for clinicians and surgeons to help them in clinical decision-making.
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http://dx.doi.org/10.1016/j.jhep.2020.04.032DOI Listing
October 2020

Influence of Besifovir Dipivoxil Maleate Combined with L-Carnitine on Hepatic Steatosis in Patients with Chronic Hepatitis B.

J Korean Med Sci 2020 May 4;35(17):e104. Epub 2020 May 4.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

Background: Besifovir dipivoxil maleate (BSV) with L-carnitine is the first-line antiviral agent for chronic hepatitis B (CHB) infection. We investigated whether BSV combined with L-carnitine improves hepatic steatosis (HS).

Methods: Treatment-naïve patients with CHB who were initiated on antiviral therapy (AVT) were enrolled. The magnitude of HS was assessed using hepatic steatosis index (HSI), and HS improvement was defined as a ≥ 10% reduction in the HSI score from the baseline.

Results: The mean age of the study patients was 56 years with a male predominance (n = 178, 64.7%). The mean body mass index (BMI), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and platelet count were 23.5 kg/m², 49.6 IU/L, 49.0 IU/L, and 191.3 × 10⁹/L, respectively. The mean HSI and fibrosis (FIB)-4 index were 32.6 and 0.5, respectively. After 6 months of AVT, platelet count (mean, 191.3→167.0 × 10⁹/L), fasting glucose (mean, 113.1→105.9 mg/dL), AST (mean, 49.6→28.0 IU/L), ALT (mean, 49.0→33.9 IU/L), and total cholesterol (mean, 170.0→162.1 mg/dL) levels significantly decreased (all < 0.05). In the BSV group, AST (mean, 95.2→30.2 IU/L) and ALT (mean, 81.1→31.1 IU/L) levels significantly reduced (all < 0.05), whereas HSI and FIB-4 index were maintained (all > 0.05). In the univariate analysis, age, BMI, diabetes, cirrhosis, fasting glucose level, and ALT were significantly associated with HS improvement (all < 0.05).

Conclusion: BSV with L-carnitine did not show any improvement of HS in patients with CHB. Further prospective randomized controlled studies are needed to validate the potential beneficial effects of BSV with L-carnitine in CHB infection.
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http://dx.doi.org/10.3346/jkms.2020.35.e104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200179PMC
May 2020

Besifovir Dipivoxil Maleate 144-Week Treatment of Chronic Hepatitis B: An Open-Label Extensional Study of a Phase 3 Trial.

Am J Gastroenterol 2020 08;115(8):1217-1225

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

Introduction: Chronic hepatitis B (CHB) remains a major worldwide public health concern. Besifovir dipivoxil maleate (BSV) is a new promising treatment for CHB. However, long-term efficacy and safety have not yet been evaluated. Therefore, the goal of the study is to determine the antiviral efficacy and safety of BSV treatment over a 144-week duration (BSV-BSV) in comparison with those of a sequential treatment with tenofovir disoproxil fumarate (TDF) followed by a 96-week duration BSV administration (TDF-BSV).

Methods: After 48 weeks of a double-blind comparison between BSV and TDF treatments, patients continued the open-label BSV study. We evaluated antiviral efficacy and drug safety up to 144 weeks for BSV-BSV and TDF-BSV groups. The primary endpoint was a virological response (hepatitis B virus DNA < 69 IU/mL).

Results: Among the 197 patients enrolled, 170 and 158 patients entered the second-year and third-year open-label phase extensional study, respectively, whereas 153 patients completed the 144-week follow-up. The virological response rate over the 144-week period was 87.7% and 92.1% in BSV-BSV and TDF-BSV groups, respectively (P = 0.36). The rates of ALT normalization and HBeAg seroconversion were similar between the groups. No drug-resistant mutations to BSV were noted. Bone mineral density and renal function were well preserved in the BSV-BSV group and were significantly improved after switching therapy in TDF-BSV patients.

Discussion: This extensional study of a phase 3 trial (NCT01937806) suggests that BSV treatment is efficacious and safe for long-term use in treatment-naïve and TDF-experienced patients with CHB.
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http://dx.doi.org/10.14309/ajg.0000000000000605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402376PMC
August 2020

Natural History of Untreated HBeAg-Positive Chronic HBV Infection With Persistently Elevated HBV DNA but Normal Alanine Aminotransferase.

Clin Transl Gastroenterol 2020 03;11(3):e00140

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.

Objectives: Nucleos(t)ide analogues (NUCs) are not routinely recommended for patients with hepatitis B e antigen-positive chronic hepatitis B virus (HBV) infection who have persistently elevated serum HBV DNA level (>20,000 IU/mL) but normal alanine aminotransferase (<40 IU/L) level. Here, we evaluated the cumulative risks of hepatocellular carcinoma (HCC) in such patients (the untreated persistently elevated serum HBV DNA [pEDNA] group) compared with inactive carriers (the IC group).

Methods: Patients with untreated pEDNA (n = 126) and IC (n = 621) were enrolled between 2006 and 2012. Patients with cirrhosis or HCC at enrollment or a history of NUC treatment were excluded.

Results: The cumulative HCC risks at 5 and 9 years in the untreated pEDNA group were 1.1% and 1.9%, which were comparable with those of the IC group (P = 0.549). Inverse probability of treatment weighting and propensity score matching also showed similar HCC risks. In the untreated pEDNA group, there were no cases of HCC in the subgroup with serum HBV DNA level >1,000,000 IU/mL (immune-tolerant phase), which was significantly (P = 0.002) different compared with those with an intermediate serum HBV DNA level (20,000-1,000,000 IU/mL).

Discussion: The cumulative HCC risk in the untreated pEDNA group was minimal and comparable with that of the IC group. Further studies are required to determine whether early NUC treatment, indeed, reduces the HCC risk in patients with an intermediate serum HBV DNA level.
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http://dx.doi.org/10.14309/ctg.0000000000000140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145045PMC
March 2020

A tool to measure the impact of inaction toward elimination of hepatitis C: A case study in Korea.

PLoS One 2020 28;15(4):e0232186. Epub 2020 Apr 28.

Department of Internal Medicine, Yonsei University, College of Medicine, Seoul, Korea.

Background And Aims: Hepatitis C virus (HCV) and its sequelae present a significant source of economic and societal burden. Introduction of highly effective curative therapies has made HCV elimination attainable. The study used a predictive model to assess the clinical and economic impact of implementing national screening and treatment policies toward HCV elimination in Korea.

Methods: A previously validated Markov disease progression model of HCV infection was employed to analyze the clinical and economic impact of various strategies for HCV diagnosis and treatment in Korea. In this analysis, the model compared the clinical and economic outcomes of current HCV-related interventions in Korea (7,000 patients treated and 4,200 patients newly diagnosed annually, starting in 2017) to four elimination scenarios: 1) initiating sufficient diagnosis and treatment interventions to meet the World Health Organization's GHSS elimination targets by 2030, 2) delaying initiation of interventions by one year, 3) delaying initiation of interventions by two years and 4) accelerating initiation of interventions to meet elimination targets by 2025. Modelled historical incidence of HCV was calibrated to match a viremic HCV prevalence of 0.44% in 2009. Elimination scenarios required 24,000 treatments and 34,000 newly diagnosed patients annually, starting in 2018, to reach the 2030 targets.

Results: Compared to current "status quo" interventions, elimination (or accelerated elimination by 2025) would avert 23,700 (27,000) incident cases of HCV, 1,300 (1,400) liver-related deaths (LRDs) and 2,900 (3,100) cases of end-stage liver disease (ESLD) over the 2017-2030 time period. Postponing interventions by one (or two) years would avert 21,100 (18,600) new HCV infections, 920 (660) LRDs and 2,000 (1,400) cases of ESLD by 2030. Following elimination or accelerated elimination strategies would save 860 million USD or 1.1 billion USD by 2030, respectively, compared to the status quo, requiring an up-front investment in prevention that decreases spending on liver-related complications and death.

Conclusions: By projecting the impact of interventions and tracking progress toward GHSS elimination targets using modelling, we demonstrate that Korea can prevent significant morbidity, mortality and spending on HCV. Results should serve as the backbone for policy and decision-making, demonstrating how aggressive prevention measures are designed to reduce future costs and increase the health of the public.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232186PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188208PMC
July 2020

HKR3 regulates cell cycle through the inhibition of hTERT in hepatocellular carcinoma cell lines.

J Cancer 2020 10;11(9):2442-2452. Epub 2020 Feb 10.

Yonsei Liver Center, Yonsei University College of Medicine, Seoul, Republic of Korea.

Hepatocellular carcinoma is a malignant disease with improved hepatic regeneration and survival, and is activated by human telomere transferase (hTERT). hTERT is expressed during early fetal development and switched off in most adult tissues, but it becomes reactivated in HCC. The exact mechanism regulating these expression changes remains unknown during HCC progress. We evaluated the relationship between hTERT expression and human kruppel-related 3 (HKR3) and cell cycle-related factors in HCC cell lines. Following transfection for hTERT knockdown and HKR3 overexpression, proteomic and transcriptomic analyses related to hTERT were performed using liquid chromatography/mass spectrometry (LC/MS) and RNA sequencing (RNAseq) in HCC cell lines. The expression levels of hTERT, HKR3, and cell cycle-related factors were measured using western blotting, and tumor growth were evaluated via cell proliferation and cell cycle assays. Transcriptomic and proteomic analyses showed that HKR3, hTERT and cyclin-dependent kinase inhibitor 2A (CDKN2A) were correlated. Up-regulation of HKR3 expression decreased hTERT and cyclin activation and suppressed the G1/S phase of the cell cycle through CDKN2A activation. Our results suggest that HKR3 induced regulation of cell cycle through hTERT inhibition and CDKN2A activation. Our results will facilitate further exploration of the pathways regulating human telomerase activity in HCC cell lines.
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http://dx.doi.org/10.7150/jca.39380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066026PMC
February 2020

The Beginning of Ending Hepatitis C Virus: A Summary of the 26th International Symposium on Hepatitis C Virus and Related Viruses.

Viruses 2020 03 11;12(3). Epub 2020 Mar 11.

Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Korea.

Hepatitis C virus (HCV) infects ~71 million people worldwide, and 399,000 people die annually due to HCV-related liver cirrhosis and hepatocellular carcinoma. The use of direct-acting antivirals results in a sustained virologic response in >95% of patients with chronic HCV infection. However, several issues remain to be solved to eradicate HCV. At the 26th International Symposium on Hepatitis C Virus and Related Viruses (HCV2019) held in Seoul, South Korea, October 5-8, 2019, virologists, immunologists, and clinical scientists discussed these remaining issues and how we can achieve the elimination of HCV.
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http://dx.doi.org/10.3390/v12030302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150740PMC
March 2020

Nonalcoholic Fatty Liver Disease and Sarcopenia Are Independently Associated With Cardiovascular Risk.

Am J Gastroenterol 2020 04;115(4):584-595

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

Objectives: Nonalcoholic fatty liver disease (NAFLD) and sarcopenia have a close association with an increased risk of atherosclerotic cardiovascular disease (ASCVD). This study investigated the influence of NAFLD and sarcopenia on ASCVD risk.

Methods: Data from the 2008-2011 Korean National Health and Nutrition Examination Surveys database were analyzed (n = 7,191). The sarcopenia index was calculated using dual-energy x-ray absorptiometry. Sarcopenia was defined as the lowest quintile sarcopenia index value (cutoffs = 0.882 for men and 0.582 for women). NAFLD was defined as a comprehensive NAFLD score ≥40. Liver fibrosis was assessed using the fibrosis-4 (FIB-4) index. ASCVD risk was evaluated using American College of Cardiology/American Heart Association guidelines. High probability of ASCVD was defined as ASCVD risk >10%.

Results: The prevalence rates of NAFLD and sarcopenia were 31.2% (n = 2,241) and 19.5% (n = 1,400), respectively. The quartile-stratified ASCVD risk scores were positively associated with NAFLD and sarcopenia (all P for trend < 0.001). Subjects with both NAFLD and sarcopenia had a higher risk for high probability of ASCVD (odds ratio = 1.83, P = 0.014) compared with controls without NAFLD and sarcopenia. Among subjects with NAFLD, FIB-4-defined significant liver fibrosis and sarcopenia additively raised the risk for high probability of ASCVD (odds ratio = 3.56, P < 0.001) compared with controls without FIB-4-defined significant liver fibrosis or sarcopenia.

Discussion: NAFLD and sarcopenia were significantly associated with an increased risk of ASCVD in the general population. In addition, NAFLD with significant liver fibrosis and sarcopenia were significantly associated with an increased risk of ASCVD in subjects with NAFLD.
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http://dx.doi.org/10.14309/ajg.0000000000000572DOI Listing
April 2020
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