Background/Aims: Quick sequential organ failure assessment (qSOFA) is believed to identify patients at risk of poor outcomes in those with suspected infection. We aimed to evaluate the ability of modified qSOFA (m-qSOFA) to identify high-risk patients among those with acutely deteriorated chronic liver disease (CLD), especially those with acute-onchronic liver failure (ACLF). Methods: We used data from both the Korean Acute-on-Chronic Liver Failure (KACLiF) and the Asian Pacific Association for the Study of the Liver ACLF Research Consortium (AARC) cohorts. qSOFA was modified by replacing the Glasgow Coma Scale with hepatic encephalopathy, and an m-qSOFA ≥2 was considered high. Results: Patients with high m-qSOFA had a significantly lower 1-month transplant-free survival (TFS) in both cohorts and higher organ failure development in KACLiF than those with low m-qSOFA (Ps<0.05). Subgroup analysis by ACLF showed that patients with high m-qSOFA had lower TFS than those with low m-qSOFA. m-qSOFA was an independent prognostic factor (hazard ratios, HR=2.604, 95% confidence interval, CI 1.353–5.013, P=0.004 in KACLiF and HR=1.904, 95% CI 1.484– 2.442, P<0.001 in AARC). The patients with low m-qSOFA at baseline but high m-qSOFA on day 7 had a significantly lower 1-month TFS than those with high m-qSOFA at baseline but low m-qSOFA on day 7 (52.6% vs. 89.4%, P<0.001 in KACLiF and 26.9% vs. 61.5%, P<0.001 in AARC). Conclusions Baseline and dynamic changes in m-qSOFA may identify patients with a high risk of developing organ failure and short-term mortality among CLD patients with acute deterioration.

Background/Aims: Efficient anti-fibrotic therapies are required for the treatment of liver cirrhosis. Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) and cyclooxygenase-2 (COX-2) inhibitors have been reported to have anti-fibrotic effects. Here, we investigated whether combined treatment with a statin and a COX-2 inhibitor has synergistic anti-fibrotic effects. Methods: The effects of treatment strategies incorporating both simvastatin and a COX-2 inhibitor, NS-398, were investigated using an immortalized human hepatic stellate cell line (LX-2) and a hepatic fibrosis mouse model developed using thioacetamide (TAA) in drinking water. Cellular proliferation was investigated via 5-bromo-2-deoxyuridine uptake. Pro- and anti-apoptotic factors were investigated through Western blotting and real-time polymerase chain reaction analysis. Results: The evaluation of the anti-proliferative effects on LX-2 cells showed that the observed effects were more pronounced with combination therapy than with single-drug therapy. Moreover, hepatic fibrosis and collagen deposition decreased significantly in TAA-treated mice in response to the combined treatment strategy. The mechanisms underlying the anti-fibrotic effects of the combination therapy were investigated. The effects of the combination therapy were correlated with increased expression levels of extracellular signal-regulated kinase 1/2 signaling molecules, upregulation of the Bax/Bcl-2 signaling pathway, inhibition of the transforming growth factor-β signaling pathway, and inhibition of tissue inhibitor of matrix metalloproteinases 1 and 2. Conclusions The combination of simvastatin and NS-398 resulted in a synergistic anti-fibrotic effect through multiple pathways. These findings offer a theoretical insight into the possible clinical application of this strategy for the treatment of advanced liver diseases with hepatic fibrosis.

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. Conclusions 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).

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 maxi-mal 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.

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. Conclusions 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).

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 maxi-mal 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.

Background/Aims: To improve the eradication rate of a first-line therapy for Helicobacter pylori infection, alternate regimens such as sequential, concomitant, and hybrid therapies have been tried. The aim of this study was to evaluate the eradication rate of the 10-day hybrid therapy as a first-line therapy. Materials and Methods: This retrospective study enrolled 124 patients from the Korea University Ansan Hospital between April 2016 and December 2019. The 10-day hybrid therapy comprised 5 days of dual therapy (proton pump inhibitor [PPI] standard dose and amoxicillin 1 g, twice daily) followed by 5 days of quadruple therapy (PPI, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg, twice daily). We compared the 10-day hybrid therapy with the 10-day concomitant therapy comprising PPI, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg, twice daily. Eradication was assessed by a 13C-urea breath test or gastroscopic biopsy at least 4 weeks after treatment completion. Results: The eradication rates of the 10-day hybrid and concomitant therapies were 74.2% (46/62) and 67.7% (42/62), respectively, in the intention-to-treat (ITT) analysis and 88.5% (46/52) and 82.4% (42/51), respectively, in the per-protocol (PP) analysis. There was no significant difference in the eradication rates between the two groups in the ITT (P=0.429) and PP analysis (P=0.380). Adverse events developed in 75.0% and 70.6% of patients in the hybrid and concomitant groups, respectively, but there was no significant difference (P=0.615). Conclusions The 10-day hybrid therapy can be an option for a first-line therapy of Helicobacter pylori infection.

Background/Aims: To improve the eradication rate of a first-line therapy for Helicobacter pylori infection, alternate regimens such as sequential, concomitant, and hybrid therapies have been tried. The aim of this study was to evaluate the eradication rate of the 10-day hybrid therapy as a first-line therapy. Materials and Methods: This retrospective study enrolled 124 patients from the Korea University Ansan Hospital between April 2016 and December 2019. The 10-day hybrid therapy comprised 5 days of dual therapy (proton pump inhibitor [PPI] standard dose and amoxicillin 1 g, twice daily) followed by 5 days of quadruple therapy (PPI, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg, twice daily). We compared the 10-day hybrid therapy with the 10-day concomitant therapy comprising PPI, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg, twice daily. Eradication was assessed by a 13C-urea breath test or gastroscopic biopsy at least 4 weeks after treatment completion. Results: The eradication rates of the 10-day hybrid and concomitant therapies were 74.2% (46/62) and 67.7% (42/62), respectively, in the intention-to-treat (ITT) analysis and 88.5% (46/52) and 82.4% (42/51), respectively, in the per-protocol (PP) analysis. There was no significant difference in the eradication rates between the two groups in the ITT (P=0.429) and PP analysis (P=0.380). Adverse events developed in 75.0% and 70.6% of patients in the hybrid and concomitant groups, respectively, but there was no significant difference (P=0.615). Conclusions The 10-day hybrid therapy can be an option for a first-line therapy of Helicobacter pylori infection.

BACKGROUND: Hepatitis B virus (HBV) infection leads to hepatic and extrahepatic manifestations including chronic kidney disease (CKD). However, the association between HBV and CKD is not clear. This study investigated the association between chronic HBV infection and CKD in a nationwide multicenter study. METHODS: A total of 265,086 subjects who underwent health-check examinations in 33 hospitals from January 2015 to December 2015 were enrolled. HBV surface antigen (HBsAg) positive cases (n = 10,048), and age- and gender-matched HBsAg negative controls (n = 40,192) were identified. CKD was defined as a glomerular filtration rate (GFR) < 60 mL/min/1.73 m² or proteinuria as at least grade 2+ of urine protein. RESULTS: HBsAg positive cases showed a significantly higher prevalence of GFR < 60 mL/min/1.73 m² (3.3%), and proteinuria (18.9%) than that of the controls (2.6%, P < 0.001, and 14.1%, P < 0.001, respectively). In the multivariate analysis, HBsAg positivity was an independent factor associated with GFR < 60 mL/min/1.73 m² along with age, blood levels of albumin, bilirubin, anemia, and hemoglobin A1c (HbA1c). Likewise, HBsAg positivity was an independent factor for proteinuria along with age, male, blood levels of bilirubin, protein, albumin, and HbA1c. A subgroup analysis showed that HBsAg positive men but not women had a significantly increased risk for GFR < 60 mL/min/1.73 m². CONCLUSION: Chronic HBV infection was significantly associated with a GFR < 60 mL/min/1.73 m² and proteinuria (≥ 2+). Therefore, clinical concern about CKD in chronic HBV infected patients, especially in male, is warranted.
Anemia ; Antigens, Surface ; Bilirubin ; Case-Control Studies* ; Female ; Glomerular Filtration Rate ; Hepatitis B Surface Antigens ; Hepatitis B virus ; Hepatitis B, Chronic* ; Hepatitis, Chronic* ; Humans ; Male ; Multivariate Analysis ; Prevalence ; Proteinuria ; Renal Insufficiency, Chronic*

BACKGROUND/AIMS: In addition to the globally endorsed Barcelona Clinic Liver Cancer (BCLC) staging system, other algorithms or staging systems have been developed, including the Hong Kong Liver Cancer (HKLC) staging system. This study aimed to validate the HKLC staging system relative to the BCLC staging system for predicting survival for hepatocellular carcinoma (HCC) patients in Korea. METHODS: From 2004 to 2013, 2,571 patients newly diagnosed with HCC were consecutively enrolled at three Korea University medical centers. RESULTS: Both staging systems differentiated survival well (p < 0.001). However, 1-year and 3-year survival were predicted better using the HKLC system than the BCLC system (area under the receiver operating characteristic curve: 0.869 vs 0.856 for 1 year, p=0.002; 0.841 vs 0.827 for 3 years, p=0.010). In hypothetical survival curves, the HKLC system exhibited better median overall survival than the BCLC system (33.1 months vs 19.2 months). In evaluations of prognosis according to either BCLC or HKLC treatment guidelines, risk of death was reduced in the group following only HKLC guidelines compared with the group following only BCLC guidelines (hazard ratio, 0.601; 95% confidence interval, 0.443 to 0.816; p=0.001). CONCLUSIONS: Although both staging systems predicted and discriminated HCC prognoses well, the HKLC system showed more encouraging survival benefits than the BCLC system.
Academic Medical Centers ; Carcinoma, Hepatocellular ; Hong Kong ; Humans ; Korea ; Liver Neoplasms ; Liver ; Neoplasm Staging ; Prognosis ; ROC Curve