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Background/Aims: Besifovir dipivoxil maleate (BSV) and tenofovir alafenamide fumarate (TAF) have been recently approved in Korea as the initial antiviral agents for chronic hepatitis B (CHB). However, the real-world outcome data for these drugs remain limited. Therefore, we conducted a noninferiority analysis using real-world data to compare the clinical outcomes of the two nucleotide analogs in treatment-naïve patients with CHB. Methods: We retrospectively investigated a cohort of patients with CHB who received BSV or TAF as first-line antiviral agents. The endpoints were virological response (VR) and liver-related clinical outcomes. Results: A total of 537 patients, consisting of 202 and 335 patients administered BSV and TAF, respectively, were followed up for 42 months. No significant difference was observed between the VRs of the patients from the two groups. The rates of biochemical response, virologic breakthrough, and incidence rates of hepatocellular carcinoma did not differ between the groups. However, the hepatitis B e antigen seroclearance rate was higher and the renal function declined less in the BSV group. Multivariable analysis indicated older age, alcohol abuse, cirrhosis and ascites, and lower serum HBV DNA level to be independently associated with increased hepatocellular carcinoma risk. The 1:1 propensity score-matched analysis with 400 patients showed VR rates of 85.0% and 88.7% in the BSV and TAF group patients, respectively, at 2 years. The absolute value of the 95% confidence interval for the difference (–0.04 to 0.12) satisfied the a priori limit of a noninferiority of 0.15. Conclusions: BSV is noninferior to TAF in terms of VR, and their clinical outcomes are comparable to CHB. [ABSTRACT FROM AUTHOR]

Background/Aims The combination of atezolizumab and bevacizumab is the leading treatment for advanced hepatocellular carcinoma (HCC), but finding a reliable biomarker to predict treatment outcomes remains challenging. This study sought to discover exosomal miRNA biomarkers that could predict favorable responses to this therapy. Methods Blood samples were collected from patients with advanced HCC before starting atezolizumab and bevacizumab treatment. Patients were divided into two groups: responders (those showing stable disease, partial, or complete response) and non-responders (those with disease progression). Serum was concentrated using a qEV isolation kit, and exosomal RNA was extracted for small RNA sequencing using next-generation sequencing (NGS). A decision tree analysis was used to identify miRNAs from the top 100 most expressed miRNAs that could differentiate between responders and non-responders. The findings were validated with a t-test. Results The study included eight patients in each group, mostly male, with the majority having viral-induced HCC. NGS identified 1076 miRNAs, with 12 showing significant differences in expression between responders and non-responders. Among these, three miRNAs were elevated, and nine were decreased in the responder group. Specifically, let7c-5p, miR-30a-5p, and miR192-5p were significantly higher in responders. Decision tree analysis highlighted 30 miRNAs from the top 100, with miR-30a-5p being significantly higher in responders (p=0.0047). Validation using quantitative reverse transcription PCR confirmed the increased expression of miR-30a-5p in responders. Additionally, transfecting miR-30a-5p into HepG2 cells led to reduced migration and proliferation. Conclusion Exosomal miRNAs show potential as biomarkers for predicting response to atezolizumab-bevacizumab therapy in HCC patients. [ABSTRACT FROM AUTHOR]

Background/Aims Tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are both recommended as first-line treatments for antiviral-naïve patients with chronic hepatitis B (CHB). However, it remains controversial which drug is more effective in preventing hepatocellular carcinoma (HCC). We aimed to compare the effects of TAF and TDF on HCC risk. Methods We included 1,628 treatment-naïve CHB patients who underwent antiviral therapy with either a TAF-based regimen (TAF group: n=335) or TDF only (TDF group: n=1,293) between 2007 and 2021. The TAF group consisted of patients who received TAF as a first-line treatment and those who switched from TDF to TAF. Propensity score (PS) matching was used to reduce the effects of confounding factors. Results After PS matching, we analyzed data from 334 patients in the TAF group (mean age: 48.0±11.7 years; 192 men [57.5%]) and 573 patients in the TDF group (mean age: 47.4±11.6 years; 326 men [56.9%]). During a 60-month follow-up, 8 patients in the TAF group (2.4%) and 46 patients in the TDF group (8.0%) developed HCC. TAF treatment was associated with a significantly lower risk of HCC compared to TDF (hazard ratio [HR], 0.34; 95% confidence interval [CI], 0.16-0.72; p<0.001). In multivariate analysis, factors independently associated with HCC development included age (adjusted HR [aHR], 1.07; p<0.001), liver cirrhosis (aHR, 2.02; p=0.045), diabetes (aHR, 4.78; p<0.001), alcohol use (aHR, 3.07; p=0.002), and TAF treatment (aHR, 0.22; p<0.001). Conclusion TAF treatment was associated with a 66% lower risk of HCC compared to TDF treatment. Further studies with larger sample sizes and longer follow-up periods are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Background/Aims The combination of atezolizumab and bevacizumab is currently used as a first-line treatment for advanced hepatocellular carcinoma (HCC). Despite extensive research, accurately predicting the response to this therapy remains a challenge. Methods This study included patients with advanced HCC who were undergoing atezolizumab and bevacizumab therapy. Blood samples were collected on days 0 and 14 of the first treatment cycle. Peripheral blood mononuclear cells (PBMCs) were isolated from these samples. Eight patients were selected for further analysis: 4 had a complete or partial response, while 4 experienced disease progression. Single-cell RNA sequencing (scRNA-seq) was conducted on the PBMC samples. Results Before treatment, patients with a positive prognosis had higher frequencies of γδ T cells, CD4+ T cells, classical monocytes, CD8+ T cells, and non-classical monocytes in their PBMCs compared to those with a poor prognosis. After treatment, patients with favorable outcomes showed a significant increase in proliferating lymphocytes. In the CD8+ T cell group, a specific cluster (cluster 4) marked by high expression of the proliferation marker MKI67 and inhibitory checkpoint genes (PDCD1, HAVCR2, CTLA4) was more prevalent in patients with a positive prognosis prior to treatment. Furthermore, the frequency of this cluster increased post-treatment in those with better outcomes. Conclusion This study mapped the diverse circulating immune cells in patients with advanced HCC before and after treatment with atezolizumab and bevacizumab. A specific subgroup of CD8+ T cells emerged as a potential biomarker for predicting responses to this combination therapy. [ABSTRACT FROM AUTHOR]

Background/Aims: Most prognostic prediction models for patients with liver cirrhosis include serum total bilirubin (TB) level as a component. This study investigated prognostic performance of serum direct bilirubin (DB) and developed new DB level-based prediction models for cirrhosis. Methods: A total of 983 hospitalized patients with liver cirrhosis were included. DB-Model for End-Stage Liver Disease (MELD) score was calculated using MELD score formula, with serum DB level replacing TB level. Results: Mean age of study population was 56.1 years. Alcoholic liver disease was the most frequent underlying condition (471 patients, 47.9%). Within 6 months, 144 patients (14.6%) died or received liver transplantation due to severe liver dysfunction. The area under the receiver operating characteristic curve (AUROC) for prediction of 6-month mortality with DB level was significantly higher than that with TB level (p<0.001). The AUROC of DB-MELD score for prediction of 6-month mortality was significantly higher than that of MELD score (p<0.001). Patients were randomly divided into training (n=492) and validation (n=491) cohorts. A new prognostic prediction model, “Direct Bilirubin, INR, and Creatinine” (DiBIC) score, was developed based on the most significant predictors of 6-month mortality. In training set, AUROC of DiBIC score for prediction of 6-month mortality was 0.892, which was significantly higher than that of the MELD score (0.875, p=0.017), but not different from that of DB-MELD score (0.886, p=0.272). Similar results were observed in validation set. Conclusions: New prognostic models, DB-MELD and DiBIC scores, have good prognostic performance in liver cirrhosis patients, outperforming other currently available models. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background/Aims: Sorafenib is the first approved systemic treatment for advanced hepatocellular carcinoma (HCC). However, its clinical utility is limited, especially in Asian countries. Several reports have suggested the survival benefits of hepatic arterial infusion chemotherapy (HAIC) for advanced HCC with main portal vein tumor thrombosis (PVTT). This study aimed to compare the efficacy of sorafenib-based therapy with that of HAIC-based therapy for advanced HCC with main PVTT. Methods: Advanced HCC patients with main PVTT treated with sorafenib or HAIC between 2008 and 2016 at Korea University Medical Center were included. We evaluated overall survival (OS), time-to-progression (TTP), and the disease control rate (DCR). Results: Seventy-three patients were treated with sorafenib (n=35) or HAIC (n=38). Baseline characteristics were not significantly different between groups, except the presence of solid organ metastasis (46% vs 5.3%, p<0.001). The median OS time was not significantly different between the groups (6.4 months vs 10.0 months, p=0.139). TTP was longer in the HAIC group than in the sorafenib group (2.1 months vs 6.2 months, p=0.006). The DCR was also better in the HAIC group than in the sorafenib group (37% vs 76%, p=0.001). Subgroup analysis, which excluded patients with extrahepatic solid organ metastasis, showed the same trends for the median OS time (8.8 months vs 11.1 months, p=0.097), TTP (1.9 months vs 6.0 months, p<0.001), and DCR (53% vs 81%, p=0.030). Conclusions: HAIC-based therapy may be an alternative to sorafenib for advanced HCC with main PVTT by providing longer TTP and a better DCR. [ABSTRACT FROM AUTHOR]

Backgrounds/Aims: Rebleeding of gastric varices (GVs) after endoscopic variceal obturation (EVO) can be fatal. This study was performed to evaluate the usefulness of computed tomography (CT) for the prediction of rebleeding after EVO GV bleeding. Methods: Patients who were treated with EVO for GV bleeding and underwent CT before and after EVO were included. CT images of the portal phase showing pretreatment GVs and feeding vessels, and nonenhanced images showing posttreatment cyanoacrylate impaction were reviewed. Results: Fifty-three patients were included. Their mean age was 60.6±11.6 years, and 40 patients (75.5%) were men. Alcoholic liver disease was the most frequent underlying liver disease (45.3%). Complete impaction of cyanoacrylate in GVs and feeding vessels were achieved in 40 (75.5%) and 24 (45.3%) of patients, respectively. During the follow-up, GV rebleeding occurred in nine patients, and the cumulative incidences of GV rebleeding at 3, 6, and 12 months were 11.8%, 18.9%, and 18.9%, respectively. The GV rebleeding rate did not differ significantly according to the complete cyanoacrylate impaction in the GV, while it differed significantly according to complete cyanoacrylate impaction in the feeding vessels. The cumulative incidences of GV rebleeding at 3, 6, and 12 months were 22.3%, 35.2%, and 35.2%, respectively, in patients with incomplete impaction in feeding vessels, and there was no rebleeding during the follow-up period in patients with complete impaction in the feeding vessels (p=0.002). Conclusions: Abdominal CT is useful in the evaluation of the treatment response after EVO for GV bleeding. Incomplete cyanoacrylate impaction in feeding vessels is a risk factor for GV rebleeding. [ABSTRACT FROM AUTHOR]

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. (Gut Liver 2018;12:94-101) [ABSTRACT FROM AUTHOR]