Metabolic dysfunction-associated steatotic liver disease and risk of cardiovascular disease.

OBJECTIVE: We explored clinical implications of the new definition of metabolic dysfunction-associated steatotic liver disease (MASLD) by assessing its prevalence and associated cardiovascular disease (CVD) risk. DESIGN: From nationwide health screening data, we identified 9 775 066 adults aged 20-79 who underwent health examination in 2009. Participants were categorised into four mutually exclusive groups: (1) MASLD; (2) MASLD with increased alcohol intake (MetALD); (3) MASLD with other combined aetiology (the three collectively referred to as MASLD/related steatotic liver disease (SLD)); and (4) no MASLD/related SLD. SLD was determined by fatty liver index ≥30. The primary outcome was CVD event, defined as a composite of myocardial infarction, ischaemic stroke, heart failure or cardiovascular death. RESULTS: The prevalence of MASLD, MetALD and MASLD with other combined aetiology was 27.5%, 4.4% and 1.5%, respectively. A total of 8 808 494 participants without prior CVD were followed up for a median of 12.3 years, during which 272 863 CVD events occurred. The cumulative incidence and multivariable-adjusted risk of CVD were higher in participants with MASLD/related SLD than in those without (HR 1.38 (95% CI 1.37 to 1.39)). Multivariable-adjusted HR (95% CI) of CVD events was 1.39 (1.38 to 1.40) for MASLD, 1.28 (1.26 to 1.30) for MetALD and 1.30 (1.26 to 1.34) for MASLD with other combined aetiology compared to the absence of any of these conditions. CVD risk was also higher in participants with metabolic dysfunction-associated fatty liver disease or non-alcoholic fatty liver disease than in those without the respective condition. CONCLUSION: Over one-third of Korean adults have MASLD/related SLD and bear a high CVD risk.

PAGE-B incorporating moderate HBV DNA levels predicts risk of HCC among patients entering into HBeAg-positive chronic hepatitis B.

BACKGROUND & AIMS: Recent studies reported that moderate HBV DNA levels are significantly associated with hepatocellular carcinoma (HCC) risk in hepatitis B e antigen (HBeAg)-positive, non-cirrhotic patients with chronic hepatitis B (CHB). We aimed to develop and validate a new risk score to predict HCC development using baseline moderate HBV DNA levels in patients entering into HBeAg-positive CHB from chronic infection. METHODS: This multicenter cohort study recruited 3,585 HBeAg-positive, non-cirrhotic patients who started antiviral treatment with entecavir or tenofovir disoproxil fumarate at phase change into CHB from chronic infection in 23 tertiary university-affiliated hospitals of South Korea (2012-2020). A new HCC risk score (PAGED-B) was developed (training cohort, n = 2,367) based on multivariable Cox models. Internal validation using bootstrap sampling and external validation (validation cohort, n = 1,218) were performed. RESULTS: Sixty (1.7%) patients developed HCC (median follow-up, 5.4 years). In the training cohort, age, gender, platelets, diabetes and moderate HBV DNA levels (5.00-7.99 log10 IU/ml) were independently associated with HCC development; the PAGED-B score (based on these five predictors) showed a time-dependent AUROC of 0.81 for the prediction of HCC development at 5 years. In the validation cohort, the AUROC of PAGED-B was 0.85, significantly higher than for other risk scores (PAGE-B, mPAGE-B, CAMD, and REAL-B). When stratified by the PAGED-B score, the HCC risk was significantly higher in high-risk patients than in low-risk patients (sub-distribution hazard ratio = 8.43 in the training and 11.59 in the validation cohorts, all p <0.001). CONCLUSIONS: The newly established PAGED-B score may enable risk stratification for HCC at the time of transition into HBeAg-positive CHB. IMPACT AND IMPLICATIONS: In this study, we developed and validated a new risk score to predict hepatocellular carcinoma (HCC) development in patients entering into hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) from chronic infection. The newly established PAGED-B score, which included baseline moderate HBV DNA levels (5-8 log10 IU/ml), improved on the predictive performance of prior risk scores. Based on a patient's age, gender, diabetic status, platelet count, and moderate DNA levels (5-8 log10 IU/ml) at the phase change into CHB from chronic infection, the PAGED-B score represents a reliable and easily available risk score to predict HCC development during the first 5 years of antiviral treatment in HBeAg-positive patients entering into CHB. With a scoring range from 0 to 12 points, the PAGED-B score significantly differentiated the 5-year HCC risk: low <7 points and high ≥7 points.

Risk Stratification for Sarcopenic Obesity in Subjects With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: The impact of the severity of sarcopenic obesity (SO) in nonalcoholic fatty liver disease (NAFLD) on the risk of significant liver fibrosis or cardiovascular disease (CVD) remains unclear. We aimed to identify high-risk subjects with SO for significant liver fibrosis or CVD among subjects with SO and NAFLD. METHODS: This multicenter, retrospective study involved 23,889 subjects with NAFLD who underwent a health screening program (2014-2020). Sarcopenia was defined based on gender-specific sarcopenia index cutoff using multi-frequency bioelectric impedance analysis. High-risk subjects with SO were defined as those with significant liver fibrosis by fibrosis-4 index >2.67 or atherosclerotic CVD risk score >20%. Multivariable logistic regression analysis for identifying high-risk subjects with SO was performed in a cross-sectional cohort with SO, and further validation was performed in a longitudinal cohort. RESULTS: SO prevalence was 5.4% (n = 1297 of 23,889). Older age (unstandardized beta [ß] = 3.23; P < .001), male (ß = 1.66; P = .027), sarcopenia index (ß = -6.25; P = .019), and metabolic syndrome (ß = 1.75; P < .001) were significant risk factors for high-risk SO. Based on a high-risk SO screening model, high-risk subjects with SO had significantly higher odds of significant liver fibrosis (training: adjusted odds ratio [aOR], 3.72; validation: aOR, 2.38) or CVD (training: aOR, 5.20; validation: aOR, 3.71) than subjects without SO (all P < .001). In subgroup analyses, the cumulative incidence of significant liver fibrosis or CVD development was significantly higher in high-risk subjects with SO than in low-risk subjects with SO in a longitudinal cohort considering all-cause mortality and liver transplantation as competing risks (sub-distribution hazard ratio, 5.37; P < .001). CONCLUSION: The high-risk screening model may enable the identification of high-risk subjects with SO with NAFLD.

Personalized Antiviral Drug Selection in Patients With Chronic Hepatitis B Using a Machine Learning Model: A Multinational Study.

INTRODUCTION: Tenofovir disoproxil fumarate (TDF) is reportedly superior or at least comparable to entecavir (ETV) for the prevention of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B; however, it has distinct long-term renal and bone toxicities. This study aimed to develop and validate a machine learning model (designated as Prediction of Liver cancer using Artificial intelligence-driven model for Network-antiviral Selection for hepatitis B [PLAN-S]) to predict an individualized risk of HCC during ETV or TDF therapy. METHODS: This multinational study included 13,970 patients with chronic hepatitis B. The derivation (n = 6,790), Korean validation (n = 4,543), and Hong Kong-Taiwan validation cohorts (n = 2,637) were established. Patients were classified as the TDF-superior group when a PLAN-S-predicted HCC risk under ETV treatment is greater than under TDF treatment, and the others were defined as the TDF-nonsuperior group. RESULTS: The PLAN-S model was derived using 8 variables and generated a c-index between 0.67 and 0.78 for each cohort. The TDF-superior group included a higher proportion of male patients and patients with cirrhosis than the TDF-nonsuperior group. In the derivation, Korean validation, and Hong Kong-Taiwan validation cohorts, 65.3%, 63.5%, and 76.4% of patients were classified as the TDF-superior group, respectively. In the TDF-superior group of each cohort, TDF was associated with a significantly lower risk of HCC than ETV (hazard ratio = 0.60-0.73, all P < 0.05). In the TDF-nonsuperior group, however, there was no significant difference between the 2 drugs (hazard ratio = 1.16-1.29, all P > 0.1). DISCUSSION: Considering the individual HCC risk predicted by PLAN-S and the potential TDF-related toxicities, TDF and ETV treatment may be recommended for the TDF-superior and TDF-nonsuperior groups, respectively.

The clinical effect of antiviral therapy in patients with hepatitis B virus-related decompensated cirrhosis and undetectable DNA.

BACKGROUND AND AIM: Antiviral therapy (AVT) is the mainstay of hepatitis B virus (HBV) management. We investigated whether AVT improves the outcomes of HBV-related decompensated cirrhosis and undetectable HBV-DNA. METHODS: Between 2000 and 2017, treatment-naïve patients with HBV-related decompensated cirrhosis and undetectable HBV-DNA were recruited from two tertiary hospitals. The endpoints included death and hepatocellular carcinoma (HCC). RESULTS: A total of 429 patients were analyzed (50 and 379 patients in the AVT and non-AVT groups, respectively). Patients in the AVT group were significantly younger and had higher alanine aminotransferase and alpha-fetoprotein levels than those in the non-AVT group (all P < 0.05). During follow-up (median 49.6 months), 98 patients died and 105 developed HCC. The cumulative incidence rates of death (2.0%, 4.1%, and 6.4%, and 4.9%, 7.2%, and 10.2% at 6 months, 1 year, and 2 years, respectively) and HCC (8.6%, 15.8%, and 26.4% vs 1.6%, 7.7%, and 24.4% at 1, 2, and 5 years, respectively) were statistically comparable between the AVT and non-AVT groups (all P > 0.05). Using Cox regression analysis, AVT was not significantly associated with death nor HCC (all P > 0.05). Similar results were observed after balancing baseline characteristics with inverse probability of treatment weighting. In the non-AVT group, the cumulative incidence rates of HBV-DNA detection at 6 months, 1 year, and 2 years were 2.0%, 3.1%, and 6.4%, respectively. CONCLUSIONS: Antiviral therapy did not attenuate the risk of death nor HCC in patients with HBV-related decompensated cirrhosis and undetectable HBV-DNA.

Therapeutic Mechanisms and Clinical Effects of Glucagon-like Peptide 1 Receptor Agonists in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) can lead to liver fibrosis and cirrhosis. Recently, glucagon-like peptide 1 receptor agonists (GLP-1RAs), a class of drugs used to treat type 2 diabetes and obesity, have shown therapeutic effects against NAFLD. In addition to reducing blood glucose levels and body weight, GLP-1RAs are effective in improving the clinical, biochemical, and histological markers of hepatic steatosis, inflammation, and fibrosis in patients with NAFLD. Additionally, GLP-1RAs have a good safety profile with minor side effects, such as nausea and vomiting. Overall, GLP-1RAs show promise as a potential treatment for NAFLD, and further studies are required to determine their long-term safety and efficacy.

An artificial intelligence model to predict hepatocellular carcinoma risk in Korean and Caucasian patients with chronic hepatitis B.

BACKGROUND & AIMS: Several models have recently been developed to predict risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). Our aims were to develop and validate an artificial intelligence-assisted prediction model of HCC risk. METHODS: Using a gradient-boosting machine (GBM) algorithm, a model was developed using 6,051 patients with CHB who received entecavir or tenofovir therapy from 4 hospitals in Korea. Two external validation cohorts were independently established: Korean (5,817 patients from 14 Korean centers) and Caucasian (1,640 from 11 Western centers) PAGE-B cohorts. The primary outcome was HCC development. RESULTS: In the derivation cohort and the 2 validation cohorts, cirrhosis was present in 26.9%-50.2% of patients at baseline. A model using 10 parameters at baseline was derived and showed good predictive performance (c-index 0.79). This model showed significantly better discrimination than previous models (PAGE-B, modified PAGE-B, REACH-B, and CU-HCC) in both the Korean (c-index 0.79 vs. 0.64-0.74; all p <0.001) and Caucasian validation cohorts (c-index 0.81 vs. 0.57-0.79; all p <0.05 except modified PAGE-B, p = 0.42). A calibration plot showed a satisfactory calibration function. When the patients were grouped into 4 risk groups, the minimal-risk group (11.2% of the Korean cohort and 8.8% of the Caucasian cohort) had a less than 0.5% risk of HCC during 8 years of follow-up. CONCLUSIONS: This GBM-based model provides the best predictive power for HCC risk in Korean and Caucasian patients with CHB treated with entecavir or tenofovir. LAY SUMMARY: Risk scores have been developed to predict the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B. We developed and validated a new risk prediction model using machine learning algorithms in 13,508 antiviral-treated patients with chronic hepatitis B. Our new model, based on 10 common baseline characteristics, demonstrated superior performance in risk stratification compared with previous risk scores. This model also identified a group of patients at minimal risk of developing HCC, who could be indicated for less intensive HCC surveillance.

Impact of HBeAg on Hepatocellular Carcinoma Risk During Oral Antiviral Treatment in Patients With Chronic Hepatitis B.

BACKGROUND & AIMS: Antiviral treatment from hepatitis B envelope antigen (HBeAg)-positive status may attenuate the integration of hepatitis B virus DNA into the host genome causing hepatocellular carcinoma (HCC). We investigated the impact of HBeAg status at the onset of antiviral treatment on the risk of HCC. METHODS: The incidence of HCC was evaluated in Korean patients with chronic hepatitis B who started entecavir or tenofovir in either HBeAg-positive or HBeAg-negative phase. The results in the Korean cohort were validated in a Caucasian PAGE-B cohort. RESULTS: A total of 9143 Korean patients (mean age, 49.2 years) were included: 49.1% were HBeAg-positive and 49.2% had cirrhosis. During follow-up (median, 5.1 years), 916 patients (10.0%) developed HCC. Baseline HBeAg positivity was not associated with the risk of HCC in the entire cohort or cirrhotic subcohort. However, in the non-cirrhotic subcohort, HBeAg positivity was independently associated with a lower risk of HCC in multivariable (adjusted hazard ratio [aHR], 0.41; 95% confidence interval [CI], 0.26-0.66), propensity score-matching (aHR, 0.46; 95% CI, 0.28-0.76), and inverse probability weighting analyses (aHR, 0.44; 95% CI, 0.28-0.70). In the Caucasian cohort (n = 719; mean age, 51.8 years; HBeAg-positive, 20.3%; cirrhosis, 34.8%), HBeAg-positivity was not associated with the risk of HCC either in the entire cohort or cirrhotic subcohort. In the non-cirrhotic subcohort, none of the HBeAg-positive group developed HCC, although the difference failed to reach statistical significance (aHR, 0.21; 95% CI, 0.00-1.67). CONCLUSIONS: This multinational cohort study implies that HBeAg positivity at the onset of antiviral treatment seems to be an independent factor associated with a lower risk of HCC in patients with chronic hepatitis B without cirrhosis, but not in those with cirrhosis.

Endoscopic variceal obturation and retrograde transvenous obliteration for acute gastric cardiofundal variceal bleeding in liver cirrhosis.

BACKGROUND/AIMS: We retrospectively compared the effect of endoscopic variceal obturation (EVO) and retrograde transvenous obliteration (RTO) in acute cardiofundal variceal bleeding. METHODS: Patients with acute cardiofundal variceal bleeding treated with EVO or RTO at two hospitals were included. RESULTS: Ninety patients treated with EVO and 86 treated with RTO were analyzed. The mean model for end-stage liver disease score was significantly higher in EVO group than in RTO group (13.5 vs. 11.7, P = 0.016). The bleeding control rates were high (97.8% vs. 96.5%), and the treatment-related complication rates were low in both EVO and RTO groups (2.2% vs. 3.5%). During the median follow-up of 18.0 months, gastric variceal (GV) and esophageal variceal rebleeding occurred in 34 (19.3%) and 7 (4.0%) patients, respectively. The all-variceal rebleeding rates were comparable between EVO and RTO groups (32.4% vs. 20.8% at 2-year, P = 0.150), while the GV rebleeding rate was significantly higher in EVO group than in RTO group (32.4% vs. 12.8% at 2-year, P = 0.003). On propensity score-matched analysis (71 patients in EVO vs. 71 patients in RTO group), both all-variceal and GV rebleeding rates were significantly higher in EVO group than in RTO group (all P < 0.05). In Cox regression analysis, EVO (vs. RTO) was the only significant predictor of higher GV rebleeding risk (hazard ratio 3.132, P = 0.005). The mortality rates were similar between two groups (P = 0.597). CONCLUSIONS: Both EVO and RTO effectively controlled acute cardiofundal variceal bleeding. RTO was superior to EVO in preventing all-variceal and GV rebleeding after treatment, with similar survival outcomes.

Long-term effects of entecavir and tenofovir treatment on the fibrotic burden in patients with chronic hepatitis B.

BACKGROUND AND AIM: Antiviral therapy (AVT) induces fibrosis regression in patients with chronic hepatitis B. We investigated long-term effects of entecavir (ETV) versus tenofovir (TDF) on fibrotic burden. METHODS: Treatment-naïve chronic hepatitis B patients who had begun ETV or TDF were recruited from four tertiary hospitals. The aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on four factors (FIB-4) were used to determine fibrotic burden. RESULTS: In the entire population (n = 3277), although patients treated with ETV had higher baseline APRI (1.71 vs 1.07, P < 0.001) and FIB-4 (3.60 vs 2.80, P < 0.001) than those treated with TDF, significant fibrosis regression was identified during 6 years of AVT in both ETV (APRI, mean 1.71 â†’ 0.48, P < 0.001; FIB-4, mean 3.60 â†’ 2.21, P < 0.001) and TDF groups (APRI, mean 1.07 â†’ 0.43, P < 0.001; FIB-4, mean 2.80 â†’ 2.19, P < 0.001). In patients without cirrhosis (n = 2366), baseline APRI was significantly higher in ETV group than in TDF group (1.72 vs 0.97, P < 0.001); however, they became similar after 6 months. Similarly, baseline FIB-4 was significantly higher in ETV group than in TDF group (3.25 vs 2.35, P < 0.001), but became similar from 4 to 6 years. In patients with cirrhosis (n = 911), baseline APRI (1.70 vs 1.34, P < 0.001) and FIB-4 (4.62 vs 3.91, P = 0.005) were higher in ETV group than in TDF, however, both parameters became statistically similar from 6 months to 6 years. CONCLUSION: Significant regression of APRI and FIB-4 was observed during long-term ETV and TDF treatment. Despite higher baseline fibrotic burden in ETV group, fibrotic burden between the groups eventually converged through significant fibrosis regression after 1 to 4 years of AVT.

Empirical Treatment With Carbapenem vs Third-generation Cephalosporin for Treatment of Spontaneous Bacterial Peritonitis.

BACKGROUND & AIMS: Third-generation cephalosporins (TGCs) are recommended as first-line antibiotics for treatment of spontaneous bacterial peritonitis (SBP). However, antibiotics against multidrug-resistant organisms (such as carbapenems) might be necessary. We aimed to evaluate whether carbapenems are superior to TGC for treatment of SBP. METHODS: We performed a retrospective study of 865 consecutive patients with a first presentation of SBP (275 culture positive; 103 with TGC-resistant bacterial infections) treated at 7 referral centers in Korea, from September 2013 through January 2018. The primary outcome was in-hospital mortality. We made all comparisons using data from patients whose baseline characteristics were balanced by inverse probability of treatment weighting. RESULTS: Of patients who initially received empirical treatment with antibiotics, 95 (11.0%) received carbapenems and 655 (75.7%) received TGCs. Among the entire study cohort, there was no significant difference in in-hospital mortality between the carbapenem (25.8%) and TGC (25.3%) groups (adjusted odds ratio [aOR], 0.97; 95% CI, 0.85-1.11; P = .66). In the subgroup of patients with high chronic liver failure-sequential organ failure assessment (CLIF-SOFA) scores (score of 7 or greater, n = 314), carbapenem treatment was associated with lower in-hospital mortality (23.1%) than in the TGC group (38.8%) (aOR, 0.84; 95% CI, 0.75-0.94; P=.002). In contrast, among patients with lower CLIF-SOFA scores (n = 436), in-hospital mortality did not differ significantly between the carbapenem group (24.7%) and the TGC group (16.0%) (aOR, 1.06; 95% CI, 0.85-1.32; P = .58). CONCLUSIONS: For patients with a first presentation of SBP, empirical treatment with carbapenem does not reduce in-hospital mortality compared to treatment with TGCs. However, among critically ill patients (CLIF-SOFA scores ≥7), empirical carbapenem treatment was significantly associated with lower in-hospital mortality than TGCs.

Validation of risk prediction scores for hepatocellular carcinoma in patients with chronic hepatitis B treated with entecavir or tenofovir.

Several prediction scores for the early detection of hepatocellular carcinoma (HCC) are available. We validated the predictive accuracy of age, albumin, sex, liver cirrhosis (AASL), RESCUE-B, PAGE-B and modified PAGE-B (mPAGE-B) scores in chronic hepatitis B (CHB) patients treated with entecavir (ETV) or tenofovir disoproxil fumarate (TDF). Between 2007 and 2014, 3171 patients were recruited (1645, ETV; 1517, TDF). The predictive accuracy of each prediction score was assessed. The mean age of the study population (1977 men; 1194 women) was 48.8 years. Liver cirrhosis was present in 1040 (32.8%) patients. During follow-up (median, 58.2 months), 280 (8.8%) patients developed HCC; these patients were significantly older; more likely to be male; had significantly higher proportions of liver cirrhosis, hypertension and diabetes; and had significantly higher values for the four risk scores than those who did not develop HCC (all P < .05). Older age (hazard ratio [HR] = 1.048), male sex (HR = 2.142), liver cirrhosis (HR = 3.144) and prolonged prothrombin time (HR = 2.589) were independently associated with an increased risk of HCC (all P < .05), whereas a higher platelet count (HR = 0.996) was independently associated with a decreased risk of HCC (P < .05). The predictive accuracy of AASL score was the highest for 3- and 5-year HCC predictions (areas under the curve [AUCs] = 0.818 and 0.816, respectively), followed by RESCUE-B, PAGE-B and mPAGE-B scores (AUC = 0.780-0.815 and 0.769-0.814, respectively). In conclusion, four HCC prediction scores were assessed in Korean CHB patients treated with ETV or TDF. The AASL score showed the highest predictive accuracy.

Association Between Curative Treatment after Transarterial Radioembolization and Better Survival Outcomes in Patients with Hepatocellular Carcinoma.

Transarterial radioembolization (TARE) is one of the therapeutic options for hepatocellular carcinoma (HCC). This study aimed to investigate the predictors and prognostic values of achieving curative treatments after TARE. Overall, 143 patients with intrahepatic HCC treated with TARE between 2011 and 2017 were recruited from two Korean tertiary institutes. Twenty-seven patients received curative treatments after TARE. Younger age than 65 years and AFP of ≤200 ng/mL independently predicted the increased probability of achieving curative treatment after TARE, and the curative treatment after TARE provided a survival benefit in patients with intrahepatic HCC.

Natural killer cell activity is a risk factor for the recurrence risk after curative treatment of hepatocellular carcinoma.

BACKGROUND: Natural killer (NK) cells have been known to contribute to surveillance and control of hepatocellular carcinoma (HCC). However, the association of NK cell activity with stage and recurrence risk of HCC have not been fully evaluated. METHODS: Untreated patients with newly diagnosed HCC were prospectively enrolled. Peripheral blood mononuclear cells were isolated at the time of diagnosis. Patients who had undergone surgery or radiofrequency ablation were classified as the curative treatment group, and their blood samples were collected again at 1 month after treatment. RESULTS: A total of 80 patients with HCC were enrolled. The mean age was 62.5 years. At baseline, interferon (IFN)-γ producing NK cell proportion was significantly lower in patients with Barcelona clinic liver cancer (BCLC) stage B, C, or D than in those with BCLC stage 0 (42.9% vs. 56.8%, P = 0.045). Among all patients, 56 patients had undergone curative treatment, and 42 patients re-visited at 1 month after curative treatment. There was no significant change in total NK cell and IFN-γ producing NK cell proportion from baseline to 1 month after treatment (all P > 0.05). During a median follow-up of 12.4 months, HCC recurred in 14 patients (33.3%). When patients were classified according to the IFN-γ producing NK cell proportion (group 1, ≥ 45%; and group 2, < 45%), HCC recurrence rate did not differ according to the IFN-γ producing NK cell proportion at baseline (log-rank test, P = 0.835). However, patients with < 45% IFN-γ producing NK cell proportion at 1 month after treatment had a significantly higher HCC recurrence rate than patients with that of ≥ 45% (log-rank test, P < 0.001). Multivariate analysis revealed that BCLC stage B (hazard ratio [HR] = 3.412, P = 0.045) and < 45% IFN-γ producing NK cell proportion at 1 month after treatment (HR = 6.934, P = 0.001) independently predicted an increased risk of HCC recurrence. CONCLUSIONS: Decreased NK cell activity is significantly associated with the advanced stage of HCC, and the increased recurrence risk of HCC after curative treatment.

Salvage External Beam Radiotherapy after Incomplete Transarterial Chemoembolization for Hepatocellular Carcinoma: A Meta-Analysis and Systematic Review.

Background and objective: Although transarterial chemoembolization (TACE) has been the commonest local modality for hepatocellular carcinoma (HCC), incomplete repsonse occurs especially for tumors with a large size or difficult tumor accessment. The present meta-analysis assessed the efficacy and feasibility of external beam radiotherapy (EBRT) as a salvage modality after incomplete TACE. Materials and Methods: We systematically searched the PubMed, Embase, Medline, and Cochrane databases. The primary endpoint was overall survival (OS), and the secondary endpoints included the response ratem toxicity of grade 3, and local control. Results: Twelve studies involving 757 patients were included; the median of portal vein thrombosis rate was 25%, and the pooled median of tumor size was 5.8 cm. The median prescribed dose ranged from 37.3 to 150 Gy (pooled median: 54 Gy in *EQD2). The pooled one- and two-year OS rates were 72.3% (95% confidence interval (CI): 60.2-81.9%) and 50.5% (95% CI: 35.6-65.4%), respectively; the pooled response and local control rates were 72.2% (95% CI: 65.4-78.1%) and 86.6 (95% CI: 80.1-91.2%) respectively. The pooled rates of grade ≥3 gastrointestinal toxicity, radiation-induced liver disease, hepatotoxicity, and hematotoxicity were 4.1%, 3.5%, 5.7%, and 4.9%, respectively. Local control was not correlated with intrahepatic (p = 0.6341) or extrahepatic recurrences (p = 0.8529) on meta-regression analyses. Conclusion: EBRT was feasible and efficient in regard to tumor response and control; after incomplete TACE. Out-field recurrence, despite favorable local control, necessitates the combination of EBRT with systemic treatments. *Equivalent dose in 2 Gy per fraction scheme.

Discontinuation of nucleos(t)ide analogues is not associated with a higher risk of HBsAg seroreversion after antiviral-induced HBsAg seroclearance: a nationwide multicentre study.

OBJECTIVE: Direct comparison of the clinical outcomes between nucleos(t)ide analogue (NA) discontinuation versus NA continuation has not been performed in patients with chronic hepatitis B who achieved HBsAg-seroclearance. Whether NA discontinuation was as safe as NA continuation after NA-induced surface antigen of HBV (HBsAg) seroclearance was investigated in the present study. DESIGNS: This multicentre study included 276 patients from 16 hospitals in Korea who achieved NA-induced HBsAg seroclearance: 131 (47.5%) discontinued NA treatment within 6 months after HBsAg seroclearance (NA discontinuation group) and 145 (52.5%) continued NA treatment (NA continuation group). Primary endpoint was HBsAg reversion and secondary endpoints included serum HBV DNA redetection and development of hepatocellular carcinoma (HCC). RESULTS: During follow-up (median=26.9 months, IQR=12.2-49.2 months), 10 patients (3.6%) experienced HBsAg reversion, 6 (2.2%) showed HBV DNA redetection and 8 (2.9%) developed HCC. Compared with NA continuation, NA discontinuation was not associated with HBsAg reversion in both univariable (HR=0.45, 95% CI=0.12 to 1.76, log-rank p=0.24) and multivariable analyses (adjusted HR=0.65, 95% CI=0.16 to 2.59, p=0.54). The cumulative probabilities of HBsAg reversion at 1, 3 and 5 years were 0.8%, 2.3% and 5.0% in the NA discontinuation group, and 1.5%, 6.3% and 8.4% in the NA continuation group, respectively. NA discontinuation was not associated with higher risk of either HBV redetection (HR=0.83, 95% CI=0.16 to 4.16, log-rank p=0.82) or HCC development (HR=0.53, 95% CI=0.12 to 2.23, log-rank p=0.38). CONCLUSION: The discontinuation of NA was not associated with a higher risk of either HBsAg reversion, serum HBV DNA redetection or HCC development compared with NA continuation among patients who achieved HBsAg seroclearance with NA.

Validation of the CAMD Score in Patients With Chronic Hepatitis B Virus Infection Receiving Antiviral Therapy.

BACKGROUND & AIMS: Researchers previously developed a scoring system to determine the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection, based on the presence of cirrhosis, patient age, male sex, and diabetes (called the CAMD scoring system). We validated the CAMD scoring system and compared its performance with that of other risk assessment models in an independent cohort. METHODS: We followed up 3277 patients with chronic HBV infection (mean age, 48.7 y; 62.6% male; 32.4% with cirrhosis) who were treated with entecavir (n = 1725) or tenofovir (n = 1552) as the first-line antiviral agent in 4 academic teaching hospitals in the Republic of Korea. The primary outcome was development of HCC. We evaluated the ability of the CAMD, PAGE-B, and mPAGE-B scoring systems to identify patients who would develop HCC using integrated area under the curve (iAUC) analysis. RESULTS: Over a median follow-up period of 58.2 months, 8.9% of the patients developed HCC. Patients who developed HCC were older, more likely to be male, and had higher proportions of cirrhosis and diabetes than patients who did not develop HCC (all P < .05). CAMD scores identified patients who developed HCC with an iAUC of 0.790, mPAGE-B scores with an iAUC of 0.769, and PAGE-B scores with an iAUC of 0.760. The 5-year cumulative risks of HCC were 1.3% in patients with low CAMD scores (<8), 8.0% in patients with intermediate CAMD scores (8-13), and 24.3% in patients with high CAMD scores (>13) (P < .001 for comparison of low- vs intermediate-score groups and between intermediate- vs high-score groups). The predicted and observed probabilities of HCC had excellent agreement. CONCLUSIONS: We validated the CAMD scoring system in determining the risk of HCC in patients with chronic HBV treatment receiving entecavir or tenofovir treatment. Validation was performed in a cohort of patients in the Republic of Korea, where most patients have genotype C2 HBV infection.

A multi-centre study of trends in hepatitis B virus-related hepatocellular carcinoma risk over time during long-term entecavir therapy.

The risk of developing hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is reduced by antiviral therapy. Here, we evaluated the chronological trends in HCC development risk starting in 2007, when entecavir reimbursement was first initiated in South Korea. Treatment-naïve patients with chronic hepatitis B (CHB) receiving entecavir 0.5 mg/d were stratified into three groups according to entecavir start time: early (2007-2010), middle (2011-2012) and late (2013-2014) cohorts Among 2442 patients, cumulative probabilities of developing HCC after 1, 3 and 5 years were, respectively, 1.7%, 5.1%, and 8.2% (early cohort; n = 672); 1.5%, 5.1% and 8.9% (middle cohort; n = 757); and 1.2%, 5.3% and 10.6% (late cohort; n = 1013; P > .05 between each pair). Older age, male, positive hepatitis B e antigen, liver cirrhosis, Child-Pugh class B (vs A) and lower platelet count significantly predicted HCC development in univariate analysis (P < .001), whereas entecavir start time (early vs middle vs late cohorts) did not affect the risk of HCC development (P = .457). A multivariate analysis revealed that older age (adjusted hazard ratio [aHR]=1.041), male gender (aHR = 2.069), liver cirrhosis (aHR = 3.771) and Child-Pugh class B (vs A, aHR = 1.548) were independently associated with an increased risk of HCC development, whereas higher platelet count was independently associated with a reduced risk of HCC development (aHR = 0.993; all P < .05). In conclusion, the risk of developing HCC among patients receiving entecavir in South Korea has been stable since 2007. To establish more effective HCC surveillance programs, further studies regarding the carcinogenic roles of nonviral factors are required.

Predictive score for hepatocellular carcinoma after hepatitis B e antigen loss in patients treated with entecavir or tenofovir.

The risk of developing hepatocellular carcinoma (HCC) after hepatitis B e antigen seroclearance (ESC) remains unclear. We established and validated a new risk prediction model for HCC development after ESC in patients with chronic hepatitis B (CHB) receiving antiviral therapy (AVT). Between 2006 and 2016, 769 patients (training cohort) and 1,061 patients (validation cohort) with CHB who experienced ESC during AVT using entecavir (ETV) or tenofovir disoproxil fumarate (TDF) were recruited. In the multivariate analysis, male sex (hazard ratio [HR] = 2.092; 95% confidence interval [CI] = 1.152-3.800), cirrhosis (HR = 5.141; 95% CI = 2.367-11.167) and fibrosis-4 index (FIB-4) of >3.25 (HR = 2.070; 95% CI = 1.184-3.620) were the independent risk factors for HCC development (all P < .05). Accordingly, a novel HCC-ESCAVT model was developed (1x[sex: male = 1, female = 0] + 3x(cirrhosis = 1, noncirrhosis = 0) + 1x(FIB-4: >3.25 = 1, ≤3.25 = 0). The cumulative risk for HCC development was significantly different among the risk groups based on the HCC-ESCAVT category (0-1, 2-4 and 5 for the low-, intermediate- and high-risk groups, respectively) (overall P < .001, log-rank test). The area under the receiver operating characteristic curve (AUC) for predicting HCC development 3, 5 and 10 years after ESC was 0.791, 0.771 and 0.790, respectively (all P < .05). The predictive value of the HCC-ESCAVT model was similar in the validation cohort (AUC = 0.802, 0.774 and 0.776 at 3, 5 and 10 years, respectively; all P < .05). Hence, we have developed and validated a new HCC-ESCAVT model for HCC development, which includes male sex, cirrhosis and FIB-4 of >3.25 as constituent variables.

Differential Impact of Serum 25-Hydroxyvitamin D3 Levels on the Prognosis of Patients with Liver Cirrhosis According to MELD and Child-Pugh Scores.

BACKGROUND: Prognosis of patients with diverse chronic diseases is reportedly associated with 25-hydroxyvitamin D levels. In this study, we investigated the potential role of 25-hydroxyvitamin D3 (25[OH]D3) levels in improving the predictive power of conventional prognostic models for patients with liver cirrhosis. METHODS: We investigated clinical findings, including serum 25(OH)D3 levels at admission, of 155 patients with cirrhosis who were followed up for a median of 16.9 months. RESULTS: Median 25(OH)D3 levels were significantly different among patients exhibiting Child-Pugh grades A, B, and C. Mortality, including urgent transplantation, was significantly associated with 25(OH)D3 levels in univariate analysis. Severe vitamin-D deficiency (serum 25[OH]D3 level < 5.0 ng/mL) was significantly related to increased mortality, even after adjusting for Child-Pugh and Model for End-stage Liver Disease (MELD) scores. In particular, the presence of severe vitamin D deficiency clearly defined a subgroup with significantly poorer survival among patients with Child-Pugh scores of 5-10 or MELD scores ≤ 20. A new combination model of MELD score and severe vitamin D deficiency showed significantly more accurate predictive power for short- and long-term mortality than MELD scores alone. Additionally, serum 25(OH)D3 levels and new model scores were significantly associated with the development of spontaneous bacterial peritonitis, overt encephalopathy, and acute kidney injury. CONCLUSION: Serum 25(OH)D3 level is an independent prognostic factor for patients with liver cirrhosis and has a differential impact on disease outcomes according to MELD and Child-Pugh scores.