Viral Load-Based Prediction of Hepatocellular Carcinoma Risk in Noncirrhotic Patients With Chronic Hepatitis B : A Multinational Study for the Development and External Validation of a New Prognostic Model.

BACKGROUND: A nonlinear association between serum hepatitis B virus (HBV) DNA levels and hepatocellular carcinoma (HCC) risk has been suggested in patients with chronic hepatitis B (CHB). OBJECTIVE: To develop and externally validate a prognostic model for HCC risk in noncirrhotic adult patients with CHB and no notable alanine aminotransferase (ALT) elevation. DESIGN: Multinational cohort study. SETTING: A community-based cohort in Taiwan (REVEAL-HBV [Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus]; REACH-B [Risk Estimation for HCC in CHB] model cohort) and 8 hospital-based cohorts from Korea and Hong Kong (GAG-HCC [Guide with Age, Gender, HBV DNA-HCC] and CU-HCC [Chinese University-HCC] cohorts). PARTICIPANTS: Model development: 6949 patients with CHB from a Korean hospital-based cohort. External validation: 7429 patients with CHB combined from the Taiwanese cohort and 7 cohorts from Korea and Hong Kong. MEASUREMENTS: Incidence of HCC. RESULTS: Over median follow-up periods of 10.0 and 12.2 years, the derivation and validation cohorts identified 435 and 467 incident HCC cases, respectively. Baseline HBV DNA level was one of the strongest predictors of HCC development, demonstrating a nonlinear parabolic association in both cohorts, with moderate viral loads (around 6 log10 IU/mL) showing the highest HCC risk. Additional predictors included in the new model (Revised REACH-B) were age, sex, platelet count, ALT levels, and positive hepatitis B e antigen result. The model exhibited satisfactory discrimination and calibration, with c-statistics of 0.844 and 0.813 in the derivation and validation cohorts with multiple imputation, respectively. The model yielded a greater positive net benefit compared with other strategies in the 0% to 18% threshold. LIMITATION: Validation in cohorts of other races and receiving antiviral treatment was lacking. CONCLUSION: Our new prognostic model, based on the nonlinear association between HBV viral loads and HCC risk, provides a valuable tool for predicting and stratifying HCC risk in noncirrhotic patients with CHB who are not currently indicated for antiviral treatment. PRIMARY FUNDING SOURCE: Korean government.

Non-linear association of baseline viral load with on-treatment hepatocellular carcinoma risk in chronic hepatitis B.

OBJECTIVE: The association between baseline pretreatment serum HBV DNA levels and on-treatment hepatocellular carcinoma (HCC) risk remains controversial in patients with chronic hepatitis B (CHB). We aimed to investigate the association between baseline HBV viral load and on-treatment HCC risk in CHB patients without cirrhosis. DESIGN: Using a multicentre historical cohort study including 4693 hepatitis B e antigen (HBeAg)-negative and HBeAg-positive, adult CHB patients without cirrhosis who initiated antiviral treatment, HCC risk was estimated by baseline HBV viral load as a categorical variable. RESULTS: During a median of 7.6 years of antiviral treatment, 193 patients developed HCC (0.53 per 100 person- years). Baseline HBV DNA level was independently associated with on-treatment HCC risk in a non-linear, parabolic pattern. Patients with moderate baseline viral loads (5.00-7.99 log10 IU/mL) exhibited the highest HCC risk (HR, 2.60; p<0.001), followed by those with low viral loads (3.30-4.99 log10 IU/mL; HR, 1.66; p=0.11). Patients with high viral loads (≥8.00 log10 IU/mL) presented the lowest HCC risk. Particularly, patients with baseline HBV DNA levels 6.00-6.99 log10 IU/mL had the highest on-treatment HCC risk (HR, 3.36; p<0.001) compared with those with baseline HBV DNA levels≥8.00 log10 IU/mL. These findings were more prominent among HBeAg-positive patients, younger patients, or those with less advanced hepatic fibrosis. CONCLUSION: Patients with moderate baseline viral load, particularly around 6 log10 IU/mL, demonstrated the highest on-treatment HCC risk, despite long-term antiviral treatment. Early initiation of antiviral treatment, tailored to viral load, should be considered to minimise HCC risk in adult CHB patients without cirrhosis.

Immune checkpoint inhibitor use and the incidence of hepatitis B virus reactivation or immune-related hepatitis in non-small cell lung cancer patients with chronic hepatitis B.

BACKGROUND: The safety of immune-checkpoint inhibitors (ICIs) has not been thoroughly investigated in non-small cell lung cancer (NSCLC) patients with chronic hepatitis B (CHB) or occult hepatitis B infection (OBI). The authors analyzed the incidence of hepatitis B virus (HBV) reactivation, immune-related hepatitis and jaundice in NSCLC patients in a real-world setting. METHODS: A total of 1277 NSCLC patients treated with ICIs were analyzed. Among them, 52 patients were hepatitis B surface antigen (HBsAg) (+) (group A, CHB), 759 patients were HBsAg (-)/hepatitis B core antibody immunoglobulin G (anti-HBc IgG) (+) (group B, OBI), and 466 patients were HBsAg (-)/anti-HBc IgG (-) (group C). Among the 52 patients with CHB, 38 (73.1%) were receiving antiviral therapy. The primary end point was HBV reactivation, immune-related hepatitis, and jaundice. The secondary end points included other immune-related adverse events and efficacy. RESULTS: HBV reactivation was observed in two patients (0.2%) who were both in group A (CHB). Among CHB patients who were not receiving antiviral therapy, HBV reactivation was observed in 14.3% (2 of 14 patients). The incidences of immune-related hepatitis and jaundice were comparable among the three groups. The incidence of ≥grade 3 other immune-related adverse events and efficacy were all comparable among the three groups (p > .05 for all comparisons). CONCLUSIONS: In this large, real-world cohort study, the safety and efficacy of ICIs were comparable in patients with CHB and OBI. HBV reactivation was observed in patients with CHB without antiviral therapy indicating antiviral prophylaxis should be required for them. For patients with OBI, the risk of HBV reactivation was minimal.

Outcome of untreated low-level viremia versus antiviral therapy-induced or spontaneous undetectable HBV-DNA in compensated cirrhosis.

BACKGROUND: Comparative outcomes of HBV-infected compensated cirrhosis with low-level viremia (LLV) versus maintained virological response (MVR) are unclear. We conducted a large, multiethnic, multicenter study to examine the natural history of LLV versus MVR in compensated cirrhosis. PATIENTS AND METHODS: We enrolled patients with HBV-infected compensated cirrhosis (n=2316) from 19 hospitals in South Korea, Singapore, and Japan. We defined the LLV group as untreated patients with ≥1 detectable serum HBV-DNA (20-2000 IU/mL), Spontaneous-MVR group as untreated patients with spontaneously achieved MVR, and antiviral therapy (AVT)-MVR group as patients achieving AVT-induced MVR. Study end points were HCC or hepatic decompensation. RESULTS: The annual HCC incidence was 2.7/100 person-years (PYs), 2.6/100 PYs, and 3.3/100 PYs for LLV (n=742), Spontaneous-MVR (n=333), and AVT-MVR (n=1241) groups, respectively ( p = 0.81 between LLV vs. Spontaneous-MVR groups and p = 0.37 between LLV vs. AVT-MVR groups). Similarly, the annual decompensation incidence was 1.6/100 PYs, 1.9/100 PYs, and 1.6/100 PYs for LLV, Spontaneous-MVR, and AVT-MVR groups, respectively ( p = 0.40 between LLV vs. Spontaneous-MVR groups and p = 0.83 between LLV vs. AVT-MVR groups). Multivariable analyses determined that HCC and decompensation risks in the LLV group were comparable to those with Spontaneous-MVR and AVT-MVR groups (all p >0.05). Propensity score matching also reproduced similar results for HCC and decompensation risks (all p >0.05 between LLV vs. Spontaneous-MVR groups and between LLV vs. AVT-MVR groups). CONCLUSIONS: Untreated LLV in HBV-infected compensated cirrhosis is not associated with increased risk of disease progression compared with Spontaneous-MVR and AVT-MVR. These data have important implications for practice and further research.

Risk of hepatocellular carcinoma after curative treatment when switching from tenofovir disoproxil fumarate or entecavir to tenofovir alafenamide: A real-world multicenter cohort study.

AIM: Antiviral treatment reduces the risk of developing hepatocellular carcinoma (HCC) in patients with chronic hepatitis B. However, there is a lack of high-quality evidence regarding the preventive effects of tenofovir alafenamide (TAF) on HCC. We evaluated the impact of TAF use after curative treatment on HCC recurrence. METHODS: Patients who underwent surgery or radiofrequency ablation as a curative treatment for HCC were selected. Those patients who continued antiviral treatment with nucleos(t)ide analogs (NAs; entecavir [ETV] or tenofovir disoproxil fumarate [TDF]) or switched to TAF were included. The primary outcome was HCC recurrence, and the time-varying effect of NA use on HCC recurrence was analyzed using various statistical methods. RESULTS: Among 2794 consecutive patients with chronic hepatitis B who received curative treatment for HCC, 199 subsequently switched from ETV or TDF to TAF. After a median of 3.0 years, 1303 patients (46.6%) experienced HCC recurrence. After propensity score matching (ratio 1:10), switching to TAF was not associated with an increased HCC recurrence (HR 1.00, 95% CI 0.68-1.47; p = 1.00) by time-varying Cox analysis. Switching to TAF was not associated with HCC recurrence in subgroups of NA (HR 1.06, 95% CI 0.67-1.67; p = 0.81 for TDF, and HR 1.09, 95% CI 0.51-2.33; p = 0.82 for ETV). Kaplan-Meier analysis showed comparable HCC recurrence-free survival between patients who switched to TAF and those who continued with their NA (p = 0.08). Time-varying Cox analyses in various subgroups confirmed the primary findings. CONCLUSIONS: TAF is as effective as TDF and ETV in preventing HCC recurrence after curative treatment.

Nonalcoholic Fatty Liver Disease Without Metabolic-associated Fatty Liver Disease and the Risk of Metabolic Syndrome.

BACKGROUND & AIMS: Metabolic (dysfunction)-associated fatty liver disease (MAFLD) was proposed to replace nonalcoholic fatty liver disease (NAFLD). Some people fulfill diagnostic criteria of NAFLD but not MAFLD (NAFLD without MAFLD), but the clinical implications of NAFLD in these subjects is unknown. METHODS: We followed cohort of 12,197 men and women 20 years of age or older without metabolic dysfunction (defined by MAFLD criteria), heavy alcohol use, chronic viral hepatitis, liver cirrhosis, or malignancy for their risk of incident metabolic syndrome defined by Adult Treatment Panel III criteria. RESULTS: By design, none of the study participants had MAFLD at baseline. The prevalence of NAFLD among participants without metabolic dysfunction meeting MAFLD criteria and without significant alcohol intake was 7.6%. During 74,508 person-years of follow-up, 2179 participants developed metabolic syndrome. The fully adjusted hazard ratio for metabolic syndrome comparing participants with NAFLD to those without it was 1.61 (95% confidence interval, 1.42-1.83). The increased risk of incident metabolic syndrome associated with NAFLD persisted for all studied subgroups, and the association was stronger for those with increased waist circumference (P for interaction = .029) and those without elevated triglycerides levels (P for interaction = .047). CONCLUSION: In this large cohort, participants with NAFLD without MAFLD were at higher risk of developing metabolic syndrome compared to participants with no NAFLD and no MAFLD. Using MAFLD criteria may miss opportunities for early intervention in these subjects.

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.

Validation of MELD 3.0 scoring system in East Asian patients with cirrhosis awaiting liver transplantation.

Recently, a new predictive model that jointly considers the Model of End-stage Liver Disease (MELD) 3.0 and albumin has been proposed. This study investigated the performance of the MELD 3.0 score in predicting the 3-month survival of East Asian patients with cirrhosis compared with the other MELD-based scores. Validation was performed with the retrospective data of 2153 patients in South Korea who were listed for liver transplantation (LT). Discrimination and calibration analyses were performed using the MELD-based scores as an independent variable. On average, patients had the original MELD score of 18.70 ± 9.65. Alcohol (39.99%) and chronic HBV (38.55%) were the 2 main etiologies. The MELD 3.0 with albumin showed slightly better discrimination [c-index = 0.738, incremental AUC (iAUC) = 0.719] compared with the MELD 3.0 without albumin (c-index = 0.737, iAUC = 0.715), MELD-Na (c-index = 0.730, iAUC = 0.707), or the original MELD (c-index = 0.718, iAUC = 0.687) for predicting 3-month survival but not significantly different compared with prior models. Likewise, in the stratified analysis according to the strata of MELD, although the performance of MELD 3.0 was better throughout all the MELD strata than MELD original, there was no statistical difference in performance. The MELD 3.0 with albumin reclassified 22.61% of cases classified by the original MELD to higher MELD score categories, and there was no significant difference in the reclassification rate between males and females. The predictive power of the MELD-based system is lower in Asian populations than in western countries. Nonetheless, the MELD 3.0 score with albumin was significantly better in predicting the short-term prognosis of East Asian patients on the LT waitlist than the current allocation system, original MELD.

Nonalcoholic fatty liver disease and accelerated loss of skeletal muscle mass: A longitudinal cohort study.

BACKGROUND AND AIMS: Whether subjects with NAFLD are at increased risk of sarcopenia is not well established. APPROACH AND RESULTS: This is a cohort study of 52,815 men and women of 20 years of age or older who underwent at least two health check-up exams with bioelectrical impedance analysis and abdominal ultrasound imaging. Bioelectrical impedance analysis was used to calculate appendicular skeletal muscle mass (ASM). NAFLD was assessed by ultrasonography, and its severity was assessed by the NAFLD fibrosis score (NFS). We estimated the 5-year change in ASM comparing participants with and without NAFLD at baseline using mixed linear models. The 5-year change in ASM in participants without and with NAFLD was -225.2 g (95% CI -232.3, -218.0) and -281.3 g (95% CI -292.0, -270.6), respectively (p < 0.001). In multivariable adjusted analysis, the difference in 5-year change in ASM comparing participants with and without NAFLD was -39.9 g (95% CI -53.1, -26.8). When participants with NAFLD were further divided by NAFLD severity, ASM loss was much faster in participants with NAFLD with intermediate to high NFS than in those with low NFS. CONCLUSIONS: Participants with NAFLD were at increased risk of sarcopenia, indicated by faster loss of skeletal muscle mass. Patients with NAFLD may need screening and early intervention to mitigate skeletal muscle mass loss.

Validation of non-invasive diagnosis of CSPH in patients with compensated advanced chronic liver disease according to Baveno VII.

BACKGROUND AND AIMS: Baveno VII consensus introduced the non-invasive criteria of clinically significant portal hypertension (CSPH) using liver stiffness measurement (LSM). We evaluated the usefulness of the Baveno VII criteria to predict the risk of decompensation in patients with compensated advanced chronic liver disease (cACLD). METHODS: We conducted a retrospective cohort study of 1966 patients with cACLD. Patients were categorized into four groups (CSPH excluded (n = 619), grey zone (low risk of CSPH (n = 699), high risk of CSPH (n = 207)), and CSPH included (n = 441)) according to Baveno VII consensus. The risk of events was estimated using a Fine and Gray competing risk regression analysis, with liver transplantation and death as competing events. We calculated standardized hazard ratios (sHR) to assess the relative risk of decompensation. RESULTS: Among 1966 patients, 178 developed decompensations over a median follow-up of 3.06 (IQR: 1.03-6.00) years. Patients with CSPH had the highest decompensation risk, followed by the grey zone high-risk group, grey zone low-risk group, and those without CSPH with 3-year cumulative risks of 22%, 12%, 3.3%, and 1.4% respectively (p < .001). Compared to CSPH excluded group, CSPH included group (sHR: 8.00, 95% CI: 4.00-16.0), grey zone high-risk group (sHR: 6.57, 95% CI: 3.16-13.6), grey zone low-risk group (sHR: 2.15, 95% CI: 1.04-4.41) had significantly higher risk of decompensation (Gray's test p < .01). CONCLUSION: Non-invasive diagnosis of CSPH according to the Baveno VII criteria can stratify the risk of decompensation.

Statin use and the risk of hepatocellular carcinoma among patients with chronic hepatitis B: an emulated target trial using longitudinal nationwide population cohort data.

BACKGROUND: No randomized controlled trials have been completed to see whether statin can decrease hepatocellular carcinoma (HCC) risk in chronic hepatitis B (CHB) patients. We used large-scale, population-based, observational data to emulate a target trial with two groups, statin user and statin non-user. METHODS: Among 1,379,708 nonunique individuals from the Korean National Health Insurance Service data, 2,915 CHB patients with serum cholesterol level of 200 mg/dL or higher who started statin therapy and 8,525 propensity-score matched CHB patients with serum cholesterol level of 200 mg/dL or higher who did not start statin therapy were analyzed for the development of HCC. In addition, liver cancer or liver-related mortality and all-cause mortality were assessed. RESULTS: During follow-up, 207 participants developed HCC. Incidence rate of HCC was 0.2 per 1,000 person-years in the statin user group and 0.3 per 1,000 person-years in the statin non-user group. Fully adjusted hazard ratio (HR) for incident HCC comparing statin user group to statin nonuser group was 0.56 (95% confidence interval [CI]: 0.39 to 0.80). The association between statin use and decreased HCC risk was consistent in all subgroups analyzed. Fully adjusted HR comparing statin user to statin nonuser was 0.59 (95% CI: 0.35 to 0.99) for liver cancer or liver-related mortality and 0.93 (95% CI: 0.78 to 1.11) for all-cause mortality. CONCLUSIONS: Statin might have a benefit for preventing HCC in CHB patients with elevated cholesterol levels. Statin should be actively considered for CHB patients with dyslipidemia.

A model for predicting poor survival in patients with cirrhosis undergoing portosystemic shunt embolization.

BACKGROUND AND AIM: Portosystemic shunt embolization (PSSE) is a promising treatment for hepatic encephalopathy (HEP) and gastric varix (GV) in cirrhotic patients with a spontaneous portosystemic shunt. However, PSSE may worsen portal hypertension causing hepatorenal syndrome, liver failure, and mortality. This study aimed to develop and validate a prognostic model that helps identify patients with a risk of poor short-term survival after PSSE. METHODS: We included 188 patients who underwent PSSE for recurrent HEP or GV at a tertiary center in Korea. To develop a prediction model for 6-month survival after PSSE, Cox proportional-hazard model was used. The developed model was validated in a separate cohort of 184 patients from two other tertiary centers. RESULTS: In multivariable analysis, the 1-year overall survival after PSSE was significantly associated with baseline levels of serum albumin, total bilirubin, and international normalized ratio (INR). We therefore developed the albumin-bilirubin-INR (ABI) score by assigning 1 point each for albumin < 3.0 g/dL, total bilirubin ≥ 1.5 mg/dL, and INR ≥ 1.5. Time-dependent areas under the curve of the ABI score for predicting 3-month and 6-month survival were 0.85 and 0.85 in the development cohort and 0.83 and 0.78 in the validation cohort, indicating good discrimination performance. The ABI score showed a better discrimination and calibration performance than the model for end-stage liver disease and the Child-Pugh scores, especially in high-risk patients. CONCLUSIONS: The ABI score is a simple prognostic model that helps decide whether to proceed with PSSE for the prevention of HEP or GV bleeding in patients with spontaneous portosystemic shunt.

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.

Modest alcohol intake and mortality in individuals with elevated alanine aminotransferase levels: a nationwide cohort study.

BACKGROUND: Alanine aminotransferase (ALT) levels are widely used to screen liver disease, and many asymptomatic individuals show elevated ALT levels. As elevated ALT level indicates liver injury, even a small amount of alcohol intake may be harmful in subjects with elevated ALT levels, but there is limited evidence of the effect of light to moderate amount of alcohol intake in this subgroup. METHODS: A cohort of 367,612 men and women without established liver diseases (including chronic viral hepatitis, alcohol-associated liver disease, cirrhosis, liver transplantation, or rare forms of liver disease) who underwent at least 1 health screening exam between 2009 and 2015 were assessed for liver-related and all-cause mortality. Elevated ALT levels were defined as ≥ 34 U/L for men and 25 U/L for women. RESULTS: In participants with normal ALT levels, the fully-adjusted hazard ratios (95% CI) for liver-related mortality comparing light and moderate drinkers to non-drinkers were 0.73 (0.51-1.05), and 1.06 (0.73-1.52), respectively. In participants with elevated ALT levels, the corresponding hazard ratios were 1.57 (1.08-2.28), and 2.09 (CI 1.46-2.99), respectively (p value for alcohol intake by ALT interaction < 0.01). For all-cause mortality, the fully-adjusted hazard ratios comparing light and moderate drinkers to non-drinkers in participants with normal ALT levels were 0.72 (0.66-0.77), and 0.89 (0.82-0.97), respectively. In participants with elevated ALT levels, the corresponding hazard ratios were 0.93 (0.81-1.08), and 1.31 (1.14-1.50), respectively (p value for alcohol intake by ALT interaction < 0.01). CONCLUSIONS: Small amounts of alcohol intake were associated with increased liver-related and all-cause mortality among individuals with elevated ALT levels. Subjects with elevated ALT levels should be advised complete abstinence from alcohol.

The Association Between Breastfeeding and Nonalcoholic Fatty Liver Disease in Parous Women: A Nation-wide Cohort Study.

BACKGROUND AND AIMS: Breastfeeding has multiple effects on maternal health outcomes. However, the effect of breastfeeding on NAFLD in parous women remains unclear. APPROACH AND RESULTS: A total of 6,893 Korean parous women aged 30-50 years who participated in the Korean National Health and Nutrition Examination Survey were assessed for the association between breastfeeding and NAFLD. Duration of lactation was calculated by dividing the total lactation period by the number of breastfed children. NAFLD was defined by the hepatic steatosis index. Of 6,893 women, 1,049 (15.2%) had NAFLD. Prevalence of NAFLD was 18.3%, 14.3%, 12.3%, 14.4%, and 15.8% in women with a breastfeeding period of <1, ≥1-<3, ≥3-<6, ≥6-<12, and ≥12 months, respectively. In a fully adjusted model, breastfeeding (≥1 month) was associated with reduced NAFLD prevalence (OR, 0.67; 95% CI, 0.51-0.89) after adjusting for metabolic, socioeconomic, and maternal risk factors. Fully adjusted ORs (95% CI) decreased with an increase of breastfeeding duration: 0.74 (0.49-1.11), 0.70 (0.47-1.05), 0.67 (0.48-0.94), and 0.64 (0.46-0.89) for women with ≥1-<3, ≥3-<6, ≥6-<12, and ≥12 months of breastfeeding duration, respectively, compared to women with <1 month of breastfeeding duration. Such an association was also observed in all predefined subgroups without interaction. CONCLUSIONS: Breastfeeding showed a protective effect against NAFLD in later life of parous women, suggesting a maternal benefit of breastfeeding on NAFLD.

Incidence and risk factors for development of hepatocellular carcinoma at young age in patients with chronic hepatitis B.

BACKGROUND: Some young adults with chronic hepatitis B virus (HBV) infection might be at high risk for hepatocellular carcinoma (HCC), enough to justify regular HCC surveillance despite the young age of the patients. However, ways to identify at-risk individuals who may benefit from HCC surveillance need further evaluations. METHODS: A hospital-based retrospective cohort of 2757 chronic HBV mono-infected young adults (median age: 34 years, males 66%) were analyzed. The primary outcome was young-onset HCC, defined as a diagnosis made under 40 years of age. We calculated the HCC incidence/1000 person-years in the overall cohort and pre-defined subgroups of patients assessed the independent risk factors that can be used to identify surveillance targets. RESULTS: The HCC incidence was low (2.55/1000 person-years) in the overall cohort. However, the HCC incidence varied widely according to baseline characteristics: lowest among young adults with FIB-4 ≤ 0.70 (0.17/1000 person-years) and highest in young adults with radiological cirrhosis (30.7/1000 person-years). In multivariable analysis, radiological cirrhosis, the FIB-4 index, and serum HBV DNA level were independent factors associated with HCC development at a young age. Performance for prediction of young-onset HCC in radiological cirrhotic patients showed the highest specificity but sensitivity was <70%. Combination with FIB-4 index and HBV DNA levels increased sensitivity to 90%. CONCLUSION: Risk stratification using FIB-4 index, HBV DNA levels, and either combining radiological cirrhosis or gender and AFP levels would be helpful to stratify young patients who would and would not benefit from regular HCC surveillance.

Imaging features of hepatobiliary MRI and the risk of hepatocellular carcinoma development.

OBJECTIVE: This study aimed to determine whether hepatocellular carcinoma (HCC) risk and time to HCC development differ according to hepatobiliary magnetic resonance imaging (MRI) findings among people at risk for developing HCC. MATERIALS AND METHODS: A total of 199 patients aged 40 years or older with liver cirrhosis or chronic liver disease who underwent gadoxetic acid-enhanced hepatobiliary MRI between 2011 and 2015 were analyzed. An independent radiologist retrospectively reviewed MRI findings, blinded to clinical information, and categorized them into low-risk features, high-risk features and high-risk nodules. High-risk features were defined as liver cirrhosis diagnosed by imaging. High-risk nodules were defined as LR-3 or LR-4 nodules based on LI-RADS version 2018. The primary outcome was development of HCC within 5-year of MRI evaluation. RESULTS: HCC was diagnosed in 28 patients (14.1%). HCC development was null for those with low-risk features (n = 84). The cumulative incidence rates of HCC were 0%, 2.3%, 13.4% and 22.1% at 1-, 2-, 3- and 5-year for those with high-risk features (n= 64), and were 19.1%, 31.8%, 37.3% and 46.7% at 1-, 2-, 3- and 5-year for those with high-risk nodules (n= 51). Among 28 patients developed HCC, the median time from baseline MRI to HCC diagnosis was 33.1 months (interquartile range: 25.9-46.7 months) for high-risk feature group, and 17.3 months (interquartile range: 6.2-26.5 months) for high-risk nodule group. CONCLUSIONS: HCC risk and time to HCC development differ according to baseline hepatobiliary MRI findings, indicating that hepatobiliary MRI findings can be used as biomarkers to differentiate HCC risk.

Clinical Outcomes of Hepatitis B Virus-Related Hepatocellular Carcinoma Patients with Undetectable Serum HBV DNA Levels.

BACKGROUND AND AIMS: Some hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients show undetectable serum HBV DNA levels at HCC diagnosis. The risk of HBV reactivation and its impact on clinical outcomes are not well-unknown. METHODS: This retrospective cohort study included a total of 985 HBV-related HCC patients with undetectable serum HBV DNA levels (< 12 IU/mL) at HCC diagnosis (112 were antiviral treatment (AVT)-naïve; 873 were receiving AVT). Incidence and risk factors for HBV reactivation (re-detection of HBV DNA in serum) during follow-up, as well as its association to overall survival, were assessed. RESULTS: During a median of 33.4 months of follow-up (range: 0.2-124.2 months), HBV reactivation was observed in 279 patients. HBV reactivation rate was significantly lower for patients receiving AVT than AVT-naïve patients (three-year cumulative incidence rate: 27.3% versus 56.0%; P < 0.001). In multivariable-adjusted analysis, the risk of HBV reactivation was lower for those receiving AVT compared to AVT-naïve patients (adjusted hazard ratio: 0.39, 95% confidence interval: 0.29-0.54). Overall survival was significantly lower for those experiencing HBV reactivation than those who did not (71.5% and 85.7% at five-year) and was associated with higher risk of overall mortality (adjusted hazard ratio: 5.15, 95% confidence interval: 3.60-7.38). CONCLUSION: More than half of AVT-naïve patients experienced HBV reactivation within three years, which was associated with increased risk of overall mortality. The risk of HBV reactivation was lower for those receiving AVT, suggesting that prompt AVT needs to be considered for AVT naïve HBV-related HCC patients with undetectable HBV DNA levels.

Effect of Microvascular Invasion Risk on Early Recurrence of Hepatocellular Carcinoma After Surgery and Radiofrequency Ablation.

OBJECTIVE: We compared surgical resection (SR) and radiofrequency ablation (RFA) as first-line treatment in patients with hepatocellular carcinoma (HCC) based on the risk of microvascular invasion (MVI). BACKGROUND: The best curative treatment modality between SR and RFA in patients with HCC with MVI remains unclear. METHODS: Data from 2 academic cancer center-based cohorts of patients with a single, small (≤3 cm) HCC who underwent SR were used to derive (n = 276) and validate (n = 101) prediction models for MVI using clinical and imaging variables. The MVI prediction model was developed using multivariable logistic regression analysis and externally validated. Early recurrence (<2 years) based on risk stratification between SR (n = 276) and RFA (n = 240) was evaluated via propensity score matching. RESULTS: In the multivariable analysis, alpha-fetoprotein (≥15 ng/mL), protein induced by vitamin K absence-II (≥48 mAU/mL), arterial peritumoral enhancement, and hepatobiliary peritumoral hypointensity on magnetic resonance imaging were associated with MVI. Incorporating these factors, the area under the receiver operating characteristic curve of the predictive model was 0.87 (95% confidence interval: 0.82-0.92) and 0.82 (95% confidence interval: 0.74-0.90) in the derivation and validation cohorts, respectively. SR was associated with a lower rate of early recurrence than RFA based on the risk of MVI after propensity score matching (P < 0.05). CONCLUSIONS: Our model predicted the risk of MVI in patients with a small (≤ 3 cm) HCC with high accuracy. Patients with MVI who had undergone RFA were more vulnerable to recurrence than those who had undergone SR.