Spray-type modifications: an emerging paradigm in post-translational modifications.

A post-translational modification (PTM) occurs when a nucleophilic residue (e.g., lysine of a target protein) attacks electrophilic substrate molecules (e.g., acyl-AMP), involving writer enzymes or even occurring spontaneously. Traditionally, this phenomenon was thought to be sequence specific; however, recent research suggests that PTMs can also occur in a non-sequence-specific manner confined to a specific location in a cell. In this Opinion, we compile the accumulated evidence of spray-type PTMs and propose a mechanism for this phenomenon based on the exposure level of reactive electrophilic substrate molecules at the active site of the PTM writers. Overall, a spray-type PTM conceptual framework is useful for comprehending the promiscuous PTM writer events that cannot be adequately explained by the traditional concept of sequence-dependent PTM events.

Inhibition of sodium-glucose cotransporter-2 and liver-related complications in individuals with diabetes: a Mendelian randomization and population-based cohort study.

BACKGROUND AND AIMS: No medication has been found to reduce liver-related events. We evaluated the effect of sodium-glucose cotransporter-2 inhibitor (SGLT2i) on liver-related outcomes. APPROACH AND RESULTS: Single nucleotide polymorphisms associated with SGLT2 inhibition were identified, and a genetic risk score (GRS) was computed using the UK Biobank data (n=337,138). Two-sample Mendelian randomization (MR) was conducted using the FinnGen (n=218,792) database and the UK Biobank data. In parallel, a nationwide population-based study using the Korean National Health Insurance Service (NHIS) database was conducted. The development of liver-related complications (ie, hepatic decompensation, HCC, liver transplantation, and death) was compared between individuals with type 2 diabetes mellitus and steatotic liver diseases treated with SGLT2i (n=13,208) and propensity score-matched individuals treated with dipeptidyl peptidase-4 inhibitor (n=70,342). After computing GRS with 6 single nucleotide polymorphisms (rs4488457, rs80577326, rs11865835, rs9930811, rs34497199, and rs35445454), GRS-based MR showed that SGLT2 inhibition (per 1 SD increase of GRS, 0.1% lowering of HbA1c) was negatively associated with cirrhosis development (adjusted odds ratio=0.83, 95% CI=0.70-0.98, p =0.03) and this was consistent in the 2-sample MR (OR=0.73, 95% CI=0.60-0.90, p =0.003). In the Korean NHIS database, the risk of liver-related complications was significantly lower in the SGLT2i group than in the dipeptidyl peptidase-4 inhibitor group (adjusted hazard ratio=0.88, 95% CI=0.79-0.97, p =0.01), and this difference remained significant (adjusted hazard ratio=0.72-0.89, all p <0.05) across various sensitivity analyses. CONCLUSIONS: Both MRs using 2 European cohorts and a Korean nationwide population-based cohort study suggest that SGLT2 inhibition is associated with a lower risk of liver-related events.

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.

A machine learning model to predict liver-related outcomes after the functional cure of chronic hepatitis B.

BACKGROUND & AIMS: The risk of hepatocellular carcinoma (HCC) and hepatic decompensation persists after hepatitis B surface antigen (HBsAg) seroclearance. This study aimed to develop and validate a machine learning model to predict the risk of liver-related outcomes (LROs) following HBsAg seroclearance. METHODS: A total of 4,787 consecutive patients who achieved HBsAg seroclearance between 2000 and 2022 were enrolled from six centers in South Korea and a territory-wide database in Hong Kong, comprising the training (n = 944), internal validation (n = 1,102), and external validation (n = 2,741) cohorts. Three machine learning-based models were developed and compared in each cohort. The primary outcome was the development of any LRO, including HCC, decompensation, and liver-related death. RESULTS: During a median follow-up of 55.2 (IQR 30.1-92.3) months, 123 LROs were confirmed (1.1%/person-year) in the Korean cohort. The model with the best predictive performance in the training cohort was selected as the final model (designated as PLAN-B-CURE), which was constructed using a gradient boosting algorithm and seven variables (age, sex, diabetes, alcohol consumption, cirrhosis, albumin, and platelet count). Compared to previous HCC prediction models, PLAN-B-CURE showed significantly superior accuracy in the training cohort (c-index: 0.82 vs. 0.63-0.70, all p <0.001; area under the receiver-operating characteristic curve: 0.86 vs. 0.62-0.72, all p <0.01; area under the precision-recall curve: 0.53 vs. 0.13-0.29, all p <0.01). PLAN-B-CURE showed a reliable calibration function (Hosmer-Lemeshow test p >0.05) and these results were reproduced in the internal and external validation cohorts. CONCLUSION: This novel machine learning model consisting of seven variables provides reliable risk prediction of LROs after HBsAg seroclearance that can be used for personalized surveillance. IMPACT AND IMPLICATIONS: Using large-scale multinational data, we developed a machine learning model to predict the risk of liver-related outcomes (i.e., hepatocellular carcinoma, decompensation, and liver-related death) after the functional cure of chronic hepatitis B (CHB). The new model named PLAN-B-CURE was constructed using seven variables (age, sex, alcohol consumption, diabetes, cirrhosis, serum albumin, and platelet count) and a gradient boosting machine algorithm, and it demonstrated significantly better predictive accuracy than previous models in both the training and validation cohorts. The inclusion of diabetes and significant alcohol intake as model inputs suggests the importance of metabolic risk factor management after the functional cure of CHB. Using seven readily available clinical factors, PLAN-B-CURE, the first machine learning-based model for risk prediction after the functional cure of CHB, may serve as a basis for individualized risk stratification.

Metabolic effects and cardiovascular disease risks of antiviral treatments in patients with chronic hepatitis B.

Different antiviral treatments for chronic hepatitis B (CHB) have been known to have different metabolic effects. This study aimed to reveal whether tenofovir alafenamide (TAF)-induced dyslipidemia and its associated outcomes are significant. This study utilized 15-year historical cohort including patients with CHB in Korea and consisted of two parts: the single-antiviral and switch-antiviral cohorts. In the single-antiviral cohort, patients were divided into four groups (entecavir [ETV]-only, tenofovir disoproxil fumarate [TDF]-only, TAF-only, and non-antiviral). Propensity score matching (PSM) and linear regression model were sequentially applied to compare metabolic profiles and estimated atherosclerotic cardiovascular disease (ASCVD) risks longitudinally. In the switch-antiviral cohort, pairwise analyses were conducted in patients who switched NAs to TAF or from TAF. In the single-antiviral cohort, body weight and statin use showed significant differences between groups before PSM, but well-balanced after PSM. Changes in total cholesterol were significantly different between groups (-2.57 mg/dL/year in the TDF-only group and +2.88 mg/dL/year in the TAF-only group; p = 0.002 and p = 0.02, respectively). In the TDF-only group, HDL cholesterol decreased as well (-0.55 mg/dL/year; p < 0.001). The TAF-only group had the greatest increase in ASCVD risk, followed by the TDF-only group and the non-antiviral group. In the switch-antiviral cohort, patients who switched from TDF to TAF had a higher total cholesterol after switching (+9.4 mg/dL/year) than before switching (-1.0 mg/dL/year; p = 0.047). Sensitivity analysis on data with an observation period set to a maximum of 3 years for NA treatment showed consistent results on total cholesterol (-2.96 mg/dL/year in the TDF-only group and +3.09 mg/dL/year in the TAF-only group; p = 0.001 and p = 0.005, respectively). Another sensitivity analysis conducted on statin-treated patients revealed no significant change in cholesterol and ASCVD risk. TAF was associated with increased total cholesterol, whereas TDF was associated with decreased total and HDL cholesterol. Both TAF and TDF were associated with increased ASCVD risks, and statin use might mitigate these risks.

Extrahepatic malignancies in metabolic dysfunction-associated fatty liver disease: A nationwide cohort study.

BACKGROUND AND AIMS: Metabolic dysfunction-associated fatty liver disease (MAFLD) encompasses heterogeneous fatty liver diseases associated with metabolic disorders. We aimed to evaluate the association between MAFLD and extrahepatic malignancies based on MAFLD subtypes. METHODS: This nationwide cohort study included 9 298 497 patients who participated in a health-screening programme of the National Health Insurance Service of Korea in 2009. Patients were further classified into four subgroups: non-MAFLD, diabetes mellitus (DM)-MAFLD, overweight/obese-MAFLD and lean-MAFLD. The primary outcome was the development of any primary extrahepatic malignancy, while death, decompensated liver cirrhosis and liver transplantation were considered competing events. The secondary outcomes included all-cause and extrahepatic malignancy-related mortality. RESULTS: In total, 2 500 080 patients were diagnosed with MAFLD. During a median follow-up of 10.3 years, 447 880 patients (6.0%) with extrahepatic malignancies were identified. The DM-MAFLD (adjusted subdistribution hazard ratio [aSHR] = 1.13; 95% confidence interval [CI] = 1.11-1.14; p < .001) and the lean-MAFLD (aSHR = 1.12; 95% CI = 1.10-1.14; p < .001) groups were associated with higher risks of extrahepatic malignancy than the non-MAFLD group. However, the overweight/obese-MAFLD group exhibited a similar risk of extrahepatic malignancy compared to the non-MAFLD group (aSHR = 1.00; 95% CI = .99-1.00; p = .42). These findings were reproduced in several sensitivity analyses. The DM-MAFLD was an independent risk factor for all-cause mortality (adjusted hazard ratio [aHR] = 1.41; 95% CI = 1.40-1.43; p < .001) and extrahepatic malignancy-related mortality (aHR = 1.20; 95% CI = 1.17-1.23; p < .001). CONCLUSION: The diabetic or lean subtype of MAFLD was associated with a higher risk of extrahepatic malignancy than non-MAFLD. As MAFLD comprises a heterogeneous population, appropriate risk stratification and management based on the MAFLD subtypes are required.

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.

Effectiveness of US Surveillance of Hepatocellular Carcinoma in Chronic Hepatitis B: US LI-RADS Visualization Score.

Background US is a standard surveillance tool of hepatocellular carcinoma (HCC), but its effectiveness varies depending on the degree of fibrosis or steatosis and the etiologies of liver disease. Purpose To evaluate the detection power of US and the occurrence of HCC according to the US Liver Imaging Reporting and Data System (LI-RADS) visualization score in chronic hepatitis B (CHB). Materials and Methods Consecutive patients with CHB undergoing regular US surveillance of HCC at a tertiary referral hospital were retrospectively included in this study. During the follow-up, all patients underwent regular HCC surveillance mainly with US and, in some cases, alternative CT or MRI. Outcomes of interest included cumulative incidence of HCC and false-negative rate of US in the optimal (LI-RADS visualization A) versus suboptimal groups (visualization B or C). Cox regression analysis was conducted to calculate the hazard ratio (HR) of HCC occurrence. Results A total of 2002 patients (median age, 54 years [IQR, 46-60 years]; 1192 men) were included: 972 and 1030 in the optimal and suboptimal groups, respectively. Causes of suboptimal visualization included parenchymal heterogeneity from advanced cirrhosis (n = 489), limited penetration from fatty liver (n = 200), and limited window from overlying organ shadow (n = 341). During a median follow-up of 75 months (IQR, 69-77 months), 163 patients developed HCC. Compared with the optimal group, the suboptimal group had a higher risk of HCC (2.38% per year vs 0.48% per year: hazard ratio, 4.93; 95% CI: 3.28, 7.41; P < .001) and higher odds of a false-negative rate of US (43.9% vs 16.7%: odds ratio, 3.90; 95% CI: 1.02, 15.00; P = .04). Conclusion Among patients with CHB, those with suboptimal US LI-RADS visualization of B or C had a higher risk of HCC and higher odds of false-negative rates of US for detecting HCC than those with optimal visualization of A. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Barr and Scoutt in this issue.

Aspirin use and risk of hepatocellular carcinoma in patients with chronic hepatitis B with or without cirrhosis.

BACKGROUND AND AIMS: Studies on differential effect of aspirin therapy on HCC risk across the spectrum of liver diseases are lacking. We investigated the association between aspirin use and risks of HCC, liver-associated death, and major bleeding in chronic hepatitis B (CHB) patients with or without cirrhosis. APPROACH AND RESULTS: We identified 329,635 eligible adults with CHB from 2007 through 2017, using the Korean National Health Insurance Service database, including patients who received aspirin for ≥90 consecutive days (n = 20,200) and patients who never received antiplatelet therapy (n = 309,435). Risks of HCC, liver-associated mortality, and major bleeding were estimated in a propensity-score-matched cohort (19,003 pairs), accounting for competing risks. With a median follow-up of 6.7 years, 10-year cumulative incidence of HCC was 9.5% in the aspirin-treated group and 11.3% in the untreated group (adjusted subdistribution hazard ratio [aSHR], 0.85; 95% CI, 0.78-0.92). However, among patients with cirrhosis (2479 pairs), an association of aspirin use with HCC risk was not evident (aSHR, 1.00; 95% CI, 0.85-1.18). Cirrhosis status had a significant effect on the association between aspirin use and HCC risk (pinteraction , n = 0.04). Aspirin use was also associated with lower liver-associated mortality (aSHR, 0.80; 95% CI, 0.71-0.90). Moreover, aspirin use was not associated with major bleeding risk (aSHR, 1.09; 95% CI, 0.99-1.21). CONCLUSIONS: Aspirin use was associated with reduced risks of HCC and liver-associated mortality in adults with CHB. Cirrhosis status had a substantial effect on the association between aspirin use and HCC risk.

Changes in liver stiffness values assessed using transient elastography in chronic hepatitis B patients treated with tenofovir disoproxil fumarate: a prospective observational study.

BACKGROUND/AIMS: Regression of liver fibrosis during antiviral therapy in chronic hepatitis B (CHB) patients has been demonstrated, but data on the influence of long-term treatment with tenofovir disoproxil fumarate (TDF) on liver stiffness (LS) measured by transient elastography are scarce. We aimed to investigate the changes in LS values during the 144-week TDF therapy in treatment-naïve CHB patients. METHODS: This prospective observational study was conducted from April 2015 to July 2020 at CHA Bundang Medical Center. Laboratory tests and LS measurements were performed at baseline and repeated at weeks 12, 24, 48, 96, and 144. A significant decline in LS was defined as ≥ 30% decrease in LS value at week 96 from baseline. RESULTS: A total of 48 treatment-naïve CHB patients initiating TDF therapy were screened, and 36 patients were included in the final analysis (median age, 46 [interquartile range, 34.5-55.8] years; 19 men [52.8%]). During TDF therapy, the median LS values decreased from 13.8 kPa at baseline to 8.7 kPa, 6.5 kPa, and 6.4 kPa at weeks 48, 96, and 144, respectively (all P < 0.001). At week 96, virological and biochemical responses were achieved in 34 (94.4%) patients and 20 (76.9%) patients, respectively. Moreover, 21 of 36 (58.3%) patients showed a significant decline in LS value. A higher baseline LS value was a single independent predictor for the reduction in LS value at week 96 from baseline (P < 0.001). CONCLUSIONS: During the 144-week TDF therapy, LS values declined significantly in treatment-naïve CHB patients.

Efficacy of Antiviral Prophylaxis up to 6 or 12 Months From Completion of Rituximab in Resolved Hepatitis B Patients: A Multicenter, Randomized Study.

BACKGROUND: Rituximab occasionally induces reactivation of hepatitis B virus (HBV) in patients with resolved HBV, at times with fatal consequences. The optimal duration of prophylactic antiviral therapy in this situation is unclear. We aimed to investigate the difference in HBV reactivation according to the duration of prophylactic tenofovir disoproxil fumarate (TDF) in patients with resolved HBV and receiving rituximab. METHODS: A multicenter, randomized, open-label, prospective study was conducted in hepatitis B surface antigen-negative and anti-HBc-positive non-Hodgkin's lymphoma patients treated with rituximab-based chemotherapy. A total of 90 patients were randomized and received prophylactic TDF from the initiation of rituximab until 6 months (the 6-month group) or 12 months (the 12-month group) after the completion of rituximab. The primary outcome was the difference in HBV reactivation and the secondary outcomes were the difference in hepatitis flare and adverse events between the two groups. RESULTS: In an intention to treat (ITT) analysis, HBV reactivation occurred in 1 of 43 patients (2.3%; 95% confidence interval [CI], 0.41-12%) at a median of 13.3 months in the 6-month group and 2 of 41 patients (4.9%; 95% CI, 1.4-16%) at a median of 13.7 months in the 12-month group. In a per protocol (PP) analysis, HBV reactivation occurred in 1 of 18 patients (5.6%; 95% CI, 0.99-26%) at 13.3 months in the 6-month group and 1 of 13 patients (7.7%; 95% CI, 1.4-33%) at 9.7 months in the 12-month group. The cumulative incidence of HBV reactivation was not significantly different between the two groups in ITT and PP analyses (P = 0.502 and 0.795, respectively). The occurrence of adverse events was not significantly different between the two groups in ITT (9.3% in the 6-month group, 22.0% in the 12-month group, P = 0.193) and PP analyses (5.6% in the 6-month group, 7.7% in the 12-month group, P > 0.999). CONCLUSION: Prophylactic TDF up to 6 months after completion of rituximab-based chemotherapy is sufficient in terms of the efficacy and safety of reducing HBV reactivation in patients with resolved HBV. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02585947.

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.

Association of Metabolic Risk Factors With Risks of Cancer and All-Cause Mortality in Patients With Chronic Hepatitis B.

BACKGROUND AND AIMS: Long-term antiviral therapy can effectively suppress viral replication and improve clinical outcomes in patients with chronic hepatitis B (CHB), but it cannot eliminate risk of HCC. We investigated the association of metabolic risk factors with the risks of cancer and all-cause mortality in patients with CHB. APPROACH AND RESULTS: This nationwide population-based study from the Korean National Health Insurance Service database consisted of adults with CHB who underwent health examinations from 2007 through 2012. We collected baseline data on metabolic risk factors, including obesity, high blood pressure, hypercholesterolemia, and diabetes. The risks of developing HCC, non-HCC cancer, and overall death were analyzed according to the metabolic risk profile. The study population composed of 317,856 patients (median age, 46 years [interquartile range, 37-54 years]; 219,418 men [69.0%]) had 2,609,523.8 person-years of follow-up. A total of 18,850 HCCs, 22,164 non-HCC cancers, and 15,768 deaths were observed during a median follow-up period of 8.5 years. The metabolic risk factor burden was positively associated with the risks of HCC, non-HCC cancer, and all-cause mortality (all P < 0.0001 for trend). Patients with ≥3 metabolic risk factors, compared with those without metabolic risk factors, showed adjusted hazard ratios of 1.23 (95% CI, 1.16-1.31) for HCC, 1.34 (95% CI, 1.27-1.41) for non-HCC cancer, and 1.31 (95% CI, 1.23-1.39) for all-cause mortality. Among patients receiving antiviral therapy for over 5 years, the risk-increasing association of the sum of metabolic risk factors with the risks of HCC and overall death was consistent. CONCLUSION: The metabolic risk factor burden was associated with increased risks of HCC, non-HCC cancer, and all-cause mortality in patients with CHB.

Comparison of biochemical response during antiviral treatment in patients with chronic hepatitis B infection.

BACKGROUND & AIMS: This multicenter cohort study aimed to compare the real-world biochemical response rates during tenofovir alafenamide (TAF), tenofovir disoproxil fumarate (TDF), and entecavir (ETV) treatment in chronic hepatitis B virus (HBV) infection patients. METHODS: Overall, 1282 treatment-naïve patients with CHB who commenced TAF (n = 270), TDF (n = 617), or ETV (n = 395) were analysed for biochemical response rates during the antiviral treatment using a time-dependent Cox proportional hazard model after the inverse probability of treatment weighting (IPTW). RESULTS: Patients treated with ETV were older (55.1 ± 11.5 years) than TAF or TDF (P < .0001). ETV was more frequently prescribed to patients with diabetes mellitus (DM, P = .003), hypertension (P < .0001), chronic kidney disease (P < .0001), and negative e-antigen (P < .0001). Cumulative biochemical response rate was independently lower in patients with radiologic fatty liver (HR, 0.75; 95% CI, 0.61-0.94) and obese patients without DM (HR, 0.85; 95% CI, 0.68-0.98) according to multivariable Cox analyses based on time-dependent variables after IPTW for age, sex, liver cirrhosis, baseline e-antigen, ALT, and HBV DNA levels. ETV treated patients (HR, 1.38; 95% CI, 1.13-1.68) showed higher biochemical response rates compared with TAF- or TDF-treated patients after adjusting for similar parameters. CONCLUSIONS: In real-world practice, ETV was preferable for older, hepatitis B e-antigen negative patients with underlying comorbidities. Biochemical responses in patients treated with ETV, TAF, and TDF were significantly affected by metabolic factors such as fatty liver, obesity, and DM. However, the mechanism behind the higher biochemical response rate in patients treated with ETV should be investigated further.

Comparison of the outcomes between sorafenib and lenvatinib as the first-line systemic treatment for HBV-associated hepatocellular carcinoma: a propensity score matching analysis.

BACKGROUND/AIM: In a randomized controlled trial, lenvatinib was non-inferior to sorafenib in overall survival (OS) of patients with unresectable hepatocellular carcinoma (uHCC). This study aimed to compare the effects of sorafenib and lenvatinib as first-line systemic therapy against uHCC with real-world data in chronic hepatitis B patients. METHODS: This retrospective single-center study involved 132 patients with HBV-related uHCC. Propensity score matching (PSM) was used to balance the baseline characteristics, including age, sex, serum alpha-fetoprotein levels, Child-Pugh class, tumor size, and tumor stage. The primary endpoint was overall survival (OS), and the secondary endpoints included progression-free survival (PFS), time to progression (TTP), and tumor response. RESULTS: After PSM, the final analysis included 44 patients treated with lenvatinib and 88 with sorafenib. The OS (7.0 vs 9.2 months, p = 0.070) and PFS (4.6 vs 2.4 months, p = 0.134) were comparable between the two drugs. Multivariable analysis showed that lenvatinib and sorafenib were not independent prognostic factors of OS (adjusted hazard ratio = 1.41, 95% confidence interval = 0.96-2.08, p = 0.077) after adjustment for baseline alpha-fetoprotein levels, total bilirubin levels, alanine aminotransferase level, performance status, tumor stage, and tumor size. However, the lenvatinib group had a significantly prolonged TTP (5.2 vs 2.5 months, p = 0.018) and a higher objective response rate (18.2% vs 4.5%, p = 0.020) and disease control rate (77.3% vs 47.7%, p = 0.001) than the sorafenib group. CONCLUSIONS: Our study demonstrated that lenvatinib had a comparable OS and PFS but longer TTP and better tumor response compared to sorafenib in patients with HBV-related uHCC.

A Prognostic Prediction Model of Transarterial Radioembolization in Hepatocellular Carcinoma: SNAP-HCC.

BACKGROUND: Prognosis prediction in patient with hepatocellular carcinoma (HCC) after transarterial radioembolization (TARE) remains difficult. The aim of this study was to develop a prognostic model to aid in the decision to use TARE. METHODS: A total of 174 patients in Korea who underwent TARE for HCC as the initial treatment were included. We developed a prediction model for overall survival (OS) based on independent risk factors for OS and validated the model by bootstrap method. RESULTS: The median maximal size of the tumors was 8.2 cm, the median number of tumors was 2, and the median albumin level was 4.0 g/dL. Portal vein tumor thrombosis was found in 46.0% (Vp1-3 [39.7%] and Vp4 [6.3%]). Four independent risk factors associated with OS (maximal tumor size, tumor number, albumin, and portal vein tumor thrombosis) were used to develop the SNAP-HCC score. Bootstrap validation of the scoring index determined that the Harrell's c-index for OS was 0.756 (95% confidence interval: 0.729-0.783). Patients grouped based on their SNAP-HCC (scores 0-5) were well discriminated, with significant differences between the groups (all P < 0.05). Patients with SNAP-HCC < 3 showed significantly longer OS than patients with SNAP-HCC ≥ 3 (P < 0.001). The respective survival probabilities at years 1 and 3 were 0.81 and 0.73 in the low-risk (SNAP-HCC < 3) and 0.32 and 0.14 in the high-risk (SNAP-HCC ≥ 3) patients. CONCLUSIONS: The SNAP-HCC scoring system predicted the outcome of HCC patients undergoing TARE as an initial treatment. This model could be helpful for initial planning the treatment of HCC patients.

Effectiveness of Lenvatinib Versus Sorafenib for Unresectable Hepatocellular Carcinoma in Patients with Hepatic Decompensation.

BACKGROUND/AIM: Lenvatinib and sorafenib are currently available to treat patients with advanced hepatocellular carcinoma (HCC). However, since the clinical trials evaluating the efficacy of lenvatinib and sorafenib included only patients with Child-Pugh class A, little is known about the effectiveness of the treatments in patients with hepatic decompensation. We compared the effectiveness of lenvatinib and sorafenib in decompensated patients with unresectable HCC. METHODS: Consecutive patients who were classified as Child-Pugh class B or C and received lenvatinib or sorafenib as first-line systemic therapy for unresectable HCC between November 2018 and April 2020 at a tertiary referral center were included in this retrospective study. The primary outcome was overall survival (OS), and the secondary outcomes were progression-free survival (PFS), time-to-progression, best overall tumor response, and safety profiles. RESULTS: Among 94 patients, 34 received lenvatinib and 60 received sorafenib. The median OS was 4.1 months (95% confidence interval [CI], 2.9-5.2): 4.2 months (95% CI, 2.9-5.3) for lenvatinib and 4.1 months (95% CI, 2.7-6.4) for sorafenib. The treatment regimen was not associated with significant improvement in OS after adjusting for covariables (adjusted hazard ratio [aHR], 0.92; 95% CI, 0.54-1.54; P = 0.74). The treatment regimen was not an independent predictor of PFS (lenvatinib vs. sorafenib; aHR, 0.77; 95% CI, 0.48-1.24; P = 0.28). HRs were maintained even after balancing with the inverse probability treatment weighting method. Objective response rates were 11.8% and 6.7% in patients receiving lenvatinib and sorafenib, respectively (P = 0.45). Ten patients in both groups (five in the lenvatinib group and five in the sorafenib group) underwent dose modification due to adverse events, and significant difference was not observed between the treatment groups (P = 0.49). CONCLUSION: The effectiveness of lenvatinib and sorafenib was comparable for the treatment of unresectable HCC in decompensated patients.

Entecavir Plus Pegylated Interferon and Sequential Hepatitis B Virus Vaccination Increases Hepatitis B Surface Antigen Seroclearance: A Randomized Controlled Proof-of-Concept Study.

BACKGROUND: Hepatitis B surface antigen (HBsAg) seroclearance is considered a functional cure for patients with chronic hepatitis B, but is rarely achievable with oral nucleos(t)ide analogues alone. We conducted a randomized controlled proof-of-concept trial to evaluate the impact of adding pegylated interferon (peg-IFN) alfa-2a plus sequential or concomitant hepatitis B virus (HBV) vaccination. METHODS: A total of 111 patients who achieved serum HBV DNA <20 IU/mL and quantitative HBsAg <3000 IU/mL with entecavir were randomly assigned (1:1:1) to the E + sVIP group (entecavir + peg-IFN alfa-2a [180 µg every week over 48 weeks] plus sequential HBV vaccination [20 µg of HBsAg on weeks 52, 56, 60, and 76]), the E + cVIP group (entecavir + peg-IFN alfa-2a + concomitant HBV vaccination [weeks 4, 8, 12, and 28]), or the control group (entecavir only). The primary endpoint was HBsAg seroclearance at week 100, and secondary endpoints included safety. RESULTS: No differences in baseline quantitative HBsAg were observed among the groups. The E + sVIP group in the intention-to-treat analysis showed a significantly higher chance of HBsAg seroclearance during week 100 than the control group (16.2% vs 0%; P = .025), but the E + cVIP group (5.4%) failed to reach a significant difference (P = .54). Adverse events were significantly more frequent in the E + sVIP (81.1%) and E + cVIP group (70.3%) than the control group (2.7%) (both P < .0001). However, the frequency of serious adverse events did not differ significantly among the 3 groups (2.7%, 5.4%, and 2.7%, respectively; P = 1.00). CONCLUSIONS: Entecavir plus an additional peg-IFN alfa-2a treatment followed by sequential HBV vaccination under an intensified schedule significantly increases the chance of HBsAg seroclearance compared to entecavir alone. CLINICAL TRIALS REGISTRATION: NCT02097004.