BACKGROUND & AIMS:Direct-acting antiviral agents (DAA)-mediated HCV cure correlates with better outcomes, but there are insufficient data on detailed mortality-related risk factors after cure. This study sought to clarify mortality and associated risk factors post-HCV cure. METHODS:The study included HCV patients with sustained virological response following DAA (DAA-SVR) from 39 REAL-C centres in North America, Europe and Asia-Pacific. The primary outcome was all-cause mortality in DAA-SVR patients. Mortality rate per 1000 patient-years (PY) was calculated as the number of deaths divided by total PY multiplied by 1000. RESULTS:A total of 10 034 DAA-SVR patients (stratified by cirrhosis status: 5611 non-cirrhosis, 4153 compensated, 270 decompensated) were included. With a median follow-up of 4.76 PY, 4.9% (491) died. The all-cause mortality rates were 6.2, 13.1, 60.0 and 10.4 per 1000 PY for patients without cirrhosis, compensated and decompensated cirrhosis, and overall patients, respectively. The 5-year cumulative survival was 95.1% (94.5%-95.6%) overall, with the lowest rate of 73.9% (67.0%-79.5%) in decompensated cirrhosis. Non-liver-related death was the main cause in non-cirrhosis (non-liver-related vs. liver: 5.2 vs. 0.8 per 1000 PY)/compensated cirrhosis (8.2 vs. 4.8 per 1000 PY), while liver-related death was dominant in decompensated cirrhosis (24.7 vs. 33.8 per 1000 PY). Risk factors for higher mortality included age > 65 (3.2-fold), male (1.5-fold), cirrhosis (decompensated 7.6-fold) and baseline DM (1.5-fold). CONCLUSION:This study showed significant age, sex, fibrosis stage and DM differences in mortality and causes among DAA-SVR patients. It provided granular subgroup data for precision medicine to support individualised care, future modelling studies and public health planning.

The impacts of cardiometabolic risk factors (CMRFs) and the biomarkers on disease severity in metabolic dysfunction-associated steatotic liver disease (MASLD) remain elusive. Accordingly, a multicenter study by recruiting MASLD patients from a nationwide registry database was conducted with a total of 2882 MASLD patients (54.1% males, mean age = 55.6 ± 13.9 years, mean body mass index [BMI] = 28.1 ± 4.9 kg/m2) being recruited. The proportions of patients carrying CMRFs of overweight/obesity, hypertension, hypertriglyceridemia, low high-density lipoprotein cholesterol level, and diabetes/prediabetes were 91.2%, 74.5%, 54.8%, 59.6%, and 74.5%, respectively. There was a significant linear trend between significant fibrosis and CMRFs (5.1%, 27%, and 54.6% in patients with one CMRF, 3 CMRFs, and ≥ 4 CMRFs, respectively, p = 0.009). The adjusted odds ratios (aOR) with 95% confidence intervals (CIs) for advanced fibrosis in patients of hemoglobin A1c (HbA1c) 5.7%-6.5%, 6.5%-8.0%, and > 8.0% were 1.02 (95% CI = 0.68-1.53, p = 0.93), 1.83 (95% CI = 1.16-2.88, p = 0.01), and 2.78 (95% CI = 1.45-5.34, p = 0.002), respectively. The significant risk factors for advanced fibrosis in MASLD were age > 60 years (aOR = 12.08, 95% CI = 6.23-23.46, p < 0.001), elevated transaminase level (aOR = 1.06, 95% CI = 1.05-1.09, p < 0.001), and diabetes (aOR = 1.51, 95% CI = 1.02-2.26, p = 0.04). In conclusion, there was a significant linear association between advanced fibrosis and the items of CMRFs. The HbA1c level could serve as a predictive biomarker for advanced fibrosis in MASLD with the implication that diabetes control is mandatory for patients with MASLD.

Background and Aims: Antiviral treatment can reduce mortality of viral hepatocellular carcinoma (HCC) but may be underutilized. Methods: In a multinational real-world consortium of HCC patients with hepatitis B (HBV-HCC) or C (HCV-HCC) from 16 centers (7 countries/regions), we assessed treatment rates of nucleos(t)ide analogs in HBV-HCC (2007-2023) and direct acting antivirals in HCV-HCC (2015-2023). Results: Among 3,973 HCC patients (3,186 HBV, 647 HCV, 140 HBV/HCV), 49.7% of HBV-HCC and 63.2% of HCV-HCC patients received antiviral treatment. For HBV, lower treatment rates were observed in female (41.7% vs. 51.8%), older (>60) (45.3% vs. 54.5%), noncirrhosis (41.3% vs. 56.8%), and Asia region (37.9% vs. 85.0%) patients; for HCV, lower rates in male (59.0% vs. 72.4%), cirrhosis (60.5% vs. 73.2%), and non-Asia region (58.2% vs. 69.9%) patients, all P <0.005. Child A cirrhosis and Barcelona Clinic Liver Cancer (BCLC) 0/A patients had highest treatment rates followed by Child B and C or BCLC B, C, or D for both HBV (78.6%, 48.3%, 43.8%; 59.9%, 50.9%, 36.7%, 41.0%) and HCV (68.2%, 53.3%, 38.6%; 72.5%, 53.3%, 51.9%, 30.2%), all P <0.001. Factors independently associated with lower treatment rates were: female, age>60, Asia region, noncirrhosis, and BCLC B or C (vs. 0/A) for HBV; male, age>65, Child B or C cirrhosis (vs. non-cirrhosis), and BCLC B or C for HCV. Antiviral treatment was independently associated with reduced mortality in both HBV-HCC (adjusted hazard ratio [aHR]=0.82) and HCV-HCC (aHR=0.31) patients. Conclusion: Despite survival benefits, antiviral therapies were substantially underutilized in both HBV-HCC and HCV-HCC, particularly in advanced patients.

BACKGROUND AND AIMS:ADH1B genetic variants have recently emerged as a novel genetic determinant of metabolic dysfunction-associated steatotic liver disease (MASLD); however, their clinical significance in Asian populations is unclear. METHODS:We used multivariable logistic regression to evaluate the association between ADH1B genetic variants and MASLD risk and mediation analysis to quantify the direct effects of ADH1B polymorphisms and the indirect effects mediated by central obesity. RESULTS:The AA genotype was associated with lower waist circumference (81.9 ± 11.0 cm) and higher liver computed tomography (CT) attenuation (58.7 ± 9.3 HU) compared with the AG (84.1 ± 11.1 cm; 56.9 ± 9.4 HU) and GG (84.7 ± 9.6 cm; 54.0 ± 9.8 HU) genotypes. Compared with the AA genotype, the GG and AG genotypes were associated with a higher MASLD risk by both ultrasonography (GG: OR = 3.97, 95% CI: 1.68-9.38, p = 0.002; AG: OR = 1.97, 95% CI: 1.16-3.35, p = 0.012) and CT criteria (GG: OR = 3.98, 95% CI: 1.75-9.02, p = 0.001; AG: OR = 2.33, 95% CI: 1.47-3.69, p < 0.001). Waist circumference mediated 17.4% and 30.2% of the associations between the ADH1B dominant genotype and MASLD by CT liver-to-spleen attenuation ratio < 1.0 and ultrasonography. Waist circumference accounted for 39.7% of the association between the ADH1B dominant genotype and hepatic steatosis assessed by liver CT attenuation. CONCLUSIONS:ADH1B variants were associated with MASLD, and mediation analysis demonstrated a statistical mediation pattern involving waist circumference that was consistent with a hypothesized adipose-liver pathway.

BACKGROUND:In the hepatitis B e antigen positive (HBeAg+) chronic infection disease phase, approved treatments have limited effects on hepatitis B surface antigen (HBsAg) and HBeAg. OBJECTIVE:The phase 2 REEF-IT study (NCT04439539) assessed safety, efficacy and pharmacokinetics of pegylated interferon-α2a (PegIFN-α2a) add-on to JNJ-73763989 (JNJ-3989)±bersacapavir+nucleos(t)ide analogues (NA) in not currently treated, HBeAg+chronic hepatitis B. DESIGN:Participants received JNJ-3989 (200 mg every 4 weeks)+NA±bersacapavir (250 mg daily) for 36-52 weeks (induction) followed by 12 weeks of PegIFN-α2a (180 µg weekly) add-on. The primary endpoint was the proportion of participants with HBsAg seroclearance 24 weeks after stopping all treatment including NA. Changes in viral markers, safety and pharmacokinetics were assessed. RESULTS:49/54 (91%) enrolled participants completed the study; 52% were male, with mean age of 33.6 years. No participant achieved the primary endpoint; one met NA completion criteria. 11/54 (20.4%) participants achieved HBsAg seroclearance at least once, 6 of them maintained it until Follow-up Week 48 (FUW48). Overall mean (SE) change from baseline in HBsAg of -2.85 (0.13), -3.61 (0.18) and -2.63 (0.26)log10IU/mL were observed at end of induction, end of treatment and FUW48. 16/53 (30.2%) participants reached HBeAg seroclearance at least once; 12 maintained it until FUW48. Similar proportions of participants experienced an adverse event (AE) during induction (83.3%), PegIFN-α2a add-on (85.7%) and follow-up (64.7%). There were no deaths or serious AEs; two participants discontinued PegIFN-α2a. CONCLUSIONS:In this population, adding PegIFN-α2a increased HBsAg declines after reductions by JNJ-3989; 20.4% achieved HBsAg seroclearance at least once. Treatment was generally safe with acceptable tolerability. TRIAL REGISTRATION NUMBER:NCT04439539.

INTRODUCTION:Direct-acting antiviral agents effectively cure chronic hepatitis C (CHC), whereas curative therapy for chronic hepatitis B (CHB) is rare. We aimed to compare hepatocellular carcinoma (HCC) incidence between suppressed CHB vs cured CHC patients with cirrhosis. METHODS:We analyzed 5,773 cirrhosis patients from 43 centers in 9 countries: 1,877 with treated and suppressed CHB and 3,896 with direct-acting antiviral agents-cured CHC using inverse probability treatment weight and competing risk analysis through Fine and Gray method. RESULTS:After inverse probability treatment weight (on age, sex, ethnicity, study location, albumin, total bilirubin, creatinine, platelet, tobacco use, alcohol use, diabetes mellitus, hypertension, hyperlipidemia, cardiovascular disease, steatotic liver disease, obesity, and follow-up years), 2 study groups became similar in relevant characteristics. The 5-year cumulative HCC incidence was significantly higher in suppressed CHB compared with cured CHC (18.1% vs 7.4%, P < 0.001) with consistent findings in subgroups by sex and Model for End-Stage Liver Disease (all P < 0.021), fast CHB responders (time from treatment to viral suppression <1 year) ( P < 0.001), and CHB suppressed for <2 years ( P < 0.001), but not among CHB suppressed for ≥2 years whose HCC incidence was similar to those of cured CHC ( P = 0.954). On multivariable analysis, CHB suppression <2 years as compared with cured CHC (subdistribution hazard ratio 20.92, P < 0.001) and total bilirubin (subdistribution hazard ratio 0.71, P = 0.04) were associated with higher HCC risk. DISCUSSION:HCC risk remains high in both treated and suppressed CHB cirrhosis and cured CHC cirrhosis. However, with prolonged CHB suppression, risk of HCC can be reduced, highlighting benefits of early treatment and viral suppression in patients with CHB.

Background To investigate the association between air pollution and hepatic steatosis in patients with chronic hepatitis B. Methods This cross-sectional study enrolled 1068 patients with chronic hepatitis B treated with nucleotide/nucleoside analogs from 2020 to 2023 in Kaohsiung and analyzed the incidence and risk factors for hepatic steatosis. Daily air pollutant concentrations were estimated for the year prior to enrolment. Results Patients with hepatic steatosis were reported in 340 (31.8%). Patients with hepatic steatosis had higher concentrations of nitrogen oxides (NOx) compared to those without steatosis (27.8 ppb vs. 25.5 ppb; P = 0.001). Logistic regression analysis revealed that non-liver-cirrhosis was the strongest factor associated with hepatic steatosis (odds ratio (OR)/confidence interval (CI): 4.63/2.85-7.52; P < 0.001), followed by hypertriglyceridemia (OR/CI: 2.09/1.29-3.39; P < 0.001),HBeAg seropositivity (OR/CI: 1.54/1.05-2.26; P = 0.04), BMI (OR/CI: 1.10/1.06-1.14; P < 0.001) and concentrations of NOx (OR/CI: 1.018/1.004-1.033; P = 0.01). Among patients without cirrhosis, logistic regression analysis revealed that the strongest factors associated with hepatic steatosis were hypertriglyceridemia (OR/CI: 1.98/1.17-3.35; P = 0.01), followed by HBeAg seropositivity (OR/CI: 1.51/1.05-2.17; P = 0.03), BMI (OR/CI: 1.10/1.05-1.14; P < 0.001) and concentrations of NOx (OR/CI: 1.02/1.01-1.04; P = 0.01). Patients in the highest quartile of annual NOx-concentration exposure had a two-fold increased risk of hepatic steatosis compared with those in the lowest quartile (OR/CI: 2.20/1.37-3.50). Among patients with cirrhosis, logistic regression analysis revealed that the strongest factors associated with hepatic steatosis were hypertriglyceridemia (OR/CI: 3.79/1.22-11.79; P = 0.02), followed by age (OR/CI: 0.95/0.92-0.99; P = 0.02). Conclusions Higher concentrations of NOx were associated with hepatic steatosis in patients with non-cirrhotic chronic hepatitis B.

The prognostic value of on-treatment hepatitis B virus (HBV) RNA, hepatitis B core-related antigen (HBcrAg), and quantitative hepatitis B surface antigen (HBsAg) for hepatocellular carcinoma (HCC) risk in patients with chronic hepatitis B (CHB) remains uncertain. We evaluate the predictive roles of these viral markers in patients with CHB receiving long-term entecavir therapy. This prospective, multicenter study enrolled patients with CHB-related cirrhosis undergoing long-term entecavir treatment and HCC surveillance in Taiwan. Serum HBV RNA, HBcrAg, and HBsAg levels were measured at enrollment. Multivariable regression identified predictors of HBV RNA positivity and HCC development. Overall, 451 patients were included. After a median of 6.2 years of antiviral therapy, the median levels of HBV RNA, HBcrAg, and HBsAg were 0.9 log10 copies/mL, 3.2 log10 U/mL, and 2.4 log10 IU/mL, respectively. During a median 3.3-year follow-up, 55 developed HCC. 57.2

Patients with chronic hepatitis C (CHC) frequently present with steatotic liver disease (SLD) and cardiometabolic risk factors (CMRFs). This study aimed to evaluate the impact of SLD and CMRFs on liver-related outcomes (LROs) in CHC patients after HCV eradication. This study evaluated 21,972 CHC patients who received curative antivirals in Taiwan. LROs included newly developed hepatocellular carcinoma and liver decompensation. During a follow-up period of 71,000 person-years (PYs), 745 (3.4%) patients developed LROs (annual incidence of 1.05%). The annual incidence of LRO (136.2 vs. 80.7 per 10,000 PYs, p < 0.001) was significantly higher in patients without SLD than in those with SLD. Cox regression analysis revealed that SLD was independently associated with a lower risk of LRO (adjusted hazard ratio [aHR]/95% confidence intervals [CI]: 0.85/0.73-0.99, p = 0.038). There was an increased trend toward increased LRO risk in patients with a higher number of CMRFs than in those without CMRFs (aHR/CI: 1.35/1.02-1.78, 1.48/1.11-1.97, and 1.53/1.15-2.05 for 1, 2, and > 3 CMRFs, respectively). Non-SLD patients who carried CMRFs were independently associated with a high risk of LROs compared to SLD patients without any CMRF carriage (aHR/CI: 1.97/1.11-3.50, p = 0.02). We concluded that CMRF burden had a dose-dependent effect on LRO risk in CHC patients after curative antivirals. Non-SLD CHC patients who possessed CMRFs were at a greater risk of LROs.

BACKGROUND & AIMS:JNJ-73763989-based treatments (evaluations ongoing) reduce hepatitis B surface antigen in patients with chronic hepatitis B, but hepatitis B surface antigen seroclearance is rare. OCTOPUS-1, an open-label, randomized phase II study, assessed the efficacy and safety of adding low-dose nivolumab (programmed death 1 inhibitor) to JNJ-73763989 + nucleos(t)ide analog. METHODS:Hepatitis B surface antigen-negative, virologically suppressed participants with chronic hepatitis B received JNJ-73763989 loading dose (200 mg once weekly) for 4 weeks then every 4 weeks until week 24 with daily nucleos(t)ide analog. Nivolumab (0.3 mg/kg) was administered at week 16 for arm 1 and at weeks 16, 20, and 24 for arm 2; both arms had 48-week follow-ups. RESULTS:Thirty-seven participants were enrolled (arm 1, 18; arm 2, 19); all completed the study. None achieved the primary endpoint of hepatitis B surface antigen seroclearance at 48-week follow-up, but 1 (arm 2) achieved hepatitis B surface antigen seroclearance at 48-week follow-up. Both arms had robust mean [standard error] hepatitis B surface antigen changes from baseline before nivolumab administration (arm 1, -1.32 [0.12]; arm 2, -1.41 [0.16] log10IU/mL), at week 24 (arm 1, -2.01 [0.09]; arm 2, -2.10 [0.13] log10IU/mL), and at 48-week follow-up (arm 1, -1.23 [0.13]; arm 2, -1.54 [0.21] log10IU/mL). The mean receptor occupancy (determined 2 hours postinfusion at week 16) was ≥70% and ≥90% in arms 1 and 2 with no clear association between hepatitis B virus-specific T-cells and hepatitis B surface antigen. No serious adverse events, grade 3/4 adverse events, or adverse events leading to discontinuation were reported; 2 participants experienced asymptomatic transient hyperthyroidism. Cross-study analysis with REEF-1 (virologically suppressed, hepatitis B e-antigen-negative participants) revealed no additional benefit of loading dose or nivolumab. CONCLUSIONS:JNJ-73763989 + nucleos(t)ide analog + nivolumab treatment was generally safe and led to robust hepatitis B surface antigen declines; no hepatitis B surface antigen seroclearance was observed. CLINICALTRIALS:gov, Number: NCT05275023.