BACKGROUND:Bulevirtide (BLV) blocks hepatitis D virus (HDV) entry by targeting the sodium taurocholate co-transporting polypeptide (NTCP). This study assessed the relationship between bile acid (BA) levels and antiviral response to BLV. METHODS:Serum BA levels were monitored in HDV-infected patients pre-, under, and post BLV treatment. Virologic response (VR) was defined by ≥ 2log10 decline in HDV-RNA and discriminated versus virologic non-response (VNR). Delta BA levels (ΔBA) were calculated and analysed in relation to HDV-RNA dynamics. Finally, the effect of BLV treatment cessation on BA was investigated. RESULTS:Twenty five patients (48% male; advanced chronic liver disease [ACLD]: 92.0%, 17 patients with VR at W48) were included. Median baseline BA levels were significantly higher in patients with ACLD and portal hypertension (n = 10; 19.2 vs. 5.1 μmol/L; p = 0.015). No difference in median on-treatment BA levels was detected between patients achieving VR or VNR at W24 (VR: 25.4 vs. VNR: 22.7 μmol/L; p = 1.000) and W48 (VR: 25.4 vs. VNR: 20.8 μmol/L; p = 1.000). Additionally, ΔBA from baseline to W48 did not differ between VR and VNR (p = 0.534). No significant association between ΔBA and HDV-RNA dynamics at W48 was detected. After BLV discontinuation, median BA levels significantly dropped to normal ranges (18.9 μmol/L at last on-BLV assessment to 7.6 μmol/L after discontinuation; p = 0.028). On-treatment BA levels did neither associate with self-reported compliance nor with treatment-related adverse events. CONCLUSION:Bulevirtide increases bile acid levels in most patients, but ΔBA does not predict virologic response or adverse events, nor does it reflect compliance to therapy. Bile acid level monitoring during and following bulevirtide treatment is thus, not advised for clinical practise.

Vascular liver diseases such as porto-sinusoidal vascular disorder (PSVD), Budd-Chiari syndrome (BCS), and non-cirrhotic portal vein thrombosis (NCPVT) are rare causes of portal hypertension (PH) but share the same phenotype with parenchymal chronic liver disease (CLD). We assessed whether blood-based and elastography-based noninvasive tests (NITs) can: (i) differentiate vascular from parenchymal liver disease, (ii) detect specific signs of portal hypertension within etiologies and (iii) identify portal vein thrombosis. Consecutive patients with PSVD, NCPVT, BCS, or CLD treated at a tertiary referral center between January 2022 and December 2024 were included. Assessed NITs included platelet count, liver stiffness measurement (LSM), spleen stiffness measurement (SSM), the SSM to LSM ratio, ANTICIPATE, and NICER. This study included 411 patients: PSVD n = 43, NCPVT n = 38, CLD n = 309, and BCS n = 21. Among patients without PVT, NIT patterns differed between etiologies. The PSVD showed low LSM despite elevated SSM, resulting in the highest SSM to LSM ratio. This ratio best discriminated PSVD from CLD and BCS (AUC ≥ 0.870); the proposed cut-off of > 2 showed good diagnostic performance. The ANTICIPATE also differentiated PSVD from CLD/BCS, whereas SSM alone did not. Detection of specific PH signs was etiology dependent. In PSVD, platelet count showed the highest accuracy (AUC 0.823). In CLD, several NITs were associated with specific PH signs but accuracy was limited. In BCS, differences of the tested NITs for specific PH signs were not statistically significant. Across etiologies, NITs showed limited accuracy for detecting PVT. Combined assessment of LSM and SSM, particularly the SSM to LSM ratio, supports differentiation of PSVD from parenchymal and posthepatic liver disease, whereas platelet counts was most informative to detect specific PH signs within PSVD.

Prenatal alcohol exposure (PAE) of the fetus may result in physiognomic alterations and/or impediment of cognitive development, summarized as fetal alcohol spectrum disorders (FASDs). Although alcohol is metabolized in the liver, the effects of PAE on the fetal liver are unknown. For this study, n = 21 prenatal MRIs of fetuses with PAE and n = 45 MRIs of fetuses without PAE were included. To assess macroscopic organ development, liver volumetry was conducted and compared to an established prenatal estimation formula. A texture-based radiomics analysis based on ensemble (random forest) and linear (L2-penalized logistic regression) models was conducted. PAE and non-PAE fetuses were age-matched (gestational age 27.4 [IQR 25.1–30.0] vs. 26.7 [25.4–29.3] weeks, p = 0.650). PAE had no effect on liver volume (normalized per gestational week, p = 0.971) or signal intensity (SI) in T1 (p = 0.574) and T2 (p = 0.104). MRI-derived liver volumetry correlated strongly with a gestational age-based volume estimation regardless of PAE (both r > 0.75, p < 0.001). A texture-based radiomics analysis was unable to discern between PAE and no-PAE fetuses (ROC-AUC = 0.43, 95

Chronic hepatitis D (CHD) is a severe viral hepatitis characterized by a rapid progression towards advanced chronic liver disease (ACLD). This study aimed to characterize the Austrian CHD epidemiology with respect to disease severity, systemic inflammation and genetic markers. Patients attending one of six participating hospitals from 2020 onwards were included and assessed regarding laboratory data, liver stiffness measurement (LSM) and biopsy, hepatic venous pressure gradient (HVPG) measurement, endoscopy and imaging. In a subset, single nucleotide polymorphisms (SNPs) in genes of interest (IL28B, PNPLA3, SERPINA1, NTCP) were assessed. Biomarkers of liver disease severity were compared to an age-matched cohort of treatment-eligible and treatment-naïve chronic hepatitis B (CHB) patients. A total of 59 CHD patients (median age: 44.0 years, 59.3

BACKGROUND & AIMS:Chronic hepatitis D (CHD) often progresses to advanced chronic liver disease (ACLD). Bulevirtide (BLV) is approved for CHD, yet treatment duration, management of suboptimal response, and the potential for finite treatment remain unclear. METHODS:Patients receiving BLV at 10 Austrian centers were included. Virological, biochemical, and combined response (VR/BR/CR) were assessed every 6 months (M6-M24). Pegylated interferon alfa-2a (PegIFN) was offered to suboptimal responders. RESULTS:Sixty-one patients (median age: 45 years, 60.7% men, ACLD: 68.9%) receiving BLV for a median of 29.0 months were included. VR (Month [M]6: 36.4%, M12: 64.2%, M24: 61.9%), BR (M6: 56.4%, M12: 69.8%, M24: 66.7%), and CR (M6: 25.5%, M12: 47.2%, M24: 42.9%) were maintained for 2 years. Liver stiffness and systemic inflammation (i.e. C-reactive protein [CRP] and procalcitonin [PCT]) decreased under BLV treatment (all p <0.01). Nineteen patients (31.1%) received add-on PegIFN to BLV monotherapy after a median of 10.5 months, inducing a further HDV-RNA decline by 1.65 (IQR 0.81-2.11) log10 copies/ml and reductions in HBsAg levels by 0.08 (IQR 0.02-0.12) log10 IU/L after 24 weeks of combined therapy (both p <0.01). Overall, 32.8% (20/61 patients) achieved HDV-RNA target not detected (TND). Ten (seven BLV mono and three BLV + PegIFN) stopped treatment after 23.0 (IQR 12.0-29.0) months. Seven patients maintained HDV-RNA TND through the last follow-up (median 36.0 months), whereas three patients relapsed but achieved TND again following BLV retreatment. CONCLUSIONS:High response rates to BLV were observed in this nationwide cohort. In suboptimal BLV responders, PegIFN add-on was associated with a significant and partly sustained decline in HDV-RNA and HBsAg, indicating a relevant contribution to long-term viral infection control. Sustained negative HDV-RNA could help identify candidates for finite BLV treatment. IMPACT AND IMPLICATIONS:CHD is a severe form of viral hepatitis with rapid progression to cirrhosis and hepatocellular carcinoma, highlighting the need for effective treatments. In this real-world cohort of 61 Austrian patients, BLV significantly reduced HDV-RNA, alanine aminotransferase, and liver stiffness (p <0.001). Add-on PegIFN resulted in a further decline of HDV-RNA and HBsAg by 24 weeks of combined treatment (p <0.01) in 19 patients with suboptimal response to BLV treatment, and long-term HDV-RNA TND allowed elective treatment discontinuation in 10 patients under close surveillance.

Treatment options for chronic hepatitis D (CHD) are limited in patients who do not respond to recommended treatment with bulevirtide ± pegylated interferon. The use of REP 2139-Mg is a novel treatment option that has recently demonstrated efficacy and safety in phase 2 trials and a compassionate access program that included three patients treated at the Vienna General Hospital with compensated advanced chronic liver disease and clinically significant portal hypertension (CSPH). Long-term outcome of CSPH patients treated with REP 2139-Mg is unknown; thus, surrogate endpoints are of interest in this population. In the 3 patients receiving REP 2139-Mg for 12 months at our center, we monitored the hepatic venous pressure gradient (HVPG) as the strongest prognostic surrogate biomarker in compensated cirrhosis at baseline, and after 3 and 12 months of treatment. The HVPG dynamics alongside additional liver function tests observed are summarized in this report and two out of three patients achieved undetectable hepatitis-D-virus(HDV)-RNA and low hepatitis B surface Antigen (HBsAg) following pronounced alanine aminotransferase (ALT) flares during REP 2139-Mg treatment. The first patient showed virologic non-response and no HVPG dynamics during treatment. The second patient developed jaundice upon treatment initiation, resulting in a transient increase in HVPG despite virologic response. The third patient achieved virologic response that was paralleled by sustained reductions in HVPG.

BACKGROUND AND AIMS:Homozygosity for the SERPINA1 Pi*Z deficiency allele is the culprit of alpha-1 antitrypsin deficiency-related liver disease, while harbouring a single Z-allele (e.g., the common Pi*MZ genotype) is the strongest genetic risk factor for advanced chronic liver disease (ACLD) and its progression. However, the impact of the Pi*MZ genotype on hepatocellular carcinoma (HCC) development in patients who have already progressed to ACLD has yet to be established. Thus, we investigated the impact of the Pi*MZ genotype on the development of HCC among longitudinally followed ACLD patients. METHODS:Patients undergoing hepatic venous pressure gradient (HVPG) measurement and genotyping at the Vienna Hepatic Haemodynamic Lab were included, excluding those with HCC. Competing risk analyses with HCC as the outcome of interest and death/liver transplantation as competing events were performed. RESULTS:We included 815 patients (mean age: 54 ± 11 years; viral hepatitis: 53%, alcohol-related liver disease: 37% and metabolic dysfunction-associated steatotic liver disease: 10%). Overall, 30 patients (4%) harboured the Pi*MZ genotype. During a median follow-up of 47.3 months, 68 patients developed an HCC (8/30 with Pi*MZ). The Pi*MZ genotype was associated with increased risks of HCC development in univariable as well as in multivariable analyses, accounting for other important factors (i.e., age, sex, removal of the primary aetiological factor, aspartate-aminotransferase, albumin and HVPG) identified in our study (adjusted subdistribution hazard ratio [aSHR]: 3.31 [95% confidence interval (CI): 1.26-8.65]; p = 0.015). The impact of the Pi*MZ genotype was confirmed adjusting for the aMAP score (aSHR: 2.94 [95% CI: 1.45-5.97]; p = 0.003). CONCLUSION:The SERPINA1 Pi*MZ genotype is associated with an increased risk of HCC development in patients with ACLD, independently of other HCC risk factors.

BACKGROUND:Complications related to portal hypertension (PH) in patients with alcohol-related liver disease (ALD) can be controlled by transjugular intrahepatic portosystemic shunt (TIPS) placement; however, the impact of ongoing alcohol use (AU) after TIPS remains scarcely investigated. METHODS:ALD patients undergoing TIPS implantation between 2000 and 2022 were included. Laboratory/demographic parameters and clinical events/outcomes were compared per post-TIPS AU status and to a group of n = 55 decompensated ALD patients with ongoing AU who did not receive TIPS. RESULTS:Overall, 248 TIPS patients (78.2% male; median age: 55.5 years; ascites: 69.8%; median MELD: 12), including 90 (36.3%) with ongoing AU after TIPS were included. AU post-TIPS was independently associated with ACLF (asHR 2.27; 95% CI 1.40-3.66; p < 0.001) and liver-related death (asHR 1.68; 95% CI 1.05-2.67; p = 0.030) among patients undergoing TIPS in adjusted multivariable competing risks analysis. When comparing matched decompensated AU patients treated versus non-treated by TIPS, multivariable competing risks regression revealed MELD (asHR 1.07; 95% CI 1.01-1.13; p = 0.033) but not TIPS use (asHR 0.70; 95% CI 0.45-1.10; p = 0.120) as independent risk factors for ACLF, despite TIPS patients having higher levels of systemic inflammation (CRP). CONCLUSION:Post-TIPS AU was frequent and an independent risk factor for ACLF and liver-related death, underlining the importance of interdisciplinary measures supporting alcohol abstinence. TIPS should still not be withheld from ALD patients developing PH complications, since it does not predispose them to ACLF and may prevent liver-related death.

Introduction:Directly observed therapy (DOT) is an effective strategy to optimize hepatitis C virus (HCV) cure rates in people who inject drugs (PWID) on stable opioid agonist therapy (OAT). While adherence to daily DOT is excellent, it remains unclear if extended DOT distribution intervals result in similar sustained virologic response (SVR) rates. Methods:PWID undergoing DOT with direct-acting antiviral agents (DAA) alongside OAT for HCV infection at a low-threshold institution were included. Social distancing requirements during the COVID19 pandemic led to an extension in DOT dispensation intervals; therefore, the study population was classified according to "tight period" (DAA start 2014-2020) and "liberal period" (DAA start 2020-2023) cohorts. Socioeconomic characteristics, DOT distribution schedules, and rates of SVR at week 12 after end of therapy (SVR12) were compared between groups. Results:We included 719 consecutive PWID (male: 76.5 %; median age: 39 years), 441 (61.3 %) were treated in the "tight period" and 278 (38.7 %) in the "liberal period". Baseline characteristics were comparable between cohorts, however, socioeconomic features of the "liberal period" group showed more problematic features (unemployment: 83.1 % vs. 67.3 %; lack of housing: 38.5 % vs. 35.1 %; ongoing injection drug use: 64.0 % vs. 57.8 %; each p < 0.001).While the "tight period" group had their DAA most commonly dispensed on a daily basis (78.9 %), the "liberal period" group received their DAA/OAT mostly once weekly (45.0 %) or 2-3x/week (24.1 %; p < 0.001). The number of missed DAA ingestions (0.3 % vs. 0.4 %; p = 0.239) and SVR12 rates by modified intention to treat analysis (exclusion of PWID who were lost to follow-up [FU] or died) were similar (401/404, 99.3 % vs. 194/195, 99.5 %; p = 1.000) between tight and liberal period, respectively.Loss of FU after end of DAA treatment was more common during the "liberal period" (28.8 % vs. 7.9 %; p < 0.001), yet no treatment interruptions or early discontinuations occurred. Conclusion:DOT originally aimed to address non-adherence among PWID by strict control through daily supervised OAT and DAA ingestion. While this approach inherently manifests a position of advanced distrust towards PWID, our findings suggest that a strategy of advanced trust and liberalization of DOT alongside effective harm reduction measures yields excellent adherence and results in similarly high HCV cure rates.

BACKGROUND & AIMS:Copeptin, an arginine-vasopressin biomarker, may confer prognostic information in patients with advanced chronic liver disease (ACLD). METHODS:Patients with ACLD included in the Vienna Cirrhosis Study (NCT03267615) between January 2017 and April 2023 and available copeptin levels were prospectively recruited and classified into 6 predefined clinical ACLD stages from S0 (subclinical portal hypertension) to S5 (further decompensation). A prognostic score (MELD-copeptin score) in patients with decompensated ACLD (dACLD) was developed in a derivation cohort (n = 150) and validated in an internal (n = 148) and an external validation cohort (n = 771). RESULTS:Among 475 patients with ACLD, 177 were compensated, whereas 298 were decompensated. Median levels of copeptin increased with progressive ACLD severity (S0, 7.5 pmol/L vs S5, 14.3 pmol/L; P < .001). Copeptin (adjusted Beta, 0.10; P < .001) was independently associated with interleukin-6 levels in dACLD. In dACLD, copeptin was linked to higher risk of further decompensation (adjusted subdistribution hazard ratio, 1.01; 95% confidence interval, 1.00-1.01; P = .039), acute-on-chronic liver failure (adjusted subdistribution hazard ratio, 1.01; 95% confidence interval, 1.01-1.02; P < .001), and liver-related death (adjusted subdistribution hazard ratio, 1.01; 95% confidence interval, 1.01-1.02; P < .001) independently of relevant cofactors. The MELD-copeptin score yielded higher area under the receiver operating characteristics (AUROCs) for liver-related events than the MELD-Na score in the internal validation cohort, accurately predicting liver-related death at 6 months (AUROC, 0.777 vs MELD-Na, 0.673), 1 year (AUROC, 0.784 vs MELD-Na, 0.661), and 2 years of follow-up (AUROC, 0.741 vs MELD-Na, 0.636). Similarly, the MELD-copeptin score consistently yielded higher AUROCS for the development of liver-related death and acute-on-chronic liver failure at 3, 6, and 12 months of follow-up in the external validation cohort. CONCLUSIONS:In patients with dACLD, copeptin is independently linked to systemic inflammation. The MELD-copeptin score identifies patients with dACLD at risk for impaired clinical outcomes.