Non-invasive tests (NITs) for clinically significant portal hypertension (CSPH) require validation in patients with hepatitis D virus (HDV)-related compensated advanced chronic liver disease (cACLD). Therefore, we aimed to validate existing NIT algorithms for CSPH in this context. Patients with HDV-cACLD (LSM ≥10 kPa or histological METAVIR F3/F4 fibrosis) who underwent paired HVPG and NIT assessment at Medical University of Vienna or Hannover Medical School between 2013 and 2023 were retrospectively included. Liver stiffness measurement (LSM), von Willebrand factor to platelet count ratio (VITRO), and spleen stiffness measurement (SSM) were assessed. Individual CSPH risk was calculated according to previously published models (ANTICIPATE, 3P/5P). The diagnostic performance of Baveno VII criteria and refined algorithms (Baveno VII-VITRO, Baveno VII-SSM) was evaluated. The prognostic utility of NITs was investigated in the main cohort and an independent, multicenter, validation cohort. Fifty-one patients (HVPG ≥10 mmHg/CSPH prevalence: 62.7%, varices: 42.2%) were included. Patients with CSPH had significantly higher LSM (25.8 [17.2-31.0] vs. 14.0 [10.5-19.8] kPa; p <0.001), VITRO (n = 31, 3.5 [2.7-4.5] vs. 1.3 [0.6-2.0] %/[G/L]; p <0.001), and SSM (n = 20, 53.8 [41.7-75.5] vs. 24.0 [17.0-33.9] kPa; p <0.001). Composite CSPH risk models yielded excellent AUROCs (ANTICIPATE: 0.885, 3P: 0.903, 5P: 0.912). Baveno VII criteria ruled out CSPH with 100% sensitivity and ruled in CSPH with 84.2% specificity. The Baveno VII 'grey zone' (41.1%) was significantly reduced by Baveno VII-VITRO or Baveno VII-SSM algorithms, which maintained diagnostic accuracy. Hepatic decompensation within 2 years only occurred in patients who had CSPH or met Baveno VII rule-in criteria. The prognostic value of NITs was confirmed in the validation cohort comprising 92 patients. Standalone and composite NIT/diagnostic algorithms are useful for CSPH diagnosis in patients with HDV-cACLD. Thus, NITs may be applied to identify and prioritize patients with CSPH for novel antiviral treatments against chronic hepatitis D. Non-invasive tests (NITs) for clinically significant portal hypertension (CSPH) have been developed to identify patients with compensated advanced chronic liver disease (cACLD) at risk of decompensation, but conflicting data has been published regarding the accuracy of liver stiffness measurement (LSM) for the staging of fibrosis in patients infected with hepatitis D virus (HDV). In our study, including 51 patients with HDV-cACLD, LSM- and lab-based NITs yielded high AUROCs for CSPH. Moreover, only patients with CSPH or high non-invasively assessed CSPH risk were at risk of decompensation within 2 years, with the prognostic value of NITs confirmed in a validation cohort. Thus, NITs should be applied and updated in yearly intervals in clinical routine to identify patients with HDV-cACLD at short-term risk of clinical events; NITs may also guide prioritization for novel antiviral treatment options.

Background & Aims: Clinically-significant portal hypertension (CSPH) in liver cirrhosis patients can lead to refractory ascites. A transjugular-intrahepatic-portosystemic shunt (TIPS) treats CSPH but may cause overt hepatic encephalopathy (oHE). Our aim was to determine the optimal reduction of the portal pressure gradient (PPG) via TIPS to control ascites without raising oHE risk. Approach: This multicenter study screened 1509 patients from three European centers (Hannover, Vienna, Hamburg) undergoing TIPS-implantation between 2000-2023. Patients with TIPS-indications other than refractory ascites/hepatic hydrothorax, vascular-liver-disease, hepatocellular-carcinoma or insufficient PPG data were excluded. PPG was measured before and after TIPS insertion. Outcome data was assessed up to one year after TIPS-insertion. Analyses were conducted utilizing a modern machine leaning model, namely a competing-risk (CR) random survival forest (RSF), partial-dependence-plots (PDP) and CR-analyses with liver transplantation/death as competitors. The cohort was divided into a 60% derivation and 40% validation cohort. Results: Overall, 729 patients (median MELD: 13 (IQR 10-16), 66% male, 23% oHE before TIPS) were analyzed. The derivation cohort comprised 438 and validation cohort 291 patients. The optimal PPG reduction, determined by maximally selected Grays-statistic and PDP of the RSF, was 60-80%. In this range, patients showed significantly fewer hepatic decompensations due to ascites (HDA) (sHR: 0.7 [0.52-0.96]) with similar oHE incidences (sHR: 0.92 [0.67-1.27]). The PPG range was confirmed in the validation cohort (HDA: sHR: 0.66 [0.46-0.96]; oHE: sHR: 0.89 [0.61-1.32]). Conclusions: A targeted PPG reduction of 60-80% showed significantly reduced HDA without increased oHE risk. Therefore, PPG reduction within this range could be a valid reduction target. Export