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Background and Aims: Chronic hepatitis D virus (HDV) infection can cause severe liver disease. With new treatment options available, it is important to identify patients at risk for liver-related complications. We aimed to investigate kinetics and predictive values of novel virological and immunological markers in the natural course of chronic HDV infection., Methods: HBcrAg, HBV RNA and quantitative anti-HBc were analysed in samples from HDV-infected patients at three consecutive time points. Results were linked to clinical outcome by univariable and multivariable analyses. Primary endpoint was the composite endpoint of any liver-related event., Results: Samples from 190 individual patients were analysed with a median clinical follow-up time of 2.69 (IQR 1.13-6.51) years. The majority of patients had cirrhosis (98/190, 52%), and the primary endpoint occurred in 33% (62/190). In univariable analysis, age, cirrhosis, lower quantitative anti-HBc, higher ratio of HBcrAg/anti-HBc and detectable HDV RNA were associated with the primary endpoint. In multivariable analysis, only the presence of liver cirrhosis (HR 7.74, p < 0.001) and age (1.06, p < 0.001) remained independently associated with the primary endpoint. Kinetics of virological parameters during follow-up were similar between the groups. Quantitative anti-HBc was significantly lower in patients with liver cirrhosis (687 (IQR 188-3388) IU/ml vs. 309 (IQR 82-924) IU/ml, p < 0.0004), and lower levels were independently associated with the development of the primary endpoint (HR 1.0, p = 0.014)., Conclusion: In chronic HDV infection, neither baseline values nor kinetics of HBV RNA, HBcrAg and anti-HBc were independently associated with clinical outcome, while stage of liver disease and age were predictors of liver-related events., (© 2025 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Background Aims: Bulevirtide (BLV) is a novel and the only approved treatment option for patients with chronic hepatitis D (CHD). BLV alleviates liver inflammation already early during treatment when only minor HDV RNA changes are observed. We hypothesized that BLV-treatment may influence immune cells in CHD patients and performed a high-resolution analysis of natural killer (NK) cells before and during BLV-therapy., Methods: BLV-treated CHD patients (n=20) from a single-center cohort were longitudinally analyzed for clinical, molecular, and virological parameters. Peripheral blood mononuclear cells (PBMCs) were studied at baseline (BL), therapy weeks 3 (TW3) and 48 (TW48) by spectral flow cytometry. Healthy donors (HD), chronic hepatitis C (CHC) patients after direct-acting antivirals (DAA)-treatment and patients with chronic hepatitis B (CHB) were used as controls., Results: Overall NK cell frequencies remained stable during BLV-treatment. However, biochemical responders (BR) showed distinct NK cell immunophenotypic features before and during therapy. TIGIT-expression increased on CD56dim and CD56bright NK cells during the course of BLV-treatment and inversely correlated with alanine aminotransferase (ALT) levels in CHD but not CHC or CHB patients. High frequencies of TIGIT- CD57+ CD56dim NK cells at BL and low levels during therapy were indicative of a biochemical response., Conclusions: We here suggest that lacking the expression of the immune checkpoint inhibitor TIGIT on NK cell subtypes may be a hallmark of liver inflammation in HDV infection. BLV-therapy is associated with a reappearance of TIGIT on these cells, which may be one mechanism of why liver enzymes rapidly improve during therapy., (Copyright © 2025 American Association for the Study of Liver Diseases.)