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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.)

Objective: Chronic HBV infection (CHB) exhausts HBV-specific T cells, develops epigenetic imprints that impair immune responses, and limits the effectiveness of immune checkpoint inhibitor (ICI) monotherapy, such as αPD-L1. This study aimed to determine whether the DNA methyltransferase inhibitor decitabine (DAC) could reverse these epigenetic imprints and enhance ICI efficacy in restoring HBV-specific T cell responses., Methods: We investigated HBV-specific T cell responses by 10-day in vitro stimulation of peripheral blood mononuclear cells (PBMCs) from patients with CHB. PBMCs were stimulated with HBV core-specific overlapping peptide pools and HLA-A*02-restricted peptides, core18 and pol455. The immunomodulatory effect of the DAC/αPD-L1 combination was assessed by flow cytometry, and our analysis included clinical characteristics, ex vivo DNA methylation of PBMCs, and IFNγ plasma levels., Results: Treatment with DAC/αPD-L1 enhanced HBV-specific CD4+ T cell responses in a significant proportion of 53 patients, albeit with some variability. This effect was independent of the HBcrAg levels. Ex vivo DNA methylation revealed hypermethylation of key genes, such as IFNG among DAC-responders versus non-responders, supported by altered ex vivo IFNγ plasma levels. Further analysis of HBV-specific CD8+ T cell responses in 22 HLA-A*02-positive patients indicated distinct response patterns between core18 and pol455 stimulation, with pol455-specific CD8+ T cells showing increased susceptibility to DAC/αPD-L1, surpassing the αPD-L1 monotherapy response., Conclusions: The combination of DAC/αPD-L1 shows promise in improving HBV-specific T cell responses in vitro, highlighting the potential of remodeling exhaustion-associated epigenetic signatures to enhance HBV-specific T cell restoration and suggesting a novel immunotherapeutic avenue for CHB., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Pregenomic hepatitis B virus RNA (HBV pgRNA) is a potential biomarker in the management of HBV infected patients. However, prior to the use in routine clinical practice potential confounders of test results need to be identified. This study investigates the stability of HBV pgRNA under various storage conditions. HBV-RNA level of 26 HBV patients were determined using the Roche cobas® 6800/8800 investigational HBV-RNA assay. Plasma and serum were stored for 6,48,169 h at 4,25 and 42 °C, respectively. Additionally, 10 serum and plasma samples underwent 4 or 11 cycles of freezing (-80 °C) and thawing (25 °C). A significant decline in mean pgRNA concentration compared to baseline was observed after storage for 48 h at 25 °C as well as after 6 h of storage at 42 °C. Accordingly, sub-analyses of predefined pgRNA baseline concentrations (≤ 10 cp/mL, > 10-100 cp/ml, > 100 cp/mL) revealed significant changes in pgRNA level after storage at 25 and 42 °C. No effect of freezing and thawing on pgRNA level was observed. A qualitative detection of HBV pgRNA is feasible in samples with > 100 cp/mL up to 48 h under storage temperatures of 4-42 °C. For most stable quantitative HBV pgRNA values storage at 4 °C should be preferred., (© 2024. The Author(s).)

Chronic hepatitis C virus (HCV) infection can be associated with neuropsychiatric symptoms like fatigue and cognitive impairment, independent of the liver status. The present study aims to assess changes in the pattern and extent of neuropsychological symptoms after successful treatment with interferon (IFN)-based and IFN-free therapy. HCV-infected patients who underwent neuropsychological assessment in previous studies were invited to a follow-up examination. Patients were grouped according to the treatment status: Sustained virological response (SVR) after IFN treatment (IFN SVR, n = 14) or after therapy with direct acting antivirals (DAA SVR, n = 28) or ongoing HCV infection (HCV RNA+, n = 11). A group of 33 healthy controls served as reference. Patients completed self-report questionnaires addressing health-related quality of life (HRQoL), mood and sleep quality and a neuropsychological test battery including tests of memory and attention (Luria's list of words, PSE test, cancelling "d" test, Word-Figure-Memory Test and computer-based test battery for the assessment of attention [TAP]). At baseline, all three patient groups had worse fatigue, depression, anxiety and HRQoL scores compared to healthy controls. Longitudinal analysis revealed that fatigue and mood slightly improved in all patient groups over time, while HRQoL improved in SVR patients but not in HCV RNA+ patients. Memory test results improved significantly in all patient groups, irrespective of their virological status. In contrast, the attention test results showed no clear change from baseline to follow-up. Our data can be considered as a hint that HCV eradication-independent of therapy regimen-does not substantially ameliorate neuropsychiatric symptoms in HCV-afflicted patients., (© 2024 The Author(s). Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

International guidelines suggest cessation of nucleos(t)ide analogues (NA) independent of HBsAg loss in HBeAg-negative patients after 2-3 years of viral suppression. Detectable HBV-RNA levels at the time of NA cessation were linked to a better prediction of relapse after NA withdrawal in small cohorts of HBeAg-negative patients. This study proves the impact of HBV-RNA levels in the prediction of relapse in a large cohort of HBeAg-negative patients, mainly infected with genotype B or C. Serum levels of HBV-RNA, HBsAg, anti-HBc and HBcrAg were determined before NA withdrawal in 154 HBeAg-negative patients, participating either in a therapeutic vaccination trial (NCT02249988) or in an observational register trial (NCT03643172). Importantly, vaccination showed no impact on relapse. Endpoints of the study were virological relapse (HBV-DNA > 2000 IU/mL) or biochemical relapse (attendant ALT levels ≥ 2 × ULN) 24 weeks after NA cessation. Virological relapse occurred in 54.5% of patients (N = 84/154), including eight patients (10%) developing an ALT flare. Baseline HBV-RNA level did not differ significantly between relapsers and off-treatment responders (p = 0.92). No significant difference occurred in proportions of detectable HBV-RNA levels between off-treatment responders (N = 27/70; 38.6%) and relapsers (N = 31/84; 36.9%) (p = 0.99). Combining predefined HBsAg cut-offs (100 IU/mL, p = 0.0013), anti-HBc cut-offs (325 IU/mL, p = 0.0117) or HBcrAg cut-offs (2 log U/mL, p = 0.66) with undetectable HBV-RNA (HBsAg, p = 0.0057; anti-HBc, p = 0.085; HBcrAg, p = 0.60) did not improve relapse prediction. The value of HBV-RNA levels at timepoint of NA cessation for the prediction of relapse is limited in HBeAg-negative patients. Trial Registration: ABX 203-002: NCT02249988; Terminator 2: NCT03643172., (© 2024 The Author(s). Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

Background and Aims: Chronic hepatitis D is the most debilitating form of viral hepatitis frequently progressing to cirrhosis and subsequent decompensation. However, the HDV entry inhibitor bulevirtide is only approved for antiviral treatment of patients with compensated disease. We aimed for the analysis of real-world data on the off-label use of bulevirtide in the setting of decompensated liver cirrhosis., Approach and Results: We conducted a retrospective study in patients with HDV with decompensated liver disease at German, Austrian, and Italian centers. We included 19 patients (47% male, mean age: 51 years) with liver cirrhosis Child-Pugh B. The median MELD score was 12 (range 9-17) at treatment initiation. The median observation period was 41 weeks. Virologic response was achieved in 74% and normal alanine aminotransferase was observed in 74%. The combined response was achieved by 42%. The most relevant adverse events included self-limited alanine aminotransferase flares, an asymptomatic increase in bile acids, and the need for liver transplantation. Despite bile acid increases, adverse events were considered unrelated. Clinical and laboratory improvement from Child-Pugh B to A occurred in 47% (n = 9/19). Improvements in the amount of ascites were observed in 58% of the patients initially presenting with ascites (n = 7/12)., Conclusions: This report on off-label bulevirtide treatment in patients with decompensated HDV cirrhosis shows similar virologic and biochemical response rates as observed in compensated liver disease. Significant improvements were observed in surrogates of hepatic function and portal hypertension. However, this improvement was not seen in all patients. Controlled trials are needed to confirm the safety and efficacy of bulevirtide in decompensated HDV cirrhosis., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Acute inflammation of the liver (hepatitis) can be triggered by at least five different hepatotropic viruses - hepatitis viruses A, B, C, D and E. Hepatitis viruses A and E are transmitted via contaminated food and smear infections, whereas hepatitis viruses B, C and D are transmitted through direct contact with blood and other body fluids when these penetrate the skin or mucous membranes. This article is intended to provide a brief overview of the different forms of acute viral hepatitis, diagnosis, course and treatment., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Following the advent of direct-acting antivirals (DAAs), hepatitis C virus (HCV) infection can be cured in almost all infected patients. This has led to a number of clinical questions regarding the optimal management of the millions of patients cured of HCV. This position statement provides specific guidance on the appropriate follow-up after a sustained virological response in patients without advanced fibrosis, those with compensated advanced chronic liver disease, and those with decompensated cirrhosis. Guidance on hepatocellular carcinoma risk assessment and the management of extrahepatic manifestations of HCV is also provided. Finally, guidance is provided on the monitoring and treatment of reinfection in at-risk patients. The recommendations are based on the best available evidence and are intended to help healthcare professionals involved in the management of patients after treatment for HCV., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: 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., Methods: 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., Results: 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., Conclusions: 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., Impact and Implications: 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., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Data on the prevalence and characteristics of so-called rare HCV genotypes (GTs) in larger cohorts is limited. This study investigates the frequency of rare GT and resistance-associated substitutions and the efficacy of retreatment in a European cohort., Methods: A total of 129 patients with rare GT1-6 were included from the European resistance database. NS3, NS5A, and NS5B were sequenced and clinical parameters and retreatment efficacies were collected retrospectively., Results: Overall 1.5% (69/4,656) of direct-acting antiviral (DAA)-naive and 4.4% (60/1,376) of DAA-failure patients were infected with rare GT. Although rare GTs were almost equally distributed throughout GT1-6 in DAA-naive patients, we detected mainly rare GT4 (47%, 28/60 GT4; of these n = 17, subtype 4r) and GT3 (25%, 15/60 GT3, of these n = 8, subtype 3b) among DAA-failures. A total of 62% (37/60) of DAA failures had not responded to first-generation regimes and the majority was infected with rare GT4 (57%, 21/37). In contrast, among patients with failure to pangenotypic DAA regimens (38%, 23/60), infections with rare GT3 were overrepresented (57%, 13/23). Although NS5A RASs were uncommon in rare GT2, GT5a, and GT6, we observed combined RASs in rare GT1, GT3, and GT4 at positions 28, 30, 31, which can be considered as inherent. DAA failures with completed follow-up of retreatment, achieved a high SVR rate (94%, 45/48 modified intention-to-treat analysis; 92%, 45/49 intention-to-treat). Three patients with GT4f, 4r, or 3b, respectively, had virological treatment failure., Conclusions: In this European cohort, rare HCV GT were uncommon. Accumulation of specific rare GT in DAA-failure patients suggests reduced antiviral activities of DAA regimens. The limited global availability of pangenotypic regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed., Impact and Implications: Data on the prevalence and characteristics of rare HCV genotypes (GT) in larger cohorts are still scarce. This study found low rates of rare HCV GTs among European HCV-infected patients. In direct-acting antiviral (DAA)-failure patients, rare GT3 subtypes accumulated after pangenotypic DAA treatment and rare GT4 after first generation DAA failure and viral resistance was detected at NS5A positions 28, 30, and 31. The limited global availability of pangenotypic DAA regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed., Competing Interests: JD: research support from Gilead. CG: speaking and/or consulting fees from AbbVie and travel support from AbbVie and Gilead. CPB: speaking and/or consulting fees: AbbVie, BMS, Gilead, Merck/MSD. KP: no conflicts to disclose. KD: speaking and/or consulting fees: Gilead, AbbVie, Alnylam. PB: speaking and/or consulting fees: AbbVie, BMS, Falk, Gilead, Janssen, Merz Pharma, Merck/MSD. K-HP: no conflicts to disclose. JV: speaking and/or consulting fees from Abbott, AbbVie, Bristol-Myers, Squibb, Gilead, Medtronic, Merck/MSD and Roche. GD: speaking and/or consulting fees from Abbvie, Gilead. AG: advisor and steering committee member for AbbVie, Advanz, Albireo, Alexion, Astra Zeneca, Bayer, BMS, CSL Behring, Eisai, Gilead, Heel, Intercept, Ipsen, Merz, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis and as speaker for AbbVie, Advanz, Alexion, BMS, Burgerstein, CSL Behring, Falk, Gilead, Intercept, Merz, MSD, Novartis, NovoNordisk, Roche; research support from Intercept and Falk (NAFLD CSG), Novartis. FPR: honoraria for lectures, consulting activities and travel support from the Falk Foundation, AbbVie, Gilead, Ipsen, Astra Zeneca, Roche and Novartis. TB: speaking and/or consulting fees or travel support from Abbvie, Gilead, SOBI, CSL Behring, Merck, Gore, Advanz. JMS: consultant: Akero, Alentis Therapeutics, Astra Zeneca, Apollo Endosurgery, 89Bio, Boehringer Ingelheim, GSK, Ipsen, Inventiva Pharma, Madrigal, MSD, Northsea Therapeutics, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, Siemens Healthineers. Research Funding: Boehringer Ingelheim, Siemens Healthcare GmbH. Stock Options: AGED diagnostics, Hepta Bio. Speaker Honorarium: Gilead Sciences, Advanz, Echosens, MedPublico GmbH. ED: speaking fees: Abbvie, Gilead. TG: advisory board for GoLiver Therapeutics. CM: speaking and/or consulting fees from Abbvie, Gilead, MSD, Intercept. Research support: Abbvie, Gilead, MSD, Intercept. JT: speaking and/or consulting fees from Abbvie, Gilead, Viiv. TD: Speaking and/or consulting fees: Abbvie, BMS, Gilead, MSD, Roche. JF: no conflicts to disclose. TB: Speaking and/or consulting fees: AbbVie, Alexion, Bayer, Boehringer Ingelheim, BMS, Gilead, GSK, Intercept, Janssen, MSD/Merck, Merz, Novartis, Sequana Medical and Roche. Research support: AbbVie, Roche, BMS, Gilead, Novartis, Merck/MSD, Intercept, Janssen, Novartis, Sequana Medical, and Pfizer. AEK: speaking and/or consulting fees: Abbvie, Advanz, Alentis, AlphaSigma, AOP Orphan, AstraZenca, Avior, Bayer, BMS, CMS, CymaBay, Eisai, Escient, Falk, Gilead, GSK, Guidepoint, Intercept, Ipsen, Lilly, Medscape, Mirum, MSD, Myr, Novartis, Roche, Takeda, Viofor, Zambon. Research support: Intercept, Gilead. BM: speaking and/or consulting fees: Merck/MSD, AbbVie, Intercept, Astra, Bayer, BMS, Gilead. Research support: Gilead. SZ: consultancy and/or speaker's bureau: Abbvie, BioMarin, Boehringer Ingelheim, Gilead, GSK, Ipsen, Madrigal, MSD/Merck, NovoNordisk, and SoBi. CS: speaking and/or consulting fees: AbbVie, Gilead, Merck/MSD. Research support: AbbVie, Gilead., (© 2024 The Authors.)

Background: Noninvasive tests (NITs) have been proposed as an alternative to liver biopsy for diagnosing liver cirrhosis. The evidence of NIT performance in patients with chronic hepatitis D (CHD) is limited., Aims: To evaluate the diagnostic performance of liver stiffness measurement (LSM) and other NITs in CHD patients., Methods: We evaluated the diagnostic performance of LSM by transient elastography for the detection of liver cirrhosis in a retrospective, multicentre cohort of 144 CHD patients with paired (±6 months) LSM and liver biopsies., Results: Cirrhosis was diagnosed histologically in 22 patients (15.3%). Mean LSM was significantly higher in patients with cirrhosis compared to those without fibrosis (23.4 vs 10.2 kPa, p < 0.0001) or with intermediate fibrosis (23.4 vs 13.5 kPa, p < 0.0001). In the detection of liver cirrhosis, LSM was superior to other NITs (AUROCs: 0.89 [LSM], 0.87 [D4FS], 0.74 [APRI], 0.73 [FIB-4], and 0.69 [AAR]). The optimal cut-off for identifying patients with liver cirrhosis was ≥15.2 kPa (Se 91%, Sp 84%, PPV 50%, NPV 98%). The ideal cut-off for diagnosing non-advanced liver fibrosis (Metavir ≤2) was <10.2 kPa (Se 55%, Sp 86%, PPV 90%, NPV 45%), correctly identifying 90% of patients. Data were validated in an independent cohort of 132 CHD patients., Conclusions: LSM is a useful tool for identifying patients at risk for liver cirrhosis and is superior to other NITs. The cut-offs of <10.2 and < 15.2 kPa reliably diagnose non-advanced liver fibrosis and exclude cirrhosis in the majority of patients. However, LSM cannot completely replace liver biopsy in CHD patients., (© 2024 John Wiley & Sons Ltd.)

Competing Interests: The overview of the authors’ conflicts of interest is published in the appendix of the guideline report.

Competing Interests: Die Übersicht über die Interessenkonflikte der Autorinnen und Autoren ist im Anhang des Leitlinienreports veröffentlicht.

Background and Aims: Hepatitis D virus (HDV) infection causes the most severe form of chronic viral hepatitis. However, it is still unclear to what extent the underlying cirrhosis may contribute to disease progression. The aim of this study was to compare the long-term outcome of HDV infection with HBV monoinfection in a single-center cohort of both non-cirrhotic and cirrhotic patients., Method: We retrospectively studied 175 patients with chronic hepatitis D (CHD) who were followed for at least 6 months (median of 6.3 (0.6-23.6) years). In addition, we selected 175 patients with HBV monoinfection (CHB) who were matched for gender, age, region of origin, HBeAg status, and bilirubin. Liver-related clinical end points were defined as hepatic decompensation (ascites, encephalopathy, variceal bleeding), liver transplantation, HCC, or liver-related death., Results: Clinical complications developed earlier (4.6 vs. 6.2 years) and more frequently (35.4% vs. 12.6%, p < 0.01) in CHD patients. In a multivariate Cox regression, HDV infection was independently associated with the development of end points (p < 0.01; HR: 3.0; 95% CI 1.4-6.4). However, in cirrhotic patients there were no significant differences between HBV and HDV in the development of end points. Besides, CHB patients with cirrhosis developed more frequently HCC (35.5%) than CHD patients with cirrhosis (18.5%)., Conclusion: Our results confirmed that HDV leads to a faster progression to cirrhosis compared to HBV. However, once cirrhosis is present, not HDV but the underlying cirrhosis is the dominate intrinsic risk factor for the development of liver-related end points and for the progression to HCC., (© 2023. The Author(s).)

Background & Aims: Infection with the hepatitis D virus (HDV) causes the most severe form of viral hepatitis with a high risk to develop clinical complications of liver disease. In addition, hepatitis delta has been shown to be associated with worse patient-reported outcomes. Until recently, only pegylated interferon alfa could be used to treat hepatitis delta., Methods: Here, we investigated quality of life (QOL) as assessed by the Short Form 36 Health Survey (SF-36) in patients undergoing antiviral therapy with pegylated interferon alfa (PEG-IFNa-2a)-based treatment in the HIDIT-II trial. HIDIT-II was a randomized prospective trial exploring PEG-IFNa-2a with tenofovir disoproxil (TDF) or placebo for 96 weeks in patients with compensated hepatitis delta. Surveys completed by 83 study participants before, during, and after treatments were available., Results: Overall, we observed a reduced QOL of HDV patients compared with a reference population, both in physical as well as mental scores. Interestingly, PEG-IFNa-2a treatment showed only minor impairment of the QOL during therapy. Moreover, HDV-RNA clearance was not associated with relevant changes in physical or social SF-36 scores, whereas an improvement of fibrosis during treatment was associated with increased QOL. Overall, slight improvements of the QOL scores were observed 24 weeks after the end of treatment as compared with baseline. TDF co-treatment had no influence on QOL., Conclusions: Overall, our findings suggest that PEG-IFNa-2a was reasonably tolerated even over a period of 96 weeks by hepatitis D patients reporting SF-36 questionnaires. Of note, several patients may benefit from PEG-IFNa-2a-based therapies with off-treatment improvements in quality of life., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Bulevirtide (BLV) is an entry inhibitor blocking entry of HBsAg into hepatocytes by interfering with the bile acid transporter Na+-taurocholate co-transporting polypeptide. We here investigated if bile acid levels before or during BLV treatment would correlate with HDV RNA declines. We studied 20 patients with compensated HDV infection receiving a daily dose of 2 mg bulevirtide subcutaneously qd for at least 24 weeks. ALT levels improved in all patients including 13/20 patients showing normal ALT values at treatment Week 24. An HDV RNA drop of at least 50% was evident in 20/20 patients at Week 24 including 10 patients showing a ≥ 2 log HDV RNA decline. Elevated bile acid levels were detected already before treatment in 10 patients and further increased during BLV administration with different kinetics. Baseline bile acids were associated with higher transient elastography values (p = .0029) and evidence of portal hypertension (p = .0004). Bile acid levels before treatment were associated with HDV RNA declines throughout therapy, but not at Week 24 (rho = -0.577; p = .0078; rho = -0.635, p = .0026; rho = -0.577, p = .0077; rho = -0.519, p = .0191; rho = -0.564, p = .0119 and rho = -0.393, p = .087 at treatment Weeks 2, 8, 12, 16, 20 and 24, respectively). However, bile acid increases during treatment were not associated with HDV RNA or ALT declines at any of the time points. BLV-induced increases in bile salts do not correlate with HDV RNA declines suggesting that the inhibitory effects of BLV on NTCP differ between blocking bile acid transport and hindering HBsAg entry. If baseline bile salt levels could be useful to predict virological response remains to be confirmed., (© 2023 The Authors. Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

The entry inhibitor bulevirtide (BLV) is a new treatment option for patients with chronic hepatitis D virus (HDV) infection and compensated liver disease. The aim of this study was to investigate the kinetic and predictive value of markers reflecting HBV cccDNA transcriptional activity and host immune response activity during BLV treatment in a real-life cohort of HDV infected patients. Levels of HDV RNA, HBV RNA, hepatitis B core related antigen (HBcrAg) and hepatitis B core antibodies (anti-HBc) were measured in 16 patients before (BL), after three (3M) and six (6M) months of treatment with BLV. All patients received nucleos(t)ide analogue treatment. HDV RNA declined in all patients during treatment. 38% (6/16) showed ≥ 2 log HDV RNA decline from BL to 6M and 11 patients (69%) normalized ALT levels. HBV RNA levels were low and only detectable in two to four patients. HBcrAg levels declined in 75% (12/16) of patients. Median HBcrAg levels declined significantly from BL to 6M (3.75 logU/ml (IQR 2.93-4.78) vs. 3.4 logU/ml (IQR 2-4.68), p=0.002). A similar trend was shown for anti-HBc between BL and 6M. Levels of HBcrAg or anti-HBc did not differ significantly between patients with or without ≥ 2 log HDV RNA decline from BL to 6M.After 6 months treatment with BLV, levels of HBcrAg showed a significant decline, while HBV RNA and anti-HBc levels did not change. Reduction of HBV cccDNA transcriptional activity and immunological effects of antiviral treatment might explain these changes., (© 2023 The Authors. Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

Background & Aims: Bulevirtide is a first-in-class entry inhibitor of hepatitis B surface antigen. In July 2020, bulevirtide was conditionally approved for the treatment of hepatitis D, the most severe form of viral hepatitis, which frequently causes end-stage liver disease and hepatocellular carcinoma. Herein, we report the first data from a large multicenter real-world cohort of patients with hepatitis D treated with bulevirtide at a daily dose of 2 mg without additional interferon., Methods: In a joint effort with 16 hepatological centers, we collected anonymized retrospective data from patients treated with bulevirtide for chronic hepatitis D., Results: Our analysis is based on data from 114 patients, including 59 (52%) with cirrhosis, receiving a total of 4,289 weeks of bulevirtide treatment. A virologic response defined as an HDV RNA decline of at least 2 log or undetectable HDV RNA was observed in 87/114 (76%) cases with a mean time to virologic response of 23 weeks. In 11 cases, a virologic breakthrough (>1 log-increase in HDV RNA after virologic response) was observed. After 24 weeks of treatment, 19/33 patients (58%) had a virologic response, while three patients (9%) did not achieve a 1 log HDV RNA decline. No patient lost hepatitis B surface antigen. Alanine aminotransferase levels improved even in patients not achieving a virologic response, including five patients who had decompensated cirrhosis at the start of treatment. Treatment was well tolerated and there were no reports of drug-related serious adverse events., Conclusions: In conclusion, we confirm the safety and efficacy of bulevirtide monotherapy in a large real-world cohort of patients with hepatitis D treated in Germany. Future studies need to explore the long-term benefits and optimal duration of bulevirtide treatment., Impact and Implications: Clinical trials proved the efficacy of bulevirtide for chronic hepatitis D and led to conditional approval by the European Medical Agency. Now it is of great interest to investigate the effects of bulevirtide treatment in a real-world setting. In this work, we included data from 114 patients with chronic hepatitis D who were treated with bulevirtide at 16 German centers. A virologic response was seen in 87/114 cases. After 24 weeks of treatment, only a small proportion of patients did not respond to treatment. At the same time, signs of liver inflammation improved. This observation was independent from changes in hepatitis D viral load. The treatment was generally well tolerated. In the future, it will be of interest to investigate the long-term effects of this new treatment., Competing Interests: CD has received travel support from Gilead. FT has received grants or contracts from any entity from Allergan, BMS, Inventiva, Gilead; consulting fees from Allergan, Bayer, Gilead, BMS, Boehringer, Intercept, Ionis, Inventiva, Merz, Pfizer, Alnylam, NGM, CSL Behring, Novo Nordisk, Novartis; payment for expert testimony from Alnylam; support for attending meetings and/or travel from Gilead; participation on a Data Safety Monitoring Board or Advisory Board from Pfizer. CZ has no COI. MD has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Gilead and MYR, support for attending meetings and/or travel from Gilead; participation on a Data Safety Monitoring Board or Advisory Board from Gilead and MYR. HS has no COI. CS received support for attending meetings and/or travel from Abbvie and Gilead, participation on a Data Safety Monitoring Board or Advisory Board form Gilead. KW has no COI. CL has received consulting fees from CSL Behring, Boston Scientific, Astra Zeneca, Eisai, Shionogi, Sobi; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie, Gilead, Falk, BSL Behring, Eisai; support for attending meetings and/or travel from Gilead and Abbvie. SW received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events Falk and Abbvie; support for attending meetings and/or travel form Orphalan, Falk, Abbvie. GD received consulting fees from Alexion, Gilead, Intercept, Novartis, Orphalan, Univar; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbvie, Falk Foundation, Gilead, Intercept, Novartis, Orphalan; support for attending meetings and/or travel support form Gilead and Intercept. CB received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Gilead; and support for attending meetings and/or travel from Gilead. JG has no COI. UM received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from CSL Behring, MSD, Falk, Univar, Microbiotica; support for attending meetings and/or travel from Gilead; participation on a Data Safety Monitoring Board or Advisory Board from Takeda, Gilead, CSL Behring; AO has no COI; SZ reports speaker’s bureau and/or consultancy for Abbvie, BioMarin, Gilead, GSK, Intercept, Janssen, Madrigal, MSD/Merck, NovoNordisk, SoBi and Theratechnologies, GSK, Gilead, Intercept; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbvie, BioMarin, Janssen, MSD/Merck; payment for expert testimony and support for attending meetings and/or travel from Gilead. KS received grants from Gilead; honoraria for lectures from Gilead, Abbvie and MSD; support for attending meetings and/or travel from Gilead and Abbvie; participated in advisory boards from Gilead. TB received grants or contracts from any entity from Abbvie, BMS, Gilead, MSD/Merck, Humedics, Intercept, Merz, Novartis, Sequana Medical, received consulting fees from Abbvie, Alexion, Bayer, Gilead, Eisai, GSK, Intercept, Ipsen, Janssen, MSD/Merck, Novartis, Roche, Sequana Medical, and Shionogi; received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbvie, Alexion, Bayer, Gilead, Eisai, Intercept, Ipsen, Janssen, MedUpdate GmbH, MSD/Merck, Novartis, and Sequana Medica; has received support for attending meetings and/or travel Gilead, Abbvie, Intercept, Janssen. FB received grants or contracts from any entity from Gilead, Ipsen, Roche, Janssen; consulting fees from Gilead, Janssen, Astra Zeneca, MSD, Janssen, Advanz Pharma; support for attending meetings and/or travel from Advanz Pharma and Gilead, reports participation on a Data Safety Monitoring Board or Advisory Board from Janssen. JW has no COI. TH received author honoraria from Falk. TS has no COI. EZ has no COI. ND has no COI. RT has no COI. CNH received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbvie, Gilead, GSK, MSD, Falk Foundation. PG has no COI. MS participated in advisory boards from Gilead. AL received consulting fees from Roche, reports participation in advisory boards from Roche, MSD and Genfit. JSW received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events and travel support from Gilead. JK has no COI. AG received payment for expert testimony from AbbVie, Alexion, Bayer, BMS, Eisai, Gilead, Intercept, Ipsen, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis, Sequana. FR received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events and support for attending meetings and/or travel from Falk Foundation, Novartis, Ipsen and Gilead. BS received honoraria for lectures from Gilead and Alnylam, received consulting fees from Gilead and Univar, received travel support from Abbvie and Gilead. JG has no COI. WH received speakers honoraria from Gilead, Abbvie, Intercept, Norgine, Novo Nordisk, Falk; support for attending meetings and/or travel from Abbvie and Gilead. PB received consulting fees from Gilead; received payment for speakers bureau from AbbVie, Falk, Gilead, Roche, MSD, Myr; support for attending meetings and/or travel from Abbvie and Gilead. JK has no COI. KP has no COI. BM received grants or contracts from any entity from Roche Diagnostics and Fujirebio; consulting fees from Abbvie, Roche, Luvos; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbvie, Roche, Gilead, Norgine, Fujirebio, Merck/MSD, Medical Tribune Forum; support for attending meetings and/or travel from Abbvie and Gilead; holds stocks or stock options from Biontech. MC received consulting fees from Abbvie, AiCuris, Gilead, GlaxoSmithKline, Janssen-Cilag, MSD Sharp & Dohme, Spring Bank Pharmaceuticals, Swedish Orphan Biovitrum AB (SOBI); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbvie, Gilead, GlaxoSmithKline, MSD Sharp & Dohme, Falk; reports participation on a Data Safety Monitoring Board or Advisory Board from Novartis; HW received grants or contracts from any entity from AbbVie, Biotest, BMS, Gilead, Merck/MSD, Novartis, Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbott, AbbVie, Altimmune, Biotest, BMS, BTG, Dicerna, Gilead, Janssen, Merck/MSD, MYR GmbH, Novartis, Roche, Siemens. KD has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Gilead, Falk, Abbvie, MSD/Merck and Alnylam. Please refer to the accompanying ICMJE disclosure forms for further details., (.)

Background & Aims: EASL guidelines recommend 8 weeks of treatment with sofosbuvir plus velpatasvir (SOF/VEL) for the treatment of acute or recently acquired HCV infection, but only 6- and 12-week data are available. Therefore, the aim of this study was to evaluate the safety and efficacy of a shortened 8-week SOF/VEL treatment for acute HCV monoinfection., Methods: In this investigator-initiated, prospective, multicentre, single-arm study, we recruited 20 adult patients with acute HCV monoinfection from nine centers in Germany. Patients received SOF/VEL (400/100 mg) as a fixed-dose combination tablet once daily for 8 weeks. The primary efficacy endpoint was the proportion of patients with sustained virological response 12 weeks after the end of treatment (SVR12)., Results: The median HCV RNA viral load at baseline was 104,307 IU/ml; the distribution of HCV genotypes was as follows: GT1a/1b/2/3/4: n = 12/1/1/3/3. Thirteen (65%) of the 20 patients were taking medication for HIV pre-exposure prophylaxis. SVR12 was achieved in all patients who complied with the study protocol (n = 18/18 [100%], per protocol analysis), but the primary endpoint was not met in the intention-to-treat analysis (n = 18/20 [90%]) because two patients were lost to follow-up. One serious adverse event (unrelated to study drug) occurred during 12 weeks of post-treatment follow-up., Conclusions: The 8-week treatment with SOF/VEL was well tolerated and highly effective in all adherent patients with acute HCV monoinfection. Early treatment of hepatitis C might effectively prevent the spread of HCV in high-risk groups., Clinical Trial Number: NCT03818308., Impact and Implications: The HepNet acute HCV-V study (NCT03818308), an investigator-initiated, single-arm, multicenter pilot study, demonstrates the efficacy and safety of 8 weeks of daily treatment with the fixed-dose combination sofosbuvir/velpatasvir (400/100 mg) in patients with acute hepatitis C virus (HCV) infection. All patients who completed therapy and were followed-up achieved sustained virologic response. Thus, early treatment with SOF/VEL which might effectively prevent the spread of HCV in high-risk groups can be recommended for patients with acute HCV monoinfection., Competing Interests: The authors declare no conflict of interest concerning the content of this manuscript. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Author(s).)

Background: Treatment with direct-acting antivirals (DAAs) in patients with chronic hepatitis C infection leads to partial restoration of soluble inflammatory mediators (SIMs). In contrast, we hypothesized that early DAA treatment of acute hepatitis C virus (HCV) with DAAs may normalize most SIMs., Methods: In this study, we made use of a unique cohort of acute symptomatic hepatitis C patients who cleared HCV with a 6-week course of ledipasvir/sofosbuvir. Plasma samples were used for proximity extension assay measuring 92 proteins., Results: Profound SIM alterations were observed in acute HCV patients, with marked upregulation of interleukin (IL)-6 and CXCL-10, whereas certain mediators were downregulated (eg, monocyte chemoattractant protein-4, IL-7). During treatment and follow-up, the majority of SIMs decreased but not all normalized (eg, CDCP1, IL-18). Of note, SIMs that were downregulated before DAA treatment remained suppressed, whereas others that were initially unchanged declined to lower values during treatment and follow-up (eg, CD244)., Conclusions: Acute hepatitis C was associated with marked changes in the soluble inflammatory milieu compared with both chronic hepatitis patients and healthy controls. Whereas early DAA treatment partly normalized this altered signature, long-lasting imprints of HCV remained., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Standard treatment of hepatitis delta virus (HDV) infection remains pegylated-interferon alfa (peg-IFNα) in most centers, which is not only associated with rather low efficacy but several adverse events. Hepatitis B core-related antigen (HBcrAg) is linked to intrahepatic covalently closed circular DNA levels and has previously been suggested as response predictor in IFN-based treatment of hepatitis B virus (HBV) mono-infection. This study aimed to investigate the value of HBcrAg in the management of patients with HBV/HDV co-infection undergoing peg-IFNα treatment. The Hep-Net-International-Delta-Hepatitis-Intervention Trial-2 study included 120 patients co-infected with HBV/HDV. Patients were treated for 96 weeks with peg-IFNα and either tenofovir or placebo. Ninety-nine patients with HDV-RNA results 24 weeks after end of treatment (FU24) were included in this analysis, of whom 32 patients (32.3%) had undetectable HDV RNA at FU24. HBcrAg was measured at baseline, week 12, 24, 48, 96, and FU24. HBcrAg levels showed no significant correlation with HDV RNA but were significantly linked to treatment outcome. HBcrAg levels < 4.5 log IU/mL at baseline, week 24, and week 48 had high negative predictive value (NPV) for achieving undetectable HDV RNA at FU24 (81.8%, 87.1% and 95.0%, respectively). Similarly, HBcrAg levels at week 96 were significantly higher in patients with viral relapse until FU24 (3.0 vs. 3.63 log IU/mL; P = 0.0089). Baseline, week 24, and week 48 HBcrAg levels were also associated with the likelihood of achieving HBsAg level < 100 IU/mL at FU24 (HBcrAg < 3.0 log IU/mL: NPV 91.7%, 90.4% and 92.3%, respectively). Test statistics improved when combining HBcrAg with additional viral and clinical parameters. Conclusion: HBcrAg is linked to treatment response to peg-IFNα in patients with HBV/HDV co-infection and could be a promising marker to determine treatment futility., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Unconventional T cells (UTCs) are a heterogeneous group of T cells that typically exhibit rapid responses toward specific antigens from pathogens. Chronic hepatitis C virus (HCV) infection causes dysfunction of several subsets of UTCs. This altered phenotype and function of UTCs can persist over time even after direct-acting antiviral (DAA)-mediated clearance of chronic HCV. However, it is less clear if and how UTCs respond in acute, symptomatic HCV infection, a rare clinical condition, and if rapid DAA treatment of such patients reverses the caused perturbations within UTCs. Here, we comprehensively analyzed the phenotype and reinvigoration capacity of three major UTC populations, mucosal-associated invariant T (MAIT) cells, γδ T cells, and CD4 and CD8 double-negative αβ T cells (DNT cells) before, during, and after DAA-mediated clearance of acute symptomatic HCV infection. Furthermore, MAIT cell functionality was systematically studied. We observed a reduced frequency of MAIT cells. However, remaining cells presented with a near-to-normal phenotype in acute infection, which contrasted with a significant dysfunction upon stimulation that was not restored after viral clearance. Notably, DNT and γδ T cells displayed a strong activation ex-vivo in acute HCV infection, which subsequently normalized during the treatment. In addition, DNT cell activation was specifically associated with liver inflammation and inflammatory cytokines. Altogether, these data provide evidence that UTCs respond in a cell type-specific manner during symptomatic HCV infection. However, even if early treatment is initiated, long-lasting imprints within UTCs remain over time., (© 2021 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Even 30 years after the discovery of the hepatitis C virus (HCV) in humans there is still no vaccine available. Reasons for this include the high mutation rate of HCV, which allows the virus to escape immune recognition and the absence of an immunocompetent animal model for vaccine development. Phylogenetically distinct hepaciviruses (genus Hepacivirus , family Flaviviridae ) have been isolated from diverse species, each with a narrow host range: the equine hepacivirus (EqHV) is the closest known relative of HCV. In this study, we used amplicon-based deep-sequencing to investigate the viral intra-host population composition of the genomic regions encoding the surface glycoproteins E1 and E2. Patterns of E1E2 substitutional evolution were compared in longitudinally sampled EqHV-positive sera of naturally and experimentally infected horses and HCV-positive patients. Intra-host virus diversity was higher in chronically than in acutely infected horses, a pattern which was similar in the HCV-infected patients. However, overall glycoprotein variability was higher in HCV compared to EqHV. Additionally, selection pressure in HCV populations was higher, especially within the N-terminal region of E2, corresponding to the hypervariable region 1 (HVR1) in HCV. An alignment of glycoprotein sequences from diverse hepaciviruses identified the HVR1 as a unique characteristic of HCV: hepaciviruses from non-human species lack this region. Together, these data indicate that EqHV infection of horses could represent a powerful surrogate animal model to gain insights into hepaciviral evolution and HCVs HVR1-mediated immune evasion strategy., (© The Author(s) 2022. Published by Oxford University Press.)