German Liver Foundation

Patients, as central actors in healthcare, should be enabled to actively participate in health services research processes. In addition, other stakeholders, such as professionals from healthcare practice, are also essential for a comprehensive participatory approach. This DNVF memorandum focuses on participatory approaches in the context of health services research. It begins by outlining the key characteristics of participatory health services research and describing its current development and institutionalization in Germany. The DNVF memorandum also highlights the potential and benefits of participatory research. Finally, it addresses two cross-cutting topics that are particularly relevant for further development in this field: the theoretical and conceptual foundations, and the investigation of effects and effectiveness of participatory approaches.

ABSTRACTThe occurrence of ascites is a frequent complication associated with the decompensation of liver cirrhosis. While it is known that cirrhosis leads to altered immune responses in the periphery, the immunological milieu of ascites remains poorly understood. In this study, we investigate the role and origin of natural killer (NK) cells in cirrhosis‐associated ascites. Using high‐dimensional flow cytometry and cytokine analysis, we analyzed matched peripheral blood and ascites fluid alongside liver and duodenum samples to discern tissue‐specific differences. Interestingly, a subset of peritoneal NK cells displayed high expression of the tissue‐residency receptor CD103. This subset of CD103+ ascites NK cells was distinct from blood, liver, and intestinal NK cells and presented with a less activated phenotype coupled with reduced effector capacity. Investigating their origin, we could identify that cytokines present in ascites, here predominantly IL‐15 in synergy with IL‐21 and TGFβ, can induce CD103 expression and that ascites supernatant further facilitates this process. These results indicate that the ascites in patients with decompensated liver cirrhosis harbor a heterogenous subset of CD103+ NK cells that is likely induced by the cytokine milieu.

Direct-acting antiviral (DAA) regimens for the treatment of hepatitis C virus (HCV) infection are endowed with sustained virological response (SVR) rates >95%. However, HCV cure does not completely eliminate the risk of hepatocellular carcinoma (HCC) development and liver decompensation. The present study investigated the impact of the administered DAA regimen on clinical long-time outcomes after SVR.Matched-pair survival analyses of 5802 chronically HCV infected patients from the German Hepatitis C-Registry compared the incidence of liver-related events 2.5 years after SVR in patients receiving either sofosbuvir (SOF)-based treatment or NS3/NS4A-protease inhibitor (PI)-containing DAA regimens. Hypothesis driven logistic regression analyses were performed to identify independent predictors for the occurrence of liver-related events.Matched-pair survival analyses revealed a borderline significant difference in the incidence of liver-related endpoints (except of HCC development) in patients receiving SOF-based treatment (4.1%) compared to PI-containing DAA regimens (2.6%) 2.5 years after SVR (p=0.061). Numerically, a trend towards a benefit of PI-based DAA treatment was observed (PI 65 events vs SOF 102 events). Hypothesis driven logistic regression analyses could not confirm SOF-based treatment as an independent predictor for the occurrence of liver-related events after HCV cure (p=0.072, OR=0.670).The incidence of liver-related events 2.5 years after HCV cure did not differ significantly between SOF-based DAA treatment and PI-containing regimens. However, numerically a trend towards a benefit of PI-based DAA treatment was observed. Therefore, a minor effect of the applied DAA regimen on the long-term incidence of liver-related events cannot be excluded.

Abstract Background Orthotopic liver transplantation (OLT) in patients with inflammatory bowel disease (IBD) represents a special patient population with high heterogeneity. The management of IBD in liver transplant recipients is challenging due to the need to balance immunosuppressive therapy, IBD flares and graft survival. Therefore, detailed analysis of clinical parameters is essential to better understand outcomes and optimize management strategies in this unique cohort. Methods This monocentric, retrospective analysis included IBD patients with concomitant OLT at our tertiary referral center. We reviewed the local database for incident cases from January 2013 to December 2023. Identified patients have been evaluated based on demographic data, detailed IBD and OLT history, complications (including re-OLT), and overall survival. Results This study included 126 IBD patients with OLT, with a mean age of 37.3 years at transplantation and a mean age of 28.2 years at IBD diagnosis. The majority of patients were male (68.3%), and ulcerative colitis (UC) was the most common diagnosis (86.5%), followed by Crohn’s disease (CD) (11.9%). Among UC patients, 79.8% had extensive colitis (E3), while in CD patients, the distribution was 40% L1, 26.7% L2, and 33.3% L3. The most common indication for OLT in this cohort was PSC (74.6%), followed by PSC/AIH variants (13.5%). Before OLT, 42.1% of patients were treated with corticosteroids, while 56.8% continued steroid treatment after OLT. Aminosalicylates were prescribed to 69.2% of patients pre-OLT, but only 49.6% continued this treatment post-OLT. 90.4% of patients did not require advanced therapies after OLT, though biologics like vedolizumab and ustekinumab were used in a small subset. 27.2% of patients required re-OLT, with UC being the most prevalent IBD entity for re-transplantation (82.4%). Colectomy after OLT was performed in 12.7% of patients, and it was associated with a higher likelihood of re-OLT (p = 0.04; OR: 3.1; 95% CI: 1.06-9.1), while post-OLT 5-ASA therapy was associated with a reduced likelihood of re-OLT (p = 0.03; OR: 0.4; 95% CI: 0.17-0.9). Overall mortality post-OLT was 26.2%. A COX-Regression analysis further revealed significant associations with overall mortality and e. g. age at IBD diagnosis (p < 0.01; HR: 1.07; 95% CI: 1.04-1.11), male sex (p = 0.045; HR: 2.95; 95% CI: 1.02-8.52), steroid use post-OLT (p=0.04: HR: 2.6, CI: 1.06-6.43) and PSC (p=0.04: HR: 0.3, CI: 0.11-0.95). Conclusion To the best of our knowledge, this is the largest monocentric IBD OLT cohort. We identified 5-ASA and steroid therapy as modifiable risk factors for re-OLT and mortality in IBD patients after OLT. Further validation of these findings in a larger multicentric setting is recommended.

Chronic hepatitis delta represents a major global health burden. Clinical features of hepatitis D virus (HDV) infection vary largely between different regions worldwide. Treatment approaches are dependent on the approval status of distinct drugs and financial resources. The Hepatitis Delta International Network (HDIN) registry involves researchers from all continents (Wranke, Liver International 2018). We here report long-term follow-up data of 648 hepatitis D patients recruited by 14 centres in 11 countries. Liver-related clinical endpoints were defined as hepatic decompensation (ascites, encephalopathy and variceal bleeding), liver transplantation, hepatocellular carcinoma or liver-related death. Patient data were available from all continents but Africa: 22% from Eastern Mediterranean, 32% from Eastern Europe and Central Asia, 13% from Central and Southern Europe, 14% from South Asia (mainly Pakistan) and 19% from South America (mainly Brazil). The mean follow-up was 6.4 (.6-28) years. During follow-up, 195 patients (32%) developed a liver-related clinical event after 3.5 (±3.3) years. Liver cirrhosis at baseline and a detectable HDV RNA test during follow-up were associated with a worse clinical outcome in multivariate regression analysis while patients receiving interferon alfa-based therapies developed clinical endpoints less frequently. Patients from South Asia developed endpoints earlier and had the highest mortality. The HDIN registry confirms the severity of hepatitis D and provides further evidence for HDV viraemia as a main risk factor for disease progression. Hepatitis D seems to take a particularly severe course in patients born in Pakistan. There is an urgent need to extend access to antiviral therapies and to provide appropriate education about HDV infection.

In 2014, an analysis was conducted to evaluate the hepatitis C virus (HCV) epidemiology and disease burden in Germany. Since then, there have been considerable developments in HCV management such as the implementation of direct acting antivirals. The aim of this analysis was to assess the recent data available for Germany, establish an updated 2020 HCV prevalence and cascade of care and evaluate the impact of what-if scenarios on the future burden of disease using modelling analysis. A dynamic Markov model was used to forecast the HCV disease burden in Germany. Model inputs were retrieved through literature review, unpublished sources and expert input. Next, three "what-if" scenarios were developed to evaluate the status quo, COVID-19 pandemic, and steps needed to achieve the WHO targets for elimination. At the beginning of 2020, there were 189,000 (95% UI: 76,700-295,000) viremic infections in Germany, a decline of more than 85,000 viremic infections since 2012. Annual treatment starts went down since 2015. Compared with 2019, the COVID-19 pandemic resulted in a further 11% decline in 2020. If this continues for two years, it could result in 110 excess HCC cases and 200 excess liver related deaths by 2030. To achieve the WHO targets, 81,200 people need to be diagnosed, with 118,600 initiated on treatment by 2030. This could also avert 1,020 deaths and 720 HCC cases between 2021 and 2030. Germany has made strides towards HCV elimination, but more efforts are needed to achieve the WHO targets by 2030.

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.

Background and aims Prevention, diagnosis and linkage to care are key factors to reach the goal of HCV elimination especially in vulnerable patient groups. A full course of direct acting antivirals (DAA) leads to HCV-cure in more than 90 % of patients chronically infected. Simplifying all aspects associated with DAA treatment may facilitate access in particular for vulnerable patient groups. To characterise patients who went lost-to-follow-up (LTFU) before end of treatment (EOT) might help to identify those in need for alternative access strategies to DAA therapy.

The number of patients diagnosed with hepatitis C virus (HCV) is markedly higher than the number initiating treatment indicating gaps in the care cascade, likely centred around reaching at-risk populations. Understanding changing characteristics of patients with HCV allows for targeted programs that increase linkage to care. We investigated changes in demographic and clinical characteristics of patients registered in the German Hepatitis C-Registry (DHC-R) from 1January 2014 to 31 December 2019. The DHC-R is an ongoing, noninterventional, multicentre, prospective, observational cohort registry including 327 German centres. Patient characteristics were analysed over time in 7 phases for all patients completing a screening visit. Overall, 14,357 patients were enrolled. The percentage of treatment-naïve/non-cirrhotic patients increased from 34.4% in phase 1 (1January-31 December 2014) to 68.2% in phase 7 (1 August-31 December 2019). The proportion of migrants, alcohol users, people who inject drugs, and those receiving opiate substitution therapy increased in later registry phases. Most patients (60.1%) were receiving comedication at baseline. The most prescribed comedications were drugs used to treat opioid dependence which increased from 9.2% in phase 1 to 24.0% in phase 7. The patients' mean age decreased from 52.3years in phase 1 to 48.7years in phase 7. From 2014 to 2019, the proportion of at-risk patients enrolling in the registry increased. To eliminate viral hepatitis as a major public health threat, a continued commitment to engaging underserved populations into the HCV care cascade is needed.

We investigated the health-related quality of life (HRQoL) of patients with gastrointestinal stromal tumours (GIST). In the multicentre PROSa study, the HRQoL of adult GIST patients was assessed between 2017 and 2019 using the European Organisation for Research and Treatment of Cancer HRQoL questionnaire (EORTC QLQ-C30). We performed group comparisons and multivariate linear regressions. Among 130 patients from 13 centres, the mean global HRQoL was 63.3 out of 100 points. Higher sores indicate better HRQoL. The highest restrictions were in emotional, social, role functioning, insomnia, fatigue, and pain. In multivariate linear regression, we found no significant differences between patients receiving tyrosine kinase inhibitor (TKI) treatment and those without TKI treatment as well as between patients treated with curative or with palliative intent. Patients who received multiple lines of TKI treatment had the most restrictions, notably in physical (unstandardized regression coefficient [B] = -15.7), role (B = -25.7), social (B = -18.4), and cognitive functioning (B = -19.7); fatigue (B = 15.93); general health (B = -14.23); and EORTC-sum score (B = -13.82) compared to all other patients. The highest HRQoL restrictions were in GIST patients receiving multiple lines of TKI therapy. Underlying causes need further investigation.