D-SOLVE

The three key clinical questions in the management of hepatitis D which will be addressed by D-SOLVE are as follows:

1. Viral control: It is completely unknown why some patients are able to control HDV infection with very low levels of HDV replication or even undetectable HDV RNA while others present with very high HDV viremia with HDV RNA levels above 10 million IU/ml. The percentage of HDV RNA negativity among anti-HDV positive patients ranges between 20-50%. Distinct factors being associated with viral control are largely undefined. Determining biomarkers indicating individual risks of viral flares and relapses is an urgent medical need for the daily management of hepatitis D patients.
2. Disease progression: Chronic viral hepatitis leads to inflammation with subsequent development of liver fibrosis which can lead to liver cirrhosis. However, for all viral hepatitis infections it has been shown that fibrosis progression may take several years and sometimes even decades. Again, the factors that distinguish between benign and aggressive disease progression are largely unknown, especially in the early stages of infection. A deeper understanding of mechanisms that explain and predict the different outcomes would be highly desirable for the clinical management of hepatitis D patients. Optimal surveillance intervals and monitoring tools are not defined and could be based on new biomarkers. In addition, the decision to initiate potentially side-effect-prone and costly antiviral treatment approaches could be individualized based on clear individual risk profiles for long- term complications of liver disease.

3. Antiviral treatment response: Pegylated interferon alfa (PEG-IFNa) has been used (off-label) to treat HDV infection for almost two decades. However, PEG-IFNa treatment is associated with frequent and sometimes severe side effects and can lead to severe hepatitis flares in patients with HDV-associated autoimmune hepatitis, a particular common and sometimes serious feature of HDV infection. Moreover, reliable factors predicting response to PEG-IFNa treatment are not defined. Thus, there is an urgent need for personalized risk stratification which patients have realistic chance to benefit from PEG-IFNa therapy. In summer 2020, EMA granted a conditional approval for the treatment of hepatitis D to bulevirtide, a novel HBV/HDV entry inhibitor targeting the bile acid transporter NTCP, based on promising results from pivotal phase 2 studies. Bulevirtide, a peptide that requires daily s.c. injections, leads to a decline in HDV RNA levels and improvement of biochemical disease activity in the majority of patients without causing major systemic side effects. However, and importantly, several key questions how to use bulevirtide are completely unclear. E.g., once the entry inhibitor has been started, the optimal duration of treatment is undefined. While some patients may require life-long maintenance treatment, there is evidence that many patients may achieve immune control once the drug is stopped. There is concern, however, that severe relapses can lead to potentially life-threatening hepatitis flares if treatment is stopped too early. Therefore, biomarkers are needed to determine factors predicting long-term control of HDV after discontinuation of bulevirtide. 

D-SOLVE will address these three key clinical questions across four translational research work- packages. We will investigate virological features of HDV infection, apply a broad and unbiased biomarker screening approach, study distinct innate and adaptive immune responses in the peripheral blood and the liver of HDV infected patients, and explore effects of identified molecules in mouse models – which could also lead to novel antiviral strategies.

In undertaking a highly challenging project as the present one, we planned a work schedule over a 48- month project period. This will ensure a maximum likelihood of success, eliminates or mitigates the risks inherent in reach of this nature, allowing continuous progress monitoring and review throughout the project lifecycle.

Interdependencies between the right research and development WPs will be ensured. To achieve the specific WP objective(s), the work plan activities are organized into eight Work Packages (WPs), each consisting of a number of associated tasks that collectively ensures the achievements of the project objectives. Progress against program, budget, and the obtained results will be monitored on a regular basis by the Project Steering Committee (PSC). Should it occur that any WP is late with respect to the programmed timing by more than one month, the Project Coordinator will bring it to the attention of the PSC, and a plan will be agreed and implemented to recover the delay.

In working towards personalized treatment of chronic hepatitis delta, the foundation of this project are large world-unique clinical cohorts (WP1) that will be utilized in upcoming WPs (2, 3, 4, and 5) in answering three key clinical questions on individual determinants of i) fibrosis progression, ii) HDV replication control, and iii) response to treatment. The project coordinator will produce the major periodic reports and minutes of progress meetings will give an update of the project progress at 6 monthly intervals during the program.

WP1 (Clinical cohorts) is the first work package starting at month 1 and lasting throughout the 48 months project period. This work package will lay the foundation for WPs 2 to 5 and in assessing the specific scientific questions on i) control of HDV replication, ii) individual determinants of fibrosis progression, and iii) treatment response. Three subprojects will be established with the first collecting in a cross-sectional approach 750 patients reflecting the entire spectrum HDV infection in Europe, the second consisting of a retrospective-prospective cohort of patients with liver biopsies taken 10-20 years ago to allow the investigation of intrahepatic immune correlates with disease progression and the third will be a prospective trial of patients being treated with the novel entry inhibitors bulevirtide.

WP2 (Clinical virology: testing for novel virological markers; HDV & HBV sequencing) starts at month 1 and lasts up to month 36. This work package will be essential to perform a comprehensive virological characterization of these patients who are infected with two viruses HBV and HDV. As local diagnostics in particular for HDV but also for novel HBV markers have not been fully standardized, central testing with optimized methodology will be required. In addition, WP2 will perform an in-depth viral sequencing of both HBV and HDV which will be crucial to determine immune pressure on the virus and to dissect host-viral interactions.

WP3 (Biomarker screening) starts at month 1 with retrospective samples (cohorts B and D) and will then continue with the other cohorts during the entire funding period until month 48. This work package will be the core project to identify novel biomarkers for the three key clinical challenges to be addressed in D-SOLVE. KI and HZI/CiiM will perform the respective screening in collaboration with MHH and INSERM.

WP4 (Innate and adaptive immunity) starts at month 1 and lasts up to month 48. This work package led by KI and MHH will explore mechanisms of biomarkers identified in WP3 but also focus on hypothesis-driven questions, in particular investigating intrahepatic immune innate and adaptive responses. Intrahepatic immune responses have rarely been studied in hepatitis D and thus completely novel data can be expected which can probably only generated within this D-SOLVE consortium combining translational clinical and basic expertise and providing the logistics to have access to the required patient material.

WP5 (Mouse models of HDV infection and HDV-induced transcriptomic and epigenetic modifications) starts at month 1 and lasts up to month 48. Given previous observations for HCV, it is likely that HDV control cure by either interferon-based therapies or in combination with novel antivirals like Bulevirtide will only partially eliminate HDV-induced modifications of the hepatocyte cell circuits or the innate and adaptive immune responses. These persistent perturbations of the liver cell circuits may contribute liver disease progression and HCC risk post cure. Supporting this concept, HDV induces DNA hypermethylation and histone modification in cell lines suggesting the existence of an epigenetic viral footprint relevant for viral pathogenesis and HCC risk. To address this question (1) we will study the HDV-induced transcriptomic and epigenetic modifications in liver tissues and PBMCs from cohorts of WP1 and study their phenotype before and after antiviral treatment. We will (2) then validate and characterize the modifications in well characterized animal models for HDV-HBV co-infection pre- and post-cure with antiviral therapies. (3) Finally, we will investigate the impact of these changes for progression of disease and cancer risk post cure. Through the understanding of these underlying mechanisms, this work program will enable the development of new biomarkers for treatment outcome, liver disease progression and HCC risk post cure.

WPs 6 (Data management), 7 (Dissemination, exploitation, IP, communication & training) and 8 (Coordination & project management) will be carried out along the whole duration of the project.

The D-SOLVE consortium is funded by the European Union in the Horizon Europe Framework Programme (HORIZON) under grant agreement No 101057917.