Liver transplantation (LT) is a life-saving procedure for decompensated cirrhosis (DC) and hepato-cellular carcinoma (HCC). Its efficacy is hampered by the risk of death/drop-out on the Wait List (WL). This risk is driven by organ shortage and is mitigated by organ offering schemes. According to a sickest first policy, offering schemes prioritize LT candidates with the highest risk of dying, as assessed by predictive models. To drive allocation, Organ Sharing Organizations (OSOs) use a 20-year-old model, the MELD, predicting mortality in DC but not in HCC. Because of a dramatic increase in % of HCC candidates (40% against 10% in early 20ties), MELD schemes are increasingly inaccurate, with persisting 15 to 30% mortality in countries with low/medium donation rate. This scenario, together with advances in prognosis in DC and HCC candidates and statistics, prompts LT community to look for up-dated algorithms to refine offering schemes. To address this issue, key European LT stakeholders including OSOs, experts in LT, Statisticians, Research Labs and SME joined LEOPARD. Building on an innovative, harmonized OSOs pre-LT dataset and advances in modeling, LEOPARD propose to design and validate 1) an AI-based LEOPARD predictive algorithm outperforming current allocation models by better stratifying patients on the risk of mortality, to be proposed OSOs to drive allocation; 2) DC & HCC LEOPARD calculators available for professional for assistance in complex decision-making processes; 3) OMICs/radiomics predictive signatures integrated in a prototype 3rd-generation exploratory model. We expect to generate computational tools improving candidates’ outcomes, with more patients transplanted on time. Adoption of these tools should result in harmonization of European heterogeneous prioritization schemes, and in a signification reduction in disparities of access to LT, a major objective pointed out by EC. LEOPARD should place Europe in leading position for organ offering schemes.

Chronic liver disease affects about 29-million Europeans accounting for about 170,000 deaths at a cost of around €15.8bn. This chronic non-communicable disease is increasing at an alarming rate due to increasing European obesity, alcohol use and ageing. The three main causes of the disease; alcohol, fatty liver and viral hepatitis are amenable to prevention and treatment. Gut-derived endotoxins and bacterial translocation are central factors implicated in the pathogenesis of fatty liver disease and, the development and progression of cirrhosis. In cirrhosis, current state-of-the-art therapy to prevent recurrent complications of advanced cirrhosis is to use poorly absorbed antibiotics but long-term antibiotic therapy has problems associated with bacterial resistance, infection with resistant organisms and the cost. Treatment of fatty liver and modulation of bacterial translocation in early cirrhosis to prevent complications is an unmet need. Our academic-industrial consortium has developed a novel, patented, safe and cheap nanoporous carbon that modulates the effects of bacterial translocation in animal models of liver disease. Our feasibility studies demonstrate that this product advances the current state-of-the-art, is a TRL 4/5 and is now ready for validation through clinical trials. We propose to investigate the safety and efficacy of this novel nanoporous carbon in patients with fatty liver disease and cirrhosis. If successful, we will be able to confirm an innovative, cost-effective and novel strategy for the management of this chronic disease in a European population. Exploitation of the results of the CARBALIVE project will support the continued development of this carbon through additional private and public sector investment. The use of this innovative therapy is expected to reduce the economic burden of the disease in Europe, allow patients to achieve enhanced quality of life, improve survival, and allow many patients to return to economic productivity.

Decompensation of liver cirrhosis and progression towards acute-on-chronic liver failure (ACLF) causes 1.2 million deaths/year. Microbiome is causally involved in cirrhosis progression and is for drugs the first interaction point with the patients. Drugs can alter the microbiome leading to unwanted effects or even facilitating their effects, but the microbiome metabolizes the drugs, shapes their effects and possibly determines the host response to drugs. As each person carries an individual microbiome, insight in these processes should help stratify or even personalize patient health care and treatment. The aims of MICROB-PREDICT are 1) to better understand the role of microbiome and the gut-liver-axis interactome with respect to microbiome functionalities, 2) to identify and validate microbiome-based biomarkers and signatures for personalized prediction of decompensation and ACLF, and response to treatment, 3) to design three new tests as easy-to-use tools and point-of-care, smartphone-connected nanobiosensors, and 4) to validate them in a randomized controlled trial. MICROB-PREDICT will assemble existing data and samples from major microbiome initiatives in hepatology (12 international studies, >10,000 patients), and enrich them with holistic and in-depth analysis using cutting-edge multi-omics technologies of host and microbiome from different body sites in samples of >1,000 patients collected in a longitudinal manner with sequential visits and controlling for confounders. MICROB-PREDICT results will foster more accurate, personalized risk stratification and significant steps towards personalized treatment of decompensated cirrhosis and ACLF. World-leading microbiome specialists, technology leaders and clinical experts make this a programme of scientific excellence; patient organisations (ELPA) and the European Association for the study of the Liver (EASL) will channel our results into a powerful dissemination, communication and exploitation programme.

Liver disease incidence is increasing and about 170K patients die from liver failure each year in Europe. In liver failure, the accumulation of protein bound toxins and increased susceptibility to infection cause multiorgan failure and death. Liver transplantation is the only treatment known to prolong the life but is limited by availability of organs. A clinically efficacious ‘liver dialysis device’ is an unmet clinical need. The ALIVER Consortium has developed and optimised a novel ‘liver dialysis device’, DIALIVE. The DIALIVE device is protected by world-wide patents and is based upon our discovery that (i) albumin, a circulating protein involved in detoxification is reduced irreversibly in function and (ii) endotoxemia contributes to increased risk of infection in liver failure. DIALIVE incorporates albumin removal and replacement and, endotoxin removal and is a TRL5. In animal models of liver failure, DIALIVE was shown to be easy to use, safe, reduced endotoxemia and, improved albumin and immune function and, prolonged survival. The ALIVER Consortium, which is comprised of experts in liver failure, SMEs and charities proposes to perform clinical trials of DIALIVE in patients with acute on chronic liver failure (ACLF). During the grant period a CE-mark will be obtained and the device will progress to a TRL7/8. Consultation with Regulatory bodies confirms that if the trials are successful, a CE-mark is highly likely. Grifols, a large plasma proteins company is a potential licensee of the technology if the studies proposed by the ALIVER Consortium are positive. We plan to take the project through regulatory and ethics approval and perform a study to define its safety in ACLF patients in 18 European hospitals; define health economic benefits to the EU and define a reimbursement strategy. The results will be disseminated widely and results exploited to benefit patients, EU healthcare system, create new jobs and grow healthcare Industry in Europe.

Humans are microbial, living in close functional interaction with their skin and mucosal microbiomes. Human-microbes interplay has proven essential for the maintenance of health and well-being and profiling of microbiomes will become an essential feature of the personalized preventive nutrition and medicine of tomorrow. Europe has gained a leading position in microbiome science and yet to fulfill societal expectations, an international consensus will be essential on key aspects. These include i) clinical trial design as well as analytical standards, ii) definitions of healthy microbiomes as a function of numerous factors, accounting for confounders, iii) means of demonstrating causality of altered host-microbes interactions in diseases and iv) processes for the development of clinically relevant, validated biomarkers. The International Human Microbiome Concertation and Support Action (IHMCSA) will tackle all necessary steps to open the perspective of managing nutrition and health of the microbial human. Involving key stakeholders representing the multiplicity of actors concerned, including citizens, IHMCSA will map existing material, delineate necessary steps and pathways for innovation and build consensus on priorities and means for the future of microbiome science and its translation. This will lead to recommendations, validated by an international Strategic Steering Committee as well as academies of medicine of the world, directed to the European Commission, international research programmes, funding and regulatory agencies and decision makers of health systems. To ensure sustainability of the proposed measures, IHMCSA will promote unified repositories for sharing standards, SOPs and data, and contribute to the structuration of the European Microbiome Centers Consortium with a role in gathering world microbiome networks of excellence. With IHMCSA, human-associated microbiomes will be recognized for their true value in contributing to secure the future of mankind.