Periodic Reporting for period 4 - LIVERHOPE (SIMVASTATIN AND RIFAXIMIN AS NEW THERAPY FOR PATIENTS WITH DECOMPENSATED CIRRHOSIS)
Reporting period: 2021-07-01 to 2023-02-28
What is the problem/issue being addressed?
The problem addressed by the LIVERHOPE project is that of chronic liver diseases, in particular, liver cirrhosis. Chronic liver diseases are diseases caused by inflammation of the liver that after a long period, more than 10 years in average, may lead to liver cirrhosis. Liver cirrhosis is a disease that is irreversible and usually progressive that causes the impairment of major functions of the liver responsible for development of many complications that usually lead to death unless liver transplantation is performed. Liver cirrhosis can also lead to development of liver cancer. There are many factors that may cause inflammation of the liver leading to liver cirrhosis, particularly excessive alcohol consumption, metabolic conditions, particularly obesity and diabetes mellitus, and chronic infections by hepatitis viruses, mainly hepatitis B and C, among others.
Why is important for the society?
Chronic liver diseases are very common worldwide and their frequency is increasing in many areas of the world. Although the frequency of hepatitis B or C infection is decreasing in many countries due to effective preventive measures, including vaccination for hepatitis C, and existence of effective drugs, the frequency of other causes of chronic liver diseases, particularly those related to alcohol consumption or metabolic factors (obesity, diabetes) is increasing in many areas of the world. Therefore, it is not surprising that the frequency of liver cirrhosis remains very high in most countries. Moreover, it is important to consider that liver cirrhosis is a major cause of death worldwide and a major cause of impaired quality of life for patients and their relatives. Liver cirrhosis is also responsible for a high number of hospitalizations and therefore the economic burden of the disease for the society is huge. Finally, it is important to note that there is no effective drug therapy to prevent progression of cirrhosis when the disease has developed. Treatment is therefore based on symptomatic management of complications and transplantation of the liver in patients who are candidates to this procedure. It is important to remind that liver transplantation is only applicable to a small proportion of patients due to shortage of donors or contraindications to the procedure. Therefore, there is need for alternative therapies for patients with liver cirrhosis that can halt liver disease and prevent progression of cirrhosis and death.
What are the overall objectives?
The LIVERHOPE project represents an international European effort to investigate the safety and efficacy of a new therapy for patients with liver cirrhosis based on the combination of simvastatin, a drug that can reduce the inflammation associated with liver disease, and rifaximin, a drug that modulates the gut microbiome and may reduce the toxic products arising from bacteria of the intestine, that are known to contribute to cirrhosis progression.
Other objectives of the LIVERHOPE project are to identify biomarkers of treatment and disease progression that can be used in clinical practice, disseminate the results of the project so that the information reaches the patient population who can benefit from the results of the study, to increase awareness about chronic liver diseases in European countries so that preventive measures can be undertaken to decrease the burden of the disease, and to reduce the social stigmatization of patients with chronic liver diseases.
The problem addressed by the LIVERHOPE project is that of chronic liver diseases, in particular, liver cirrhosis. Chronic liver diseases are diseases caused by inflammation of the liver that after a long period, more than 10 years in average, may lead to liver cirrhosis. Liver cirrhosis is a disease that is irreversible and usually progressive that causes the impairment of major functions of the liver responsible for development of many complications that usually lead to death unless liver transplantation is performed. Liver cirrhosis can also lead to development of liver cancer. There are many factors that may cause inflammation of the liver leading to liver cirrhosis, particularly excessive alcohol consumption, metabolic conditions, particularly obesity and diabetes mellitus, and chronic infections by hepatitis viruses, mainly hepatitis B and C, among others.
Why is important for the society?
Chronic liver diseases are very common worldwide and their frequency is increasing in many areas of the world. Although the frequency of hepatitis B or C infection is decreasing in many countries due to effective preventive measures, including vaccination for hepatitis C, and existence of effective drugs, the frequency of other causes of chronic liver diseases, particularly those related to alcohol consumption or metabolic factors (obesity, diabetes) is increasing in many areas of the world. Therefore, it is not surprising that the frequency of liver cirrhosis remains very high in most countries. Moreover, it is important to consider that liver cirrhosis is a major cause of death worldwide and a major cause of impaired quality of life for patients and their relatives. Liver cirrhosis is also responsible for a high number of hospitalizations and therefore the economic burden of the disease for the society is huge. Finally, it is important to note that there is no effective drug therapy to prevent progression of cirrhosis when the disease has developed. Treatment is therefore based on symptomatic management of complications and transplantation of the liver in patients who are candidates to this procedure. It is important to remind that liver transplantation is only applicable to a small proportion of patients due to shortage of donors or contraindications to the procedure. Therefore, there is need for alternative therapies for patients with liver cirrhosis that can halt liver disease and prevent progression of cirrhosis and death.
What are the overall objectives?
The LIVERHOPE project represents an international European effort to investigate the safety and efficacy of a new therapy for patients with liver cirrhosis based on the combination of simvastatin, a drug that can reduce the inflammation associated with liver disease, and rifaximin, a drug that modulates the gut microbiome and may reduce the toxic products arising from bacteria of the intestine, that are known to contribute to cirrhosis progression.
Other objectives of the LIVERHOPE project are to identify biomarkers of treatment and disease progression that can be used in clinical practice, disseminate the results of the project so that the information reaches the patient population who can benefit from the results of the study, to increase awareness about chronic liver diseases in European countries so that preventive measures can be undertaken to decrease the burden of the disease, and to reduce the social stigmatization of patients with chronic liver diseases.
The EC H2020 Funded LIVERHOPE Project has achieved its primary objective of completing TWO randomized double-blind trials (SAFETY and EFFICACY Trials) to investigate the efficacy of the combination of simvastatin plus rifaximin in patients with decompensated cirrhosis to halt progression to acute-on-chronic liver failure (ACLF), decrease complications of the disease, reduce hospital readmissions, improve cost-effectiveness, improve patients quality-of-life, and increase survival. The Efficacy Trial has been performed in 14 hospitals in 7 European countries. The administration of the combined treatment with simvastatin and rifaximin is a very innovative approach to therapy of cirrhosis that targets both the systemic inflammation and the alteration in gut microbiome and gut-liver axis that characterize advanced chronic liver diseases. The recruitment of patients with decompensated cirrhosis in the LiverHope Efficacy trial was completed on the 30th November 2022 with a sample size of 254 patients.
The results of the trial will be presented at the International EASL Meeting June 2023. Furthermore the secondary objectives of the project, assessment of biomarkers in decompensated cirrhosis and evaluation of the changes in plasma metabolome during cirrhosis progression are currently being studied with the preliminary results due later 2023.
STIGMA in Liver Diseases has been an important objective of the project and the role of the Patients Association and the Expert Nurses team have been essential in achieving results. The qualitative results have been presented at international congresses and published PLoS One 2022 and an extensive review in Journal of Hepatology 2023.
Besides, activities are carried out for the scientific dissemination and for raising awareness about chronic liver diseases in the population
The results of the trial will be presented at the International EASL Meeting June 2023. Furthermore the secondary objectives of the project, assessment of biomarkers in decompensated cirrhosis and evaluation of the changes in plasma metabolome during cirrhosis progression are currently being studied with the preliminary results due later 2023.
STIGMA in Liver Diseases has been an important objective of the project and the role of the Patients Association and the Expert Nurses team have been essential in achieving results. The qualitative results have been presented at international congresses and published PLoS One 2022 and an extensive review in Journal of Hepatology 2023.
Besides, activities are carried out for the scientific dissemination and for raising awareness about chronic liver diseases in the population
Currently, the treatment of patients with decompensated cirrhosis is based on management of individual complications that patients may develop during the course of their disease. In general, patients develop a large number of different complications that require frequent hospitalizations and a large array of interventions, including ICU stays and liver transplantation. Mortality is very high. The LiverHope project is unique in that it represents the first approach to develop a new combination therapy able to prevent the progression of the disease. Therefore, if the results are positive this may represent a treatment to stabilize the disease and prevent it from progressing. This will have a huge impact in the natural history of the disease by decreasing mortality and improving quality of life of patients and their families, and will reduce costs for health systems by decreasing the number of hospitalizations and need for therapeutic interventions, including liver transplantation.