Demographic, morbidity and mortality data associated with the STOP-HCV Cirrhosis Study cohort.

This Data Sharing Agreement relates to a research study on Hepatitis C Virus (HCV) cirrhosis of the liver, underpinned by the HCV Research UK (HCVRUK). This data sharing agreement is being extended for a further year.

HCV Research UK (HCVRUK) is a consortium of many parties across the UK whose aim was to create a cohort of patients infected with the hepatitis C virus (HCV) in order to facilitate research into all aspects of this infection. The project was funded by the Medical Research Foundation (MRF). University of Glasgow's Centre for Virus Research are the Fund Holders and Managing Party and thereby responsible for execution of the Grant on behalf of the MRF. Nottingham University Hospitals NHS Trust are the Clinical Sponsors of the project and their R&I Department oversee the ethical execution of this study. Thus the University of Glasgow and Nottingham University Hospitals NHS Trust are Joint Data Controllers.

The day-to-day management of the data collected by HCVRUK is conducted by members of the HCVRUK Management Group. Asckey Data Services hosts the HCVRUK Research Clinical Database on secure systems and are also involved in general maintenance of the database and technical support. Asckey have no involvement with this Agreement and will not have access to the data provided by NHS England. The data requested under this agreement will be stored and processed separately to data held by HCVRUK. The data requested under this agreement will be disseminated to and stored by the Robertson Centre for Biostatistics at the University of Glasgow only. No additional storage locations will be used.

Approximately 12,000 patients have signed a consent form to join HCVRUK, of which approximately 4500 patients have been diagnosed with cirrhosis. Information including how patients contracted the infection, how long they have had it, any health complications as a result of the infection (including liver disease), and the treatments they receive to clear the infection is collected into a Clinical Research Database, which provides a resource to underpin a variety of specific research studies. Biological samples are stored in the HCVRUK Biobank. Researchers may apply to the HCVRUK Tissue and Data Access Committee (TDAC) for access to clinical data held on the HCVRUK database and/or samples. If permission is granted by TDAC, the clinical data/samples are supplied under a Material Transfer Agreement whereby any secondary data (eg generated by experimental manipulation of the biological samples) is returned to HCVRUK. HCVRUK do not share any NHS England data.

For the purpose of this Agreement The University of Glasgow and Nottingham University Hospitals NHS Trust will act as joint data controllers. Nottingham University Hospitals NHS Trust will provide the cohort identifying data to NHS England. The University of Glasgow (Robertson Centre for Biostatistics) will receive and process the data from NHS England, as such they are listed as the sole data processor.

The project requires continued access to, and further disseminations of HES, diagnostic imaging, mortality and cancer data for HCVRUK participants with liver cirrhosis. Data from NHS England relating specifically and only to the subgroup of HCV Research UK patients with a diagnosis of liver cirrhosis (about 4264 individuals in total) will be used to answer a number of clinically relevant questions. These questions fall into four broad categories:

• Can the new (or existing) diagnostic tests for liver disease progression, be used to predict which patients with HCV cirrhosis liver disease will progress to life-threatening complications (including ascites [fluid in the abdomen], encephalitis [confusion, brain damage], variceal haemorrhage [bleeding] and primary liver cancer) within 5 years of follow up?

• Do new direct acting antiviral therapies for hepatitis C alter long-term clinical outcomes in addition to providing viral cure?

• Do other co-morbidities associated with HCV cirrhosis (especially alcohol and diabetes) result in increased morbidity and mortality from associated conditions such as cardiovascular disease?

• What patient and clinical factors are associated with uptake of liver cancer screening following viral cure? How can compliance to screening interventions be improved?

None of these questions can be robustly answered without complete and reliable data on hospital admissions, cancer diagnoses and death certification. The only mechanism which can provide access to robust and comprehensive data relating to a large and geographically widespread patient cohort is through NHS England. Therefore, there is no alternative or less intrusive means of achieving the purpose stated within this Agreement.

The lawful basis of processing falls under General Data Protection Regulation (GDPR) Article’s 6(1)(e) ‘Public Interest’ and 9 (2)(j). The processing of the data is in the public interest for a number of reasons. Premature mortality from liver disease in the UK continues to rise and finding better tools to predict which patients are at increased risk of developing cirrhosis complications is essential at an individual and healthcare level. Novel clinical algorithms which will arise from these data will allow individualised clinical management plans, with patients identified at increased risk of disease progression undergoing enhanced surveillance, and therefore achieving earlier diagnosis and treatment of life-threatening complications, whilst those patients at lower risk may be discharged from clinic. In addition to these benefits at an individual patient level, there are likely to be significant health economic benefits. Earlier diagnosis and treatment of potentially life-threatening complications may result in patients not needing to undergo expensive healthcare technologies such as liver transplantation. Appropriate relaxation of cancer surveillance in patients at very low risk will result in less clinic attendances and less surveillance intervention (ultrasound and MRI scanning) costs. Furthermore, this particular study has arisen at precisely the point of introduction of the expensive DAA drugs. Long-term liver-related outcome data, as intended in this proposal, will provide solid data to NHS England on the cost-effectiveness of the DAA revolution in HCV treatment.

The time span of data requested reflects the natural history of clinical events to occur. There are no ethical issues raised by dissemination and the level of data is proportionate to answer the questions posed. There are no foreseeable harmful effects to the public from release and publication of the intended research analyses outlined.

Answers to the aforementioned research questions will further improve understanding of HCV-related liver disease, and thus benefit patient care.

Specific outputs expected to be delivered in the next three years are:

1. Analysis to assess the uptake of 6 monthly ultrasound screening for early detection of HCC following hepatitis C viral cure (completion of analysis, Mar 23)

2. Analysis to assess whether the risk of liver cancer changes with time since achievement of a hepatitis C virus sustained viral response. (Dec 25)

3. Analysis to assess the harms associated with hepatocellular carcinoma in patients with cirrhosis (Dec 23).

4. Analysis to assess all-cause mortality in patients with cirrhosis and a hepatitis C cure, relative to the general population (Jun 24).

5. Analysis to identify genetic risk factors associated with all-cause mortality, cirrhosis decompensation and liver cancer among patients with HCV cirrhosis (Jun 25).

These outputs will be disseminated through two main routes:

(i) Presentation at international liver meetings. Immediate targets are to submit novel findings arising from analysis of the cohort to the American Association for the Study of the Liver - The Liver Meeting® and the European Association for the Study of the Liver International Liver Congress. The primary audience at the international meetings comprises academics, clinicians and possibly pharma representatives. However, the audience may also include public health physicians and policy makers, especially given the current WHO HCV Elimination agenda.

(ii) Publications in peer-reviewed journals with a high impact. These will include Hepatology, Journal of Hepatology and Gastroenterology.

Research outputs will also be communicated to Patients with HCV infection and the general public through the study team's close links with the Hepatitis C Trust who are the largest patient support group in the UK. Members of the Hepatitis C Trust are part of the STOP-HCV/HCVRUK Steering Committees and have significantly influenced the research directions of HCVRUK. They are fully supportive of this application/study and have effective mechanisms for disseminating any advances in the management of HCV infection through an extensive network of patient support groups across the country. In addition, it is the policy of HCVRUK and STOP-HCV to list all publications on their respective websites.

The overarching objective of this work will be to inform clinicians, the scientific community, and commissioners of health care of the risks of and factors associated with progressive liver disease in patients with HCV-induced cirrhosis, in order to optimise patient management and healthcare planning.

Using the existing NHS linkage data provided, an analysis has been completed to assess the performance of various competing risk scores for predicting risk of hepatocellular carcinoma in patients with hepatitis C cirrhosis. See: https://www.jhep-reports.eu/article/S2589-5559(21)00160-9/fulltext.

An analysis has also been completed assessing the performance of a broad set of biomarkers with respect to predicting the risk of a severe liver-related event in patients with HCV cirrhosis. The biomarkers tested include routine laboratory tests genetic risk scores, and innovative biological markers that measure liver scarring. Ultimately, these biomarkers will help clinicians to identify in advance those patients who are likely to develop severe liver disease outcomes. This analysis should be published in the “Clinical and Translational Gastroenterology” shortly. The outcome events in this analysis (i.e. "severe liver events") are determined directly from NHS England data.is available at: https://journals.lww.com/ctg/Fulltext/2022/03000/Comprehensive_Comparative_Analysis_of_Standard.6.aspx

Data have also contributed to two recent studies publications shining light on the genetic determinants of HCC. These studies are published at: https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep4.1886

And

https://pubmed.ncbi.nlm.nih.gov/35788059/

An analysis reporting mortality rates in this cohort following achievement of a hepatitis C cure has also been published. See link: https://www.bmj.com/content/382/bmj-2022-074001 This article has highlighted the need for an holistic response to manage patients with chronic hepatitis C infection.

We have also published a study exploring the uptake of liver cancer surveillance in patients with cured hepatitis C. See link: https://pubmed.ncbi.nlm.nih.gov/36708150/ . This study has highlighted the stark underuse of liver cancer surveillance in this patient group.

Other benefits will be forthcoming.

This Data Sharing Agreement relates to a research study on Hepatitis C Virus (HCV) cirrhosis of the liver, underpinned by the HCV Research UK (HCVRUK). This data sharing agreement is being extended for a further year.

HCV Research UK (HCVRUK) is a consortium of many parties across the UK whose aim was to create a cohort of patients infected with the hepatitis C virus (HCV) in order to facilitate research into all aspects of this infection. The project was funded by the Medical Research Foundation (MRF). University of Glasgow's Centre for Virus Research are the Fund Holders and Managing Party and thereby responsible for execution of the Grant on behalf of the MRF. Nottingham University Hospitals NHS Trust are the Clinical Sponsors of the project and their R&I Department oversee the ethical execution of this study. Thus the University of Glasgow and Nottingham University Hospitals NHS Trust are Joint Data Controllers.

The day-to-day management of the data collected by HCVRUK is conducted by members of the HCVRUK Management Group. Asckey Data Services hosts the HCVRUK Research Clinical Database on secure systems and are also involved in general maintenance of the database and technical support. Asckey have no involvement with this Agreement and will not have access to the data provided by NHS Digital. The data requested under this agreement will be stored and processed separately to data held by HCVRUK. The data requested under this agreement will be disseminated to and stored by the Robertson Centre for Biostatistics at the University of Glasgow only. No additional storage locations will be used.

Approximately 12,000 patients have signed a consent form to join HCVRUK, of which approximately 4500 patients have been diagnosed with cirrhosis. Information including how patients contracted the infection, how long they have had it, any health complications as a result of the infection (including liver disease), and the treatments they receive to clear the infection is collected into a Clinical Research Database, which provides a resource to underpin a variety of specific research studies. Biological samples are stored in the HCVRUK Biobank. Researchers may apply to the HCVRUK Tissue and Data Access Committee (TDAC) for access to clinical data held on the HCVRUK database and/or samples. If permission is granted by TDAC, the clinical data/samples are supplied under a Material Transfer Agreement whereby any secondary data (eg generated by experimental manipulation of the biological samples) is returned to HCVRUK. HCVRUK do not share any NHS Digital data.

For the purpose of this Agreement The University of Glasgow and Nottingham University Hospitals NHS Trust will act as joint data controllers. Nottingham University Hospitals NHS Trust will provide the cohort identifying data to NHS Digital. The University of Glasgow (Robertson Centre for Biostatistics) will receive and process the data from NHS Digital, as such they are listed as the sole data processor.

The project requires continued access to, and further disseminations of HES, diagnostic imaging, mortality and cancer data for HCVRUK participants with liver cirrhosis. Data from NHS Digital relating specifically and only to the subgroup of HCV Research UK patients with a diagnosis of liver cirrhosis (about 4264 individuals in total) will be used to answer a number of clinically relevant questions. These questions fall into four broad categories:

• Can the new (or existing) diagnostic tests for liver disease progression, be used to predict which patients with HCV cirrhosis liver disease will progress to life-threatening complications (including ascites [fluid in the abdomen], encephalitis [confusion, brain damage], variceal haemorrhage [bleeding] and primary liver cancer) within 5 years of follow up?

• Do new direct acting antiviral therapies for hepatitis C alter long-term clinical outcomes in addition to providing viral cure?

• Do other co-morbidities associated with HCV cirrhosis (especially alcohol and diabetes) result in increased morbidity and mortality from associated conditions such as cardiovascular disease?

• What patient and clinical factors are associated with uptake of liver cancer screening following viral cure? How can compliance to screening interventions be improved?

None of these questions can be robustly answered without complete and reliable data on hospital admissions, cancer diagnoses and death certification. The only mechanism which can provide access to robust and comprehensive data relating to a large and geographically widespread patient cohort is through NHS Digital. Therefore, there is no alternative or less intrusive means of achieving the purpose stated within this Agreement.

The lawful basis of processing falls under General Data Protection Regulation (GDPR) Article’s 6(1)(e) ‘Public Interest’ and 9 (2)(j). The processing of the data is in the public interest for a number of reasons. Premature mortality from liver disease in the UK continues to rise and finding better tools to predict which patients are at increased risk of developing cirrhosis complications is essential at an individual and healthcare level. Novel clinical algorithms which will arise from these data will allow individualised clinical management plans, with patients identified at increased risk of disease progression undergoing enhanced surveillance, and therefore achieving earlier diagnosis and treatment of life-threatening complications, whilst those patients at lower risk may be discharged from clinic. In addition to these benefits at an individual patient level, there are likely to be significant health economic benefits. Earlier diagnosis and treatment of potentially life-threatening complications may result in patients not needing to undergo expensive healthcare technologies such as liver transplantation. Appropriate relaxation of cancer surveillance in patients at very low risk will result in less clinic attendances and less surveillance intervention (ultrasound and MRI scanning) costs. Furthermore, this particular study has arisen at precisely the point of introduction of the expensive DAA drugs. Long-term liver-related outcome data, as intended in this proposal, will provide solid data to NHS England on the cost-effectiveness of the DAA revolution in HCV treatment.

The time span of data requested reflects the natural history of clinical events to occur. There are no ethical issues raised by dissemination and the level of data is proportionate to answer the questions posed. There are no foreseeable harmful effects to the public from release and publication of the intended research analyses outlined.

Answers to the aforementioned research questions will further improve understanding of HCV-related liver disease, and thus benefit patient care.

Specific outputs expected to be delivered in the next three years are:

1. Analysis to assess the uptake of 6 monthly ultrasound screening for early detection of HCC following hepatitis C viral cure (completion of analysis, Mar 23)

2. Analysis to assess whether the risk of liver cancer changes with time since achievement of a hepatitis C virus sustained viral response. (Dec 25)

3. Analysis to assess the harms associated with hepatocellular carcinoma in patients with cirrhosis (Dec 23).

4. Analysis to assess all-cause mortality in patients with cirrhosis and a hepatitis C cure, relative to the general population (Jun 24).

5. Analysis to identify genetic risk factors associated with all-cause mortality, cirrhosis decompensation and liver cancer among patients with HCV cirrhosis (Jun 25).

These outputs will be disseminated through two main routes:

(i) Presentation at international liver meetings. Immediate targets are to submit novel findings arising from analysis of the cohort to the American Association for the Study of the Liver - The Liver Meeting® and the European Association for the Study of the Liver International Liver Congress. The primary audience at the international meetings comprises academics, clinicians and possibly pharma representatives. However, the audience may also include public health physicians and policy makers, especially given the current WHO HCV Elimination agenda.

(ii) Publications in peer-reviewed journals with a high impact. These will include Hepatology, Journal of Hepatology and Gastroenterology.

Research outputs will also be communicated to Patients with HCV infection and the general public through the study team's close links with the Hepatitis C Trust who are the largest patient support group in the UK. Members of the Hepatitis C Trust are part of the STOP-HCV/HCVRUK Steering Committees and have significantly influenced the research directions of HCVRUK. They are fully supportive of this application/study and have effective mechanisms for disseminating any advances in the management of HCV infection through an extensive network of patient support groups across the country. In addition, it is the policy of HCVRUK and STOP-HCV to list all publications on their respective websites.

The overarching objective of this work will be to inform clinicians, the scientific community, and commissioners of health care of the risks of and factors associated with progressive liver disease in patients with HCV-induced cirrhosis, in order to optimise patient management and healthcare planning.

Using the existing NHS linkage data provided, an analysis has been completed to assess the performance of various competing risk scores for predicting risk of hepatocellular carcinoma in patients with hepatitis C cirrhosis. See: https://www.jhep-reports.eu/article/S2589-5559(21)00160-9/fulltext.

An analysis has also been completed assessing the performance of a broad set of biomarkers with respect to predicting the risk of a severe liver-related event in patients with HCV cirrhosis. The biomarkers tested include routine laboratory tests genetic risk scores, and innovative biological markers that measure liver scarring. Ultimately, these biomarkers will help clinicians to identify in advance those patients who are likely to develop severe liver disease outcomes. This analysis should be published in the “Clinical and Translational Gastroenterology” shortly. The outcome events in this analysis (i.e. "severe liver events") are determined directly from NHS Digital data.is available at: https://journals.lww.com/ctg/Fulltext/2022/03000/Comprehensive_Comparative_Analysis_of_Standard.6.aspx

Data have also contributed to two recent studies publications shining light on the genetic determinants of HCC. These studies are published at: https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep4.1886

And

https://pubmed.ncbi.nlm.nih.gov/35788059/

Other benefits will be forthcoming.

This Data Sharing Agreement relates to a research study on Hepatitis C Virus (HCV) cirrhosis of the liver, underpinned by the HCV Research UK (HCVRUK). This data sharing agreement is being extended for a further year.

HCV Research UK (HCVRUK) is a consortium of many parties across the UK whose aim was to create a cohort of patients infected with the hepatitis C virus (HCV) in order to facilitate research into all aspects of this infection. The project was funded by the Medical Research Foundation (MRF). University of Glasgow's Centre for Virus Research are the Fund Holders and Managing Party and thereby responsible for execution of the Grant on behalf of the MRF. Nottingham University Hospitals NHS Trust are the Clinical Sponsors of the project and their R&I Department oversee the ethical execution of this study. Thus the University of Glasgow and Nottingham University Hospitals NHS Trust are Joint Data Controllers.

The day-to-day management of the data collected by HCVRUK is conducted by members of the HCVRUK Management Group. Asckey Data Services hosts the HCVRUK Research Clinical Database on secure systems and are also involved in general maintenance of the database and technical support. Asckey have no involvement with this Agreement and will not have access to the data provided by NHS Digital. The data requested under this agreement will be stored and processed separately to data held by HCVRUK. The data requested under this agreement will be disseminated to and stored by the Robertson Centre for Biostatistics at the University of Glasgow only. No additional storage locations will be used.

Approximately 12,000 patients have signed a consent form to join HCVRUK, of which approximately 4500 patients have been diagnosed with cirrhosis. Information including how patients contracted the infection, how long they have had it, any health complications as a result of the infection (including liver disease), and the treatments they receive to clear the infection is collected into a Clinical Research Database, which provides a resource to underpin a variety of specific research studies. Biological samples are stored in the HCVRUK Biobank. Researchers may apply to the HCVRUK Tissue and Data Access Committee (TDAC) for access to clinical data held on the HCVRUK database and/or samples. If permission is granted by TDAC, the clinical data/samples are supplied under a Material Transfer Agreement whereby any secondary data (eg generated by experimental manipulation of the biological samples) is returned to HCVRUK. HCVRUK do not share any NHS Digital data.

For the purpose of this Agreement The University of Glasgow and Nottingham University Hospitals NHS Trust will act as joint data controllers. Nottingham University Hospitals NHS Trust will provide the cohort identifying data to NHS Digital. The University of Glasgow (Robertson Centre for Biostatistics) will receive and process the data from NHS Digital, as such they are listed as the sole data processor.

The project requires continued access to, and further disseminations of HES, diagnostic imaging, mortality and cancer data for HCVRUK participants with liver cirrhosis. Data from NHS Digital relating specifically and only to the subgroup of HCV Research UK patients with a diagnosis of liver cirrhosis (about 4264 individuals in total) will be used to answer a number of clinically relevant questions. These questions fall into four broad categories:

• Can the new (or existing) diagnostic tests for liver disease progression, be used to predict which patients with HCV cirrhosis liver disease will progress to life-threatening complications (including ascites [fluid in the abdomen], encephalitis [confusion, brain damage], variceal haemorrhage [bleeding] and primary liver cancer) within 5 years of follow up?

• Do new direct acting antiviral therapies for hepatitis C alter long-term clinical outcomes in addition to providing viral cure?

• Do other co-morbidities associated with HCV cirrhosis (especially alcohol and diabetes) result in increased morbidity and mortality from associated conditions such as cardiovascular disease?

• What patient and clinical factors are associated with uptake of liver cancer screening following viral cure? How can compliance to screening interventions be improved?

None of these questions can be robustly answered without complete and reliable data on hospital admissions, cancer diagnoses and death certification. The only mechanism which can provide access to robust and comprehensive data relating to a large and geographically widespread patient cohort is through NHS Digital. Therefore, there is no alternative or less intrusive means of achieving the purpose stated within this Agreement.

The lawful basis of processing falls under General Data Protection Regulation (GDPR) Article’s 6(1)(e) ‘Public Interest’ and 9 (2)(j). The processing of the data is in the public interest for a number of reasons. Premature mortality from liver disease in the UK continues to rise and finding better tools to predict which patients are at increased risk of developing cirrhosis complications is essential at an individual and healthcare level. Novel clinical algorithms which will arise from these data will allow individualised clinical management plans, with patients identified at increased risk of disease progression undergoing enhanced surveillance, and therefore achieving earlier diagnosis and treatment of life-threatening complications, whilst those patients at lower risk may be discharged from clinic. In addition to these benefits at an individual patient level, there are likely to be significant health economic benefits. Earlier diagnosis and treatment of potentially life-threatening complications may result in patients not needing to undergo expensive healthcare technologies such as liver transplantation. Appropriate relaxation of cancer surveillance in patients at very low risk will result in less clinic attendances and less surveillance intervention (ultrasound and MRI scanning) costs. Furthermore, this particular study has arisen at precisely the point of introduction of the expensive DAA drugs. Long-term liver-related outcome data, as intended in this proposal, will provide solid data to NHS England on the cost-effectiveness of the DAA revolution in HCV treatment.

The time span of data requested reflects the natural history of clinical events to occur. There are no ethical issues raised by dissemination and the level of data is proportionate to answer the questions posed. There are no foreseeable harmful effects to the public from release and publication of the intended research analyses outlined.

Answers to the aforementioned research questions will further improve understanding of HCV-related liver disease, and thus benefit patient care.

Specific outputs expected to be delivered in the next two years are:

1. Analysis to assess the uptake of 6 monthly ultrasound screening for early detection of HCC following hepatitis C viral cure (completion of analysis, Apr 22)

2. Analysis to assess whether the risk of liver cancer changes with time since achievement of a hepatitis C virus sustained viral response. (Apr 22)

3. Analysis to assess the harms associated with hepatocellular carcinoma in patients with cirrhosis (Dec 22).

4. Analysis to assess all-cause mortality in patients with cirrhosis and a hepatitis C cure, relative to the general population (Apr 22).

5. Analysis to identify genetic risk factors associated with all-cause mortality, cirrhosis decompensation and liver cancer among patients with HCV cirrhosis (Dec 22).

These outputs will be disseminated through two main routes:

(i) Presentation at international liver meetings. Immediate targets are to submit novel findings arising from analysis of the cohort to the American Association for the Study of the Liver - The Liver Meeting® and the European Association for the Study of the Liver International Liver Congress. The primary audience at the international meetings comprises academics, clinicians and possibly pharma representatives. However, the audience may also include public health physicians and policy makers, especially given the current WHO HCV Elimination agenda.

(ii) Publications in peer-reviewed journals with a high impact. These will include Hepatology, Journal of Hepatology and Gastroenterology.

Research outputs will also be communicated to Patients with HCV infection and the general public through the study team's close links with the Hepatitis C Trust who are the largest patient support group in the UK. Members of the Hepatitis C Trust are part of the STOP-HCV/HCVRUK Steering Committees and have significantly influenced the research directions of HCVRUK. They are fully supportive of this application/study and have effective mechanisms for disseminating any advances in the management of HCV infection through an extensive network of patient support groups across the country. In addition, it is the policy of HCVRUK and STOP-HCV to list all publications on their respective websites.

The overarching objective of this work will be to inform clinicians, the scientific community, and commissioners of health care of the risks of and factors associated with progressive liver disease in patients with HCV-induced cirrhosis, in order to optimise patient management and healthcare planning.

Using the existing NHS linkage data provided, an analysis has been completed to assess the performance of various competing risk scores for predicting risk of hepatocellular carcinoma in patients with hepatitis C cirrhosis. See: https://www.jhep-reports.eu/article/S2589-5559(21)00160-9/fulltext.

An analysis has also been completed assessing the performance of a broad set of biomarkers with respect to predicting the risk of a severe liver-related event in patients with HCV cirrhosis. The biomarkers tested include routine laboratory tests genetic risk scores, and innovative biological markers that measure liver scarring. Ultimately, these biomarkers will help clinicians to identify in advance those patients who are likely to develop severe liver disease outcomes. This analysis should be published in the “Clinical and Translational Gastroenterology” shortly. The outcome events in this analysis (i.e. "severe liver events") are determined directly from NHS Digital data.

Other benefits will be forthcoming.

This Data Sharing Agreement relates to a research study on Hepatitis C Virus (HCV) cirrhosis of the liver, underpinned by the HCV Research UK (HCVRUK). This data sharing agreement is being extended for a further year.

HCV Research UK (HCVRUK) is a consortium of many parties across the UK whose aim was to create a cohort of patients infected with the hepatitis C virus (HCV) in order to facilitate research into all aspects of this infection. The project was funded by the Medical Research Foundation (MRF). University of Glasgow's Centre for Virus Research are the Fund Holders and Managing Party and thereby responsible for execution of the Grant on behalf of the MRF. Nottingham University Hospitals NHS Trust are the Clinical Sponsors of the project and their R&I Department oversee the ethical execution of this study. Thus the University of Glasgow and Nottingham University Hospitals NHS Trust are Joint Data Controllers.

The day-to-day management of the data collected by HCVRUK is conducted by members of the HCVRUK Management Group. Asckey Data Services hosts the HCVRUK Research Clinical Database on secure systems and are also involved in general maintenance of the database and technical support. Asckey have no involvement with this Agreement and will not have access to the data provided by NHS Digital. The data requested under this agreement will be stored and processed separately to data held by HCVRUK. The data requested under this agreement will be disseminated to and stored by the Robertson Centre for Biostatistics at the University of Glasgow only. No additional storage locations will be used.

Approximately 12,000 patients have signed a consent form to join HCVRUK, of which approximately 4500 patients have been diagnosed with cirrhosis. Information including how patients contracted the infection, how long they have had it, any health complications as a result of the infection (including liver disease), and the treatments they receive to clear the infection is collected into a Clinical Research Database, which provides a resource to underpin a variety of specific research studies. Biological samples are stored in the HCVRUK Biobank. Researchers may apply to the HCVRUK Tissue and Data Access Committee (TDAC) for access to clinical data held on the HCVRUK database and/or samples. If permission is granted by TDAC, the clinical data/samples are supplied under a Material Transfer Agreement whereby any secondary data (eg generated by experimental manipulation of the biological samples) is returned to HCVRUK. HCVRUK do not share any NHS Digital data.

For the purpose of this Agreement The University of Glasgow and Nottingham University Hospitals NHS Trust will act as joint data controllers. Nottingham University Hospitals NHS Trust will provide the cohort identifying data to NHS Digital. The University of Glasgow (Robertson Centre for Biostatistics) will receive and process the data from NHS Digital, as such they are listed as the sole data processor.

The project requires continued access to, and further disseminations of HES, diagnostic imaging, mortality and cancer data for HCVRUK participants with liver cirrhosis. Data from NHS Digital relating specifically and only to the subgroup of HCV Research UK patients with a diagnosis of liver cirrhosis (about 4264 individuals in total) will be used to answer a number of clinically relevant questions. These questions fall into four broad categories:

• Can the new (or existing) diagnostic tests for liver disease progression, be used to predict which patients with HCV cirrhosis liver disease will progress to life-threatening complications (including ascites [fluid in the abdomen], encephalitis [confusion, brain damage], variceal haemorrhage [bleeding] and primary liver cancer) within 5 years of follow up?

• Do new direct acting antiviral therapies for hepatitis C alter long-term clinical outcomes in addition to providing viral cure?

• Do other co-morbidities associated with HCV cirrhosis (especially alcohol and diabetes) result in increased morbidity and mortality from associated conditions such as cardiovascular disease?

• What patient and clinical factors are associated with uptake of liver cancer screening following viral cure? How can compliance to screening interventions be improved?

None of these questions can be robustly answered without complete and reliable data on hospital admissions, cancer diagnoses and death certification. The only mechanism which can provide access to robust and comprehensive data relating to a large and geographically widespread patient cohort is through NHS Digital. Therefore, there is no alternative or less intrusive means of achieving the purpose stated within this Agreement.

The lawful basis of processing falls under General Data Protection Regulation (GDPR) Article’s 6(1)(e) ‘Public Interest’ and 9 (2)(j). The processing of the data is in the public interest for a number of reasons. Premature mortality from liver disease in the UK continues to rise and finding better tools to predict which patients are at increased risk of developing cirrhosis complications is essential at an individual and healthcare level. Novel clinical algorithms which will arise from these data will allow individualised clinical management plans, with patients identified at increased risk of disease progression undergoing enhanced surveillance, and therefore achieving earlier diagnosis and treatment of life-threatening complications, whilst those patients at lower risk may be discharged from clinic. In addition to these benefits at an individual patient level, there are likely to be significant health economic benefits. Earlier diagnosis and treatment of potentially life-threatening complications may result in patients not needing to undergo expensive healthcare technologies such as liver transplantation. Appropriate relaxation of cancer surveillance in patients at very low risk will result in less clinic attendances and less surveillance intervention (ultrasound and MRI scanning) costs. Furthermore, this particular study has arisen at precisely the point of introduction of the expensive DAA drugs. Long-term liver-related outcome data, as intended in this proposal, will provide solid data to NHS England on the cost-effectiveness of the DAA revolution in HCV treatment.

The time span of data requested reflects the natural history of clinical events to occur. There are no ethical issues raised by dissemination and the level of data is proportionate to answer the questions posed. There are no foreseeable harmful effects to the public from release and publication of the intended research analyses outlined.

Answers to the aforementioned research questions will further improve understanding of HCV-related liver disease, and thus benefit patient care.

Specific outputs expected to be delivered in the next two years are:

1. Analysis to assess the uptake of 6 monthly ultrasound screening for early detection of HCC following hepatitis C viral cure (completion of analysis, Apr 22)

2. Analysis to assess whether the risk of liver cancer changes with time since achievement of a hepatitis C virus sustained viral response. (Apr 22)

3. Analysis to assess the harms associated with hepatocellular carcinoma in patients with cirrhosis (Dec 22).

4. Analysis to assess all-cause mortality in patients with cirrhosis and a hepatitis C cure, relative to the general population (Apr 22).

5. Analysis to identify genetic risk factors associated with all-cause mortality, cirrhosis decompensation and liver cancer among patients with HCV cirrhosis (Dec 22).

These outputs will be disseminated through two main routes:

(i) Presentation at international liver meetings. Immediate targets are to submit novel findings arising from analysis of the cohort to the American Association for the Study of the Liver - The Liver Meeting® and the European Association for the Study of the Liver International Liver Congress. The primary audience at the international meetings comprises academics, clinicians and possibly pharma representatives. However, the audience may also include public health physicians and policy makers, especially given the current WHO HCV Elimination agenda.

(ii) Publications in peer-reviewed journals with a high impact. These will include Hepatology, Journal of Hepatology and Gastroenterology.

Research outputs will also be communicated to Patients with HCV infection and the general public through the study team's close links with the Hepatitis C Trust who are the largest patient support group in the UK. Members of the Hepatitis C Trust are part of the STOP-HCV/HCVRUK Steering Committees and have significantly influenced the research directions of HCVRUK. They are fully supportive of this application/study and have effective mechanisms for disseminating any advances in the management of HCV infection through an extensive network of patient support groups across the country. In addition, it is the policy of HCVRUK and STOP-HCV to list all publications on their respective websites.

The overarching objective of this work will be to inform clinicians, the scientific community, and commissioners of health care of the risks of and factors associated with progressive liver disease in patients with HCV-induced cirrhosis, in order to optimise patient management and healthcare planning.

Using the existing NHS linkage data provided, an analysis has been completed to assess the performance of various competing risk scores for predicting risk of hepatocellular carcinoma in patients with hepatitis C cirrhosis. See: https://www.jhep-reports.eu/article/S2589-5559(21)00160-9/fulltext.

An analysis has also been completed assessing the performance of a broad set of biomarkers with respect to predicting the risk of a severe liver-related event in patients with HCV cirrhosis. The biomarkers tested include routine laboratory tests genetic risk scores, and innovative biological markers that measure liver scarring. Ultimately, these biomarkers will help clinicians to identify in advance those patients who are likely to develop severe liver disease outcomes. This analysis should be published in the “Clinical and Translational Gastroenterology” shortly. The outcome events in this analysis (i.e. "severe liver events") are determined directly from NHS Digital data.

Other benefits will be forthcoming.

This Data Sharing Agreement relates to a research study on Hepatitis C Virus (HCV) cirrhosis of the liver, which is a sub-study of HCV Research UK (HCVRUK).

HCV Research UK (HCVRUK) is a consortium of many parties across the UK whose aim was to create a cohort of patients infected with the hepatitis C virus (HCV) in order to facilitate research into all aspects of this infection. The project was funded by the Medical Research Foundation (MRF). University of Glasgow's Centre for Virus Research are the Fund Holders and Managing Party and thereby responsible for execution of the Grant on behalf of the MRF. Nottingham University Hospitals NHS Trust are the Clinical Sponsors of the project and their R&I Department oversee the ethical execution of this study. Thus the University of Glasgow and Nottingham University Hospitals NHS Trust are Joint Data Controllers.

The day-to-day management of the data collected by HCVRUK is conducted by members of the HCVRUK Management Group. Asckey Data Services hosts the HCVRUK Research Clinical Database on secure systems and are also involved in general maintenance of the database and technical support. Asckey have no involvement with this Agreement and will not have access to the data provided by NHS Digital. The data requested under this agreement will be stored and processed separately to data held by HCVRUK. The data requested under this agreement will be disseminated to and stored by the Robertson Centre for Biostatistics at the University of Glasgow only. No additional storage locations will be used.

Approximately 12,000 patients have signed a consent form to join HCVRUK, of which approximately 4500 patients have been diagnosed with cirrhosis. Information including how patients contracted the infection, how long they have had it, any health complications as a result of the infection (including liver disease), and the treatments they receive to clear the infection is collected into a Clinical Research Database, which provides a resource to underpin a variety of specific research studies. Biological samples are stored in the HCVRUK Biobank. Researchers may apply to the HCVRUK Tissue and Data Access Committee (TDAC) for access to clinical data held on the HCVRUK database and/or samples. If permission is granted by TDAC, the clinical data/samples are supplied under a Material Transfer Agreement whereby any secondary data (eg generated by experimental manipulation of the biological samples) is returned to HCVRUK. HCVRUK do not share any NHS.

This application seeks to extend the numbers of patients with HCV-associated cirrhosis from the original 1264 co-enrolled within the STOP-HCV Cirrhosis study to include all cirrhotic patients within HCV Research UK (ie irrespective of whether or not each patient was co-enrolled within STOP-HCV). The enhanced patient numbers will increase both the number of critical clinical endpoints achieved (decompensation of liver disease, diagnosis of hepatocellular carcinoma) and this in turn will increase the number of variables that can be analysed for their value in predicting the development of complications of cirrhosis.

One research programme supported by HCVRUK is a Medical Research Council Stratified Medicine programme awarded in 2013 entitled Stratified Medicine to Optimise Treatment for Hepatitis C Virus infection (STOP-HCV) (reference MR/K01532X/1). One aim of STOP-HCV is to define the long term clinical outcomes of patients with HCV cirrhosis, including the long-term impact of the recently introduced direct-acting antiviral (DAA) therapy in patients with cirrhosis, and the factors which increase or decrease the risk of cirrhosis progression to life-threatening complications. To that end, a subgroup of around 4500 HCVRUK enrolled patients with HCV cirrhosis have been enrolled, with additional specific consent, into the STOP-HCV cirrhosis study (REC reference 14/WM/1128). STOP-HCV has generated extensive and detailed research data from these patients, including a number of novel diagnostic tests for liver disease progression. This study has already received NHS Digital Data for a subgroup of 1264 HCVRUK patients with cirrhosis. The project is now seeking to amend the application in order to receive historic data for 3300 new cohort members with liver cirrhosis from HCVRUK who are not in the STOP-HCV cirrhosis study.

For the purpose of this Agreement The University of Glasgow and Nottingham University Hospitals NHS Trust will act as joint data controllers. Nottingham University Hospitals NHS Trust will provide the cohort identifying data to NHS Digital. The University of Glasgow (Robertson Centre for Biostatistics) will receive and process the data from NHS Digital, as such they are listed as the sole data processor.

The project requires continued access to, and further disseminations of HES, diagnostic imaging, mortality and cancer data for HCVRUK participants with liver cirrhosis. Data from NHS Digital relating specifically and only to the subgroup of HCV Research UK patients with a diagnosis of liver cirrhosis (about 4264 individuals in total) will be used to answer a number of clinically relevant questions. These questions fall into four broad categories:

• Can the new (or existing) diagnostic tests for liver disease progression, be used to predict which patients with HCV cirrhosis liver disease will progress to life-threatening complications (including ascites [fluid in the abdomen], encephalitis [confusion, brain damage], variceal haemorrhage [bleeding] and primary liver cancer) within 5 years of follow up?

• Do new direct acting antiviral therapies for hepatitis C alter long-term clinical outcomes in addition to providing viral cure?

• Do other co-morbidities associated with HCV cirrhosis (especially alcohol and diabetes) result in increased morbidity and mortality from associated conditions such as cardiovascular disease?

• What patient and clinical factors are associated with uptake of liver cancer screening following viral cure? How can compliance to screening interventions be improved.

None of these questions can be robustly answered without complete and reliable data on hospital admissions, cancer diagnoses and death certification. The only mechanism which can provide access to robust and comprehensive data relating to a large and geographically widespread patient cohort is through NHS Digital. Therefore, there is no alternative or less intrusive means of achieving the purpose stated within this Agreement.

The lawful basis of processing falls under General Data Protection Regulation (GDPR) Article’s 6(1)(e) ‘Public Interest’ and 9 (2)(j). The processing of the data is in the public interest for a number of reasons. Premature mortality from liver disease in the UK continues to rise and finding better tools to predict which patients are at increased risk of developing cirrhosis complications is essential at an individual and healthcare level. Novel clinical algorithms which will arise from these data will allow individualised clinical management plans, with patients identified at increased risk of disease progression undergoing enhanced surveillance, and therefore achieving earlier diagnosis and treatment of life-threatening complications, whilst those patients at lower risk may be discharged from clinic. In addition to these benefits at an individual patient level, there are likely to be significant health economic benefits. Earlier diagnosis and treatment of potentially life-threatening complications may result in patients not needing to undergo expensive healthcare technologies such as liver transplantation. Appropriate relaxation of cancer surveillance in patients at very low risk will result in less clinic attendances and less surveillance intervention (ultrasound and MRI scanning) costs. Furthermore, this particular study has arisen at precisely the point of introduction of the expensive DAA drugs. Long-term liver-related outcome data, as intended in this proposal, will provide solid data to NHS England on the cost-effectiveness of the DAA revolution in HCV treatment.

The time span of data requested reflects the natural history of clinical events to occur. There are no ethical issues raised by dissemination and the level of data is proportionate to answer the questions posed. There are no foreseeable harmful effects to the public from release and publication of the intended research analyses outlined.

Answers to the aforementioned research questions will further improve understanding of HCV-related liver disease, and thus benefit patient care.

Specific outputs expected to be delivered in the next two years are:

1. Analysis to assess whether change in simple liver blood tests (ALT; AST; bilirubin etc) upon achieving hepatitis C viral cure can predict future occurrence of liver cancer and decompensated liver cirrhosis (completion of analysis, Sept-21).

2. Analysis to assess the uptake of 6 monthly ultrasound screening for early detection of HCC following hepatitis C viral cure (completion of analysis, Dec-21

3. Analysis to assess whether the risk of liver cancer changes with time since achievement of a hepatitis C virus sustained viral response. (Apr 21)

4. Analysis to externally validate the performance of various risk scores that estimate a patient’s individual risk of developing liver cancer. (Apr 21)

5. Analysis to identify genetic risk factors associated with all-cause mortality, cirrhosis decompensation and liver cancer among patients with HCV cirrhosis. (Dec 21).

These outputs will be disseminated through two main routes:

(i) Presentation at international liver meetings. Immediate targets are to submit novel findings arising from analysis of the STOP-HCV Cirrhosis study cohort data to the American Association for the Study of the Liver - The Liver Meeting® November 2021 and the European Association for the Study of the Liver International Liver Congress April 2022. The primary audience at the international meetings comprises academics, clinicians and possibly pharma representatives. However, the audience may also include public health physicians and policy makers, especially in light of the impending WHO HCV Elimination agenda.

(ii) Publications in peer-reviewed journals with a high impact. It is anticipated that the first publication will be a description of the characteristics of the STOP-HCV Cirrhosis study cohort ready for submission to the International Journal of Epidemiology. Further publications will relate to the utility or otherwise of a range of novel diagnostic tests in predicting liver disease progression in patients with HCV Cirrhosis. The project plans submissions to the journals Gastroenterology and Hepatology from the second quarter of 2021.

Research outputs will also be communicated to Patients with HCV infection and the general public through the study team's close links with the Hepatitis C Trust who are the largest patient support group in the UK. Members of the Hep C Trust are part of the STOP-HCV Steering Committee and have significantly influenced the research directions of STOP-HCV. They are fully supportive of this application/study and have effective mechanisms for disseminating any advances in the management of HCV infection through an extensive network of patient support groups across the country. In addition, it is the policy of HCVRUK and STOP-HCV to list all publications on their respective websites

The overarching objective of this work will be to inform clinicians, the scientific community, and commissioners of health care of the risks of and factors associated with progressive liver disease in patients with HCV-induced cirrhosis, in order to optimise patient management and healthcare planning.

Using the existing NHS linkage data provided, researchers have completed an analysis to assess the performance of a broad set of biomarkers with respect to predicting the risk of a severe liver-related event in patients with HCV cirrhosis. The biomarkers tested include routine laboratory tests genetic risk scores, and innovative biological markers that measure liver scarring. Ultimately, these biomarkers will help clinicians to identify in advance those patients who are likely to develop severe liver disease outcomes. This analysis is about to be submitted to the Hepatology for publication.

This agreement is for a research study on Hepatitis C Virus (HCV) cirrhosis of the liver, which is a sub-study of HCV Research UK (HCVRUK).

HCV Research UK (HCVRUK) is a consortium of many parties across the UK whose aim was to create a cohort of patients infected with the hepatitis C virus (HCV) in order to facilitate research into all aspects of this infection. The project was funded by the Medical Research Foundation (MRF). University of Glasgow's Centre for Virus Research are the Fund Holders and Managing Party and thereby responsible for execution of the Grant on behalf of the MRF. Nottingham University Hospitals NHS Trust are the Clinical Sponsors of the project and their R&I Department oversee the ethical execution of the project and the Principal Investigators for the Biomarker workstrand (of which the cirrhosis study is part) are based there. Thus the University of Glasgow and Nottingham University Hospitals NHS Trust are Joint Data Controllers.

The day-to-day management of the data collected by HCVRUK is conducted by members of the HCVRUK Management Group while Asckey Data Services Ltd hosts the HCVRUK Research Clinical Database on secure systems. The data requested under this agreement will be stored and processed separately to data held by HCVRUK. The data requested under this agreement will be disseminated to and stored by the Robertson Centre for Biostatistics at the University of Glasgow only.

Approximately 12,000 patients have signed a consent form to join HCVRUK. Information including how patients contracted the infection, how long they have had it, any health complications as a result of the infection (including liver disease), and the treatments they receive to clear the infection is collected into a Clinical Research Database, which provides a resource to underpin a variety of specific research studies. Biological samples are stored in the HCVRUK Biobank. Researchers may apply to the HCVRUK Tissue and Data Access Committee (TDAC) for access to data and/or samples. If permission is granted by TDAC, the data/samples are supplied under a Material Transfer Agreement whereby any secondary data (eg generated by experimental manipulation of the biological samples) is returned to HCVRUK.

One research programme supported by HCVRUK is a Medical Research Council Stratified Medicine programme awarded in 2013 entitled Stratified Medicine to Optimise Treatment for Hepatitis C Virus infection (STOP-HCV) (reference MR/K01532X/1). One aim of STOP-HCV is to define the long term clinical outcomes of patients with HCV cirrhosis, including the long-term impact of the recently introduced direct-acting antiviral (DAA) therapy in patients with cirrhosis, and the factors which increase or decrease the risk of cirrhosis progression to life-threatening complications. To that end, a subgroup of around 1200 HCVRUK enrolled patients with HCV cirrhosis have been enrolled, with additional specific consent, into the STOP-HCV cirrhosis study (REC reference 14/WM/1128). STOP-HCV has generated extensive and detailed research data from these patients, including a number of novel diagnostic tests for liver disease progression. This agreement relates to this sub-study only.

For this specific research project the joint Data Controllers are University of Glasgow and Nottingham University Hospitals NHS Trust. Nottingham University Hospitals NHS Trust will provide the cohort identifying data to NHS Digital and University of Glasgow (Robertson Centre for Biostatistics) will receive and process the data from NHS Digital.

The project requires HES, diagnostic imaging, mortality and cancer data for use in the STOP-HCV Cirrhosis study analysis. Data from NHS Digital relating specifically and only to the subgroup of HCV Research UK patients who are also co-enrolled into the STOP-HCV cirrhosis study (about 1,200 individuals) will be used to answer a number of clinically relevant questions. These questions fall into four broad categories:

• Can the new (or existing) diagnostic tests for liver disease progression, be used to predict which patients with HCV cirrhosis liver disease will progress to life-threatening complications (including ascites [fluid in the abdomen], encephalitis [confusion, brain damage], variceal haemorrhage [bleeding] and primary liver cancer) within 5 years of follow up?

• Do new direct acting antiviral therapies for hepatitis C alter long-term clinical outcomes in addition to providing viral cure?

• Do other co-morbidities associated with HCV cirrhosis (especially alcohol and diabetes) result in increased morbidity and mortality from associated conditions such as cardiovascular disease?

• What patient and clinical factors are associated with uptake of liver cancer screening following viral cure? How can compliance to screening interventions be improved.

None of these questions can be robustly answered without complete and reliable data on hospital admissions, cancer diagnoses and death certification. The only mechanism which can provide access to robust and comprehensive data relating to a large and geographically widespread patient cohort is through NHS Digital. Therefore, the data provided by NHS Digital are a critical aspect of delivering on this research.

Processing of the data is in the public interest for a number of reasons. Premature mortality from liver disease in the UK continues to rise and finding better tools to predict which patients are at increased risk of developing cirrhosis complications is essential at an individual and healthcare level. Novel clinical algorithms which will arise from the STOP-HCV Cirrhosis Study will allow individualised clinical management plans, with patients identified at increased risk of disease progression undergoing enhanced surveillance, and therefore achieving earlier diagnosis and treatment of life-threatening complications, whilst those patients at lower risk may be discharged from clinic. In addition to these benefits at an individual patient level, there are likely to be significant health economic benefits. Earlier diagnosis and treatment of potentially life-threatening complications may result in patients not needing to undergo expensive healthcare technologies such as liver transplantation. Appropriate relaxation of cancer surveillance in patients at very low risk will result in less clinic attendances and less surveillance intervention (ultrasound and MRI scanning) costs. Furthermore, this particular study has arisen at precisely the point of introduction of the expensive DAA drugs. Long-term liver-related outcome data, as intended in this proposal, will provide solid data to NHS England on the cost-effectiveness of the DAA revolution in HCV treatment.

The time span of data requested reflects the natural history of clinical events to occur. There are no ethical issues raised by dissemination and the level of data is proportionate to answer the questions posed. There are no foreseeable harmful effects to the public from release and publication of the intended research analyses outlined.

Answers to the aforementioned research questions will further improve understanding of HCV-related liver disease, and thus benefit patient care.

Specific outputs expected to be delivered in the next two years are:

1. Analysis to assess whether change in simple liver blood tests (ALT; AST; bilirubin etc) upon achieving hepatitis C viral cure can predict future occurrence of liver cancer and decompensated liver cirrhosis (completion of analysis, Sept-19).

2. Analysis to assess the relevance of both host and viral genetic variants vis-à-vis risk of liver cancer and decompensated cirrhosis following hepatitis C viral cure (completion of analysis, Sept-19).

3. Analysis to assess whether a polygenomic risk score for coronary artery disease predicts survival, decompensated cirrhosis and liver cancer in patients with hepatitis C viral cure (completion of analysis, Dec-19)

4. Analysis to assess the uptake of 6 monthly ultrasound screening for early detection of HCC following hepatitis C viral cure (completion of analysis, Dec-20)

All outputs will contain only data that is aggregated with small numbers suppressed in line with the HES Analysis Guide.

These outputs will be disseminated through two main routes:

(i) Presentation at international liver meetings. Immediate targets are to submit novel findings arising from analysis of the STOP-HCV Cirrhosis study cohort data to the American Association for the Study of the Liver - The Liver Meeting® November 2019 and the European Association for the Study of the Liver International Liver Congress April 2020. The primary audience at the international meetings comprises academics, clinicians and possibly pharma representatives. However, the audience may also include public health physicians and policy makers, especially in light of the impending WHO HCV Elimination agenda.

(ii) Publications in peer-reviewed journals with a high impact. It is anticipated that the first publication will be a description of the characteristics of the STOP-HCV Cirrhosis study cohort ready for submission to the International Journal of Epidemiology. Further publications will relate to the utility or otherwise of a range of novel diagnostic tests in predicting liver disease progression in patients with HCV Cirrhosis. The project plans submissions to the journals Gastroenterology and Hepatology in the second quarter of 2020.

Research outputs will also be communicated to Patients with HCV infection and the general public through the study team's close links with the Hepatitis C Trust who are the largest patient support group in the UK. Members of the Hep C Trust are part of the STOP-HCV Steering Committee and have significantly influenced the research directions of STOP-HCV. They are fully supportive of this application/study and have effective mechanisms for disseminating any advances in the management of HCV infection through an extensive network of patient support groups across the country. In addition, it is the policy of HCVRUK and STOP-HCV to list all publications on their respective websites

The overarching objective of this work will be to inform clinicians, the scientific community, and commissioners of health care of the risks of and factors associated with progressive liver disease in patients with HCV-induced cirrhosis, in order to optimise patient management and healthcare planning.

This agreement is for a research study on Hepatitis C Virus (HCV) cirrhosis of the liver, which is a sub-study of HCV Research UK (HCVRUK).

HCV Research UK (HCVRUK) is a consortium of many parties across the UK whose aim was to create a cohort of patients infected with the hepatitis C virus (HCV) in order to facilitate research into all aspects of this infection. The project was funded by the Medical Research Foundation (MRF). University of Glasgow's Centre for Virus Research are the Fund Holders and Managing Party and thereby responsible for execution of the Grant on behalf of the MRF. Nottingham University Hospitals NHS Trust are the Clinical Sponsors of the project and their R&I Department oversee the ethical execution of the project and the Principal Investigators for the Biomarker workstrand (of which the cirrhosis study is part) are based there. Thus the University of Glasgow and Nottingham University Hospitals NHS Trust are Joint Data Controllers.

The day-to-day management of the data collected by HCVRUK is conducted by members of the HCVRUK Management Group while Asckey Data Services Ltd hosts the HCVRUK Research Clinical Database on secure systems. The data requested under this agreement will be stored and processed separately to data held by HCVRUK. The data requested under this agreement will be disseminated to and stored by the Robertson Centre for Biostatistics at the University of Glasgow only.

Approximately 12,000 patients have signed a consent form to join HCVRUK. Information including how patients contracted the infection, how long they have had it, any health complications as a result of the infection (including liver disease), and the treatments they receive to clear the infection is collected into a Clinical Research Database, which provides a resource to underpin a variety of specific research studies. Biological samples are stored in the HCVRUK Biobank. Researchers may apply to the HCVRUK Tissue and Data Access Committee (TDAC) for access to data and/or samples. If permission is granted by TDAC, the data/samples are supplied under a Material Transfer Agreement whereby any secondary data (eg generated by experimental manipulation of the biological samples) is returned to HCVRUK.

One research programme supported by HCVRUK is a Medical Research Council Stratified Medicine programme awarded in 2013 entitled Stratified Medicine to Optimise Treatment for Hepatitis C Virus infection (STOP-HCV) (reference MR/K01532X/1). One aim of STOP-HCV is to define the long term clinical outcomes of patients with HCV cirrhosis, including the long-term impact of the recently introduced direct-acting antiviral (DAA) therapy in patients with cirrhosis, and the factors which increase or decrease the risk of cirrhosis progression to life-threatening complications. To that end, a subgroup of around 1200 HCVRUK enrolled patients with HCV cirrhosis have been enrolled, with additional specific consent, into the STOP-HCV cirrhosis study (REC reference 14/WM/1128). STOP-HCV has generated extensive and detailed research data from these patients, including a number of novel diagnostic tests for liver disease progression. This agreement relates to this sub-study only.

For this specific research project the joint Data Controllers are University of Glasgow and Nottingham University Hospitals NHS Trust. Nottingham University Hospitals NHS Trust will provide the cohort identifying data to NHS Digital and University of Glasgow (Robertson Centre for Biostatistics) will receive and process the data from NHS Digital.

The project requires HES, diagnostic imaging, mortality and cancer data for use in the STOP-HCV Cirrhosis study analysis. Data from NHS Digital relating specifically and only to the subgroup of HCV Research UK patients who are also co-enrolled into the STOP-HCV cirrhosis study (about 1,200 individuals) will be used to answer a number of clinically relevant questions. These questions fall into four broad categories:

• Can the new (or existing) diagnostic tests for liver disease progression, be used to predict which patients with HCV cirrhosis liver disease will progress to life-threatening complications (including ascites [fluid in the abdomen], encephalitis [confusion, brain damage], variceal haemorrhage [bleeding] and primary liver cancer) within 5 years of follow up?

• Do new direct acting antiviral therapies for hepatitis C alter long-term clinical outcomes in addition to providing viral cure?

• Do other co-morbidities associated with HCV cirrhosis (especially alcohol and diabetes) result in increased morbidity and mortality from associated conditions such as cardiovascular disease?

• What patient and clinical factors are associated with uptake of liver cancer screening following viral cure? How can compliance to screening interventions be improved.

None of these questions can be robustly answered without complete and reliable data on hospital admissions, cancer diagnoses and death certification. The only mechanism which can provide access to robust and comprehensive data relating to a large and geographically widespread patient cohort is through NHS Digital. Therefore, the data provided by NHS Digital are a critical aspect of delivering on this research.

Processing of the data is in the public interest for a number of reasons. Premature mortality from liver disease in the UK continues to rise and finding better tools to predict which patients are at increased risk of developing cirrhosis complications is essential at an individual and healthcare level. Novel clinical algorithms which will arise from the STOP-HCV Cirrhosis Study will allow individualised clinical management plans, with patients identified at increased risk of disease progression undergoing enhanced surveillance, and therefore achieving earlier diagnosis and treatment of life-threatening complications, whilst those patients at lower risk may be discharged from clinic. In addition to these benefits at an individual patient level, there are likely to be significant health economic benefits. Earlier diagnosis and treatment of potentially life-threatening complications may result in patients not needing to undergo expensive healthcare technologies such as liver transplantation. Appropriate relaxation of cancer surveillance in patients at very low risk will result in less clinic attendances and less surveillance intervention (ultrasound and MRI scanning) costs. Furthermore, this particular study has arisen at precisely the point of introduction of the expensive DAA drugs. Long-term liver-related outcome data, as intended in this proposal, will provide solid data to NHS England on the cost-effectiveness of the DAA revolution in HCV treatment.

The time span of data requested reflects the natural history of clinical events to occur. There are no ethical issues raised by dissemination and the level of data is proportionate to answer the questions posed. There are no foreseeable harmful effects to the public from release and publication of the intended research analyses outlined.

Answers to the aforementioned research questions will further improve understanding of HCV-related liver disease, and thus benefit patient care.

Specific outputs expected to be delivered in the next two years are:

1. Analysis to assess whether change in simple liver blood tests (ALT; AST; bilirubin etc) upon achieving hepatitis C viral cure can predict future occurrence of liver cancer and decompensated liver cirrhosis (completion of analysis, Sept-19).

2. Analysis to assess the relevance of both host and viral genetic variants vis-à-vis risk of liver cancer and decompensated cirrhosis following hepatitis C viral cure (completion of analysis, Sept-19).

3. Analysis to assess whether a polygenomic risk score for coronary artery disease predicts survival, decompensated cirrhosis and liver cancer in patients with hepatitis C viral cure (completion of analysis, Dec-19)

4. Analysis to assess the uptake of 6 monthly ultrasound screening for early detection of HCC following hepatitis C viral cure (completion of analysis, Dec-20)

All outputs will contain only data that is aggregated with small numbers suppressed in line with the HES Analysis Guide.

These outputs will be disseminated through two main routes:

(i) Presentation at international liver meetings. Immediate targets are to submit novel findings arising from analysis of the STOP-HCV Cirrhosis study cohort data to the American Association for the Study of the Liver - The Liver Meeting® November 2019 and the European Association for the Study of the Liver International Liver Congress April 2020. The primary audience at the international meetings comprises academics, clinicians and possibly pharma representatives. However, the audience may also include public health physicians and policy makers, especially in light of the impending WHO HCV Elimination agenda.

(ii) Publications in peer-reviewed journals with a high impact. It is anticipated that the first publication will be a description of the characteristics of the STOP-HCV Cirrhosis study cohort ready for submission to the International Journal of Epidemiology. Further publications will relate to the utility or otherwise of a range of novel diagnostic tests in predicting liver disease progression in patients with HCV Cirrhosis. The project plans submissions to the journals Gastroenterology and Hepatology in the second quarter of 2020.

Research outputs will also be communicated to Patients with HCV infection and the general public through the study team's close links with the Hepatitis C Trust who are the largest patient support group in the UK. Members of the Hep C Trust are part of the STOP-HCV Steering Committee and have significantly influenced the research directions of STOP-HCV. They are fully supportive of this application/study and have effective mechanisms for disseminating any advances in the management of HCV infection through an extensive network of patient support groups across the country. In addition, it is the policy of HCVRUK and STOP-HCV to list all publications on their respective websites

The overarching objective of this work will be to inform clinicians, the scientific community, and commissioners of health care of the risks of and factors associated with progressive liver disease in patients with HCV-induced cirrhosis, in order to optimise patient management and healthcare planning.

Yielded Benefits is not a requirement for new applications.