Herpesvirus Immunology in Solid Organ Transplant Recipients - Liver Transplant Study (HISTORY)

Liver transplantation is the only curative treatment of end-stage liver disease, and every year, around 60 patients undergo liver transplantation in Denmark. Immunosuppressive therapy is necessary to avoid rejection of the transplanted organ.

Over 90% of adults have been infected with at least one herpesvirus, and it is characteristic for herpesviruses that after a first-time infection, the virus remains dormant in the body and may reactivate, particularly if the host is immunosuppressed. An effective immune response against reactivation depends highly on T cells, but T cells are suppressed by immunosuppressive drugs given to organ transplant recipients. Infections caused by herpesviruses are therefore very common in organ transplant recipients, and particularly two herpesviruses, cytomegalovirus (CMV) and varicella-zoster virus (VZV) pose challenges after transplantation.

CMV causes significant morbidity in transplant recipients, contributes to increased mortality and may contribute to loss of the transplanted organ. CMV infections occur in around 40% of liver transplant recipients within a year of transplantation. VZV causes chickenpox at first-time infection and shingles at reactivation. VZV is the second-most common infection in transplant recipients and occurs in around 9% of liver transplant recipients each year. Organ transplant recipients are at higher risk for disseminated disease with complications compared to immunocompetent persons.

A limited number of drugs exist that reduce the risk of and treat CMV infection, but they may cause significant adverse events, and drug resistance is emerging. To avoid CMV infection, some liver transplant recipients receive prophylactic therapy, but due to toxicity, new treatment modalities are warranted. This requires knowledge about herpesvirus specific T cell function in liver transplant recipients, which currently is limited.

The aim of this study is to provide an in-depth description of the protective immune response and immunological risk factors for CMV and VZV infections in liver transplant recipients and to identify patients at high risk in order to provide a platform for future treatment modalities against CMV and VZV infections in liver transplant recipients.

Study Overview

• Status: Active, not recruiting
• Conditions: Varicella Zoster Virus Infection; Cytomegalovirus Infections; Liver Transplant; Complications

Detailed Description

The Herpesvirus Immunology in Solid Organ Transplant Recipients - Liver Transplant Study (HISTORY) is a prospective cohort study that aims to provide in-depth characterisation of the protective immune response and immunological risk factors for CMV and VZV infections in liver transplant recipients and to identify patients at high risk of infection based on clinical and immunological risk factors. All adult patients enlisted for liver transplantation at the Copenhagen University Hospital - Rigshospitalet will be invited to participate regardless of indication for transplantation.

At study entry, participants will fill out a questionnaire regarding health and medication use. Blood samples will be collected at study entry when enlisted for transplantation, at pre-defined intervals after transplantation, and if primary infection with or reactivation of CMV or VZV occurs during follow-up. Health data will be collected from hospital records and national registries.

Blood samples will be separated into peripheral blood mononuclear cells (PBMC) and plasma and stored in a biobank for analysis of PBMC phenotype and function, concentrations of inflammatory markers and mediators, CMV and VZV viral load and serology and other in-depth immunological analyses. Analyses will be performed at the Technical University of Denmark.

• Study Type: Observational
• Enrollment (Estimated): 80

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Department of Infectious Diseases, Copenhagen University Hospital - Rigshospitalet
  • Copenhagen, Denmark, 2100
    • Department of Surgical Gastroenterology, Copenhagen University Hospital - Rigshospitalet
  • Lyngby, Denmark, 2800
    • Department of Health Technology, Technical University of Denmark

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

All adults enlisted for liver transplantation at Copenhagen University Hospital - Rigshospitalet (N = around 60 per year) will be invited to participate.

Description

Inclusion Criteria:

• Enlisted for liver transplantation at Copenhagen University Hospital - Rigshospitalet
• Aged 18 years or older

Exclusion Criteria:

• Inability to understand the study information

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Liver transplant recipients; All adults enlisted for liver transplantation at Copenhagen University Hospital - Rigshospitalet (N = around 60 per year) will be invited to participate regardless of indication for liver transplantation. These participants are expected to undergo a liver transplantation and will continue in the study after the procedure.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency, phenotype and function of CMV- and VZV-specific T cells (descriptive)	Including: TCR clonotypes, cell surface markers and cytokine profile of T cell populations specific towards immunodominant CMV and VZV epitopes.	1.5 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Primary CMV infection	10 years
VZV reactivation	10 years
CMV reactivation	10 years

Collaborators and Investigators

• Sponsor: Susanne Dam Nielsen, MD, DMSc
• Collaborators: Rigshospitalet, Denmark; Technical University of Denmark
• Investigators: Study Director: Annemette Hald, RN, Department of Infectious Diseases, Copenhagen University Hospital - Rigshospitalet; Study Director: Sunil K Saini, MSc, PhD, Department of Health Technology, Technical University of Denmark; Principal Investigator: Susanne D Nielsen, Professor, MD, DMSc, Department of Infectious Diseases, Copenhagen University Hospital - Rigshospitalet; Principal Investigator: Sine R Hadrup, Professor, MSc, PhD, Department of Health Technology, Technical University of Denmark; Study Director: Moises Alberto Suarez Zdunek, MD, Department of Infectious Diseases, Copenhagen University Hospital - Rigshospitalet; Study Director: Sebastian R Hamm, BSc, Department of Infectious Diseases, Copenhagen University Hospital - Rigshospitalet; Study Director: Allan Rasmussen, MD, Department of Surgical Gastroenterology, Copenhagen University Hospital - Rigshospitalet; Study Director: Jens G Hillingsø, MD, PhD, Department of Surgical Gastroenterology, Copenhagen University Hospital - Rigshospitalet; Study Director: Christian R Pedersen, MD, Department of Surgical Gastroenterology, Copenhagen University Hospital - Rigshospitalet

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2023
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2033

Study Registration Dates

• First Submitted: September 3, 2022
• First Submitted That Met QC Criteria: September 3, 2022
• First Posted (Actual): September 8, 2022

Study Record Updates

• Last Update Posted (Actual): April 3, 2025
• Last Update Submitted That Met QC Criteria: April 2, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: Inflammation; Cytomegalovirus; T-Lymphocytes; Liver Transplantation; Major Histocompatibility Complex; Herpesvirus 3, Human; Immunodominant Epitopes
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Virus Diseases; DNA Virus Infections; Herpesviridae Infections; Varicella Zoster Virus Infection; Infections; Communicable Diseases; Herpes Zoster; Cytomegalovirus Infections
• Other Study ID Numbers: H-22039226; 0073947 (Other Grant/Funding Number: Novo Nordisk Foundation)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No