Periodic Reporting for period 3 - TTV GUIDE TX (PERSONALISATION OF IMMUNOSUPPRESSION BY MONITORING VIRAL LOAD POST KIDNEY TRANSPLANTATION - A RANDOMISED CONTROLLED PHASE II TRIAL)
Reporting period: 2023-11-01 to 2025-04-30
Our project is establishing a tool to quantify the activity of the immune system in kidney transplant patients and thereby reducing infections and organ rejections.
End stage renal disease (ESRD) causes a high socioeconomic burden for citizens and the healthcare system in Europe. If the kidneys stop working, a kidney transplant can restore the kidney function. However, the immune system would recognize the new kidney as foreign and attack it. Therefore kidney-transplant recipients need drugs to reduce the function of their immune system. These drugs are called immunosuppressive drugs. If the patients take too many of these drugs though, their immune system gets weak, and they get other life-threatening infections.
Therefore, transplant physicians need a tool to quantify the activity of the immune system and optimize the drug dose. The recently discovered TT virus (TTV) might be able to do this job: TTV is naturally occurring in the blood of almost every healthy person and every kidney transplant recipient, but it causes no disease. If the immune system is strong, the TTV load is low; this indicates a risk for organ rejection. If the immune system is weak, the TTV load is high; this indicates a risk for infection.
The quantification of the TTV load in the blood of kidney transplant recipients might help optimize immunosuppressive drugs and thus reduce infections and rejection. Within the TTVguideTX project TTV-guided dosing of immunosuppressive drugs is being tested in a clinical trial including hundreds of kidney transplant recipients from all over Europe. Once established in routine clinical care, TTV-guidance might reduce thousands of infections and kidney transplant rejection each year. In the future the TTV might not only help kidney transplant recipients but also patients with liver, heart and lung transplantation and guide therapy in autoimmune, infectious, and oncologic diseases.
The main aim of the project therefore can be summarised in demonstrating the safety and preliminary efficacy of TTV-guided dosing of immunosuppressive drugs in kidney transplant recipients. In parallel, the scientific rationale for the routine clinical application of a commercially available TTV assay will be provided.
End stage renal disease (ESRD) causes a high socioeconomic burden for citizens and the healthcare system in Europe. If the kidneys stop working, a kidney transplant can restore the kidney function. However, the immune system would recognize the new kidney as foreign and attack it. Therefore kidney-transplant recipients need drugs to reduce the function of their immune system. These drugs are called immunosuppressive drugs. If the patients take too many of these drugs though, their immune system gets weak, and they get other life-threatening infections.
Therefore, transplant physicians need a tool to quantify the activity of the immune system and optimize the drug dose. The recently discovered TT virus (TTV) might be able to do this job: TTV is naturally occurring in the blood of almost every healthy person and every kidney transplant recipient, but it causes no disease. If the immune system is strong, the TTV load is low; this indicates a risk for organ rejection. If the immune system is weak, the TTV load is high; this indicates a risk for infection.
The quantification of the TTV load in the blood of kidney transplant recipients might help optimize immunosuppressive drugs and thus reduce infections and rejection. Within the TTVguideTX project TTV-guided dosing of immunosuppressive drugs is being tested in a clinical trial including hundreds of kidney transplant recipients from all over Europe. Once established in routine clinical care, TTV-guidance might reduce thousands of infections and kidney transplant rejection each year. In the future the TTV might not only help kidney transplant recipients but also patients with liver, heart and lung transplantation and guide therapy in autoimmune, infectious, and oncologic diseases.
The main aim of the project therefore can be summarised in demonstrating the safety and preliminary efficacy of TTV-guided dosing of immunosuppressive drugs in kidney transplant recipients. In parallel, the scientific rationale for the routine clinical application of a commercially available TTV assay will be provided.
During the last 48 months
• The project was successfully and timely coordinated, monitored, reported and administered.
• The clinical trial protocol and the registration in the EU registry for clinical trials (CTIS) was completed, the trial initiated at all centres, and 260 patients recruited. On May 26 the trial officially ended with the last patient visit in Vienna, Austria.
• The Ethical, Legal and Social Issues study has been designed and approved in all clinical centers and data collection is almost finished. Initial results have been presented.
• Specific training on the inclusion of sex and gender in biomedical research as well as therapeutic misconception and informed consent have been provided.
• All virology departments participating in the study received validation for their appropriate use of the TTV quantification assay as highlighted by the External Quality Assessment program.
• Reliable TTV load quantification from patient samples was confirmed throughout the trial by continuous internal quality control and external quality assessment.
• Patient safety was reviewed at of the Data Safety Monitoring Board and no objections were raised against the continuation of the study.
• Numerous communication and dissemination actions were taken to maximise the project’s visibility and impact, resulting in over 25 scientific publications during this period, reaching over 40,000 participants via over 40 scientific conferences, workshops, webinars, trade shows, and lectures. Continuous contact was established with patient organisations in all countries with actively recruiting centers as well as the European umbrella organistations for kidney transplant patients EKPF. Outreach activities to the general public were intensified. Project coordination, monitoring, reporting, and quality assurance was effectively set in motion at the project start and continued supporting the project partners. Members of the Ethics and Governance Council (EGC) were chosen, nominated, and meetings took place frequently. Recommendations by the EGC members were implemented into the project.
• The project was successfully and timely coordinated, monitored, reported and administered.
• The clinical trial protocol and the registration in the EU registry for clinical trials (CTIS) was completed, the trial initiated at all centres, and 260 patients recruited. On May 26 the trial officially ended with the last patient visit in Vienna, Austria.
• The Ethical, Legal and Social Issues study has been designed and approved in all clinical centers and data collection is almost finished. Initial results have been presented.
• Specific training on the inclusion of sex and gender in biomedical research as well as therapeutic misconception and informed consent have been provided.
• All virology departments participating in the study received validation for their appropriate use of the TTV quantification assay as highlighted by the External Quality Assessment program.
• Reliable TTV load quantification from patient samples was confirmed throughout the trial by continuous internal quality control and external quality assessment.
• Patient safety was reviewed at of the Data Safety Monitoring Board and no objections were raised against the continuation of the study.
• Numerous communication and dissemination actions were taken to maximise the project’s visibility and impact, resulting in over 25 scientific publications during this period, reaching over 40,000 participants via over 40 scientific conferences, workshops, webinars, trade shows, and lectures. Continuous contact was established with patient organisations in all countries with actively recruiting centers as well as the European umbrella organistations for kidney transplant patients EKPF. Outreach activities to the general public were intensified. Project coordination, monitoring, reporting, and quality assurance was effectively set in motion at the project start and continued supporting the project partners. Members of the Ethics and Governance Council (EGC) were chosen, nominated, and meetings took place frequently. Recommendations by the EGC members were implemented into the project.
The measurement of TTV load is a novel, innovative and holistic concept that allows for global assessment of the immune system and, thus, goes beyond state of the art. There have been no major improvements in immunosuppressive drug efficacy and safety realised in the recent years and no novel compounds are on the horizon. The personalisation of existing drugs is a novel and innovative concept in solid organ transplantation though. Thus, the optimisation of drugs via TTV personalisation is a promising strategy.
In Europe, the prevalence of kidney transplantation recipients is 500k and the incidence of kidney transplantation is 30k per year. The percentage of patients suffering from clinically relevant infections is 10% per year and the 5-year death rate is 10%, with 15% of deaths due to infections. The 5-year graft loss rate is 20%, with 50% lost due to rejection, and the percentage of patients suffering from acute rejection in the first year after transplantation is 15%. In total, 50k kidney transplant recipients suffer from infections and 1500 die due to infection each year, 3000 kidney grafts are lost due to rejection per year in the first 5 years and 4000 patients experience acute rejection within the first year after transplantation in Europe. The anticipated 20% reduction in rejection and infection rates by TTV-guided immunosuppression would prevent 10k infections, 300 deaths due to infection, 800 rejections and 600 graft losses in Europe per year.
Lower infection and rejection rates achieved through optimisation of immunosuppression will result in reduced hospitalisation and harm due to the side effects of antimicrobial and anti-rejection therapy. The prolongation of graft survival reduces the need for dialysis, which is a very burdensome procedure for ESRD patients, and thus improvs quality of life. Improved graft survival would also reduce the number of patients re-entering the waiting-list for a kidney transplant after terminal graft failure, thereby shortening the waiting- time for ESRD patients on the waiting list for a suitable kidney. These changes would result in significant improvement in health-related quality of life for ESRD patients.
The assessment of an individual patient’s immune function enables their clinician to personalise immunosuppression, thereby benefiting patients with ESRD. Moreover, the project will act as a proof of principle for TTV-guided immunosuppression and thus pave the way for broader clinical application: for example, emerging oncologic therapies, including checkpoint inhibitors that enhance the immune function and thus control tumor growth, or biological disease-modifying agents in rheumatologic disease might also benefit from TTV guidance. In addition, TTV-guided therapy might be applicable to transplantation of other solid organs, including heart, lung and liver. Immunosuppressed transplant recipients represent one of the most fragile cohorts when it comes to emerging, community-acquired respiratory viruses, since even mild pathogens can replicate if they are not kept in control by the immune system.
In Europe, the prevalence of kidney transplantation recipients is 500k and the incidence of kidney transplantation is 30k per year. The percentage of patients suffering from clinically relevant infections is 10% per year and the 5-year death rate is 10%, with 15% of deaths due to infections. The 5-year graft loss rate is 20%, with 50% lost due to rejection, and the percentage of patients suffering from acute rejection in the first year after transplantation is 15%. In total, 50k kidney transplant recipients suffer from infections and 1500 die due to infection each year, 3000 kidney grafts are lost due to rejection per year in the first 5 years and 4000 patients experience acute rejection within the first year after transplantation in Europe. The anticipated 20% reduction in rejection and infection rates by TTV-guided immunosuppression would prevent 10k infections, 300 deaths due to infection, 800 rejections and 600 graft losses in Europe per year.
Lower infection and rejection rates achieved through optimisation of immunosuppression will result in reduced hospitalisation and harm due to the side effects of antimicrobial and anti-rejection therapy. The prolongation of graft survival reduces the need for dialysis, which is a very burdensome procedure for ESRD patients, and thus improvs quality of life. Improved graft survival would also reduce the number of patients re-entering the waiting-list for a kidney transplant after terminal graft failure, thereby shortening the waiting- time for ESRD patients on the waiting list for a suitable kidney. These changes would result in significant improvement in health-related quality of life for ESRD patients.
The assessment of an individual patient’s immune function enables their clinician to personalise immunosuppression, thereby benefiting patients with ESRD. Moreover, the project will act as a proof of principle for TTV-guided immunosuppression and thus pave the way for broader clinical application: for example, emerging oncologic therapies, including checkpoint inhibitors that enhance the immune function and thus control tumor growth, or biological disease-modifying agents in rheumatologic disease might also benefit from TTV guidance. In addition, TTV-guided therapy might be applicable to transplantation of other solid organs, including heart, lung and liver. Immunosuppressed transplant recipients represent one of the most fragile cohorts when it comes to emerging, community-acquired respiratory viruses, since even mild pathogens can replicate if they are not kept in control by the immune system.