A multicentre, patient- and assessor-blinded, non-inferiority, randomised and controlled phase II trial to compare standard and torque teno virus-guided immunosuppression in kidney transplant recipients in the first year after transplantation: TTVguideIT

Abstract

Background Immunosuppression after kidney transplantation is mainly guided via plasma tacrolimus trough level, which cannot sufficiently predict allograft rejection and infection. The plasma load of the non-pathogenic and highly prevalent torque teno virus (TTV) is associated with the immunosuppression of its host. Non-interventional studies suggest the use of TTV load to predict allograft rejection and infection. The primary objective of the current trial is to demonstrate the safety, tolerability and preliminary efficacy of TTV-guided immunosuppression. Methods For this purpose, a randomised, controlled, interventional, two-arm, non-inferiority, patient- and assessor-blinded, investigator-driven phase II trial was designed. A total of 260 stable, low-immunological-risk adult recipients of a kidney graft with tacrolimus-based immunosuppression and TTV infection after month 3 post-transplantation will be recruited in 13 academic centres in six European countries. Subjects will be randomised in a 1:1 ratio (allocation concealment) to receive tacrolimus either guided by TTV load or according to the local centre standard for 9 months. The primary composite endpoint includes the occurrence of infections, biopsy-proven allograft rejection, graft loss, or death. The main secondary endpoints include estimated glomerular filtration rate, graft rejection detected by protocol biopsy at month 12 post-transplantation (including molecular microscopy), development of de novo donor-specific antibodies, health-related quality of life, and drug adherence. In parallel, a comprehensive biobank will be established including plasma, serum, urine and whole blood. The date of the first enrolment was August 2022 and the planned end is April 2025. Discussion The assessment of individual kidney transplant recipient immune function might enable clinicians to personalise immunosuppression, thereby reducing infection and rejection. Moreover, the trial might act as a proof of principle for TTV-guided immunosuppression and thus pave the way for broader clinical applications, including as guidance for immune modulators or disease-modifying agents. Trial registration EU CT-Number: 2022-500024-30-00

Quantification of Torque Teno Virus Load to Monitor Short-term Changes in Immunosuppressive Therapy in Kidney Transplant Recipients

“…These promising results prompted the development of an ongoing multicentric randomized controlled interventional trial to assess TTV-guided immunosuppression in KTRs during the first-year posttransplantation. 11…”

The kinetics of Torque Teno virus plasma load following calcineurin inhibitor dose change in kidney transplant recipients

“…Our work might also have impact on planned interventional clinical trials on TTV-guided immunosuppression. [6][7][8] A significant reduction in TTV load following a CNI dose decrease was observed, whereas the rise in TTV load following a CNI dose increase did not reach the predefined level of statistical significance.…”

“…Currently, three randomized controlled trials are recruiting over 500 kidney and lung transplant recipients in seven European countries to test the value of TTV‐guided immunosuppression, with results expected from 2024 onwards 6–8 . Until then, TTV load cut‐off values for the risk stratification of graft rejection and infections based on observational studies might be applied for routine post‐transplant care 9–11 …”

“…This finding, in conjunction with previously published data on MPA pause, recommends the interpretation of TTV load not earlier than 2 months after changes in immunosuppression. Ongoing interventional trials will provide further insight into the dynamics of TTV load following adaptation of immunosuppression [6][7][8]. AUTHOR CONTRIBUTIONSFlorina Regele: Conceptualization; investigation; data curation; methodology; visualization; writing-original draft.…”

Respiratory torque teno virus load at emergency department visit predicts intensive care unit admission of SARS‐CoV‐2 infected patients

“…However, its presence in blood is indicative of immune function, and TTV load is currently being investigated in clinical trials for adjusting immunosuppression in solid organ transplant cases to prevent opportunistic infections and graft rejection. [8][9][10][11] The respiratory tract stands as a hypothesized primary entry site for initial infection and serves as a frequent shedding source. 12 TTV is detectable in respiratory samples from nearly all individuals.…”