Infection, Cancer, Rejection, Kidney Transplantation
Conditions
Keywords
TTV, Biomarker, immunosuppression, precision medicine, kidney transplantation
Brief summary
Long-term outcomes in kidney transplantation remain a significant challenge, as complications such as donor-specific antibodies (DSA), antibody-mediated rejection, infections, and cancer increasingly threaten graft and patient survival over time. The development of non-invasive biomarkers to guide the management of therapeutic immunosuppression beyond the first year post-transplantation is therefore a crucial unmet need. Torque Teno Virus (TTV), a non-pathogenic virus with a high prevalence worldwide, has emerged as a promising biomarker in this context. Its replication inversely reflects immune control by T cells, correlating with the depth of therapeutic immunosuppression. Additionally, its slow replication kinetics make TTV DNAemia a useful marker for evaluating patient adherence to immunosuppressive treatments. The TAOIST study tests whether longitudinal monitoring of TTV DNAemia every three months, starting from the second year after transplantation, can guide the personalization of immunosuppressive therapy. The primary endpoint is the time to the first occurrence of complications linked to inadequate immunosuppression, including dnDSA, biopsy-proven rejection, infection, cancer, or graft loss. Secondary objectives include evaluating the acceptability of TTV DNAemia among healthcare professionals and assessing its cost-effectiveness compared to standard care. An ancillary objective examines the link between TTV DNAemia and the immunosuppressant possession ratio (IPR) to explore its potential as a marker of treatment adherence.
Interventions
BIOLOGICALTTV DNAemia
Every 3 months, one sample added at the same time (7mL) of a routine laboratory analysis for TTV DNAemia
Completed every 6 months and each time a complication of interest occurs
BIOLOGICALBiological tests
Biological tests as routine care procedure (creatinine, CNI pre-dose trough level) will be performed every 6 months
Sponsors
BioMérieux
Hospices Civils de Lyon
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
SINGLE (Investigator)
Masking description
TTV DNAemia will be measured every 3 months for all patients but the results will not be communicated to the physicians for patients from the control group.
Intervention model description
Prospective, interventional, multicentric, open-label, parallel group, superiority randomized controlled trial. Kidney transplant recipients from the 4 enrollment centers will be randomly assigned with a 1:1 allocation into experimental and control groups between 12- and 48-months post-transplantation, and prospectively followed for 36 months for the occurrence of a complication due to inadequate (over or under) immunosuppression.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult ≥ 18 years-old * Recipient of a kidney allograft (third graft at most) * 12 to 48 months post-transplantation * Stable graft function (defined as: delta creatininemia over the previous 6 months \< 20% and proteinuria \< 30mg/mmol) * On maintenance immunosuppression, which includes CNI (cyclosporin or tacrolimus) and MMF (Cellcept or Myfortic) with or without corticosteroids * Detectable TTV DNAemia at enrollment * No circulating DSA in solid phase assay * Undetectable BKV DNAemia at enrollment * Written informed consent
Exclusion criteria
* Recipient of an HLA identical graft * Mutiple organ transplantation or functional transplant other than kidney * Maintenance immunosuppression that includes a mTOR inhibitor, belatacept or imurel * Presence of histological sign of active rejection (i+t \> 2 and g+cpt \> 2) on graft biopsy performed within 3 months before enrollment * Uncontrolled infection at inclusion * Infection requiring hospitalization or vaccination within 3 months before inclusion * Pregnant, unwillingness to practice adequate contraception or patient with a pregnancy plan during 3 years of study * Person not affiliated to a social security scheme or beneficiary of a similar scheme * Person subject to a legal protection measure (guardianship, curatorship) or deprived of liberty
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Compare the time from inclusion to first complication of inadequate immunosuppression between the experimental group, whose treatment is tailored on quarterly TTV viral load results, and the control group. | through study completion, an average of 6 years | Time from inclusion to occurrence of the first complication of inadequate immunosuppression: development of dnDSA, biopsy-proven rejection, infection, cancer, graft loss. Patients lost to follow-up or died without an event before will be right censored at this date. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Compare the rate of complications of inadequate immunosuppression between patients in the experimental and control groups. | through study completion, an average of 6 years | Number of complications of inadequate immunosuppression/patient/month of follow-up |
| Describe the nature and timing of various complications of inadequate immunosuppression in the experimental and control groups. | through study completion, an average of 6 years | Percentage of patients (at 36 months) and time to first complication for each of the complications of interest: development of dnDSA, biopsy-proven rejection, infection, cancer, graft loss. |
| Compare the proportion of patients with adequate immunosuppressive therapy between the experimental and control groups. | through study completion, an average of 6 years | Percentage of patients with TTV viral load between 3.8 and 5.1 log cp/ml at the majority (\>6/12) of quarterly routine controls. |
| Proportion of patients with at least one complication of inadequate immunosuppression between the experimental and control groups at 36 months | through study completion, an average of 6 years | Percentage of patients with at least one complication of inadequate immunosuppression during the 36 months of follow-up. |
| Model the impact of variations in dose and residual rates (pre-dose trough levels or AUC) of the various immunosuppressive drugs on TTV viral load. | every 3 months | Joint analysis of the evolution of dose variations, residual immunosuppression rates of immunosuppressive drugs and TTV viral load. |
| Evaluate how nephrologists and biologists feel about using the new test in clinical practice. | 6th year | Questionnaires specific to each sub-populations (nephrologists and biologists) using open-ended questions and Likert scale-coded responses. |
| Assess the cost-effectiveness of the intervention compared to standard care at 36 months from the French Health care System perspective | through study completion, an average of 6 years | Cost-effectiveness ratio (ICER) is defined as the difference in cost between the intervention and the standard care, divided by the difference in their effect (QALY). |
| Compare the proportion of quarterly systematic checks of TTV DNAemia in the target between patients in the experimental and control groups. | Every 3 months | Percentage of quarterly routine TTV viral load tests between 3.8 and 5.1 log cp/ml. |
Countries
France
Contacts
Primary ContactOlivier THAUNAT, Professor MD, PhD
Outcome results
None listed