Immune Monitoring by Torque Teno Virus Load in Addition to Virus-Specific T Cells After Pediatric Kidney Transplantation

Abstract Pharmacokinetic monitoring is insufficient to estimate the intensity of immunosuppression after kidney transplantation (Tx). The randomized controlled IVIST trial demonstrated that additional steering of immunosuppressive therapy by virus-specific CD4+ T cells (Tvis) is safe and reduces exposure to immunosuppressants. The adenovirus (ADV)-Tvis proved to be particularly suitable due to their stability and high prevalence. Another promising biomarker for post-Tx immunomonitoring is the Torque Teno virus (TTV) but pediatric data are very limited. This descriptive longitudinal analysis aimed to evaluate the post-Tx course of TTV load compared to Tvis levels after pediatric Tx. In the IVIST trial, 31 pediatric kidney recipients were randomized to the intervention group with Tvis-guided immunosuppression. The immunosuppressive therapy consisted of basiliximab, cyclosporine A (CsA), everolimus (Eve) and prednisolone. In 27 out of 31 intervention group patients, TTV-DNA was measured retrospectively in frozen plasma samples from 20 visits (1–24 months (mo) after Tx). Associations of TTV-DNA with ADV-Tvis and with immunosuppressants over the post-Tx period were evaluated using linear mixed models, adjusted for time since Tx and accounting for repeated measurements within patients. Mean TTV-DNA (n = 474) ±SD was 4.4 ± 1.3 log10 copies/ml (1.4 to 9.4 log10). TTV-DNA was associated with post-Tx follow-up time. Under intensive immunosuppression immediately after Tx, TTV-DNA increased, peaking at 3 mo post-Tx (5.5 ± 1.4 log10); after reduction of immunosuppression, TTV load decreased (6mo: 4.3 ± 1.1 log10; 16mo: 3.9 ± 0.9 log10). Mean ADV-Tvis levels showed a minimum at 2 mo post-Tx and increased over time: from 1.5 ± 1.1 cells/µl (2 mo) to 2.0 ± 1.8 (6 mo) and 2.4 ± 1.7 (22 mo). TTV-DNA showed overall positive correlations with mean daily doses and trough levels of CsA and Eve. The longitudinal analysis of TTV load presented an opposite post-Tx course compared to ADV-Tvis. TTV-DNA was associated with post-Tx follow-up time and with immunosuppressants after pediatric Tx. In comparison to ADV-Tvis minimum, the mean TTV-DNA showed a late peak at 3 mo post-Tx suggesting delayed response to drug dose changes.