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

Background: Pharmacokinetic monitoring alone is insufficient to estimate the intensity of immunosuppression after kidney transplantation (Tx). The IVIST RCT demonstrated that additional steering of immunosuppressive therapy by virus-specific T cells (Tvis) is safe and reduces exposure to immunosuppressants. Another promising biomarker is the torque teno virus (TTV) load that was associated with risk for rejections and infections in some observational trials. We have now evaluated a possible benefit of additional analysis of TTV load to improve immune monitoring in the IVIST cohort. Methods: In the IVIST trial, 31 pediatric kidney recipients were randomized to the intervention group with additional steering by Tvis levels. The immunosuppressive regimen consisted of cyclosporine A (CsA), everolimus (Eve) and glucocorticoids. In 27/31 patients of the intervention group (11.7±3.3 years) a retrospective analysis of TTV-DNA was performed by PCR in frozen plasma samples obtained from 20 visits (1-24 months after Tx). TTV and Tvis changes from baseline levels have been evaluated by paired t-test, the correlations to CsA and Eve trough levels by Pearson correlation coefficients. Results: Median TTV-DNA of all plasma samples (n=474) was 2.5E4 cop/ml (2.3E1 to 2.8E9). High TTV loads were found under the intensified immunosuppression during the initial post-transplant period (2 mo post Tx: mean log number 11.6) and a significant TTV-decrease after reduction of immunosuppression (6 mo post Tx: 9.8, p=0.009; 22 mo post Tx: 9.3, p=0.005). In contrast, ADV-Tvis levels increased over time: from 1.47 cells/µl (2 mo post Tx) to 1.98 (6 mo post Tx, p=0.056) and 2.36 (22 mo post Tx, p=0.008). (Figure 1). TTV-load showed weak correlations to trough levels of CsA and Eve (24 mo post Tx: TTV vs. CsA r=0.33; vs. Eve r=0.37). Conclusion: The first combined analysis of TTV load and ADV-Tvis showed an opposite course over the first two years after Tx. Both biomarkers were related to the intensity of immunosuppression but with high interindividual variations and weak correlations to trough levels of immunosuppressants. Therefore, a combined post-Tx monitoring may have an additional value to identify over- and underimmunosuppression. Further randomized controlled trials are needed to confirm the benefit of a combined use of TTV and Tvis to optimize dosing of immunosuppressants.