Torque Teno Virus–guided monitoring of immunosuppressive therapy

Abstract

This editorial outlines the characteristics of Torque Teno Virus (TTV) and explores its potential applications in guiding immunosuppressive therapy for kidney transplantation and autoimmune kidney diseases. It also provides a concise overview of TTV's use as an immunometer in infectious and oncological diseases. The two main areas of application for immunosuppressive therapy in the field of nephrology are kidney transplantation on one hand, and the treatment of autoimmune diseases on the other. Treatment success in these areas depends on optimizing the type and amount of immunosuppression. Too much immunosuppression increases the risk of infections and oncological diseases, while too little immunosuppression leads to allograft rejection on one hand and insufficient control of the autoimmune disease on the other. To find the optimal immunosuppression level, it would be necessary to measure the individual immune function. Unfortunately, such an ‘immunometer’ has not been introduced into routine clinical care as yet. Quantification of the function of the immune system might also be of great value for post-transplant care of lung, heart and liver transplant recipients, for optimizing vaccine responses in immunosuppressed patients, for risk stratification of patients with infectious disease, and for optimizing immune-modulating agents in oncology (Fig. 1). Illustration of the role of TTV as an immunometer. On the left side of the scale, high levels of immunosuppression are indicated, shown by an elevated TTV load in the patient's blood, which correlate with a higher risk of infections in kidney transplant patients. Conversely, the right side depicts insufficient immunosuppression, characterized by low TTV load, resulting in a higher risk of organ rejection. The optimal balance is in the centre, where immunosuppression is well-regulated, and TTV load is in an optimal range. Additionally, the figure references various fields where TTV load might be indicative: CAR-T-cell therapy response and ICANS risk in bone marrow transplantation, DMARD response in autoimmune diseases, ICU admission risk due to COVID-19 and seroconversion after SARS-CoV-2 vaccination. The figure was adapted from the original provided by Manon Zuurmond and Joris Rotmans from the Department of Internal Medicine at the University Leiden, The Netherlands. ICU, intensive care unit. TTV monitoring is a promising innovative strategy for quantifying the immune function in kidney transplant recipients and thus might serve as such an immunometer [1]. TTV can be detected in up to 90% of healthy individuals and has not been linked to any human disease. The prevalence of TTV in immunocompromised patients after transplantation is up to 100% and the virus is unaffected by any conventional antiviral therapy. The TTV load in the blood is directly associated with the amount and type of immunosuppressive drugs administered to the transplant recipient and is thus indirectly associated with graft rejection, and infectious and oncologic disease. TTV-DNA is quantified via polymerase chain reaction (PCR) in various samples, including serum, plasma and whole blood. Currently, an in-house PCR developed by Maggi and colleagues and a commercially available In Vitro Medical Devices Regulation (IVDR)-labelled PCR are mostly in use, which can easily be set up in any microbiological laboratory [2]. Summarizing data from non-interventional single-centre case–control and cohort studies including adult kidney transplant recipients with calcineurin inhibitor (CNI)-based immunosuppression, an optimal range for TTV plasma load has been proposed for Months 4–12 after kidney transplantation. While a high TTV load indicates an increased risk for infection, and a low TTV load indicates a risk for allograft rejection, the immunosuppression might be personalized and balanced if TTV load is within the optimal range [1]. A randomized controlled interventional multinational trial—TTVguideIT—has recruited almost 300 kidney transplant recipients to test the value of TTV-guided immunosuppression based on this concept for risk stratification, and results are expected in 2026 [3]. This year, an adapted trial protocol will start to recruit kidney transplant recipients from Year 2 after transplantation in France TAOIST (TTV-guided mAnagement Of long-term ImmunosuppreSsion in kidney Transplantation). Further non-interventional studies have suggested that the optimal TTV load range, which has been defined for CNI-based immunosuppressive regimen, is also applicable for recipients treated with belatacept-based immunosuppression [4]. Hitherto it is not clear whether a similar TTV range can also be applied for patients with an mTor inhibitor–based regimen. Previous studies have consistently shown that TTV load peaks in Month 3–4 after initiation of immunosuppression in kidney transplant recipients. These finding prompted the analyses of TTV kinetics following dose adaptions of immunosuppressive drugs in post-transplant care. Recently, it has been described that a state of equilibrium in TTV load is not achieved earlier than 2 months after modifications in either mycophenolate acid (MPA) or CNI dosage [5, 6]. The promising results in the field of kidney transplantation have led to the expansion of the concept of a TTV-based immunometer to guide immunosuppression in autoimmune diseases. In the first multicentre prospective study lead by Daniel Aletaha, TTV load was analysed in patients with rheumatoid arthritis undergoing disease-modifying anti-rheumatic drug (DMARD) therapy. TTV load—and thus the level of immunosuppression—was highest in patients showing the most substantial treatment response [7]. More recently, a research group led by Andreas Kronbichler investigated whether TTV load could predict treatment response in patients with ANCA-associated vasculitis, analysing samples from the RAVE (Rituximab in ANCA-associated vasculitis) and RITAZAREM (Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease) trials. Preliminary results, presented at the American College of Rheumatology Convergence, demonstrated that a low TTV load—representing a low level of immunosuppression—was predictive for disease relapses in patients receiving rituximab- or cyclophosphamide-based therapy [8]. Future research should focus on defining TTV load cut-off values for the optimal treatment response of DMARDs in autoimmune disease and reduced infectious complications. Several studies have analysed the value of TTV-based immune monitoring in the context of the response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in solid organ transplant recipients. The team of Elisabeth Puchhammer-Stöckl retrospectively quantified plasma TTV load in samples from a prospective German multi-centre study aiming to evaluate the efficacy and safety of mRNA-based SARS-CoV-2 vaccines in kidney transplant recipients. Consistent with several other publications, TTV load was inversely associated with seroconversion rates. The researchers identified a TTV load cut-off above which there was little chance of seroconversion and no cellular response [9]. Considering the contradictory results regarding the effectiveness of temporarily stopping MPA to enhance vaccination response in kidney transplant recipients [5], an interventional study testing the effect of TTV-guided MPA cessation might be a promising approach. Another promising application for TTV-guided immune monitoring might be risk stratification during infectious disease. The group of Jérôme LeGoff recently presented data from a retrospective single-centre study [10]. Nasopharyngeal swabs from patients presenting to the emergency department with SARS-CoV-2 infection were retrospectively tested for TTV load. Notably, the cohort was unselected and thus included patients without immunosuppressive drug treatment. Interestingly, a high TTV load cut-off was identified as an independent risk factor for admission to the intensive care unit due to COVID-19. These data support the initiation of interventional studies to test the value of TTV-based triage in supporting medical personnel in making decisions about patient admission or therapy initiation in infectious disease scenarios. Recently, first data on TTV load in the context of chimeric antigen receptor T-cell (CAR-T) therapy have been presented by the group of David Navarro [11]. Patients who demonstrated a declined or stable TTV load between lymphodepletion and CAR-T infusion—indicating increasing or stable immune competence—exhibited better progression-free survival compared with those with rising TTV loads. After CAR-T cell infusion, a low TTV load at the onset of immune effector cell-associated neurotoxicity syndrome (ICANS) identified patients at risk of severe ICANS. These findings suggest that monitoring TTV load can predict both CAR-T efficacy and toxicity. The next step is to define an optimal range for TTV load increase peri-CAR-T therapy, balancing sufficient immune activation for therapeutic efficacy with the risk of overstimulation and consequent side effects. In addition to CAR-T therapy, the value of TTV load to guide checkpoint inhibitor therapy in oncologic disease is currently under investigation. Patients with high TTV loads, indicating reduced immune function, could benefit the most from these immune modulators. Conversely, patients who do not exhibit a decrease in TTV load following therapy might require increased drug doses or a change in medication. Finally, TTV load may be a promising candidate for monitoring drug adherence. In kidney transplantation, non-adherence is a significant barrier to adequate immunosuppression and limiting allograft survival. Recognizing this, medical guidelines recommend routine medication adherence monitoring in post-transplant care. Despite these recommendations, a definitive method for detecting non-adherence is yet to be established. TTV load reflects the exposure to immunosuppressive drugs over the previous 2–3 months, potentially offering greater sensitivity for detecting non-adherence compared with direct drug level measurements. To evaluate the efficacy of low TTV load in detecting non-adherence to immunosuppressive drugs post-kidney transplantation, the AdTorque study was designed [12]. This prospective single-centre study measured TTV load, self-reported adherence using the BAASIS (Basel Assessment of Adherence to Immunosuppressive Medication Scale) questionnaire, electronic drug monitoring (MEMS caps), pharmacy refill records, evaluation by a clinical psychologist and CNI trough level variations at six visits over 2 years post-transplant. The primary outcome was biopsy-proven graft rejection over a 4-year follow-up. Preliminary, unpublished analysis showed that patients with multiple instances of non-adherence, as defined by the BAASIS, had lower TTV loads compared with adherent patients. This suggests that low TTV loads in non-adherent patients might indicate insufficient immunosuppression. The full dataset analysis—to be published this year—aims to assess the value of TTV in detecting clinically significant non-adherence alongside other measures, to define an optimal screening strategy. TTV-based screening for non-adherence may also benefit clinicians treating patients with autoimmune kidney diseases, helping to distinguish between disease flares despite sufficient immunosuppression and the consequences of non-adherence. In summary, TTV load quantification is a promising and innovative strategy for monitoring the status of the immune system in solid organ transplantation, as well as autoimmune, infectious and oncologic diseases. Upcoming interventional randomized controlled trials will shed light on the value of TTV-based immune monitoring for routine clinical care in the coming years. So far, the concept of TTV-based immune monitoring has brought us one step closer to an immunometer, but there is still some way to go. We are grateful to Manon Zuurmond and Joris Rotmans from the Department of Internal Medicine at the University Leiden, The Netherlands, for providing the graphic used in Fig. 1. This work was funded by the Austrian Science Fund (grant number KLI1152; grant holder: G.B.) and the European Union Framework Programme for Research and Innovation Horizon 2020 (grant agreement ID 896932; project coordinator: G.B.). Conceptualization: G.B. Funding acquisition: G.B. Writing—original draft: F.H., S.K. and G.B. All authors critically revised, edited and approved the final version of the manuscript. G.B. received a fee for a talk at a scientific conference and the preparation of communication material on the TTV-RGENE PCR from bioMérieux.

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