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Torque Teno Virus Load and Acute Rejection After Orthotopic Liver Transplantation

Simonetta, Federico MD, PhD1; Pradier, Amandine PhD1; Masouridi-Levrat, Stavroula MD1; van Delden, Christian MD2; Giostra, Emiliano MD3; Morard, Isabelle MD3; Mueller, Nicolas MD4; Muellhaupt, Beat MD5; Valli, Piero V. MD5; Semmo, Nasser MD6; Seebach, Jörg MD7; Chalandon, Yves MD1; Kaiser, Laurent MD2; Roosnek, Eddy PhD1 Swiss Transplant Cohort Study (STCS)

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doi: 10.1097/TP.0000000000001723
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Replication of torque teno virus (TTV), a nonpathogenic, highly prevalent anellovirus, increases considerably during immunesuppression.1,2 Recently, Schiemann and coworkers published the inverse association of TTV load with rejection after kidney transplantation.3 We report similar findings in 39 patients (median age, 60 years [range, 1-73 years]; male subjects, 59%) enrolled in the Swiss Transplant Cohort Study after orthotopic liver transplantation (OLT) for liver disease of viral (33%), toxic (10%), or other (57%) origins.

We measured TTV-DNA levels by real-time polymerase chain reaction4 at time of transplantation and at 6 and 12 months posttransplant for the 19 patients with available serum samples. Seventy-four healthy subjects served as controls (HC). TTV-DNA was detectable (detection limit 25 viral copies/mL of plasma) in 29 (74%) of 39 patients at transplantation, a prevalence similar to the one observed in controls (51/74, 69%; P = 0.8035; χ2 test). However, median TTV-DNA levels were significantly higher in OLT recipients (median, 4.54 × 103 copies/mL; range, 25-1.2 × 108) compared with controls (median, 1.7 × 102 copies/mL; range, 25-5.4 × 104; P = 0.0014, Mann–Whitney U test) (Figure 1A). As shown previously,1,2 TTV titers in OLT recipients increased significantly after transplantation (median, 2 × 106; range, 25-5.4 × 108 at 6 months; and median, 2.2 × 105; range, 25-1.7 × 107 at 12 months) (Figure 1A). We further assessed the relationship between TTV-loads at transplantation with the risk of biopsy-proven acute cellular graft rejection (Rejection Activity Index score ≥3 or ≥2 with significant necrosis) during the first year after transplantation. Interestingly, 1-year cumulative incidence of rejection in OLT recipients with detectable TTV-DNA plasma levels at transplantation was significantly lower (21% [95% confidence interval (CI), 8%-37%]) than in patients with undetectable TTV titers (70% [95% CI, 28%-90%]; P = 0.0042, Gray test; Figure 1B).

FIGURE 1
FIGURE 1:
TTV load kinetics and impact on the frequency of rejection episodes after OLT. A, TTV-DNA titers in OLT recipients (filled dots) compared with healthy controls (HC, white dots). Gray filled dots identify patients analyzed at time of transplantation (M0) exclusively. Black filled dots identify patients analyzed at time of transplantation (M0) and 6 (M6) and 12 months (M12) after transplantation. Comparison was performed using the Mann–Whitney U test, and P values are indicated when significant (P < 0.05). B, One-year biopsy-proven acute rejection cumulative incidence in patients displaying detectable (gray line) and undetectable (black line) TTV-DNA at transplantation. Cumulative incidence of rejection analysis was performed using Gray test with death without rejection as a competing event.

To account for factors with potential impact on TTV replication and rejection such as age, gender, HBV, HCV, and HIV serostatus, underlying disease, number of immunosuppressive drugs used, hepatic encephalopathy, and presence of human leukocyte antigen donor-specific antibodies, we performed a multivariate analysis using Fine-Gray proportional hazard regression for competing events. This analysis confirmed the reduced 1-year cumulative incidence of rejection in patients with detectable TTV titers at time of transplantation (HR, 9 × 10−3 [95% CI, 1 × 10−3 to 9.2 × 10−2; P = 0.00008]).

Our results in OLT recipients are in agreement with those reported by Schiemann et al for kidney transplant recipients and reinforce the results of De Vlaminck and coworkers who found that anellovirus levels in heart and lung transplant recipients with acute rejection episodes were lower than in nonrejecting patients.5 It is tempting to speculate that a higher immunocompetence in TTV-negative patients at transplantation could be responsible for the higher incidence of rejection episodes observed during the first year after transplantation.

Obviously, our study presents several limitations. First, because serological testing for TTV is currently unavailable, we cannot exclude that some patients are TTV-negative simply because they never have been infected. However, we do believe that the high prevalence of TTV in the population makes this unlikely. Second, the study remains somewhat incomplete because the lack of posttransplant serum samples precluded the analysis of a potential prognostic value of TTV titers after OLT. Larger prospective studies with more patients than in our retrospective pilot study are needed to assess whether monitoring TTV titers could help identifying patients at higher risk of acute rejection after OLT.

ACKNOWLEDGMENTS

This study has been conducted in the framework of the Swiss Transplant Cohort Study, supported by the Swiss National Science Foundation and the Swiss University Hospitals (G15) and transplant centers.

Swiss Transplant Cohort Study (STCS) Members: Rita Achermann, Patrizia Amico, John-David Aubert, Vanessa Banz, Guido Beldi, Christian Benden, Christoph Berger, Isabelle Binet, Pierre-Yves Bochud, Heiner Bucher, Thierry Carell, Emmanuelle Catana, Yves Chalandon, Sabina de Geest, Olivier de Rougemont, Michael Dickenmann, Michel Duchosal, Laure Elkrief, Thomas Fehr, Sylvie Ferrari-Lacraz, Christian Garzoni, Paola Gasche Soccal, Christophe Gaudet, Emiliano Giostra, Déla Golshayan, Karine Hadaya, Jörg Halter, Dominik Heim, Christoph Hess, Sven Hillinger, Hans H. Hirsch,Günther Hofbauer, Uyen Huynh-Do, Franz Immer, Richard Klaghofer, Michael Koller (Head of the data center), Bettina Laesser, Roger Lehmann, Christian Lovis, Pietro Majno; Oriol Manuel, Hans-Peter Marti, Pierre Yves Martin, Pascal Meylan (Head, Biological Samples Management Group), Paul Mohacsi, Philippe Morel, Ulrike Mueller, Nicolas J Mueller (Chairman, Scientific Committee), Helen Mueller-McKenna (Head, Local Data Management), Antonia Müller, Thomas Müller, Beat Müllhaupt, David Nadal, Manuel Pascual (Executive Office), Jakob Passweg, Juliane Rick, Eddy Roosnek, Anne Rosselet, Silvia Rothlin, Frank Ruschitzka, Urs Schanz, Stefan Schaub, Aurelia Schnyder, Christian Seiler, Susanne Stampf, Jürg Steiger (Head, Executive Office), Guido Stirnimann, Christian Toso, Christian Van Delden (Executive Office), Jean-Pierre Venetz, Jean Villard, Madeleine Wick (STCS Coordinator), Markus Wilhelm, and Patrick Yerly.

REFERENCES

1. Shang D, Lin Y, Rigopoulou I, et al. Detection of TT virus DNA in patients with liver disease and recipients of liver transplant. J Med Virol. 2000;61:455–461.
2. Béland K, Dore-Nguyen M, Gagné M-J, et al. Torque teno virus in children who underwent orthotopic liver transplantation: new insights about a common pathogen. J Infect Dis. 2014;209:247–254.
3. Schiemann M, Puchhammer-Stöckl E, Eskandary F, et al. Torque teno virus load-inverse association with antibody-mediated rejection after kidney transplantation. Transplantation. 2017;101:360–367.
4. Masouridi-Levrat S, Pradier A, Simonetta F, et al. Torque teno virus in patients undergoing allogeneic hematopoietic stem cell transplantation for hematological malignancies. Bone Marrow Transplant. 2016;51:440–442.
5. De Vlaminck I, Khush KK, Strehl C, et al. Temporal response of the human virome to immunosuppression and antiviral therapy. Cell. 2013;155:1178–1187.
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