The mean (±standard error) time to occurrence of first viremia was significantly longer in the prophylaxis group (335.7±6.1 days vs. 133.2±5.9 days, P<0.0001, prophylaxis vs. preemptive therapy; accounting for patients who were free of viremia beyond 12 months) (Table 3). In addition, Figure 1 displays the Kaplan-Meier analysis of time to first viremia during the initial 12 months after transplantation. This protective effect was also observed for both R+ groups, although a longer mean time to first viremia was seen in D+/R+ recipients receiving prophylaxis compared with D−/R+ patients (328.8±8.48 days vs. 192.5±4.88 days). For patients who experienced viremia, the viral burden (copies/mL, mean±SD) was similar for both treatment groups, but viral burden was lower in D+/R+ patients receiving prophylaxis (1819.9±1713.9 copies/mL vs. 4904.6±9850.6 copies/mL, P>0.05, prophylaxis vs. preemptive therapy). For patients in both the prophylaxis and preemptive groups, the rate of viremia did not change notably after approximately 200 days posttransplantation (Fig. 1). Creatinine clearance (mL/min, mean±SD) was also similar between treatment groups at 12 months posttransplantation. There was a trend toward more episodes of biopsy-proven acute rejection with prophylaxis (18.5% vs. 12.0%, P>0.05, prophylaxis vs. preemptive therapy), but a significantly higher rate of rejection was only observed in the D−/R+ group (21.4% vs. 8.3%, P=0.042, prophylaxis vs. preemptive therapy), with no difference in the D+/R+ group (16.7% vs. 15.4%, P>0.05, prophylaxis vs. preemptive therapy). Numerically, graft loss occurred more often in preemptive recipients (4 patients, 2.7% vs. 7 patients, 4.7% P>0.05, prophylaxis vs. preemptive therapy) (Table 3).
Within the last few years, evidence has grown that not only CMV disease but also asymptomatic (subclinical) CMV infection correlates with increased long-term morbidity, graft loss, diabetes, atherosclerosis, and mortality following SOT (3–7). Prophylaxis may prevent early organ damage or chronic graft alteration due to asymptomatic CMV infection, whereas patients on a preemptive regimen may experience subclinical CMV infection and CMV viremia (or more intense viremia) for longer periods before therapy is initiated (8). They may also be at higher risk due to the known immunomodulatory effects of CMV (14–16). Prophylaxis has been suggested as beneficial in preventing both the direct and indirect effects of CMV infection in transplant recipients (9, 17). Our results underline the importance of targeted CMV prevention based on CMV serostatus, and improvements in outcomes may also provide significant benefits in terms of overall costs of treatment per patient.
Overall, rejection rates between the two treatment cohorts did not differ; however, in the D−/R+ subgroup, there were significantly fewer rejection episodes (P=0.042) in the preemptive arm. Possibly, the CMV-negative serotype of the donor organ-in concert with the stringent prophylactic study protocol may have prompted investigators to moderate the immunosuppressive regimen, thus increasing the risk for rejection. However, this explanation is only hypothetical and the data available do not provide a definitive explanation for this observation (i.e., mycophenolate mofetil dosing seemed similar in both treatment groups; data not shown). As graft survival at 12 months was similar between treatment groups, the clinical relevance of this difference in rejection rates is unclear.
Overall tolerability was good for both treatments, with the lowest rate of serious adverse events in D+/R+ patients receiving prophylaxis. Rates of opportunistic infections were also similar between regimens, but higher rates of posttransplantation diabetes were observed with prophylaxis. No differences in the rates of any safety assessments by treatment group or R+ status were statistically significant (although the incidence of leukopenia and neutropenia was higher in the prophylaxis group). Graft loss at 12 months posttransplantation occurred more frequently for preemptive patients, but this did not reach statistical significance and no direct evidence of CMV induced chronic graft alteration was available for the current analysis. Patients have entered a long-term follow-up, where graft and patient survival along with a specific urine proteomic pattern of chronic graft alteration will be assessed (18–20).
This prospective, randomized, multicenter, open-label clinical trial was performed at 24 transplant centers in Germany and Austria. The study protocol was approved by the ethics committees at Hannover Medical School and was carried out according to the Helsinki Declaration and good clinical practice guidelines. The clinical trial was registered at ClinicalTrials.gov Identifier NCT00372229.
Renal graft recipients were centrally randomized into either study group (1:1 ratio) by phone (ClinIT AG, Freiburg, Germany). Patients were stratified by center and presence of immunosuppression induction therapy with depleting antibodies, such as antithymocyte globulin or OKT 3. All recipients were adults at intermediate risk for CMV disease with a positive CMV IgG serostatus (R+), but currently negative for CMV viral load. Other eligibility criteria were an absolute leukocyte count more than 3500 cells/μL, platelet count more than 100,000 cells/μL, hemoglobin more than 8.0 g/dL, and an estimated creatinine clearance of more than 10 mL/min before randomization, and a standardized immunosuppressive regimen including a calcineurin inhibitor, mycophenolate mofetil, and steroids. All patients had to be able to tolerate oral medication within 14 days posttransplantation. Patients were excluded if they were hypersensitive to acyclovir, valacyclovir, ganciclovir, valganciclovir or had evidence of malabsorption. Women who were pregnant, lactating, or considered at risk of pregnancy were not eligible. Every patient was informed about the nature and aim of the study, and written informed consent was obtained.
The study phase was 12 months posttransplantation, after which patients were treated according to the local site's standard of care. Recipients could complete a further written informed consent to participate in a long-term follow-up program for 4 years. CMV manifestations were defined based on standardized criteria as latent CMV infection (asymptomatic CMV IgG-positive serostatus), CMV infection (asymptomatic CMV viral load proven by CMV-PCR ≥400 CMV DNA copies/mL), CMV syndrome (unspecific clinical symptoms and CMV viral load), and CMV disease (tissue-invasive, proven CMV-related organ dysfunction or failure, and CMV viral load), respectively.
Sample size was based on the number of patients required to show a difference in graft loss between treatment groups. For the 12-month study phase, the following primary efficacy variables were analyzed: the proportion of patients with CMV infection within 12 months and the proportion of patients with CMV disease (including CMV syndrome and tissue-invasive disease) within 12 months. Secondary efficacy variables were the proportion of patients with CMV syndrome or disease, time to occurrence of first viremia, viral burden at viremia (area under the curve of plasma PCR), creatinine clearance at month 12, and the proportion of patients with treated and biopsy-proven acute rejection episodes within 12 months. For the primary endpoint analysis, the Fisher exact test was used. For the time to occurrence of first viremia Kaplan-Meier methods (24) were used; for all other variables descriptive statistics were prepared. An initial two-step hierarchical test procedure was planned using a global type I error of α=5%; first the difference between the two treatment groups in the proportion of recipients with CMV infection within 12 months was tested, followed by the difference between the two treatment groups in the proportion of patients with CMV disease within 12 months (including CMV syndrome and tissue-invasive disease). The difference in proportions of patients with CMV viremia or disease at 12 months was calculated along with the 95% CI. All analyses were performed by treatment and risk subgroups (donor [D]/recipient [R] CMV serostatus) for the intent-to-treat population (consisting of randomized and treated patients where the primary variable was measured at least once under study medication). Additional analyses of long-term graft and patient survival are planned after the completion of the follow-up phase. Only 12-month data from the initial study phase are presented in this article, and an extended test procedure investigating influence on graft loss and proteomic pattern is planned during follow-up and at study end (25).
Safety analysis was based primarily on the incidence of serious adverse events and the evaluation of hematological parameters (including incidence of leukopenia and neutropenia during the first year), the proportion of patients with opportunistic infections within 12 months, patient and graft survival up to the first year, the proportion of patients with posttransplant diabetes mellitus according to fasting glucose, and the incidence of CMV infection not responding to valganciclovir or ganciclovir treatment. For the comparison of safety variables, the Fisher exact test was used.
The authors thank Prof., Dr. Volker Kliem (Department of Nephrology, Lower Saxony Center for Nephrology, Transplantation Center, Hann. Muenden, Germany) for critical discussion and review of this manuscript, and Keith Dawes, Ph.D. (PRA International, Reading, UK) for medical writing support.
The study group was as follows: Universitätsklinikum Aachen, Medizinische Klinik II, Nephrologie und klinische Immunologie (Eitner, Floege, Mühlfeld, Lepper, Rauen, Dahmen, Michaelis, Kranz); Charité-Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Nephrologie und Intensivmedizin, Campus Virchow (Reinke, Babel, Schaeffner, Bachmann, Böhnisch, Schweiar, Eibl, Schammann, Hampel, Bold, Hinrichs, Lübeck, Sefrin); Universitätsklinikum Düsseldorf, Klinik für Nephrologie (Voiculescu, Dierkes, Königshauser, Zgoura, Won, Vonend, Siekierka-Harreis, Tiedtke, Dübbers); Universitätsklinikum Erlangen, Medizinische Klinik IV, Nephrologie (Koch, Nonnast-Daniel, Zapf, Pressmar, Buchholz, Opgenoorth, Beck, Teichmann, Jacobi, Hohenstein, Krauss, Streubert, Semprich, Alberth, Weißbrod, Metzeova); Universitätsklinikum Essen, Zentrum für Innere Medizin, Klinik für Nieren- und Hochdruckkrankheiten (Witzke, Pietruck, Kribben, Türk, Schütz, Michell, Nürnberger, Bruck, Feldkamp, Combe, Hörbelt, Tyczynski, Wieneke, Graf, Augustiniak, Schüssler, Behrendt, Huke, Quandt); Klinikum der Johann-Wolfgang-Goethe Universität, Med. Klinik III/Nephrologie (Hauser, Scheuermann, Goßmann, Asbe-Vollkopf, Pliquett, Kachel, Jung, Holzmann, Zimmermann, Henning); Medizinische Hochschule Hannover (Klempnauer, Neipp, Grannas, Schwarz, Haller, Timrott, Merkel, Bode, Scheuer, Erdbrügger, Richter, Emmanouilidis, Wagner, Becker, Kaudel, Beckmann, Reichert, Richter, Kleine, Bittscheidt, Hecker, Kespohl, Müller-Schöner, Koczur, Pfeiffer, Geyer, Mogilevskaja, Ike, Ruggenini, Bahlmann); Nephrologisches ZentrumNiedersachsen, Innere Medizin/Nephrologie (Kliem, Burg, Schocke, Riedel); Universitätsklinikum Jena, Klinik für Innere Medizin III, Abteilung Nephrologie (Wolf, Ott, Gerth, Marx, Traut, Busch, Ulbricht, Sämann, Hartwig, Martin); Universitätsklinikum Leipzig, Zentrum für Chirurgie, Klinik f. Viszeral-, Thorax- u. Gefäßchirurgie (Bartels, Schreiber, Weimann, Quante, Thelen, Jentzsch, Fischer, Linnert, Gnodtke, Reiche); Universitätsklinikum Schleswig-Holstein, Campus Lübeck/Medizinische Klini I, Transplantationszentrum (Nitschke, Kramer, Meier, Derad, Kodal, Schlieter); Klinikum der Universität München, Chirurgische Klinik u. Poliklinik Großhadern, Transplantationschirurgie (Rentsch, Wendler, Eder); Universitätsklinikum Münster, Klinik und Poliklinik für Allgemeine Chirurgie (Wolters, Bahde, Menningen, Pankratious, Kebschull, Irmscher, Utech, Palmes, Anthoni, Eissing, Lamann); Klinikum der Universität Regensburg, Klinik und Poliklinik für Innere Medizin II, Nephrologie (Banas, Kammerl, Böger, Götz, Emmer, Kühn, Müller, Conrad); Universitätsklinikum Tübingen, Klinik für Allgemeine, Viszoral- u. Transplantationschirurgie (Nadalin, Thiel, Knubben, Witte, Wichmann, Templin, Wagner, Walter); Universitätsklinikum Würzburg, Medizinische Klinik und Poliklinik I, Abteilung Nephrologie (Lopau, Swoboda, Kirchner); Universitätsklinikum Eppendorf, Zentrum für Innere Medizin, 3. Medizinische Klinik (Stahl, Thaiss, Tenschert, Vernauer, Lange-Hüsingen, Kinzler, Wittenburg, Passoter, Bürgel, Gebhardt); Klinikum Rechts der Isar der, Technischen Universität München (Lutz, Thorban, Valentin, Riediger, Sollinger, Seibel, Schuster, Engelhardt, Schossow); Uniklinikum Köln, Innere Medizin IV, Nephrologie (Teschner, Prenzel, Yavuzyasar, Hörl, Schiffer-Oberländer); Charité-Universitätsmedizin Berlin, Medizinische Klinik IV für Nephrologie, Campus Benjamin Franklin (van der Giet, Straub-Hohenblaicher, Tölle, Westkämper, van der Giet); Klinikum Bremen-Mitte GmbH, Innere Medizin III (Zantvoort, Meyer-Jürgens); Landeskrankenhaus-Universitätskliniken Innsbruck, Universitätsklinik für Chirurgie (Pratschke, Bösmüller, Bergmann, Neyer, Siegele); and Medizinische Universität Wien, Univeritätsklinik für Innere Medizin III, Klein. Abt. f. Nephrologie u. Dialyze (Hörl, Schmaldienst, Plischke).
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