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Valganciclovir Prophylaxis Versus Preemptive Therapy in Cytomegalovirus-Positive Renal Allograft Recipients: Long-term Results After 7 Years of a Randomized Clinical Trial

Witzke, Oliver, MD1; Nitschke, Martin, MD2; Bartels, Michael, MD3; Wolters, Heiner, MD4; Wolf, Gunter, MD5; Reinke, Petra, MD6; Hauser, Ingeborg, A., MD7; Alshuth, Ulrich, PhD8; Kliem, Volker, MD9

doi: 10.1097/TP.0000000000002024
Original Clinical Science—General

Background The VIPP study compared valganciclovir prophylaxis with preemptive treatment regarding efficacy, safety, and long-term graft outcome in cytomegalovirus (CMV)-positive (R+) renal transplant recipients.

Methods Multicenter, open-label, randomized clinical study with a 12-month study phase and a follow-up of up to 84 months. Patients in the prophylaxis group received 2 × 450 mg/d oral valganciclovir for 100 days adjusted to renal function. Preemptive treatment with 2 × 900 mg/d valganciclovir was initiated at a viral load of 400 CMV copies/mL or greater (polymerase chain reaction) and maintained over ≥14 days, followed by secondary prophylaxis. Patients were stratified by donor CMV IgG serostatus (donor CMV IgG positive [D+]/R+, donor CMV IgG negative [D−]/R+).

Results The 12-month results were reported previously (Witzke et al Transplantation 2012). The intent-to-treat/safety population comprised 148 patients in the prophylaxis (61.5% D+/R+) and 151 patients in the preemptive group (52.3% D+/R+). Overall, 47% patients completed the follow-up. Significantly fewer patients in the prophylaxis compared with preemptive group experienced a CMV infection or disease up to month 84 (11.5%; 95% confidence interval [95% CI], 6.8-17.8%] vs 39.7%; 95% CI, 31.9-48.0%; P < 0.0001 and 4.7%; 95% CI, 1.9-9.5% vs 15.9%; 95% CI, 10.5-22.7%; P = 0.002). Incidences of graft loss (7.4% vs 8.6%), death (9.5% vs 11.3%), rejection (29.1% vs 28.5%), and renal function (estimated glomerular filtration rate [mean ± SD]: 58.2 ± 26.3 vs 59.9 ± 25.7 mL/min per 1.73 m2) were not significantly different between prophylaxis and preemptive treatment. Tolerability was comparable between groups.

Conclusions Prophylaxis was more effective than the preemptive approach, applying a low-intense surveillance protocol in preventing CMV infection and disease in intermediate-risk patients. Both strategies were similarly effective in preventing graft loss and death under the conditions of this long-term trial with a threshold of 400 copies/mL for initiation of anti-CMV treatment.

In renal transplant recipients, 7-year follow up of a randomized clinical trial demonstrates that a strategy of prophylaxis is more effective than a preemptive strategy to prevent CMV infection and disease, but both strategies are similarly effective in preventing graft loss and death.

1 Department of Infectious Diseases and Department of Nephrology, University Duisburg‐Essen, Essen, Germany.

2 Transplantation Center, Medical Clinic I, University Hospital Schleswig-Holstein, Luebeck, Germany.

3 Department of General and Visceral Surgery, Helios Park Hospital, Leipzig, Germany.

4 Department of General and Visceral Surgery, University Hospital Muenster, Muenster, Germany.

5 MHBA Division of Nephrology, Department of Internal Medicine III, University Hospital Jena, Jena, Germany.

6 Department of Nephrology and Internal Intensive Care, Charité University Medicine Berlin, Berlin, Germany.

7 Department of Nephrology/Medical Clinic III, University Hospital, Goethe University Frankfurt, Frankfurt, Germany.

8 Roche Pharma AG, Medical Management Established Products, Grenzach-Wyhlen, Germany.

9 Department of Internal Medicine and Nephrology, Nephrology Center of Lower Saxony, Klinikum Hann. Muenden, Hann, Muenden, Germany.

Received 27 July 2017. Revision received 2 October 2017.

Accepted 21 October 2017.

ClinicalTrials.gov Identifier: NCT00372229.

The VIPP study was sponsored by Roche Pharma AG, Grenzach-Wyhlen, Germany.

The authors declare no conflicts of interest.

O.W. and M.N. contributed to data acquisition, data analysis and interpretation, manuscript preparation/editing, and manuscript review. M.B., H.W., and G.W. contributed to data acquisition, data interpretation, and manuscript review. I.A.H. contributed to the design of the study, data acquisition, data analysis and interpretation, and manuscript review. P.R. contributed to the design of the study, data acquisition, data interpretation, and manuscript review. U.A. contributed to data analysis and interpretation, manuscript preparation/editing, and manuscript review. V.K. contributed to the design of the study, data acquisition, data analysis and interpretation, manuscript editing, and manuscript review. O.W. has received research funds and/or honoraria for lectures and consultancy from Alexion, Astellas, Basilea, Bristol-Myers Squibb, Chiesi, Janssen-Cilag, MSD, Novartis, Pfizer, Roche and Shire. M.N. has received research funds and/or honoraria for lectures and consultancy from Alexion, Astellas, Chiesi, Roche and Sanofi-Aventis. M.B., H.W. and P.R. declare no conflict of interest. G.W. has received honoraria for lectures from Novartis and Roche. I.A.H. has received honoraria for lectures or travel grants from Alexion, Astellas, Chiesi, Hexal, Novartis, Roche, Sanofi and Teva. U.A. is an employee of Roche Pharma AG. V.K. has received honoraria for lectures from Astellas, DaVita, Pfizer, Raptor and Roche.

Correspondence: Oliver Witzke, MD, Department of Infectious Diseases, University Duisburg‐Essen, Hufelandstrasse 55, 45147 Essen, Germany. (Oliver.witzke@uk-essen.de).

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Cytomegalovirus (CMV) infection is one of the most common complications after solid-organ transplantation (SOT).1 Immunosuppression after transplantation facilitates CMV infection, which can result in symptomatic CMV disease with severe morbidity and occasional mortality.2 Possible indirect negative effects of CMV disease are acute allograft rejection and cardiovascular events among others.1-3 There has been increasing evidence that asymptomatic CMV infection is associated with acute allograft rejection,4 graft loss,5 mortality,6,7 and diabetes8 in SOT patients. Therefore, preventing CMV infection after SOT is important.

Preemptive therapy or prophylaxis with intravenous or oral ganciclovir, oral valganciclovir, or valacyclovir can be used to prevent CMV infection.9 Serologic anti-CMV immunoglobulin G (IgG) should be tested in all patients undergoing SOT because the serostatus of donor and recipient are predictors of the infection risk and help guide management.1 Recipients without immunity against CMV (R−) who receive an organ from a CMV-positive donor (D+) are at the highest risk of developing CMV disease through primary infection with the virus, transmitted by the allograft. CMV-positive recipients receiving an organ from a CMV-positive or -negative donor (D+/R+ or D−/R+) are at intermediate risk. Prophylaxis is favored in high-risk patients (D+/R−), although currently available data do not suggest a clear superiority regarding long-term graft and patient survival of neither prophylaxis nor preemptive therapy in renal transplant recipients of any risk category.1,10-12 Available study results for long-term graft survival comparing prophylactic and preemptive treatment are controversial: graft survival is either similar between both strategies13 or improved with either strategy over the other.14,15 Differences in the outcome of these studies may result from different monitoring intervals and the use of different antiviral drugs for prophylaxis and preemptive therapy.1

To further reveal which strategy is better to prevent CMV effects in intermediate-risk R+ patients, we carried out a prospective, randomized multicenter trial comparing valganciclovir prophylaxis versus preemptive therapy. After 1 year, the rates of CMV infection and CMV disease were significantly lower in the prophylaxis than in the preemptive group, particularly in the D+/R+ subgroup.16 In this article, we provide the long-term results of this study after an additional 6 years of follow-up including the effect of valganciclovir prophylaxis versus preemptive therapy on graft and patient survival.

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MATERIALS AND METHODS

Study Design and Patients

Study design and treatment of this open-label, prospective, randomized trial were previously described in detail.16 CMV infection prophylaxis with valganciclovir versus preemptive therapy after renal transplantation was compared in 22 centers in Germany and in 2 centers in Austria. The study included a recruitment period of 29 months, a study phase of 12 months after transplantation, and a follow-up period of 6 years. Independent ethics committees approved the study protocol. The study was conducted in accordance with the Helsinki Declaration and Good Clinical Practice guidelines. The clinical trial is registered at ClinicalTrials.gov (NCT00372229).

Eligible patients were adult CMV IgG seropositive kidney transplant recipients (R+) receiving immunosuppression during the first 14 days after transplantation with a calcineurin inhibitor, mycophenolate mofetil, and steroids. The allograft originated from a CMV IgG seropositive (D+) or seronegative (D−) living or cadaveric donor.

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Treatment

Patients in the prophylaxis group received oral CMV prophylaxis with 450 mg valganciclovir twice daily adjusted to renal function. Treatment started within 14 days after transplantation and continued until day 100 after transplantation. All patients were closely monitored for CMV virus load in the plasma by quantitative polymerase chain reaction (PCR) with Cobas Amplicor CMV Monitor (Roche Diagnostics GmbH, Mannheim, Germany). From January 2011 onward, DNA isolation was performed on a Chemagic MSM I instrument (PerkingElmer chemagen Technologie GmbH, Baesweiler, Germany), and DNA was amplified and evaluated with a CMV-DNA TaqMan assay on a LightCycler 480 (Roche Diagnostics GmbH). Blood samples were analyzed within 36 hours by a central laboratory to ensure effective management of patients with suspected CMV disease. The patient monitoring protocol was adapted from Kliem et al.15 Monitoring was performed at least once weekly during weeks 1 to 4, every 3 weeks between weeks 6 and 28, in week 40 and week 52, twice a year in the remaining follow-up phase and additionally as clinically indicated. As soon as 400 CMV copies/mL or greater15 were detected in the plasma, patients in the preemptive group received 900 mg valganciclovir twice daily for at least 14 days until PCR results were negative on 2 consecutive assessments within 1 week (<400 copies/mL). A secondary prophylaxis for 28 days with 1 × 900 mg valganciclovir followed.

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Outcome Measurements

Primary endpoints were the proportions of patients with active CMV infection (plasma PCR ≥400 copies/mL) and CMV disease (including CMV syndrome and tissue-invasive disease) within 12 months, the urine proteomic pattern at month 12, and time to graft loss up to 84 months. Results for the urine proteomic pattern will be described elsewhere. Secondary endpoints included proportions of patients with active CMV infection and disease during follow-up, acute graft rejection, patient survival, graft loss, renal function at month 12 and during follow-up, and adverse events (AEs). Days of hospitalization were recorded between days 7 and 364 after transplantation, overall, as well as separately for the stay at the transplantation unit, ward, intensive care unit, and rehabilitation unit.

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Statistics

Patients were randomized by the 2 prevention concepts (prophylaxis or preemptive therapy). Statistical analysis of the 1-year data was previously described.16 The patient number reported here slightly differs from the previous publication because the definition of the intent-to-treat (ITT) population had changed. The ITT population was defined to include all randomized patients. According the earlier definition, the ITT population included randomized patients who received at least 1 dose of the study medication and who had at least 1 measurement of the primary variable under study medication. The per-protocol population consisted of all patients of the ITT population who completed the study without major protocol violations; it excluded patients who terminated the study prematurely due to an AE with at least likely relation to the study medication or due to lack of efficacy.

A 3-step hierarchical test using a type I error of α = 4% was used to test for statistically significant differences between the 2 treatment arms (step 1, CMV infection within 12 months; step 2, CMV disease within 12 months; step 3, graft loss within 84 months). The sample size calculation was based on the third step of the hierarchic test procedure assuming a graft loss rate of 10% for patients with prophylaxis and 25% for patients with preemptive therapy.

Times to occurrence of the first CMV infection and to graft loss/death were analyzed for each treatment group using the method of Kaplan-Meier. Treatments were compared using the log-rank test. Categorical and continuous variables at months 12, 48 and 84—overall and by donor CMV IgG status (D+/R+, D−/R+)—were analyzed descriptively and compared between treatment groups using Fisher exact test or Wilcoxon rank sum test, respectively. A multivariate Cox proportional hazard model including CMV infection as a time-dependent covariate was used to assess the impact of CMV infection on the endpoints graft loss and death, as well as on the combined endpoint. Days of hospitalization were compared between the 2 treatment groups using descriptive methods and Wilcoxon rank-sum test. Missing entries regarding hospitalization in the different departments (transplantation unit, ward, intensive care unit, rehabilitation unit) and overall were defined as 0 days.

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RESULTS

Patient Population and Monitoring

The patient disposition of this prospective, randomized trial, conducted between May 2006 and October 2015, is provided in Figure 1. The ITT and safety population included all randomized patients (N = 299). The prophylaxis group contained 148 patients (91 [61.5%] D+/R+), and the preemptive group contained 151 patients (79 [52.3%] D+/R+) (Table 1). In total, 82 patients were excluded from the per-protocol population due to major protocol violations, mainly visit date differences (Figure 1). Discontinuation was reported for 60 patients (prophylaxis group, n = 31; preemptive group, n = 29) of the ITT/safety population during the first 12 months and for 98 patients (prophylaxis group, n = 46; preemptive group, n = 52) during the follow-up phase. The most common reasons for discontinuation were withdrawn consent and loss of follow-up.

FIGURE 1

FIGURE 1

TABLE 1

TABLE 1

Compliance with the CMV monitoring protocol was good with a low percentage of missed scheduled PCR assessments (prophylaxis group, 6.8%; preemptive group, 6.0%).

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Baseline Characteristics

Patient demographics and clinical characteristics in the 2 treatment groups at baseline are shown in Table 1. Overall, patients had a mean (± standard deviation) age of 52.7 ± 12.8 years (range, 21-76 years), and approximately twice as many males than females were included in this study. Demographic and clinical baseline characteristics were generally balanced between the treatment groups, except for some differences in clinical characteristics: the number of patients receiving a transplant from a living donor was higher in the prophylaxis than in the preemptive group (16.9% vs 8.6%). Additionally, more D+/R+ patients were included in the prophylaxis (61.5%) versus the preemptive group (52.3%). In both treatment groups, most patients did not have previous transplants (prophylaxis group, n = 125 [84.5%]; preemptive group, n = 128 [84.8%]). The most frequently documented underlying kidney diseases overall were glomerulonephritis (20.4%), adult polycystic kidney disease (14.4%), and IgA nephropathy (12.0%). Some between-group differences in the incidence of underlying kidney diseases were observed, for example, glomerulonephritis was less common in the prophylaxis than in the preemptive group (14.9% vs 25.8%).

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Efficacy

Significantly fewer patients of the prophylaxis group compared to the preemptive group had a CMV infection up to 12 months (10.8%; 95% confidence interval [95% CI], 6.3-17.0% vs 39.1%; 95% CI, 31.2-47.3%; P < 0.0001) as also described earlier.16 After the first 12 months, only 1 more patient with CMV infection was reported in the sixth study year in each group (Figure 2A). Thus, the between-group difference remained stable during the long-term follow-up (month 48: 10.8%; 95% CI, 6.3-17.0% vs 39.1%; 95% CI, 31.2-47.3%; month 84: 11.5%; 95% CI, 6.8-17.8% vs 39.7%; 95% CI, 31.9-48.0%; both P < 0.0001) (Table 2 with 12-month and 84-month data, Figure 2A) and was also evident in both donor subgroups. The majority of CMV infections occurred in the preemptive arm of D+/R+ patients (Table 2).

FIGURE 2

FIGURE 2

TABLE 2

TABLE 2

Significantly fewer patients of the prophylaxis group compared with the preemptive group had a CMV disease up to 12 months (4.7%; 95% CI, 1.9-9.5% vs 15.2%; 95% CI, 9.9-22.0%; P = 0.0033). Again, this difference remained stable during the long-term follow-up (month 48: 4.7%; 95% CI, 1.9-9.5% vs 15.2%; 95% CI, 9.9-22.0%; P = 0.0033; month 84: 4.7%; 95% CI, 1.9-9.5% vs 15.9%; 95% CI, 10.5-22.7%; P = 0.0020) (Table 2 with 12-month and 84-month data). A statistically significant difference between the prophylaxis and preemptive group was also observed in the subgroup with D+/R+ patients after 12, 48 (data not shown), and 84 months. Due to the small number of D−/R+ patients with CMV disease at the 3 timepoints (2.3%), the difference between the 2 treatment strategies was not statistically significant in this patient subgroup (Table 2).

No statistically significant differences between the 2 treatment strategies were observed for graft loss, death, rejection, and renal function up to month 84 (Table 2). However, incidences of graft loss and death were numerically lower in the prophylaxis group after 48 (data not shown) and 84 months (Table 2). Additionally, the Kaplan-Meier curve for the combined endpoint (graft loss and/or death), especially between months 24 and 72, shows that the number of patients who had lost their transplant or died tended to be lower for the prophylaxis group; however, the difference was not statistically significant (P = 0.4987) (Figure 2B).

A multivariate Cox proportional hazard model was used to assess the impact of CMV infection on the endpoints graft loss and death, as well as on the combined endpoint. The analysis yielded inconclusive results with a very broad confidence interval as the number of events was low. Thus, it was not possible to show whether or not a CMV infection may have an impact on any of the endpoints.

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Safety

In total, 145 (98.0%) patients of the prophylaxis group experienced 1796 AE episodes, and 146 patients (96.7%) of the preemptive group experienced 2009 AE episodes. The number of patients with AEs was balanced between treatment groups for most of the preferred terms (Table 3). Most frequently reported AEs overall were urinary tract infection (in 36.5% of patients), diarrhea (29.1%), leukopenia (25.8%), and increase in serum creatinine (25.1%). Slightly more patients in the prophylaxis than in the preemptive group experienced leukopenia (28.4 % vs 23.2%). Severity of leukopenia was mild or moderate, apart from 1 life-threatening case, related to immunosuppressive treatment, in the prophylaxis group that was resolved. In 1 patient of the prophylaxis group, treatment with granulocyte colony-stimulating factor was initiated to treat a possibly treatment-related moderate leukopenia. The vast majority of AE episodes was assessed as unrelated to the study drug (prophylaxis group, 87.0%; preemptive group, 95.5%). Because only 71 (47%) patients in the preemptive group received valganciclovir, the number of related AEs is not directly comparable between the 2 treatment groups. The number of patients with AEs leading to premature study discontinuation was comparable between the prophylaxis and the preemptive group (10.1% vs 9.9%). Up to month 84, 94 (63.5%) patients of the prophylaxis group and 96 (63.6%) patients of the preemptive group experienced serious AEs. Fatal AEs occurred in 3 patients of the prophylaxis group (myopathy and pancreatitis, acute cardiac failure, septic shock) and in 4 patients of the preemptive group (sepsis, septic shock, acute myocardial infarction, unknown reason). All fatal AEs were assessed as unrelated to the study drug.

TABLE 3

TABLE 3

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Hospitalization Time

The median duration of hospitalization, including the stay at the rehabilitation unit, between day 7 and day 364 in the ITT population tended to be shorter in the prophylaxis compared with the preemptive group (26.5 [range, 0-258] days vs 32.0 [range, 0-221] days, P = 0.2445). This difference was driven by a numerically shorter median stay at the ward in the prophylaxis group (10.0 [range, 0-199] days vs 13.0 [range, 0-177] days, P = 0.0584). For the per-protocol population, the P value for the difference between the prophylaxis and preemptive group concerning the stay at the ward was 0.0266 in favor of valganciclovir prophylaxis (10.0 [range, 0-199] days vs 15.0 [range, 0-177] days).

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DISCUSSION

Preemptive CMV therapy and prophylaxis are strategies to control CMV infection after SOT.1 There is no consensus which treatment is more effective to prevent symptomatic CMV disease and other indirect effects of CMV such as graft loss, especially for intermediate-risk patients (D+/R+ and D−/R+).1

This study is the largest and longest randomized study directly comparing prophylaxis and preemptive CMV treatment in intermediate-risk renal transplant patients. The numbers of patients with CMV infection and CMV disease were significantly lower using valganciclovir prophylaxis compared with preemptive therapy throughout the whole study period of 84 months after transplantation. However, viral load was not monitored weekly in the first 3 to 4 months after transplantation as recommended by the current guidelines from 2013.1 As discussed in the publication of the 1-year data, late-onset CMV infection and disease in the prophylaxis group was not observed.16 However, some CMV episodes might have been missed after week 28 due to less frequent monitoring (in weeks 40 and 52 and afterwards twice a year up to month 84 or additionally as clinically indicated).

CMV infection and disease are potential risk factors for acute allograft rejection4 and reduced long-term patient survival.6,7 The role of asymptomatic CMV infection on graft loss is still unclear. According a prospective cohort study with a median follow-up of 13.7 years involving 471 patients after kidney transplantation, early CMV infection after transplantation is a predictor of graft loss and overall mortality but not of death-censored graft loss.6,17 Several studies suggest that a high CMV viral load, more than the CMV infection per se, is related to irreversible sequelae. In a recent prospective cohort study with 180 participants, renal transplant recipients with a CMV viral load of 2000 copies/mL or greater (whole blood) were at increased risk for graft loss, irrespective of the time to onset.5 Likewise, a high viral load of 2000 copies/mL or greater (plasma) or greater than 20 infected lymphocytes per 100 000 leukocytes (whole blood) was associated with a poorer survival in a recent retrospective analysis of 233 older intermediate-risk (D+/R+) renal transplant recipients.7 High CMV DNAemia (>1043 copies/mL in whole blood, >6310 IU/mL) early after renal transplantation was also associated with irreversible renal impairment in another retrospective study with 264 renal transplant recipients undergoing preemptive anti-CMV therapy.18 However, because the test results for DNA copy numbers show a great variability between different laboratories and different specimens used, and because the international WHO standard from 2010 (IU/mL) was not applied in all studies, the direct comparison between these studies and VIPP is hampered.19

Probably due to the small number of events, the multivariate Cox proportional hazard model applied in this study, including CMV infection as a time-dependent variable, could not show whether or not a CMV infection may have an impact on graft loss and death.

In the present study, incidences of graft loss and death were numerically lower in the prophylaxis compared with the preemptive group after 48 and 84 months, yet a statistically significant difference was not reached. Although prophylaxis significantly prevented early CMV infection and disease, the long-term results did not show a superiority of valganciclovir prophylaxis over preemptive treatment for graft loss and death. This finding is supported by the similar renal function of the patients in both groups over the whole study duration. Our result is in agreement with previous meta-analyses of randomized controlled trials comparing the outcomes of prophylactic and preemptive CMV treatments in intermediate- and high-risk patients after renal transplantation (n = 560)20 or SOT in general (n = 2744).21 These did not show a significant difference between the 2 strategies for graft loss, death-censored graft loss, and mortality. However, the endpoints in these studies were assessed much earlier than in the present study. In contrast, our result is not consistent with the findings of Kliem et al15 who showed in a randomized trial with 138 patients a statistically significantly decreased incidence of long-term graft loss for ganciclovir prophylaxis compared with preemptive therapy after 4 years (7.8% vs 21.7%; P = 0.043). Notably, the difference was not statistically significant for death-censored graft loss.15 The differences in the study outcomes may result from the use of different antiviral drug forms and different patient characteristics. Due to the larger number of involved centers in the present study, the patient cohort was more heterogeneous compared with the patient cohort of the Kliem study, which involved only 3 German transplant centers.15 The cutoff for initiation of anti-CMV treatment in the preemptive arm was similar in both studies (≥400 copies/mL in plasma).15 However, the present study exclusively included intermediate-risk patients, whereas the Kliem study15 included 32% high-risk patients (D+/R−), which might at least partly explain the different results. The incidences of graft loss in the prophylaxis group were comparable between the present study (7.4%) and Kliem et al15 (7.8%). In contrast, the incidence of graft loss in the preemptive group was much lower in the present study (8.6%) than in the Kliem study (21.7%), although the follow-up was even 3 years longer in the present study. Two facts might have contributed to this discrepancy: first, the 2 treatment groups in the present study were not perfectly matched for donor status (D+/R+: prophylaxis, 61.5%; preemptive, 52.3%). Second, the prophylaxis group in the Kliem study had a lower HLA mismatch with a lower rate of treated rejections in the first year than the preemptive group (HLA mismatch: 1.98 ± 1.33 vs 2.56 ± 1.37; treated rejections: 19.2% vs 27.7%).15

With respect to tolerability, the study raised no new safety issues. Overall, the number of patients with AEs was balanced between the treatment groups. Only slightly more patients in the prophylaxis than in the preemptive group experienced leukopenia (28.4% vs 23.2%) which is a common adverse drug reaction of valganciclovir.22 Nevertheless, the number of premature study discontinuations due to AEs was similar in both groups.

The numerical reduction of hospitalization time in the prophylaxis compared with the preemptive group may be due to more effective prevention of CMV infection and disease and may lead to a subsequent reduction of treatment costs.

The limitations of the present study include the differences of the 2 treatment groups with respect to donor serostatus, which might have contributed to the failed statistical significance level for the effect of prophylaxis on graft loss and death. The lower than expected number of long-term events in both treatment groups clearly reduced the power to detect a between-group statistical difference for graft loss and death and to confirm the impact of CMV infections on both outcomes. Furthermore, viral load monitoring in the preemptive group was not as intense as recommended by the current guidelines.1

In summary, the present 7-year study showed a significant reduction of CMV infection and disease with valganciclovir prophylaxis compared with preemptive treatment with a low-intense CMV surveillance protocol in intermediate-risk renal transplant recipients. Both treatment strategies had a comparable tolerability profile, and they were similarly effective in preventing long-term graft loss and death under the conditions of this trial with a threshold for initiation of anti-CMV treatment of 400 copies/mL or greater in the preemptive group.

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ACKNOWLEDGMENTS

The authors had complete access to the data that support this publication. They directed and are fully responsible for all content and editorial decisions. Medical writing assistance was provided by Physicians World Europe GmbH, Mannheim, Germany, funded by Roche Pharma AG. Statistical analysis was performed by Therametrics AG, Essen, Germany, funded by Roche.

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REFERENCES

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