Asymptomatic CMV reactivation has been associated with notorious effects on morbidity and mortality in renal transplantation recipients.1–3 CMV risk is determined according to the overall immunosuppression status as a result of host conditions such as age, co-morbidity, and genetic factors. However, the two most relevant risk factors depend on the CMV serological status, which has the highest incidence among high-risk (donor (D)+/recipient (R)−) and intermediate-risk groups (R+/D+, R+/D−),4 as well as on the selected immunosuppression protocol.5 Clinical studies have demonstrated important differences between anti-thymocyte globulin (thymoglobulin) and basiliximab with regard to efficiency, particularly for outcomes such as biopsy-proven acute rejection, delayed graft function, graft loss, and death.6–10 Induction with thymoglobulin causes profound and long term CD4+ T cell depletion increasing the risk of CMV11,12; however, the impact of basiliximab is less clear.13,14 Clinical trials comparing the two drugs in different populations to assess the risk of CMV infection or disease onset have generally provided sparse evidence of significant differences; however, these findings have been difficult to interpret due to inclusion of multiples CMV risk groups.6,9,15–17

Since the introduction of CMV prophylaxis, disease incidence was reduced from greater than 60% to less than 30% in the first three months post-transplant.2,18,19 Two strategies for preventing CMV disease have been adopted: (1) universal prophylaxis with administration of an antiviral agent to all transplant recipients, or (2) a preemptive strategy that administers an antiviral agent only when a laboratory-confirmed infection is found during a scheduled screening. Preemptive therapy was found to be effective compared to placebo; however, its effectiveness relative to universal prophylaxis is unclear due to significant heterogeneity of the published studies.20

International consensus guidelines on CMV management in solid organ transplantation recommend the use of universal prophylaxis over preemptive therapy for high-CMV-risk patients21; however, recommendations for seropositive recipients vary, particularly in the context of varying induction therapies. Few studies have evaluated the efficiency of preemptive therapy in this population. Our study's aim was to evaluate the effectiveness of preemptive therapy in two renal transplantation cohorts, induced with low dose thymoglobulin or basiliximab at two transplantation centers in Colombia.

Outcomes: CMV infection, CMV disease, mortality, acute rejection, renal function and histological findings.

Our study provides the first preemptive strategy-based analysis of seropositive recipients with a comparison of two different induction strategies.

This retrospective analysis found that preemptive therapy via two different induction strategies appeared to have a significant impact in the prevention of CMV disease in CMV R+ renal transplantation recipients (3.6% in the basiliximab group and 2.1% in the thymoglobulin group). These results were similar to the recent report of a study of 1239 patients from a multicenter prospective cohort in Switzerland; a 4.4% incidence of disease onset was observed after implementing a preemptive strategy in CMV seropositive transplant recipients; however, the Swiss study did not compare the outcomes associated with different induction modalities.22

Some guidelines recommend that all renal transplantation recipients, except in cases of CMV D−/R−, receive antiviral prophylaxis treatment.23–25 There is evidence regarding the efficiency of antiviral prophylaxis among CMV R+ recipients compared to placebo/no treatment26; however, only recently has the efficiency of a preemptive strategy been compared with the efficiency of antiviral prophylaxis in CMV R+.27–29 In a retrospective study, Couzi and collaborators highlighted that preemptive therapy and universal prophylaxis were equally effective at preventing CMV disease onset in CMV R+ transplant recipients who received thymoglobulin induction.27 In contrast; Witzke, in a prospective randomized clinical trial, compared the efficiencies of preemptive therapy and universal prophylaxis in seropositive recipients. They found that CMV disease was significantly higher in recipients receiving the preemptive strategy (12.7% vs. 4.1%; p=0.01). This was a higher incidence compared to other studies. Interestingly, only 3% of the patients received induction with thymoglobulin.28 Weclawiak conducted a retrospective study to evaluate the efficiency of preemptive ganciclovir therapy vs valganciclovir prophylaxis in CMV R+ patients who received different induction treatments (52% basiliximab and 25% thymoglobulin; preemptive group) and found that prophylactic treatment significantly reduced the risk of CMV disease (9.8% vs. 2.68%; p<0.021).29 The increased incidence of CMV disease in patients receiving preemptive therapy in these previous studies has been attributed to the two- to four-week follow-up intervals during the critical period from the first to fourth month; in contrast, our study showed a low incidence of CMV disease onset with the same frequency of follow-up. This may be explained by the difference in protocol involving early conversion to mTOR inhibitors, guided by the implemented protocol biopsy in our center; affecting 77.2% of patients; 64/84 (76.3%) and 38/48 (79.2%) basiliximab and thymoglobulin respectively. Recently, Andrassy et al. performed a meta-analysis and systematic review and concluded that mTOR inhibitor treatment significantly reduced the incidence of CMV after organ transplantation30 and that such treatment might similarly reduce the infection severity in renal transplantation recipients.31

Our study did not find statistically significant differences in the incidence of disease onset between the basiliximab and thymoglobulin cohorts, despite previous reports claiming that the use of thymoglobulin was associated with up to a five-fold increase in the CMV disease onset1,32 compared to lower disease onset in patients receiving basiliximab induction.19,33 However, Khoury, in a single-center study, demonstrated that both preemptive and prophylactic strategies may effectively reduce symptomatic CMV reactivation in patients receiving thymoglobulin as the induction therapy.34 It is possible that the lower incidence of CMV disease onset in the thymoglobulin group may have resulted from use of low doses thymoglobulin, in our experience. The higher incidence of acute rejection episodes and increased use of immunosuppression in the basiliximab group may have been associated.

Regarding the risk of acute renal graft rejection, certain authors have suggested that the post-transplant viremia observed in patients subjected to a preemptive strategy is associated with a higher alloreactive immune response that might be responsible for the higher risk of acute renal graft rejection, chronic rejection, graft loss and mortality.35–44 These data are controversial and have not been verified in systematic comparisons of antiviral prophylactic and preemptive strategies.41 Our findings are supported by a higher level of validity; 95.5% of the patients were subjected to protocol biopsies, which revealed reduced subclinical rejection rates among patients induced basiliximab vs thymoglobulin (18% vs 14% p 0.387) and viremic patients vs non-viremic patients (15% vs 18% p 0.423). Similarly, Atabani identified equal numbers of viremic and non-viremic patients with biopsy-proven rejection (21/158 vs. 19/210) within three months post-transplant; although in most cases, the rejection was detected prior to viremia onset (17/21, 81%).45 In our experience, 92% of the biopsies were performed after viremia onset. An observational study performed by Sagedal and collaborators reported an association between asymptomatic viremia and CMV disease onset along with a higher risk of acute renal graft rejection, although only 38% of the rejections were biopsy-confirmed.35 In contrast to the aforementioned study, no clear association was found between viremia and acute rejection in our cohort, even when utilizing thymoglobulin induction therapy; viremia was early onset and was more intense than was observed in the basiliximab cohort.

In line with recent publications,19,46 we did not find a negative impact on mortality and graft survival within 12 months post-transplant when patients with or without viremia were compared. Reischig, performed a long-term comparison of antiviral prophylaxis and preemptive strategies in a single-center, randomized, open clinical trial and found that the cumulative incidence of viremia at 36 months was significantly higher in the preemptive strategy group than in the antiviral prophylaxis group (92% vs. 59%; p<0.001); despite these results, the patient survival rates were similar in both groups. The four-year graft survival rate was significantly higher in the preemptive strategy group (92% vs. 74%; p=0.049), suggesting a possible negative impact of late viral replication in patients who received antiviral prophylaxis.47 However, Kliem reported other findings from a randomized clinical trial that compared antiviral prophylactic and preemptive strategies found that the graft survival rate was significantly lower in the preemptive strategy group (9% vs. 25% in the prophylactic group; p=0.00117).42 For our cohort, we plan on continuing the long-term follow-up to determine the existence of a negative impact in the patients who presented with asymptomatic viremia.

In contrast to reports by Reischig and collaborators, describing an increased incidence of interstitial fibrosis and tubular atrophy in protocol biopsies collected three months post-transplant in patients receiving a preemptive strategy vs. patients receiving antiviral prophylaxis,48 our study did not find differences in the chronicity indexes. There was a tendency toward a higher incidence of glomerulitis in the group presenting with viremia compared to the group without viremia. Although this difference did not reach statistical significance, it warrants long-term historically follow up to determine if a difference exits.

Preemptive therapy has been associated with lower drug costs and fewer side effects; however, there are also different limitations such as difficulties in technique standardization, consequent absence of a validated cut-off point that signals therapy initiation due to variations in test performance, trial design, and study population diversity,48 and the implementation of a strict protocol. First; in our cohort the cut-off point was 4000copies, although four patients with CMV disease onset presented viral loads exceeding 50,000copies, suggesting the possibility of introducing higher cut-off points for therapy initiation. In this case, a kinetic evaluation of replication according to the different immunosuppression protocols is important. Second, the study conducted at our transplant center underscored the relevance of establishing strict protocols, follow-up systems, surveillance and adherence strategies that aim to ensure compliance. By monitoring the viral load, initiating early therapy once infection has been detected, we have provided evidence that approximately 77% and 68% of patients in the basiliximab and thymoglobulin cohorts complied with the viral load schedules. The average time intervals between viremia detection and treatment initiation were 7 days in the basiliximab group and 6 days in the thymoglobulin group; these delays represented logistical issues with respect to patient compliance and were related to the geographical locations of their homes, socioeconomic situations, or barriers in local administrative processes with respect to medication dispensation. Consequently the preemptive strategy was effective for the prevention of CMV infection and disease onset, it continues to require strict and coordinated processes between the transplant centers and other institutions, this requirement has been confirmed by others.49

The short follow-up duration did not allow assessment of the impact of viral replication on graft survival, patient survival and histological changes; however, our study suggest that preemptive therapy can effectively prevent CMV disease onset during the first year post-transplant without affecting subclinical or acute rejection under basiliximab induction. The high incidence rates of CMV infection and early onset and the high post-treatment replication rate in the thymoglobulin group, despite the use of low doses, suggests that universal prophylaxis might be a better strategy in this population; in contrast, the preemptive strategy might be more cost-effective among patients receiving basiliximab.

The results obtained using different induction treatments (basiliximab and thymoglobulin) in CMV R+ recipients exhibited differences with respect to the CMV infection incidence and time to viremia onset. Even at low doses of thymoglobulin (thymoglobulin dose was higher in patients with viremia than in the patients without viremia), this result explains why the influences of different induction schemes on solid-organ transplants should be evaluated much more stringently to identify preventive behaviors based on different immunosuppression regimens.

Finally, anecdotal observations have indicated that transplant centers use different protocols for handling post-transplant CMV that are generally not sufficiently rigorous; Le Page recently performed an international multi-center study to evaluate the CMV handling strategies in accordance with the published guidelines and provided evidence that 26% of the respondents reported no implementation of preventive measures50; which should change.

Different limitations are found, between these a higher frequency of samples in basiliximab group expecting less risk CMV reactivation which could lead to greater number of cases in thymoglobulin group and follow up until week 16 due to limited resources.

Funding for this research was provided in part by Roche. Dr. Montero and Dr. Torres have received research support from Roche, Bristol-Myers Squibb, Pfizer, Novartis, and Janssen and participated in Speaker's Bureaus for Wyeth, Novartis, and Roche.

The authors declare that they have no conflict of interest.