Effect of delaying prophylaxis against CMV in D+/R− solid organ transplant recipients in the development of CMV-specific cellular immunity and occurrence of late CMV disease
Introduction
Incidence of Cytomegalovirus (CMV) disease in solid organ transplant (SOT) recipients who are CMV seronegative with a seropositive donor (D+/R−) can be as high as 55% without prophylaxis.1 Long term prophylaxis either with oral ganciclovir or valganciclovir effectively reduces the incidence and severity of CMV disease in these high-risk patients2, 3 but late CMV disease after prophylaxis withdrawal still occurs in 20–50% of patients.4, 5, 6, 7, 8 Effective suppression of CMV replication in patients receiving antiviral prophylaxis likely hampers the development of an adequate CMV-specific CD4+ and CD8+ T-cell responses, which appears to be crucial in protection against CMV disease.9, 10, 11
In a previous study, we observed a lower incidence of CMV disease (5.5% vs 27%; p = 0.07), mostly end-organ CMV disease (0% vs 19%; p = 0.048), in SOT recipients receiving delayed prophylaxis.12 We hypothesized that delaying the initiation of CMV prophylaxis by 14 days would increase the likelihood of priming CMV-specific T cells by allowing a certain degree of viral replication.
The results of this pilot study encouraged us to design the current study, which was aimed at further testing the above hypothesis in a broader multicenter cohort, and to investigate whether this effect was due to a higher rate of acquisition of CMV-specific cell-mediated immunity (CMI).
Section snippets
Design of the study and included patients
We designed a prospective observational study in which we included all heart, kidney or liver transplant recipients seronegative against CMV with a seropositive donor (D+/R−) performed at the 6 participating Spanish transplanting centers between September 2009 and September 2012 and receiving long term prophylaxis against CMV, either early or delayed prophylaxis. Based on data from our pilot study,12 a total of 100 patients (50 in each arm of early and delayed prophylaxis respectively) was
Baseline characteristics
Overall 99 SOT recipients D+/R− were initially enrolled from September, 2009 to September, 2012. Four were excluded from the analyses because of a delay (>one month) in the initiation of CMV prophylaxis. Finally, 95 patients from the six participating centers were included in the study. Baseline characteristics of the study population are shown in Table 1. Both strategies were comparable regarding the type of transplant and other general characteristics. The distribution of patients on each
Discussion
A delay of 14 days in the initiation of long term CMV prophylaxis was related with a low one-year incidence of CMV disease and end-organ CMV disease in a multicenter study of D+ R− solid organ transplant recipients. Although the results of this study did not allow us to demonstrate a statistically significant advantage of delayed onset universal prophylaxis with respect to early onset universal prophylaxis, a clear trend was shown, mostly in the protective effect against end organ CMV disease.
Contributions of the authors
San-Juan R: Participated in research design, analysis of results and writing of the paper.
Navarro D: Participated in research design and writing of the paper. Developed and performed the technique of CMV-specific CMI determination.
A. Garcia-Reyne. Participated in the performance of the research.
Montejo M: Participated in the performance of the research.
Muñoz P: Participated in the performance of the research.
Carratala J: Participated in the performance of the research.
Len O: Participated in the
Conflict of interest
The authors of the present manuscript do not have a commercial or other association that might pose a conflict of interest (e.g., pharmaceutical stock ownership, consultancy, advisory board membership, relevant patents, or research funding).
Acknowledgements
This study was supported by Health Research Fund (FIS), Department of Health, Spain; Agency for Health Technology Assessment and Research Supported by Ministerio de Economía y Competitividad, Instituto de Salud Carlos III (PS09/00801)– co-financed by European Development Regional Fund “A way to achieve Europe” ERDF, Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015).
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