Additional evidence to support routine cytomegalovirus prophylaxis for all D+/R+ renal graft recipients.

The recent publication by Witzke et al. 1 indicates that significant benefits can be obtained for renal graft recipients in reduced cytomegalovirus (CMV) infection and disease with oral valganciclovir prophylaxis, compared with preemptive therapy, and that the benefits are greatest in donor/recipient seropositive (D+/R+) patients. The authors present 12-month data from an ongoing long-term study and they conclude that the effectiveness of CMV prevention may be dependent on the CMV status of the donor and that routine prophylaxis for all D+/R+ recipients should be considered. Interestingly, the authors also state that the results correlate with our previous and similar head-to-head trial with ganciclovir, where prophylaxis reduced CMV infection and provided a statistically significant benefit on 4-year graft survival (2). This previous study included renal graft recipients for all risk subgroups for CMV (D+/R−, D+/R+, and D−/R+ subgroups). A recent supportive subanalysis of the data from our original publication with ganciclovir also indicated specific benefits for D+/R+ patients, including reduced CMV infection and overall improved graft survival (3). This directly supports the results observed by Witzke et al. because valganciclovir is a prodrug of ganciclovir. In our subanalysis, D+/R+ patients (n=36) receiving ganciclovir prophylaxis experienced a significantly longer time to first active CMV infection (documented by CMV-polymerase chain reaction) than patients in the preemptive group (n=35; 118.3±25.1 vs. 52.9±28.7 days, mean±standard deviation, P=0.0175), with 3 patients experiencing CMV infection compared with 15 in the preemptive group (P=0.0002). The mean duration of CMV infection was also markedly longer in the preemptive group at 47.2±72.0 days compared with 20.7±10.0 days for prophylaxis. CMV disease/syndrome (6 vs. 1 patient, P=0.0553) was also more common in the preemptive group. Four-year survival data showed graft loss only occurred in the preemptive group (0 vs. 7 patients, P=0.0035), and overall tolerability was good for both treatments. However, the truly interesting result of our new subanalysis was observed when survival data were analyzed for patients without CMV infection by treatment group. Notably, in patients with no documented CMV infection survival rates (both uncensored and censored for death) were higher after prophylaxis than preemptive therapy (see Fig. 1). Hence, graft loss including death occurred more often in the preemptive group than in the prophylaxis group even when active CMV infection was not observed (0 vs. 4 patients, P=0.0021). This supports the conclusion that additional factors have influenced graft survival in these patients. As outlined by Witzke et al., preemptive patients may experience subclinical CMV infection below the limit of detection for prolonged periods and CMV viremia (or more intense viremia) for longer periods before preemptive therapy is effective. It cannot be discounted that prolonged undetected asymptomatic CMV exposure could lead by development of CMV-associated vasculopathy to allograft damage or coronaropathy in preemptive patients and thus decrease long-term graft and patient survival. The overall impact of subclinical or asymptomatic CMV infection on patients following solid organ transplantation cannot be directly assessed, but routine prophylaxis will reduce the likelihood of any early CMV damage and it seems to improve long-term graft outcomes. We await the long-term follow-up results and graft survival analysis from Witzke et al. with interest.FIGURE 1: (A) Graft loss in the absence of CMV infection including death (B) graft loss in the absence of CMV infection excluding death. Patients with D+/R+ serostatus beyond 100 days posttransplantation are included (in total 4 years). P values are from the log-rank test. IV-PT, intravenous preemptive therapy; O-GP, oral ganciclovir prophylaxis; CMV, cytomegalovirus.Volker Kliem Lutz Fricke Lower Saxony Center for Nephrology, Transplantation Center Department of Nephrology Hann. Muenden, Germany University of Schleswig-Holstein, Campus Luebeck Medical Clinic 1 Luebeck, Germany