What Is the Impact of Late-Onset Cytomegalovirus Disease After Valganciclovir Prophylaxis in Kidney Transplantation?

Abstract

Antiviral prophylaxis reduces the incidence of cytomegalovirus (CMV) disease after organ transplantation (1). However, its increasing use has been associated with the emergence of “late-onset CMV disease” whose clinical consequences may differ from those of “early-onset CMV disease” (2). To evaluate the impact of late- onset CMV disease, we reviewed all consecutive adult kidney transplant recipients (2003–2005; n=61) who received a 3-month antiviral prophylaxis (valganciclovir 450 mg onceper day) and completed a 2-year posttransplantation follow-up at our institution. Patients who developed late-onset CMV disease were compared with the group of CMV disease-free patients for allograft function and for the incidence of other complications. Overall, 8 of 61 (13%) patients developed late-onset CMV disease (median, 131 days after transplantation; range, 98–220): four CMV syndromes and four tissue-invasive diseases. This incidence was significantly higher among patients with high-risk CMV serostatus (donor positive/recipient negative) when compared with those with intermediate-risk (39% vs. 2%, P<0.001). All eight patients were treated with oral valganciclovir with a complete resolution of symptoms and clearance of viremia. Baseline characteristics were similar between CMV disease and disease-free patients (age, sex, panel-reactive antibody, pretransplant diabetes and immunosuppression). Serum creatinine or estimated glomerular filtration rate remained stable during the 2-year posttransplantation follow-up and did not differ at any point between the two groups. No graft loss, acute rejection, death, opportunistic infection, or malignancy was observed in patients with late-onset CMV disease. There was a trend toward a higher incidence of posttransplant diabetes in these patients, but this difference was not significant. This analysis showed a high incidence of late-onset CMV disease despite a 3-month valganciclovir prophylaxis, especially in high-risk (D+/R−) patients (39%). These patients were all successfully treated by a new course of oral valganciclovir and they did not develop any further complication suggesting a relatively benign course of late-onset CMV disease. These results contrast with those of recent studies reporting an association between late-onset CMV disease and graft loss or mortality (3, 4). In our analysis, we evaluated the impact of late-onset CMV disease by monitoring the serum creatinine that is a more sensitive measure for graft function than graft survival. This parameter remained absolutely stable and similar to the control group. It should be emphasized that the history of late-onset CMV disease may differ from one center to another, depending on the duration of prophylaxis, postprophylaxis screening strategy, or differences in the management of immunosuppression. Most cases in our analysis were diagnosed in the first 3 months after discontinuing prophylaxis (while CMV screening was performed) and thus promptly treated, which may explain this favorable outcome. The hypothesis that late-onset CMV disease may be associated with mild or fewer indirect effects is supported by the results of recent studies suggesting a protective effect of anti-CMV prophylaxis on graft outcome and patients survival (1, 2, 5, 6). Unfortunately, a long-term follow-up of the numerous trials evaluating antiviral prophylaxis strategies is lacking to adequately address this issue. In conclusion, the clinical consequences of late-onset CMV disease in morbidity and mortality remain unclear and should be further investigated in upcoming trials. Frédéric Lamoth Oriol Manuel Infectious Diseases Service Department of Medicine Centre Hospitalier Universitaire Vaudois and University of Lausanne Switzerland Transplantation Centre Centre Hospitalier Universitaire Vaudois and University of Lausanne Switzerland Jean-Pierre Venetz Transplantation Centre Centre Hospitalier Universitaire Vaudois and University of Lausanne Switzerland Mohamed Faouzi Centre of Clinical Epidemiology Institute of Social and Preventive Medicine Centre Hospitalier Universitaire Vaudois and University of Lausanne Switzerland Pascal Meylan Infectious Diseases Service Department of Medicine Centre Hospitalier Universitaire Vaudois and University of Lausanne Switzerland Institute of Microbiology Centre Hospitalier Universitaire Vaudois and University of Lausanne Switzerland Manuel Pascual Transplantation Centre Centre Hospitalier Universitaire Vaudois and University of Lausanne Switzerland