Decreased Incidence of Cytomegalovirus Infection in Thymoglobulin-Treated Transplant Patients with 6 Months of Valganciclovir Prophylaxis

Abstract

To the Editor: Cytomegalovirus (CMV) infection is still the most common opportunistic infection following solid organ transplantation despite the introduction of newer anti-viral medications for prophylaxis, such as ganciclovir, valacyclovir, and valganciclovir (1). We recently reported that the overall incidence of CMV disease at 1 year post transplant was 14% (4% tissue-invasive, 10% non-invasive) in 129 kidney or pancreas transplant recipients with 3 months of ganciclovir or valganciclovir prophylaxis (2). However, of the 18 patients who developed CMV disease, 83% (n = 15) had received thymoglobulin induction treatment, and 25% of all thymoglobulin-treated patients developed CMV disease. Four of 15 (27%) patients had tissue-invasive CMV disease (two CMV colitis, one CMV gastritis, and one CMV nephritis). In light of these findings, we extended CMV prophylaxis with valganciclovir to 6 months in thymoglobulin-treated patients and prospectively investigated the incidence, time-course, and clinical patterns of CMV disease. Thirty-seven consecutive thymoglobulin-treated patients, transplanted between February and December 2002, received 6 months of CMV prophylaxis with valganciclovir 450 mg p.o. q.d. There were 20 males and 17 females; 29 of them were Caucasian or Hispanic, and 8 African-American; ages were 29–67 years. Thirty-two patients received kidney-, and five pancreas transplantation. Median follow-up is 13 months (range 8–19 months). In terms of CMV antibody status, 21 were Donor (D)+/Recipient (R)+, eight were D–/R+, four were D+/R–, and four were D–/R–. All patients received quadruple immunosuppression with thymoglobulin 1.5 mg/kg for 5 days after transplantation, corticosteroids, mycophenolate mofetil (MMF), and microemulsion cyclosporin or tacrolimus. All patients received valganciclovir prophylaxis regardless of donor/recipient CMV antibody status. No patient developed tissue-invasive CMV disease. Only three patients (8%) developed non-invasive CMV disease, characterized by fever, leukopenia (less than 3000) and CMV viremia, as detected by qualitative blood PCR (with Southern blot confirmation). CMV-PCR titers were 4590, 21 900, and over 100 000 in those three patients by quantitative CMV-PCR (Cobas amplicor CMV monitor). Two were D+/R+ and one D–/R–. Patients developed CMV viremia 5–6 weeks after completion of 6 months of CMV prophylaxis. All three patients responded to valganciclovir treatment, and the control CMV-PCR titers were undetectable. A recent phase III clinical trial in D+/R– solid-organ recipients, using valganciclovir at 900 mg daily, demonstrated similar incidences of CMV disease in valganciclovir- or oral ganciclovir-treated patients (3). We preferred to extend the course of valganciclovir treatment to 6 months instead of increasing the dose to 900 mg daily for 3 reasons: A 450-mg dose of prophylactic valganciclovir prevented CMV viremia in all but one of the patients during prophylaxis. Half of our valganciclovir-treated patients required the MMF and/or valganciclovir doses to be decreased or held due to neutropenia at our previous experience (2). Two of them had prolonged neutropenia requiring granulocyte colony stimulating factor. Using higher doses of valganciclovir might have further increased the incidence of neutropenia. Patients with creatinine clearance of less than 60 mL/min are recommended to take 450 mg daily (3, 4). It is unlikely that a kidney transplant recipient will have a better creatinine clearance early after transplantation. These results indicate that 6 months of valganciclovir prophylaxis significantly decreases CMV incidence (from 25% to 8%) in thymoglobulin-treated patients, and abrogates the development of tissue-invasive CMV disease. The expected number of patients with CMV disease in 37 thymoglobulin-treated patients with 3 months of valganciclovir prophylaxis would be nine (three tissue-invasive, six non-invasive). Six months of valganciclovir prophylaxis prevented the development of CMV disease in six patients. To extend the prophylaxis to 6 months is cost effective by decreasing the incidence of CMV disease, to avoid not only the cost of CMV treatment but also the indirect effects of CMV disease, such as chronic rejection, thrombotic microangiopathy, and decreased graft survival.