Sir, Valganciclovir (VGC) is now considered a pre-emptive [1] and curative [2,3] treatment of CMV infection in renal transplant recipients. Leucopenia has been reported as a side effect of VGC therapy at a frequency of 10–13% [1,4] but incidence of severe leucopenia was low (4.9%) with no leucopenia-associated sepsis reported [1]. The percentage of patients discontinuing treatment because of leuco or neutropenia was not different compared with patients treated with ganciclovir (2 vs 2.4%). Interestingly, when leucopenia occurs, physicians are more likely to taper mycophenolate mofetil (MMF) rather than VGC dose. Nevertheless, as has been clearly proven, any MMF dose reduction increases the risk of acute rejection and graft lost [5]. We present here our experience in using VGC for prevention therapy in 16 kidney transplant recipients. The CMV antibody donor/recipient pattern was D+/R− (n = 7), D+/R+ (n = 8), D−/R+ (n = 1). Immunosuppressive protocol consisted of anti-interleukin-2 receptor antibodies, prednisone, MMF and cyclosporine. Moreover, all patients were treated with trimethoprim-sulfamethoxazole (TMP), 400 mg per day. Renal function of patients, MMF and VGC doses are summarized in Table 1. Creatinine clearance, drugs doses and mycophenolate mofetil monitoring of the six patients with neutropenia Creatinine clearance, drugs doses and mycophenolate mofetil monitoring of the six patients with neutropenia Six patients (37.5%) developed severe leucopenia in the third month of transplantation and met the criteria of agranulocytosis (neutrophil count <500/mm3). Three of them experienced neutropenia-associated sepsis (one diarrhoea secondary to campylobacter jejuni infection, one fever with angina, and one pyelonephritis). In patients 4–6, the area under the concentration–time curve of mycophenolic acid was performed at the date of leucopenia. Only one patient was over-exposed (78.8 mg h/ml). CMV-pp65 antigenaemia and CMV IgM detection were negative. Bone marrow aspirate was performed in three patients, showing non-specific bone marrow hypoplasia. In all patients, VGC and TMP were immediately stopped. Interestingly, when this treatment modification was made early after neutropenia was discovered, it was effective in one patient without modifying his MMF dose of 2.5 g/day. For the rest of the patients, MMF was tapered or temporarily stopped. Patients with infection received antibiotics and GmCSF. All six patients recovered from 2 to 19 days without any sequel. VGC was not reintroduced, and no CMV infection was noted after discontinuation of treatment. MMF was reintroduced in all patients without relapse of leucopenia. Leucopenia has rarely been described as a complication of VGC therapy and is usually considered a benign condition. Our experience is different with the occurrence of agranulocytosis in 37.5% of the patients treated with VGC and a high frequency (3/6) of associated sepsis. The association of VGC with two other drugs (MMF and TMP), which can also induce neutropenia, may have enhanced the toxic effect of VGC and may explain the high frequency of severe leucopenia observed here. In our experience, VGC should be withdrawn when leucopenia occurs, and this can be effective as the only treatment modification. If not, MMF can be reduced and then stopped, but only temporarily, because of the risk of acute rejection. Monitoring of the area under the concentration–time curve of MMF in this condition was not very helpful, with only one patient over-exposed. However, some pharmacokinetics interactions between VGC and MMF have been suggested [6] and VGC drug monitoring could be a way to better use these two drugs in association and to avoid severe leucopenia. Conflict of interest statement. J.-P.R. and J.-C.S. have no conflict of interest; L.M. is a consultant for ROCHE.
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Rérolle et al. (2006) studied this question.