St George's Hospital, Department of Renal Medicine and Transplantation, London, UK
Sir,
In a recent editorial, Kuypers and Vanrenterghem critically analysed all published data on cytomegalovirus (CMV) prophylaxis in renal transplantation, in particular the use of valaciclovir [1]. This review followed a randomized controlled study by Lowance et al. [2] showing that prophylaxis with valaciclovir resulted in a significant reduction in CMV disease in high-risk renal transplant recipients. As already pointed out by Kuypers and Vanrenterghem, these results have to be interpreted with care as more than 50% of patients received routine induction therapy with monoclonal or polyclonal antibodies.
We report our experience with valaciclovir prophylaxis in patients who received only tacrolimus and corticosteroids without antibody induction. Since August 1999, all CMV-negative recipients of a kidney from a CMV-positive donor, and any renal transplant patient who required an increase in immunosuppression (i.e. for rejection or when re-transplanted), were started on a 90-day course of prophylactic valaciclovir within the first 24 h of initial immunosuppression or treatment for rejection. This group also included CMV-negative recipients of a kidney from a CMV-negative donor as CMV disease can result from transmission of CMV following transfusion of blood products. Patients undergoing re-transplantation or with previous transplantation of another organ were initially treated with an increased dosage of the calcineurin antagonist and steroids. One patient also received mycophenolate mofetil. Acute rejection was treated with three doses of i.v. methylprednisolone (0.5 g) and polyclonal antibodies were reserved for steroid-resistant rejection. CMV disease was diagnosed by a combination of clinical signs and symptoms, investigations showing organ involvement and a positive detection of early antigen fluorescent foci test indicating the presence of CMV antigen. Table 1 shows the baseline characteristics of patients during the 12-month period when valaciclovir prophylaxis was used compared to data from the preceding year.
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Valaciclovir prophylaxis significantly reduced the incidence of CMV disease from 22% to 2% (Table 2). The total group of patients with CMV disease was heterogeneous with regards to CMV status, immunosuppressive therapy, preceding rejection and type of anti-rejection therapy; none of them had had a transplant before (Table 3
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We also performed some crude cost calculations and compared the costs for valaciclovir prophylaxis with the total costs for treatment of CMV disease. The average cost of a 3-month course of valaciclovir at doses gradually increasing from 1.5 g to 8 g/day was £2000 per patient. Each in-patient day cost £750, and a 10-day course of ganciclovir costs £360. The total cost for all 28 patients who received valaciclovir and the cost for i.v. ganciclovir for one patient who developed CMV disease was £63900. Eleven out of 50 or 10.3 out of 47 patients in the preceding year developed CMV disease, treated at a cost of £81000, suggesting that valaciclovir prophylaxis was cost effective.
We conclude that valaciclovir is effective in preventing CMV disease in high-risk renal transplant recipients immunosuppressed with tacrolimus and corticosteroids. The greatest benefit was seen among CMV negative recipients of a kidney from a CMV positive donor. We also noted a reduced incidence of CMV disease following episodes of rejection in patients on valaciclovir prophylaxis, but we cannot exclude the reduced use of antibody therapy for rejection as the reason.
References
Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
Sir,
Ostermann et al. report their single-centre experience with the prophylactic use of valacyclovir in renal allograft recipients treated with tacrolimus and steroids.
Twenty-eight high-risk patients for cytomegalovirus (CMV) disease (D+/R- status, retransplantation and acute rejection treatment) were selected out of a total of 47 and treated with prophylactic valacyclovir for 90 days post-transplantation. These 47 patients were compared with a historical control group of 50 patients transplanted in the previous year without CMV prophylaxis. It is not clear from the presented data exactly how many control patients in total were at high-risk for CMV disease: nine had a D+/R- status, six were retransplants and 29 were treated for acute rejection of which seven received anti-thymocyte globulin (ATG). The exact number of high-risk patients in both groups is of course important for the interpretation of the subsequent results since 60% of the recipients in the prophylaxis group were high-risk and should be compared to an equal proportion of matched controls. Furthermore ATGa known risk factor for CMV diseasewas used in three control patients that subsequently developed tissue-invasive CMV infection.
The overall low incidence of CMV disease in the total study group is caused by a statistically significant lower incidence of CMV disease in the D+/R- and the D+/R+ group (Table 2). Two out of the four historical control patients in the D+/R+ group that developed CMV disease, received ATG-induction therapy and in our opinion they represent a higher risk category than the matched study patients that were treated for example with a higher initial tacrolimus dose because of re-transplantation.
This retrospective study suggests that valacyclovir provides effective CMV-prophylaxis in CMV donor-positive/receptor-negative renal transplant recipients that are treated with tacrolimus and steroids. However, due to the heterogeneity of the patient groups, it cannot be advocated from these results that identifying additional high-risk patients for CMV disease purely on the basis of clinical criteria (re-transplantation, acute rejection) is sufficient to decide, within the other recipient CMV risk groups, which patients would benefit from prophylactic treatment. Prospective monitoring of viral load (pp65 Ag, DNA-PCR, NASBA, etc.) remains at this point in time the most reliable method for effectively identifying patients at risk for CMV disease, especially in the D+/R+ and D-/R+ group. It would have been particularly interesting in this study to have sequential viral load monitoring data that were blinded to the investigators for the time of the study.
Also, for the same reasons stated above, we do not think that the results from this study allow a confirmation of a cost-neutral pharmaco-economical evaluation of valacyclovir, as was recently done for renal transplant recipients treated with a cyclosporine-based immunosuppressive regimen [1].
Another point of interest is the fact that, despite the small numbers in this study, the incidence of CMV disease in the control D-/R- group is high (20%) when compared with other trials [2]. The use of CMV-negative blood products in this very low-risk group constitutes a relatively low-cost measure to prevent post-transplantation transmission of CMV infection.
Overall drug tolerance was good in this trial including neurological side effects. No renal dysfunction occurred and thrombotic microangiopathy was not reported. The renal safety of high doses of valacyclovir was recently confirmed in a small study in renal transplant patients [3].
It would be interesting to know what happened to the three recipients in the control group that received induction therapy with anti-LFA-1 monoclonal antibodies, since in vitro data suggest that activated T cell-mediated cytotoxicity against CMV-infected fibroblasts can be blocked by anti-LFA-1 antibody [4]. In a multicentre trial [5] comparing odulimomab induction therapy (monoclonal antibody against the -chain of LFA-1) to induction with rabbit ATG, the investigators found a equally high incidence (27% (14/49) vs 29% (14/52)) of CMV disease in both study groups.
In summary, valacyclovir has proven its clinical efficacy in the setting of renal transplantation with a cyclosporine-based immunosuppressive regimen. The present study provides a stimulus for further prospective evaluation of the drug in combination with other immunosuppressive protocols (and other solid organ transplantations) and this will hopefully lead to a randomized comparative trial with ganciclovir.
References