Because of the advances in diagnosis and the use of antiviral agents made in recent years, control of cytomegalovirus (CMV) infection after solid-organ transplantation has improved notably (1,2). Still, a variety of issues remain to be resolved. Special attention should be given to the indirect effects of CMV such as increased risk for allograft rejection and opportunistic infection (3–6). Ganciclovir is currently widely used for the treatment and prophylaxis of CMV disease after renal transplantation (RTx) (7). However, there are also negative implications. In addition to drug toxicity, there has been an increase in ganciclovir-resistant CMV disease associated with a grim prognosis (8,9).
Several years ago, a large placebo-controlled study showed that valacyclovir-based prophylaxis significantly decreases the incidence of CMV disease after RTx (10). Moreover, a decrease in acute rejection episodes was seen in valacyclovir-treated patients at risk for primary CMV infection (CMV seropositive donor/seronegative recipient; D+/R−) (10). Valacyclovir, a valine ester of acyclovir with several times higher bioavailability (11), could thus be an alternative to ganciclovir in CMV prophylaxis. Our pilot randomized study, including mostly patients at risk for secondary CMV infection, demonstrated that valacyclovir-based prophylaxis after RTx is as effective and cost-effective as oral ganciclovir (12). Still, we noted a nonsignificant decrease in asymptomatic CMV viremia in the valacyclovir group. More important, we observed a trend toward a reduction in acute rejection in either prophylaxis group compared with patients managed by deferred therapy (12). The statistical nonsignificance of these findings may have been because of the small number of patients enrolled. Therefore, we extended the study and continued randomizing additional patients. The final results of our study with 2-year follow-up are presented in this article.
MATERIALS AND METHODS
A total of 83 adult RTx recipients were included in a prospective, randomized, controlled study. Ineligible were patients with D−/R− CMV serostatus before RTx and those taking systemic antivirotics. The study protocol was approved by the local ethics committee. All patients signed informed consent forms. The study was independent and not funded by any commercial sources. In the period from April 1999 to December 2000, 38 patients were randomized at a 1:1:1 ratio to 3-month therapy with either oral ganciclovir (Cymevene; Hoffman-La Roche, UK) at a dose of 1 g three times per day or valacyclovir (Valtrex; Glaxo Wellcome, UK) at a dose of 2 g four times per day. A control group of patients were not receiving anti-CMV prophylaxis and were managed by deferred therapy (13). After analysis of data from the first part of the study (12), enrollment of patients in the control group was stopped for ethical reasons, with additional patients (n=45) randomized at a 1:1 ratio only to therapy with either ganciclovir or valacyclovir from January 2001 to January 2003. Prophylaxis was initiated within 3 days post-RTx. The doses of both drugs were adjusted according to renal function (12).
Immunosuppression was based on cyclosporine (Neoral; Novartis, Basel, Switzerland) at a starting dose of 10 mg/kg per day or on tacrolimus (Prograf; Fujisawa, Killorglin Co. Kerry, Ireland) at a dose of 0.2 mg/kg per day. Patients at high immunologic risk received additional induction therapy with OKT3 (Orthoclone; Cilag, Switzerland) or rabbit antithymocyte globulin (Fresenius, Germany). All patients—except for two treated with azathioprine (Imuran; Glaxo Wellcome)—were given mycophenolate mofetil (Cellcept; Hoffman-La Roche, Basel, Switzerland) at a dose of 2 g per day. Recipients of grafts from highly marginal donors (including non–heart-beating donors; n=6) were initially treated with anti-interleukin-2R monoclonal antibody (Simulect; Novartis, Basel, Switzerland) and sirolimus (Rapamune; Wyeth Laboratories, UK). Low-dose cyclosporine was not instituted until after development of graft function (serum creatinine < 250 μmol/L). Dosing of corticosteroids has been described previously (12).
Patients were on follow-up for 24 months post-RTx (median 24.0; range 12.5–24.0 months) or until death. CMV activity was monitored using nested polymerase chain reaction (PCR) for CMV DNA from 200 μL of whole blood once per week over the first 15 weeks and then at months 5 and 6 post-RTx (12). In cases of suspected CMV disease, pp65 antigenemia on isolated polymorphonuclear cells was additionally examined using a commercially available CINA kit (Argene BIOSOFT; France). The results were expressed as the number of positive cells per 100,000 tested. Moreover, pp65 antigenemia was performed in the majority of recipients with asymptomatic CMV DNAemia. CMV culture from bronchoalveolar lavage, urine, and biopsy samples was performed on human fibroblasts. CMV was identified by the cytopathic effect and by immunofluorescence using monoclonal antibody (Monofluokit CMV; Sanofi, Czech Republic). CMV serology was determined by enzyme-linked immunosorbent assay (Test-Line, Czech Republic) and indirect immunofluorescence (Vidia, Czech Republic). Physicians assessing PCR, pp65 antigenemia, and other methods of CMV detection were blinded to the study group and the clinical status of the patients.
The primary endpoint was the incidence of CMV disease within the first 12 months post-RTx. Secondary endpoints included CMV DNAemia, acute rejection, graft and patient survival, incidence of other infections, graft function, and safety profile. The study also assessed the costs associated with CMV. Active CMV infection was defined by CMV DNAemia (positive PCR). CMV disease was defined as symptomatic active infection. Clinical symptoms included CMV syndrome (fever plus one or more of the following: constitutional symptoms, leukopenia, thrombocytopenia, or liver enzyme elevations) or tissue-invasive CMV disease (12,14–16). Given the high sensitivity yet relatively low specificity of nested PCR, CMV disease was always confirmed by positive pp65 antigenemia (≥5 positive cells/100,000). CMV disease was treated by intravenous ganciclovir (Cymevene; Hoffman-La Roche) at a dose of 5 mg/kg every 12 hr for a minimum of 3 weeks. Doses were adjusted according to renal function. Acute rejection episodes were confirmed by biopsy, and the histologic finding was assessed by using the Banff 1997 classification (17). Core biopsy was performed on clinically suspected rejection (≥20% increase in serum creatinine) and on day 7 post-RTx if delayed graft function (DGF) persisted. In addition, biopsy was performed in patients who did not have a rapidly decreasing serum creatinine post-RTx, but did not require dialysis (slow graft function). Finally, biopsy was performed before discharge after transplantation in patients in whom satisfactory graft function had failed to develop (serum creatinine >160 μmol/L). Rejection episodes were treated initially by high-dose intravenous methylprednisolone. Steroid-resistant episodes were treated by antilymphocyte antibody (OKT3 or rabbit antithymocyte globulin). In cases of severe or recurrent rejection, patients were switched from cyclosporine to tacrolimus. The cost analysis involved analysis of all real costs directly related to CMV. These included not only the costs of hospitalization and treatment of CMV disease and costs of prophylaxis but also the costs of diagnostic procedures on CMV activation and CMV monitoring post-RTx. However, the analysis did not include the costs associated with the treatment of acute rejection episodes or other infections. The costs are expressed in U.S. dollars. Conversion to U.S. dollars was made using the average exchange ratio over the course of the study (1 U.S. $=35.48 Czech crowns).
Data were analyzed by the intention-to-treat principle. Treatment failure was defined as CMV disease, graft failure, death and/or withdrawal of a patient from the study. Quantitative data were compared using one-way analysis of variance for parametric data and the Kruskal-Wallis test for nonparametric data. Qualitative parameters were compared by Fisher’s exact test. The incidences of CMV disease and DNAemia, first biopsy-confirmed acute rejection, graft failure, death, and treatment failure were calculated by the Kaplan-Meier method, and groups were compared using the log-rank test. Values are given as means ± standard deviation. A value of P less than 0.05 was considered statistically significant. Calculations were made using SPSS for Windows Version 2.03 software (SPSS Inc., Chicago, IL).
Overall, 83 patients were included. Of these patients, 36 were treated with ganciclovir at a mean daily dose of 1.4±0.7 g (GAN group), 35 received valacyclovir at a dose of 5.6±1.2 g per day (VAL group), and 12 had no prophylaxis and were managed by the deferred therapy approach (DEF group). Two patients (one from the GAN and VAL groups each) lost their grafts within 2 weeks post-RTx; both were included in the intention-to-treat analysis. The groups did not differ significantly in their basic demographic characteristics, immunologic parameters, and immunosuppressive therapy. The pattern of distribution of D/R CMV serologic combinations was similar in the groups (Table 1). There were no significant differences in organ donors. The majority of grafts were obtained from cadaveric donors. Grafts from marginal donors were commonly used (Table 1).
During the 12 months post-RTx, there were two episodes of CMV disease in two patients (5.7%) in the GAN group (CMV syndrome in one and pneumonitis + hepatitis in one) and one episode of CMV disease (pneumonitis) in one patient (2.9%) in the VAL group (P=0.575). In contrast, there were 13 CMV disease episodes in eight patients in the DEF group (66.7%; P<0.001 DEF vs. GAN; P<0.001 DEF vs. VAL). Only two patients (16.7%) developed a tissue-invasive disease (gastrointestinal disease in both cases), with the mild form of CMV disease (syndrome) involved in the remaining cases. Four of the eight patients in the DEF group experienced recurrent CMV disease; in contrast, no recurrence was observed in the GAN or VAL group. In either prophylactic group, CMV disease did not develop until after prophylaxis had been stopped (6–12 months post-RTx), whereas all first episodes of CMV disease in the DEF group occurred within 3 months post-RTx (P<0.001). There was no case of CMV disease after the first year post-RTx (Fig. 1). All episodes of CMV disease were successfully treated by intravenous ganciclovir; there was no case of CMV-related death or ganciclovir resistance. None of the nine D+/R− patients in the prophylactic groups developed CMV disease, whereas a single patient in the DEF group developed CMV disease with recurrence. However, the small number of D+/R− patients did not allow statistical analysis.
Cumulative incidences of CMV DNAemia throughout the course of prophylaxis were 8.6% and 8.8% in the GAN and VAL groups, respectively. Although the incidences of DNAemia after stopping prophylaxis increased to 20% in the GAN group and 32.4% in the VAL group (P=0.267) at the end of 6 months post-RTx, the differences remained highly significant compared with the 91.7% incidence in the DEF group (P<0.001 GAN vs. DEF; P<0.001 VAL vs. DEF) (Fig. 1). pp65 antigenemia was obtained in 25 of 29 patients with CMV DNAemia. Antigenemia was positive in 84% (83%, 80%, and 89% in the GAN, VAL, and DEF groups, respectively). The mean peak value of pp65-positive cells was 163±208 in the DEF group compared with 10±19 and 18±34 in the GAN and VAL groups, respectively (P=0.090).
Except for a decrease in clinical herpes simplex viral infection in the GAN (P=0.018) and VAL groups (P=0.009) compared with the DEF group, no significant differences were seen in the incidences of other viral, bacterial, fungal, and parasitic infections.
The incidence of biopsy-confirmed acute rejection in the group of valacyclovir-treated patients was significantly lower compared with the GAN (P=0.030) and DEF groups (P<0.001). The biopsy-confirmed acute rejection rates at 12 months were 11.8%, 34.3%, and 58.3% in the VAL, GAN, and DEF groups, respectively (Fig. 2). The difference between the GAN and DEF groups did not reach statistical significance (P=0.087). The histologic and main clinical characteristics of rejection episodes are shown in Table 2. A subanalysis in the GAN group suggests that the incidence of acute rejection was only higher in patients with DGF (53.3%; P=0.001) compared with the VAL group, whereas the difference was not significant in the GAN group minus the patients with DGF (20.0%; P=0.704).
To exclude the possibility that a higher incidence of rejection in the GAN group was because more biopsies were performed in this group, we analyzed the number of biopsies. There were no significant differences in the number of early (within 1 month post-RTx) biopsies. In the GAN group, 57.1% of patients underwent early biopsy compared with 47.1% in the VAL group (P=0.473) and 75.0% in the DEF group (P=0.324). The mean numbers of early biopsies per patient were 0.8±0.8, 0.6±0.7, and 0.8±0.6 in the GAN, VAL, and DEF groups, respectively (P=0.326). Similarly, no significant differences were observed in the 12-month biopsy analysis.
In the GAN group, there was a higher incidence (42.9%) of DGF defined by the need for dialysis in the first week post-RTx (Table 3). However, the difference did not reach statistical significance both when compared with the VAL group (20.6%; P=0.070) and with the DEF group (16.7%; P=0.165). Graft function, as expressed by serum creatinine and calculated glomerular filtration rate (using the Cockroft-Gault formula), was the most favorable in the VAL group throughout the study. However, the differences were not significant at any time point (Table 3).
Patient and graft survival rates were similar between the groups. The 24-month patient survival rates were 94.4%, 94.4%, and 100% in the GAN, VAL, and DEF groups, respectively. The corresponding values for graft survival were 83.0%, 91.0%, and 83.3%, respectively. There were four deaths during the study. Two deaths occurred in the GAN group: one patient died of pulmonary embolism, and one patient died of sudden cardiac death after cardiac surgery. Both died with a functioning graft. There were also two deaths in the VAL group: One patient died of invasive aspergillosis (without previous evidence of CMV activity), and one patient died of acute necrotizing pancreatitis. In addition to the two patients who died with functioning grafts, graft loss occurred in another four patients in the GAN group (renal vein thrombosis, chronic rejection, infarcted kidney, and immunosuppression withdrawn). Graft failure occurred in three patients in the VAL group (primary nonfunction, multiorgan failure caused by severe pancreatitis, and acute vascular rejection). Graft failure in two recipients in the DEF group was the result of acute rejection and chronic allograft nephropathy, respectively. The cumulative incidence of treatment failure at 24 months was significantly lower in the GAN (19.8%) and VAL (11.8%) groups compared with the DEF group (66.7%; P<0.001).
Adverse events requiring dose reduction or prophylaxis discontinuation occurred in 10 ganciclovir-treated patients (28.6%) and 6 valacyclovir-treated patients (17.6%; P=0.394) (Table 4). With ganciclovir, changes in dosing were undertaken primarily because of thrombocytopenia or leukopenia, whereas the reasons for changes with valacyclovir included, in addition to hematologic side effects, hallucinations or confusion. The high incidence of hematologic abnormalities in the DEF group was attributable to CMV disease in most cases (Table 4). The main clinical complaints associated with valacyclovir treatment were hallucinations and confusion (26.5%) experienced within the first days post-RTx predominantly in patients with DGF. In two cases, hallucinations and confusion required 1-day discontinuation of valacyclovir therapy. However, these side effects quickly resolved in all patients without recurrence during full-dose valacyclovir.
Total 12-month direct CMV-related costs per patient were U.S. $3,072±$2,006, U.S. $2,906±$2,433, and U.S. $4,906±$5,686 in patients randomized to the GAN, VAL, and DEF groups, respectively. This means 37% and 41% cost reductions with ganciclovir and valacyclovir, respectively, compared with deferred therapy. The actual price of prophylactic drugs was U.S. $2,444±$1,334 for ganciclovir and U.S. $2,221±$549 for valacyclovir.
The results of the present study are consistent with our preliminary data (12) suggesting that valacyclovir is an equivalent alternative to ganciclovir in the prophylaxis of CMV disease in RTx recipients. Both prophylactic regimens resulted in an appreciable decrease in the incidence of CMV disease and DNAemia compared with patients not receiving prophylaxis. A novel finding is that valacyclovir is as effective as ganciclovir in reducing not only the incidence of CMV disease but also asymptomatic CMV active infection (DNAemia). It is a well-known fact that acyclovir has a substantially lower in vitro anti-CMV activity compared with ganciclovir (18). A randomized study comparing acyclovir with ganciclovir in the prophylaxis of CMV disease post-RTx showed the superiority of ganciclovir (19). Nonetheless, the bioavailability of valacyclovir, which is converted into acyclovir soon after administration, is three to five times higher compared with oral acyclovir (11). This may explain the higher clinical efficacy of valacyclovir. Our results are supported by data emerging from a multicentric study in bone-marrow transplant recipients, demonstrating that valacyclovir was as effective as intravenous ganciclovir in the prophylaxis of CMV disease (20). The low proportion of D+/R− CMV serostatus in our group, a feature typical of the population in continental Europe, made it impossible to adequately compare valacyclovir with ganciclovir in RTx recipients at risk of primary CMV infection. Still, none of the D+/R− patients treated with ganciclovir or valacyclovir developed CMV disease.
The high incidence of CMV disease and the associated morbidity in our patients managed by deferred therapy were unacceptable. Some authors report a lower incidence of CMV disease compared with that documented in our group (10), whereas many others observed a high incidence of CMV disease in patients at risk for superinfection or reinfection (14,21). For ethical reasons, the results of analysis of data from the first part of our study (12) prevented us from further enrollment of patients in the DEF group, so additional patients were only included in the prophylactic groups. However, all other therapeutic and diagnostic procedures and immunosuppressive protocols remained unaltered throughout the study. Another ethically acceptable option was to change the deferred therapy approach to preemptive treatment (13). However, it would decrease the incidence of CMV disease, making the control group heterogenous. Furthermore, the impact of CMV asymptomatic reactivation and CMV disease on acute rejection may differ (3).
The most important finding of the study was that valacyclovir-based prophylaxis reduces the incidence of biopsy-confirmed acute rejection. A number of studies have shown that acute rejection is a powerful adverse prognostic factor for long-term graft function (22). Compared with placebo, valacyclovir-based prophylaxis has been shown to reduce the incidence of acute rejection in patients at risk for primary CMV infection (10). However, no reduction in the incidence of rejection was demonstrated in CMV seropositive recipients. In addition, most patients in this study were treated with cyclosporine in combination with azathioprine. Less than 5% were receiving mycophenolate mofetil, a difference from current clinical practice (10). Our study is the first to demonstrate the antirejection effect of valacyclovir in a group with markedly predominating CMV seropositive patients and with immunosuppression including, in a great majority, mycophenolate mofetil. Compared with our study, the study performed by Lowance et al. (10) reported a notably lower incidence of CMV disease in seropositive recipients in their control group, which may explain the differences in the effect of valacyclovir on acute rejection. A new finding is that valacyclovir was associated with a lower incidence of acute rejection compared with patients receiving ganciclovir prophylaxis.
Because valacyclovir does not exert immunosuppressive effects (11), it can be reasonably assumed that the reduced risk for acute rejection is because of its effect on CMV. Some clinical data indicate that CMV infection and disease increase the risk for acute rejection (3,23,24). A number of mechanisms by which CMV may affect the incidence of rejection have been suggested (25). These include up-regulation of major histocompatibility complex class II antigens on allograft tissue mediated by interferon-γ, enhanced expression of adhesion molecules on endothelial and other cells, and release of various cytokines. It is more difficult and remains speculative to explain that valacyclovir was associated with a lower risk for acute rejection even when compared with ganciclovir, despite their similar efficacy in the prevention of CMV disease and DNAemia. Our study comprised unselected RTx recipients including those at high immunologic risk and—most important—a high proportion of recipients of grafts from marginal donors commonly accepted by our center in a bid to reduce waiting times for RTx. Marginal donor grafts are much more vulnerable to ischemia-reperfusion injury and the nephrotoxic action of drugs, a fact that may reflect an increased incidence of DGF (26). There is evidence that DGF increases the risk for acute rejection (27). Nephrotoxicity is an undesirable effect of ganciclovir (28,29). Although the difference did not reach statistical significance, the incidence of DGF in our study was approximately twice as much in ganciclovir-treated patients compared with those in the other groups. This was despite the fact that the pretransplant characteristics of donors and recipients were comparable among the groups. The difference in the incidence of acute rejection between valacyclovir-treated patients and ganciclovir-treated patients was because of the high incidence of rejection in ganciclovir-treated patients with DGF. It can therefore be speculated that the beneficial anti-CMV effect of ganciclovir may have been adversely affected by its contribution to the development of DGF, predisposing patients to rejection. We also tested a hypothesis that the hematologic adverse effects of ganciclovir resulted in a decreased mycophenolate mofetil exposure. Altering the dose of mycophenolate mofetil correlates with a significantly higher incidence of acute rejection (30). However, we performed a detailed analysis of mycophenolate mofetil dosing patterns and found no differences among the study groups (data not shown). Although the incidence of acute rejection in ganciclovir-treated patients was lower compared with patients managed by deferred therapy, the differences were not statistically significant. Other authors were likewise unable to demonstrate, in a meta-analysis, a beneficial effect of ganciclovir on the risk for acute rejection (31). Compared with oral ganciclovir, prophylaxis with valganciclovir has not been shown to be more effective in preventing CMV disease, and the incidence of acute rejection was also similar in both groups (32).
Although our study was randomized and controlled, it should be noted that it was a single-center study with a limited number of enrolled patients. It is not clear whether the same results could be obtained in patients with more favorable donor characteristics or in recipients at risk of primary CMV infection. On the other hand, immunosuppression based on calcineurin inhibitors in combination with mycophenolate mofetil used in the majority of our patients is standard therapy in industrialized nations, and although acceptance of marginal donors is common in Europe, it is also becoming a trend in the United States (33).
The costs of prophylaxis of valacyclovir and oral ganciclovir are approximately the same in this country. Both regimens resulted in a reduction of CMV-related costs by approximately U.S. $2,000 per patient compared with the cost of deferred therapy. In addition, the costs did not include those associated with acute rejection, which may have further favored prophylaxis. The undesirable effects of ganciclovir and valacyclovir were acceptable and consistent with earlier reports (10,11,28). The incidence of undesirable psychiatric effects in the early post-RTx period with valacyclovir was relatively high. As a result, some authors have tested low-dose valacyclovir (34). However, it is not clear whether low-dose valacyclovir prophylaxis will also be comparable with ganciclovir.
The encouraging results of valacyclovir-based prophylaxis seen in our study may have major clinical implications. Given the increasing incidence of ganciclovir-resistant CMV disease, which may result from previous long-term prophylaxis with ganciclovir, valacyclovir could be a suitable drug for the prophylaxis of CMV disease (9,35). Ganciclovir could thus be reserved solely for the treatment of symptomatic CMV infection. The reduced incidence of acute rejection is another argument supporting the use of valacyclovir.
Three-month treatment with valacyclovir of RTx recipients is as effective in preventing CMV disease and CMV DNAemia as oral ganciclovir. The costs of both regimens are comparable; both are cost-effective and lead to an approximate 40% reduction in CMV-related costs compared with those for patients not receiving prophylaxis. In addition, valacyclovir is associated with a significant reduction of the risk for acute renal allograft rejection both when compared with patients managed by deferred therapy and with patients treated with ganciclovir prophylaxis.
The authors thank Gabriela Fikrlova for her assistance in data collection.
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