Mirko Bouda

Effect of cytomegalovirus viremia on subclinical rejection or interstitial fibrosis and tubular atrophy in protocol biopsy at 3 months in renal allograft recipients managed by preemptive therapy or antiviral prophylaxis.

Background. Cytomegalovirus (CMV) is a risk factor for acute renal allograft rejection. The aim of this study was to determine the impact of CMV viremia on subclinical rejection (SCR) and interstitial fibrosis and tubular atrophy (IF/TA) in protocol biopsy at 3 months after transplantation. Methods. A total of 118 consecutive renal transplant recipients at risk for CMV (donor and recipient CMV seropositive) were included and followed up prospectively. Protocol biopsies with sufficient tissue were obtained in 102 patients. CMV activity was monitored using real-time polymerase chain reaction in whole blood. Three-month prophylaxis with valacyclovir or ganciclovir was given in 60 patients, whereas the remaining 42 patients were managed by preemptive therapy. Multivariate logistic stepwise regression analysis was used to estimate the effect of CMV viremia and other covariates on SCR and IF/TA. Results. CMV viremia occurred in 41% of the patients with a median peak viral load of 1300 copies/mL. The incidence of SCR and IF/TA was 29% and 28%, respectively. CMV viremia was not a risk factor for SCR (OR=0.77, P=0.551); however, viremia of more than or equal to 2000 copies/mL increased the risk of IF/TA (OR=3.83, P=0.023). Biopsy-proven acute rejection (OR=3.34, P=0.009) and sirolimus-based immunosuppression (OR=6.13, P=0.008) were independent predictors of SCR. Delayed-graft function (OR=6.02, P=0.001) and donor age (OR=1.53 per 10-year increase, P=0.009) were associated with IF/TA. Conclusions. CMV viremia is not an independent risk factor for SCR. CMV viremia with viral load of more than or equal to 2000 copies/mL is associated with increased risk of IF/TA in protocol biopsy at 3 months after transplantation.

Long-Term Outcomes of Pre-emptive Valganciclovir Compared with Valacyclovir Prophylaxis for Prevention of Cytomegalovirus in Renal Transplantation

Prevention of cytomegalovirus (CMV) is essential in organ transplantation. The two main strategies are pre-emptive therapy, in which one screens for and treats asymptomatic CMV viremia, and universal antiviral prophylaxis. We compared these strategies and examined long-term outcomes in a randomized, open-label, single-center trial. We randomly assigned 70 renal transplant recipients (CMV-seropositive recipient or donor) to 3-month prophylaxis with valacyclovir (n=34) or pre-emptive valganciclovir for significant CMV viremia detected at predefined assessments through month 12 (n=36). Among the 55 patients who had a protocol biopsy specimen available at 3 years to allow assessment of the primary outcome, 9 (38%) of 24 patients in the prophylaxis group and 6 (19%) of 31 patients in the pre-emptive therapy group had moderate to severe interstitial fibrosis and tubular atrophy (odds ratio, 2.50; 95% confidence interval, 0.74-8.43; P=0.22). The prophylaxis group had significantly higher intrarenal mRNA expression of genes involved in fibrogenesis. The occurrence of CMV disease was similar in both groups, but pre-emptive therapy improved 4-year graft survival (92% versus 74%; P=0.049) as a result of worse outcomes in patients with late-onset CMV viremia. In conclusion, compared with valacyclovir prophylaxis, pre-emptive valganciclovir therapy may lead to less severe interstitial fibrosis and tubular atrophy and to significantly better graft survival.

A randomized prospective controlled trial of oral ganciclovir versus oral valacyclovir for prophylaxis of cytomegalovirus disease after renal transplantation

Abstract.Oral ganciclovir and valacyclovir reduce the incidence of cytomegalovirus (CMV) disease after renal transplantation (RTx). Our study was designed to compare the efficacy, costs, and safety of oral ganciclovir and valacyclovir in the prophylaxis of CMV disease over the first 6 months after RTx. A total of 38 patients was randomized to 3-month treatment with either oral ganciclovir (1 g t.i.d., n=14, GAN group) or oral valacyclovir (2 g q.i.d., n=12, VAL group). A third group (C, n=12) received no prophylaxis. The patients were monitored by CMV-nested PCR in whole blood. No differences were found between the groups in their demographic characteristics, immunosuppressive protocols, or donor and recipient CMV serology. Thirty-six out of 38 (94.7%) recipients were CMV-seropositive. Over the 6-month post-RTx period, there were 13 episodes of CMV disease in eight (66.7%) patients of the C group compared with none in the GAN and VAL groups (P=0.0005, GAN vs C; P=0.001, VAL vs C). The incidence of CMV viremia was 30.8%, 50.0%, and 91.7% in the GAN, VAL, and C groups, respectively (P=0.004, GAN vs C; P=0.07, VAL vs C; P=NS, GAN vs VAL). Treatment failure (death, graft loss, CMV disease, or withdrawal from study) occurred in 14.3%, 0% and 66.7% in the GAN, VAL, and C groups, respectively (P=0.014, GAN vs C; P=0.001, VAL vs C; P=NS, GAN vs VAL). The average CMV-associated costs per patient (in 2001 euros) were 2,449±1,178, 2,485±581, and 4,259±4,616 in the GAN, VAL, and C groups, respectively. Ganciclovir and valacyclovir were well tolerated, with ganciclovir having had to be withdrawn shortly in one patient only because of thrombocytopenia. In conclusion, oral ganciclovir and valacyclovir are equally safe and effective in the prophylaxis of CMV disease after RTx. Both are cost-effective and help reduce CMV-associated costs by some 40% compared with patients without prophylaxis.

Intragraft cytomegalovirus infection: a randomized trial of valacyclovir prophylaxis versus pre-emptive therapy in renal transplant recipients.

BACKGROUND In a randomized study, we observed a higher incidence of biopsy-proven acute rejection with pre-emptive valganciclovir therapy as compared with valacyclovir prophylaxis for prevention of cytomegalovirus (CMV) disease after renal transplantation (RTx). Persistence of the virus within the allograft could stimulate the alloimmune response. The aim of our study was to evaluate intragraft CMV infection in patients randomized to the trial. METHODS RTx recipients at risk of CMV were randomized to pre-emptive therapy with valganciclovir (n=36) for significant CMV viraemia (> or =2,000 copies/ml by quantitative PCR in whole blood samples) or 3-month prophylaxis with valacyclovir (n=34). Renal biopsies performed during 12 months post-RTx were analysed for the presence of CMV by real-time PCR and immunohistochemical staining. RESULTS A total of 35 patients (59 biopsies) in the pre-emptive group and 31 patients (57 biopsies) with valacyclovir prophylaxis had > or =1 biopsy specimen with sufficient material for intragraft CMV determination. Cumulative incidence of intragraft CMV infection was 14% and 7% (P=0.315) with pre-emptive therapy and prophylaxis, respectively. Patients at risk for primary CMV infection (CMV serological donor-positive and recipient-negative) were at higher risk for intragraft CMV infection (40% versus 5%; P=0.008). CMV viraemia at the time of biopsy was associated with the presence of CMV within the allograft (P<0.001). CONCLUSIONS During the first year after RTx, the incidence of intragraft CMV infection was relatively low with comparable rates in patients managed by pre-emptive valganciclovir therapy and valacyclovir prophylaxis.

Randomized trial of valganciclovir versus valacyclovir prophylaxis for prevention of cytomegalovirus in renal transplantation.

BACKGROUND AND OBJECTIVES Both valganciclovir and high-dose valacyclovir are recommended for cytomegalovirus prophylaxis after renal transplantation. A head-to-head comparison of both regimens is lacking. The objective of the study was to compare valacyclovir prophylaxis with valganciclovir, which constituted the control group. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS In a randomized, open-label, single-center trial, recipients of renal transplants (recipient or donor cytomegalovirus-seropositive) were randomly allocated (1:1) to 3-month prophylaxis with valacyclovir (2 g four times daily) or valganciclovir (900 mg daily). Enrollment occurred from November of 2007 to April of 2012. The primary end points were cytomegalovirus DNAemia and biopsy-proven acute rejection at 12 months. Analysis was by intention to treat. RESULTS In total, 119 patients were assigned to valacyclovir (n=59) or valganciclovir prophylaxis (n=60). Cytomegalovirus DNAemia developed in 24 (43%) of 59 patients in the valacyclovir group and 18 (31%) of 60 patients in the valganciclovir group (adjusted hazard ratio, 1.35; 95% confidence interval, 0.71 to 2.54; P=0.36). The incidence of cytomegalovirus disease was 2% with valacyclovir and 5% with valganciclovir prophylaxis (adjusted hazard ratio, 0.21; 95% confidence interval, 0.01 to 5.90; P=0.36). Significantly more patients with valacyclovir prophylaxis developed biopsy-proven acute rejection (18 of 59 [31%] versus 10 of 60 [17%]; adjusted hazard ratio, 2.49; 95% confidence interval, 1.09 to 5.65; P=0.03). The incidence of polyomavirus viremia was higher in the valganciclovir group (18% versus 36%; adjusted hazard ratio, 0.43; 95% confidence interval, 0.19 to 0.96; P=0.04). CONCLUSIONS Valganciclovir shows no superior efficacy in cytomegalovirus DNAemia prevention compared with valacyclovir prophylaxis. However, the risk of biopsy-proven acute rejection is higher with valacyclovir.

Pharmacoeconomic Impact of Different Regimens to Prevent Cytomegalovirus Infection in Renal Transplant Recipients

Background: The aim of this study was to determine the cost impact of four different strategies for prevention of cytomegalovirus (CMV) disease after renal transplantation. Methods: Hospitalization data and medical resource utilization data were prospectively collected alongside two randomized trials. In the first trial, the patients were randomized to 3-month prophylaxis with either oral ganciclovir (1 g t.i.d., n = 36) or valacyclovir (2 g q.i.d., n = 35), and to the control group (n = 12) managed by deferred therapy. In the second trial, the patients were randomly assigned to 3-month valacyclovir prophylaxis (n = 34) or preemptive therapy with valganciclovir (900 mg b.i.d. for a minimum of 14 days, n = 36) for significant CMV DNAemia. The cost analysis involved all real costs directly related to CMV during the first year after renal transplantation. Results: The mean CMV-associated costs per patient were EUR 4,581, 2,577, 4,968, and 8,050 in patients in the ganciclovir, valacyclovir, preemptive, and deferred therapy groups, respectively (p < 0.001). Valacyclovir prophylaxis was significantly less expensive than any other regimen. The cost of one episode of CMV disease was EUR 7,510 per patient. Due to excessive incidence of CMV disease, deferred therapy was the most expensive strategy (p < 0.001). Conclusions: Valacyclovir prophylaxis is less expensive strategy compared with any other regimen.

Valganciclovir prophylaxis against cytomegalovirus impairs lymphocyte proliferation and activation in renal transplant recipients.

BACKGROUND Antiviral prophylaxis against cytomegalovirus has been associated with reduced risk of allograft rejection and improved allograft survival after renal transplantation. This phenomenon might not be fully explained by preventing the indirect effects of cytomegalovirus. The effect of antiviral agents on lymphocyte function in patients treated with modern immunosuppression has not been studied to date. METHODS Adult renal transplant recipients were assigned to 3-month prophylaxis with either valganciclovir (900 mg once daily; n=19) or valacyclovir (2 g four times daily; n=17) as part of an ongoing randomized trial. Subsets of lymphocytes, lymphocyte proliferation and/or cytokine production after in vitro mitogen stimulation were evaluated at the end of prophylaxis and 1 month after withdrawal of antiviral drugs. RESULTS Lymphocyte proliferation was significantly decreased both after phytohemagglutinine (25% ±15% versus 32% ±18%; P=0.025) and concanavalin A stimulation (17% ±9% versus 25% ±16%; P=0.011) during valganciclovir, but not valacyclovir therapy. Moreover, a lower activated T-cell count (CD3(+)HLA-DR(+) cells) was noted in valganciclovir-treated patients (13% ±10% versus 17% ±12% of total CD3(+) T-cells; P=0.005). CONCLUSIONS Valganciclovir suppresses lymphocyte proliferation and activation in patients after renal transplantation.

The impact of viral load and time to onset of cytomegalovirus replication on long-term graft survival after kidney transplantation.

BACKGROUND Asymptomatic cytomegalovirus (CMV) infection is associated with graft dysfunction and failure. However, no study assessed CMV viral load in terms of the risk for graft failure. METHODS In a prospective cohort of kidney transplant recipients, we assessed the impact of CMV DNAemia on the overall graft survival and the incidence of moderate-to-severe interstitial fibrosis and tubular atrophy (IF/TA) in protocol biopsy at 36 months. CMV DNAemia was stratified by viral load in whole blood. RESULTS A total of 180 patients transplanted from October 2003 through January 2011 were included and followed for 4 years; 87 (48%) patients received 3-month prophylaxis with valacyclovir and 45 (25%) with valganciclovir; 48 (27%) were managed by pre-emptive therapy. Within 12 months of transplantation, CMV DNAemia developed in 102 (57%) patients with 36 (20%) having a viral load of ≥2,000 copies/ml. Multivariate Cox analysis identified CMV DNAemia as an independent risk factor for graft loss (hazard ratio 3.42; P=0.020); however, after stratification by viral load, only CMV DNAemia ≥2,000 copies/ml (hazard ratio 7.62; P<0.001) remained significant. Both early-onset (<3 months; P=0.048) and late-onset (>3 months; P<0.001) CMV DNAemia ≥2,000 copies/ml were risk factors for graft loss. The incidence of moderate-to-severe IF/TA was not significantly influenced by CMV DNAemia. CONCLUSIONS Kidney transplant recipients having CMV DNAemia with a higher viral load irrespective of the time to onset are at increased risk for graft loss.

Valganciclovir versus valacyclovir prophylaxis for prevention of cytomegalovirus: an economic perspective.

Valganciclovir (vGCV) and valacyclovir (vACV) are used in cytomegalovirus (CMV) prophylaxis in renal transplant recipients. The aim of this study was to compare the economic impact of both regimens during 1‐year follow‐up.

Impact of Viral Load in Polyoma-BK Virus Viremia on Histologic Findings in Late Protocol Biopsy in Kidney Transplant Recipients

Background Polyoma-BK virus associated nephropathy (PVAN) progress from interstitial nephritis to advanced interstitial fibrosis and tubular atrophy (IF/TA) with premature graft loss. Systematic surveillance for asymptomatic BK virus (BKV) viremia with pre-emptive reduction of immunosuppression is the only proved preventive strategy to reduce the risk of PVAN. However, the safe level of BKV viremia without risk of IFTA development is not established. Materials and Methods In prospective cohort of kidney transplant recipients, we assessed the impact of BKV viremia on the incidence of moderate-to-severe IF/TA in protocol biopsy at 36 months. Except for cases of graft dysfunction plasma PCR for BKV DNA was monitored monthly during first 6 months and at months 9, 12, 15, 18, 21, 24, and 36 thereafter. Lower detection limit was 50 copies/mL. High grade BKV viremia was defined as ≥10,000 copies/mL. Results A total of 207 patients transplanted from Oct 2003 through Mar 2012 were included nd followed for 5 years. Within 36 months of transplantation, BKV viremia developed in 57 (28%) patients; 10 (5%) patients suffered from biopsy-proven PVAN. High grade BKV viremia (median viral load, 27,200 copies/mL) occurred in 10/57 (18%) patients with low grade (median viral load, 100 copies/mL, P<0.001) in 35/57 (61%). In 12 patients BKV viral load could not be determined. The incidence of PVAN was significantly higher in high grade compared to low grade BKV viremia (70% vs. 6%, P<0.001). In late protocol biopsy the incidence of moderate-to-severe IFTA was comparable in patients with BKV viremia compared to patients without BKV (31% vs. 25%, P=0.409); however, after stratification by viral load, high grade BKV viremia was associated with increased incidence of moderate-to-severe IF/TA (71%, P=0.007) while the impact of low grade BKV viremia was negligible (22%, P=0.776). Overall graft survival at 5 years was similar in BKV viremia and patients without BKV (81% vs 87%, P=0.215). Only patients with PVAN showed lower graft survival (50% vs. 87%, P<0.001). Conclusions Low grade BKV viremia did not increase the risk of advanced IF/TA at 3 years after kidney transplantation. High grade BKV viremia is associated with PVAN development and resulted in high incidence of moderate-to-severe IF/TA.