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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2015  |  Volume : 26  |  Issue : 3  |  Page : 453-459
Comparison between valganciclovir and aciclovir/valaciclovir for CMV prophylaxis in pediatric renal transplantation


1 Pediatric Nephrology Department, CHU Robert Debré, Paris, France
2 INSERM U738, CHU Hôtel Dieu, Paris, France
3 Pediatric Pharmacology and Pharmacogenetics Department, Clinical Investigation Centre 9202, INSERM, Robert Debré Hospital, Assistance Publique Hôpitaux de Paris, Paris, France

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Date of Web Publication20-May-2015
 

   Abstract 

Prophylaxis has dramatically decreased the occurrence of cytomegalovirus (CMV) infection after renal transplantation. Optimal regimens of treatment remain controversial, especially in pediatric recipients. The aim of this study was to evaluate the effectiveness of valganciclovir (VGC) versus aciclovir/valaciclovir (ACV) in a pediatric renal transplant population. Data from 101 renal transplantations were retrospectively analyzed. Except those with R-/Dstatus, all patients received prophylaxis either with ACV, n = 39 or VGC, n = 38. Incidences of positive CMV antigenemia and disease, as well as the delay in relation to the prophylaxis, were collected during at least 12 months after the end of treatment. Positive CMV antigenemia was reported in 34 patients (ACV: 16, VGC: 16, no prophylaxis: 2). CMV disease occurred in 15 patients (ACV: 5; VGC: 8) (ns). For the majority of patients under VGC, positive CMV antigenemia occurred within the year following the withdrawal of prophylaxis (VGC: 14; ACV: 5, P <0.05), whereas it occurred during prophylaxis in 11 patients under ACV versus two under VGC (P <0.05). The over-all incidence of positive CMV antigenemia was similar between ACV and VGC prophylaxis. However, VGC was more efficient to prevent early CMV infection while patients treated with ACV had less CMV infection or disease after the end of the prophylaxis.

How to cite this article:
Fila M, Dechartes A, Maisin A, Dossier C, Zhao W, Deschênes G, Baudouin V. Comparison between valganciclovir and aciclovir/valaciclovir for CMV prophylaxis in pediatric renal transplantation. Saudi J Kidney Dis Transpl 2015;26:453-9

How to cite this URL:
Fila M, Dechartes A, Maisin A, Dossier C, Zhao W, Deschênes G, Baudouin V. Comparison between valganciclovir and aciclovir/valaciclovir for CMV prophylaxis in pediatric renal transplantation. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2021 Apr 14];26:453-9. Available from: https://www.sjkdt.org/text.asp?2015/26/3/453/157306

   Introduction Top


Before the use of specific antiviral treatment as therapy and for prophylaxis, cytomegalovirus (CMV) was a major factor of morbidity and mortality among post-transplant patients, accounting for more than 80% of fever among them and 60% of overall infections. [1] Clinical manifestations of CMV disease in transplanted patients are non-specific and commonly include fever with flu-like syndrome, gastrointestinal disorders and hematologic and respiratory manifestations. [2],[3] In addition, early CMV disease has also been recognized to be associated with an increased risk of acute graft rejection and chronic allograft nephropathy. [4],[5],[6],[7] Currently, the use of specific antiviral drugs has changed the prognosis of graft survival and outcome of transplant patients. Several published data are available to confirm the efficiency of prophylaxis, but only a few are specific to pediatric patients. [8],[9] Different drugs (aciclovir, valaciclovir, ganciclovir and valganciclovir) are available for the prophylaxis of CMV infection. Valganciclovir seems to be the gold standard for CMV prophylaxis now in solid organ transplantation. However, few specific data are available to compare the efficiency of valganciclovir to other types of prophylaxis in pediatric solid organ transplanttation. The aim of this retrospective study was to compare the efficiency of aciclovir/valaciclovir versus valganciclovir in our series of pediatric renal transplantation.


   Patients and Methods Top


Study design

Clinical records of pediatric patients undergoing kidney transplantation in the Pediatric Nephrology department, Hôpital Robert Debré - Paris, between December 1999 and September 2009, have been retrospectively analyzed. All patients included were prospectively followedup for at least 12 months after the end of prophylaxis.

Immunosuppressive therapy

Induction was performed with an anti-IL2R monoclonal antibody (basiliximab® Novartis Pharmaceuticals® Reuil Malmaison France) except for high-risk patients (second transplantation and/or patient with panel-reactive antibodies) that received rabbit antithymocyte globulin (ATG - Fresenius®or Thymoglobuline Merieux®-Lyon France). The standard maintenance immunosuppressive therapy included corticosteroids, mycophenolate mofetil (MMF) and calcineurin inhibitors (tacrolimus or ciclosporine). T2 levels of cyclosporine were targeted to 1200 ng/mL for the first month, 900 ng/mL for the second and the third months and 700 ng/mL for the first year after transplantation. Trough levels (T 0 ) of tacrolimus were targeted to 10 ng/mL. Pharmacokinetics of MMF was assessed one month after transplantation and posology was adjusted to target an area under the concentration- time curve of 30-60 μg/mL × h. All patients received a prophylaxis against pneumocystis using cotrimoxazole and against fungal infection using oral amphotericin B for six months.

Antiviral prophylaxis

All patients received a CMV prophylaxis except when donors and recipients had a negative CMV serology (R-/D-).

From 1999 to 2005, oral aciclovir (Zovirax® GlaxoSmithKline®-Marly le Roi France) was given at a dose of 12.5 mg/kg four times a day for 90-120 days. Valaciclovir (Zelitrex®-GlaxoSmithKline®-Marly le Roi-France) was given in children more than eight years old at a dose of 2000 mg four times a day for 90-120 days. Both types of prophylaxis were adjusted to glomerular filtration rate.

From 2005-2009, valganciclovir (Rovalcyte® - Roche® - Boulogne Billancourt - France) was given to patient once a day. The dose was adjusted to renal function, age and body surface area according to the following formula: Daily dose (mg) = 7 × body surface area (m²) × creatinine clearance (mL/min/1.73 m²). [10] The maximum daily dose was 900 mg. Pharmacokinetic evaluation of valganciclovir was performed after one month of prophylaxis and posology was adjusted to target area under curve between 20 and 40 μg/mL × h. Prophylaxis was given for 90-180 days.

Definitions of CMV infection and CMV disease

CMV antigenemia was monitored using a pp65 kit (CMV Brite™ Turbo Kit, IQ Products BV, Groningen, The Netherlands). Monitoring started at 15 days after renal transplantation. Antigenemia was prospectively followed every eight days during the first three months after transplantation, then monthly until the end of the first year of transplantation. CMV infection was defined by the positivity of CMV antigenemia in two consecutive blood samples while neither clinical nor laboratory signs were evidenced. CMV disease was defined by the positivity of CMV antigenemia in two consecutive blood samples associated with fever and/or organ involvement (hepatitis, pneumonia, colitis, gastritis, chorioretinitis, encephalitis) or hematologic features including leukopenia, thrombocytopenia, severe anemia. Curative therapy was started using intravenous ganciclovir or oral valganciclovir at full dose when CMV infection or disease was proved.

Acute graft rejection

Acute graft rejection was suspected when an acute increase of serum creatinine higher than 20% could not be explained otherwise. Renal biopsy was always performed and biopsy data were analyzed according to the Banff criteria. Data about the occurrence of acute rejection in the following six months after a CMV infection or disease were collected. Otherwise, a systematic renal biopsy was performed at three and 12 months after transplantation.


   Statistical Analysi Top


Quantitative and qualitative data were compared using the Student t-test and Fisher exact test, respectively. Incidence of CMV infection and CMV disease were described using Kaplan Meier curves. The log rank test was used for comparison and the univariate Cox regression model was used to calculate the hazard ratio (HR) and the confidence interval (IC) between the two groups. All analyses were performed using statistic software R version 2.8.0. P-values <0.05 were considered statistically significant.


   Results Top


A total of 104 consecutive renal transplantations have been performed on 101 patients during the period of the study. Two patients who received a combined hepatic and renal graft as well as one who received a sequential combination of antiviral drugs (aciclovir then valganciclovir) were excluded from the analysis. Because of an R-/DCMV serostatus, 24 patients did not receive any kind of prophylaxis. Aciclovir/valaciclovir (ACV) was given in 39 patients and valganciclovir (VCG) was given in 38 patients. Median age, gender and CMV serostatus was not different between the VGC and ACV groups [Table 1]. The immunosuppressive regimen was comparable in both groups except for the type of calcineurin antagonists: Patients mostly received cyclosporine in the ACV group and tacrolimus in the VGC group [Table 1].
Table 1: Baseline characteristics of the patients.

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During the first 18 months of renal transplantation, 34 patients had a positive CMV antigenemia, 19 patients had only CMV infection and 15 patients had CMV disease. Among these 34 patients, 32 received antiviral drugs during the first months and two did not receive prophylaxis (one R-/Dand one R+/Dwho had intolerance to the treatment).

Digestive tract involvement was the most frequent form of CMV disease. Severe gastroenteritis, pancreatitis or hepatitis occurred in 11/15 patients. Fever and flu-like syndrome was observed in 3/15 patients and severe pneumonitis was observed in one patient. In addition, five patients presented with leukopenia, two with anemia and two with thrombopenia. No neurological involvement was observed. [Table 2] presents the distribution of CMV infection and CMV disease according to the R/D serostatus. Independent of the type of prophylaxis, R-/D+ had the higher risk to develop a CMV complication and R+ had an intermediate risk compared with R-/D-.
Table 2: CMV infection and disease according to recipient CMV serostatus.

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During the first months, 32 patients who developed CMV infection or disease were treated with an antiviral treatment, 16 received VCG and the others received ACV. Under viral prophylaxis, CMV antigenemia occurred in only 2/38 patients in the VGC group versus 11/39 patients in the ACV group (P <0.003) [Figure 1]. By contrast, within the 12 months following the end of the viral prophylaxis, positive CMV anti-genemia occurred in 14/38 patients in the VCG group and in 5/39 patients in the ACV group (P <0.02). CMV prophylaxis with valganciclovir was more efficient than aciclovir to prevent CMV infection during prophylaxis time and decreased the risk of positive CMV antigénémia by 86% (HR: 0.14; 95% CI: 0.03-0.62; P ≤0.01). By contrast, the risk of CMV infection or disease after the withdrawal of viral prophylaxis increased in the VCG group up to more than 150% compared with the ACV group (HR: 2.74; 95% CI: 1- 7.62; P ≤0.05). Among the 13 cases of CMV disease, five occurred in the ACV group, four out of five during the time of viral prophylaxis and eight occurred in the VCG group; all of them after the withdrawal of viral prophylaxis. When considering the overall period of viral prophylaxis and 12 months of follow-up, 16 patients in the VGC group and 16 patients in the ACV group developed a CMV infection or disease [Figure 2].
Figure 1: Cumulative probability of absence of CMV infection/disease while on CMV prophylactic treatment.

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Figure 2: Cumulative probability of absence of CMV infection/disease according to CMV prophylaxis.

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A mutation of viral DNA polymerase (UL97) was found in one of the two patients who developed a CMV infection in the valganciclovir group during the time of prophylaxis. This mutation M460 and L545 is known to confer a resistance of CMV against therapy with ganciclovir and valganciclovir.

Acute renal rejection was biopsy proven in 15/104 patients in the first year following renal transplantation. Only six patients developed acute renal rejection within the six months following CMV infection or disease ( P ≤0.01). Five of them received prophylaxis with ACV and only one received prophylaxis with VGC. Six patients presented positive CMV antigenemia within the six months after acute graft rejection probably as a consequence of an intensification of immunosuppressive therapy.


   Discussion Top


This study suggests that in a pediatric population undergoing renal transplantation, prophylaxis with aciclovir/valaciclovir was as efficient as in those with valganciclovir when both earlyand late-onset CMV infection and disease were considered. Previous works including meta-analysis of solid organ transplant clearly showed the benefit of CMV prophylaxis in patients with immunological risks for CMV infection whatever the type of prophylaxis that was used (aciclovir, valaciclovir, valganciclovir or oral ganciclovir). [8],[9],[11] Some trials comparing prophylaxis with aciclovir versus valganciclovir showed that valganciclovir was more efficient than aciclovir but the duration of follow-up was mostly limited to six months beyond the end of prophylaxis. In our study, late-onset CMV infection (after the end of prophylaxis) was higher in the VGC group than in the ACV group. Therefore, a limited follow-up of six months after the discontinuation of prophylaxis will miss the 25% of CMV infection or disease that occur beyond this delay. [12]

Actually, valganciclovir is considered as the most efficient prophylaxis against CMV infection in solid organ transplant recipients. According to our results as well as to those of the literature, valganciclovir is more efficient in the prevention of the development of a CMV infection/CMV disease as long as the prophylaxis is continued. [13] A recent retrospective study performed by Jongsma et al on pediatric renal recipients highlighted that valganciclovir was more efficient than aciclovir during the prophylaxis time. All CMV infections occurred only when prophylaxis was discontinued. [14]

An extended prophylaxis with valganciclovir up to six months after transplantation is associated with a delayed CMV seroconversion compared with patients receiving only three months of prophylaxis. [12] A plausible hypothesis is that the lack of exposure of the recipient to CMV, as a consequence of an early effective prophylaxis, would impair the development of a specific immune response against CMV. [13] The lack of a full specific immune response would facilitate the development of a CMV infection/CMV disease after the withdrawal of the prophylaxis. The ratio of lateonset CMV disease/CMV infection in recipients who received valganciclovir compared with those who received aciclovir gives some credit to this hypothesis. A comparison between delayed prophylaxis with valganciclovir, which started 14 days after transplantation, and undelayed prophylaxis, which started on the day of transplantation, showed a significant decrease of late-onset CMV disease in the delayed prophylaxis group. [15]

Our results highlight the issue of the optimal length of prophylaxis. Recent trials comparing CMV prophylaxis with VGC in renal recipients during six months versus three months showed contradictory results. Helantra et al showed that an increased duration of prophylaxis with valganciclovir from three to six months after graft only delayed the onset of CMV infection/CMV disease and that infection occurs early after the end of prophylaxis. [16] By contrast, Luan et al found that a longer duration of prophylaxis up to six months decreased the occurrence of a late-onset CMV disease. [17] Another prospective multicentre trial with a long-term follow-up of two years after transplantation (IMPACT trial) gave similar results. [12] Subsequently, a longer duration of prophylaxis with valganciclovir is more efficient to prevent the occurrence of CMV, at least in R-/D+. No data were available comparing the use of an extended prophylaxis with aciclovir or valaciclovir to six months after transplantation.

Another potential matter is the increased occurrence of viral resistance secondary to a widespread use of antiviral drugs in prophylaxis. In 2004, the overall risk of developing a confirmed or probable ganciclovir resistance mutation during treatment was similar for patients treated with ganciclovir or valganciclovir (about 3%). Recent studies confirm these results: The resistance level is not higher with valganciclovir than with other kinds of prophylaxis. [18],[19],[20],[21] However, only scarce data are available for a prophylaxis with valganciclovir extended to six months and more data are needed to confirm the safety of an extended prophylaxis to six months with valganciclovir, especially in pediatric solid organ transplant.

The type of immunosuppressive therapy used and recipient serostatus are independent risk factors for the occurrence of CMV infection. Indeed, patients with immunosuppressive therapy, including an induction with antithymocyte globulin and/or using tacrolimus as calcineurin inhibitors instead of cyclosporine, have a higher risk for occurrence of CMV infection. [16] In our study, patient serostatus and induction therapy were similar in the valganciclovir and acyclovir groups. By contrast, tacrolimus was more commonly used in the valganciclovir group than in the acyclovir group and could be associated with an increased risk of CMV infection and disease in these patients.

In conclusion, valganciclovir prophylaxis in pediatric renal transplants is more effective in the prevention of CMV infection and disease than aciclovir/valaciclovir during the time of prophylaxis. On the other hand, more CMV infection and disease occurred after the withdrawal of prophylaxis with valganciclovir than with aciclovir/valaciclovir. Considering both earlyand late-onset CMV infection, valganciclovir is as efficient as aciclovir/valaciclovir prophylaxis. However, the high occurrence of late CMV infection in the valganciclovir group highlights the need for further prospective controlled trials to compare longer periods of prophylaxis and their impact on the prevention of late-onset disease.

Conflict of Interest: None

 
   References Top

1.
Peterson PK, Balfour HH Jr, Marker SC, Fryd DS, Howard RJ, Simmons RL. Cytomegalovirus disease in renal allograft recipients: A prospective study of the clinical features, risk factors and impact on renal transplantation. Medicine (Baltimore) 1980;59:283-300.  Back to cited text no. 1
    
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Snydman DR. Infection in solid organ transplantation. Transpl Infect Dis 1999;1:21-8.  Back to cited text no. 2
    
3.
Fishman JA. Infection in Solid-Organ Transplant Recipients. N Engl J Med 2007;357: 2601-14.  Back to cited text no. 3
    
4.
Boratyñska M, Banasik M, Watorek E, Patrza³ek D, Szyber P, Klinger M. Influence of cytomegalovirus disease on early and late renal graft function. Transplant Proc 2006;38:14750.  Back to cited text no. 4
    
5.
Reischig T, Jindra P, Hes O, Bouda M, Kormunda S, Treska V. 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. Transplantation 2009;87:436-44.  Back to cited text no. 5
    
6.
Reischig T, Jindra P, Mares J, et al. Valacyclovir for cytomegalovirus prophylaxis reduces the risk of acute renal allograft rejection. Transplantation 2005;79:317-24.  Back to cited text no. 6
    
7.
Smith JM, Corey L, Bittner R, et al. Subclinical viremia increases risk for chronic allograft injury in pediatric renal transplantation. J Am Soc Nephrol 2010;21:1579-86.  Back to cited text no. 7
    
8.
Hodson EM, Ladhani M, Webster AC, Strippoli GF, Craig JC. Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev 2013;2:CD003774.  Back to cited text no. 8
    
9.
Hodson EM, Jones CA, Webster AC, et al. Antiviral medications to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: A systematic review of randomised controlled trials. Lancet 2005;365: 2105-15.  Back to cited text no. 9
    
10.
Vaudry W, Ettenger R, Jara P, et al. Valganciclovir dosing according to body surface area and renal function in pediatric solid organ transplant recipients. Am J Transplant 2009;9: 636-43.  Back to cited text no. 10
    
11.
Reischig T, Opatrny K Jr, Bouda M, Treska V, Jindra P, Svecova M. A randomized prospective controlled trial of oral ganciclovir versus oral val acyclovir for prophylaxis of cytomegalovirus disease after renal transplantation. Transpl Int 2002;15:615-22.  Back to cited text no. 11
    
12.
Humar A, Lebranchu Y, Vincenti F, et al. The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Am J Transplant 2010;10:1228-37.  Back to cited text no. 12
    
13.
Camacho-Gonzalez AF, Gutman J, Hymes LC, Leong T, Hilinski JA. 24 weeks of valganciclovir prophylaxis in children after renal transplantation: A 4-year experience. Transplantation 2011;91:245-50.  Back to cited text no. 13
    
14.
Jongsma H, Bouts AH, Cornelissen EA, Beersma MF, Cransberg K. Cytomegalovirus prophylaxis in pediatric kidney transplantation: The Dutch experience. Pediatr Transplant 2013;17:510-7.  Back to cited text no. 14
    
15.
San Juan R, Yebra M, Lumbreras C, et al. A new strategy of delayed long-term prophylaxis could prevent cytomegalovirus disease in (D+/R-) solid organ transplant recipients. Clin Transplant 2009;23:666-71.  Back to cited text no. 15
    
16.
Helanterä I, Lautenschlager I, Koskinen P. Prospective follow-up of primary CMV infections after 6 months of valganciclovir prophylaxis in renal transplant recipients. Nephrol Dial Transplant 2009;24:316-20.  Back to cited text no. 16
    
17.
Luan FL, Stuckey LJ, Park JM, Kaul D, Cibrik D, Ojo A. Six-month prophylaxis is cost effective in transplant patients at high risk for cytomegalovirus infection. J Am Soc Nephrol 2009;20:2449-58.  Back to cited text no. 17
    
18.
Eid AJ, Arthurs SK, Deziel PJ, Wilhelm MP, Razonable RR. Emergence of drug-resistant cytomegalovirus in the era of valganciclovir prophylaxis: Therapeutic implications and outcomes. Clin Transplant 2008;22:162-70.  Back to cited text no. 18
    
19.
Boivin G, Goyette N, Rollag H, Jardine AG, Pescovitz MD, Asberg A, et al. Cytomegalovirus resistance in solid organ transplant recipients treated with intravenous ganciclovir or oral valganciclovir. Antivir Ther (Lond) 2009;14:697-704.  Back to cited text no. 19
    
20.
Martin M, Goyette N, Ives J, Boivin G. Incidence and characterization of cytomegalovirus resistance mutations among pediatric solid organ transplant patients who received valganciclovir prophylaxis. J Clin Virol 2010; 47:321-4.  Back to cited text no. 20
    
21.
Boutolleau D, Deback C, Bressollette-Bodin C, et al. Resistance pattern of cytomegalovirus (CMV) after oral valganciclovir therapy in transplant recipients at high-risk for CMV infection. Antiviral Res 2009;81:174-9.  Back to cited text no. 21
    

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Correspondence Address:
MD, PhD M Fila
Pediatric Nephrology Department, CHU Robert Debré, Assistance Publique Hôpitaux de Paris, Paris
France
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DOI: 10.4103/1319-2442.157306

PMID: 26022014

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