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Volume: 17 Issue: 3 June 2019

FULL TEXT

ARTICLE
Extended Efficacy of Low-Dose Valganciclovir for Prevention of Cytomegalovirus Disease in Intermediate-Risk Kidney Transplant Recipients: Two-Year Follow-Up

Objectives: In a previous study, we evaluated 1-year outcomes of using low-dose valganciclovir prophylaxis for cytomegalovirus infection in intermediate-risk kidney transplant recipients. Whether this effect persists in the long term is unknown. We aimed to evaluate the 2-year follow up of such adopted prophylaxis.

Materials and Methods: We randomized 2 matched groups of kidney transplant recipients (1:1) to receive valganciclovir as 450 mg daily (group 1) or 900 mg daily (group 2) for the first 6 months after kidney transplant. The final analysis included 196 patients as intermediate-risk patients (98 in each treatment group) after exclusion of 5 high-risk patients. Serologically, all patients were at moderate risk for cytomegalovirus infection. Long-term outcomes including cytomegalovirus disease, acute rejection, new-onset diabetes after transplant, graft loss, and patient survival were assessed.

Results: Through year 2 of follow-up, cytomegalovirus infection was reported in only 1 patient in group 1 (at month 13) and 1 patient in group 2 (at month 19) (not significant). Biopsy-proven acute rejection episodes were not statistically different between the groups (2 episodes in group 1 and 6 in group 2; P = .431). New-onset diabetes posttransplant was reported in 8.1% in group 1 and 13.2% in group 2 (P = .535). Graft failure was equal in both groups (1 in each group) at 2 years of follow up (not significant). Patient survival was comparable in both groups (100% in group 1 versus 97.9% in group 2; P = .661). The total number of cytomegalovirus infections at 2 years was numerically less in group 1 (P = .128).

Conclusions: Low-dose valganciclovir prophylaxis for 6 months was associated with sustained reduction of cytomegalovirus infection up to 2 years after kidney transplant without significant impact on the acute rejection, new-onset diabetes posttransplant, or patient and graft outcomes.


Key words : Long-term outcomes, Renal transplant, Viral infection

Introduction

Cytomegalovirus (CMV) is linked to viral syndrome, CMV disease, and other indirect effects of infection. These effects may be graft rejection, posttransplant diabetes mellitus (PTDM), or opportunistic super infections, and they may lead to patient loss.1-3 Published data are scarce about the effects of CMV prophylaxis in intermediate-risk kidney transplant recipients (donor negative/recipient positive [D-/R+] or donor positive/recipient positive [D+/R+]).4-6 The present guidelines recommend giving anti-CMV prophylaxis for 3 to 6 months for high-risk (donor positive/recipient negative) kidney transplant recipients.7,8 Late-onset CMV infection is defined as CMV that occurs 3 months posttransplant, usually after prophylaxis has stopped.8

Although extended prophylaxis with either low-dose or standard-dose valganciclovir regimens has reduced the incidence of CMV disease, late-onset CMV disease could still occur.4,5,9,10 Late-onset CMV is associated with increased morbidity and mortality.11 It has atypical presentations that may result in delayed diagnosis.12-14 Several studies have reported the benefits of prolonging anti-CMV prophylaxis in different organ transplant groups.12,15-17 This benefit was clear in the IMPACT study in which extending anti-CMV prophylaxis in high-risk kidney transplant recipients to 200 days significantly reduced the incidence of CMV up to 1 year posttransplant.15 The extended IMPACT study confirmed the long-term benefits to these patients of up to 2 years with regard to CMV disease, rejection episodes, and graft outcomes.18

In our transplant center, most patients are at intermediate risk for CMV infection.4,5 Low-dose valganciclovir is found to be effective and safe for anti-CMV prophylaxis.4,5,19-22 We recently published a randomized controlled study comparing low-dose (450 mg daily) valganciclovir versus standard-dose (900 mg daily) valganciclovir for CMV prophylaxis for 6 months posttransplant.4 We concluded that 6 months of low-dose valganciclovir was as effective as standard dose with a much better safety profile (less leukopenia attacks, rejection episodes, and CMV infections). In addition, we demonstrated that a low-dose valganciclovir regimen is less costly than the usual standard-dose regimens.5 Whether a post-transplant 6-month course of low-dose valganciclovir for anti-CMV prophylaxis is as effective as standard-dose valganciclovir for intermediate-risk transplant patients over the long term is not known. In this study, we evaluated the effects of low-dose valganciclovir prophylaxis versus the standard-dose regimen up to 2 years posttransplant. Cytomegalovirus infection, PTDM, rejection episodes, and graft and patient outcomes were studied.

Materials and Methods

Study design
In our previous study, we enrolled 201 kidney transplant recipients from 2010 through 2013 to receive universal anti-CMV prophylaxis as low-dose valganciclovir (450 mg) in group 1 (100 patients) or as high-dose valganciclovir (900 mg) in group 2 (101 patients) for 6 months posttransplant (treatment phase).4 Patients were sequentially randomized (1:1) using the simple randomization method. The study was conducted in full accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines and adhered with local and national regulatory requirements and laws, and patients provided informed consent. Eligible patients were only adult kidney transplant recipients (> 18 y old) who could tolerate oral valganciclovir within 1 week posttransplant. Doses were given according to estimated glomerular filtration rate calculated by the Cockcroft-Gault formula.

Cytomegalovirus definitions
In the previous 1-year study4 and in our present 2-year follow-up study, we defined CMV disease in accordance with the current International Consensus Guidelines for CMV.8 Cytomegalovirus syndrome or tissue-invasive disease was considered as CMV disease. Tissue-invasive CMV disease was defined as evidence of localized CMV infection in a biopsy plus symptoms of organ dysfunction. Cytomegalovirus syndrome was defined as CMV viremia and at
least 1 of the following: fever, new-onset severe malaise, leukopenia, thrombocytopenia, atypical lym-phocytosis, or elevation of hepatic transaminases.

Long-term study assessments
During year 2 posttransplant, patients were followed for the development of CMV infection, PTDM, biopsy-proven acute rejection, and patient and graft survival. Patients were monitored daily during hospital stays and then at each outpatient visit with complete blood examinations, serum creatinine level, estimated glomerular filtration rate, liver function tests (serum bilirubin, albumin, and liver enzymes), and drug levels. Quantitative real-time polymerase chain reaction (PCR) for CMV DNA was tested at our center’s immunology laboratory at the time of transplant and at 1, 2, 3, 6, 9, 12, 18, and 24 months after transplant with the same assay. Patients with significant CMV PCR titer associated with any sign of CMV disease were treated with therapeutic doses of valganciclovir or intravenous ganciclovir according to the clinical situation. Treatment was given for at least 3 weeks or until the CMV PCR became negative according to weekly monitoring. This was followed by secondary valganciclovir prophylaxis (900 mg daily) to complete a total period of 3 months. Sustained significant viremia without any clinical or laboratory evidence of CMV disease were treated as CMV syndrome. Our immunosuppression protocol and definition and management of leukopenia attacks were described in detail in our previous 1-year study.4

Statistical analyses
Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 20.0,IBM Corporation, Armonk, NY, USA). Analyses of secondary endpoints after 2 years were performed in a similar fashion to analyses of primary and secondary parameters reported for the 1-year results and are described in detail elsewhere.4 The intent-to-treat population included all randomized patients. High-risk patients (donor positive/recipient negative) were excluded from analysis (2 patients from group 1 and 3 patients from group 2) to stratify our patients into a homogenous group of kidney transplant recipients with intermediate risk for CMV infection (D-/R+ or D+/R+). Variables and means were compared using paired sample t test, independent sample t test, chi-square test, Fisher exact test, and analysis of variance as appropriate. Results are expressed as means and standard deviation, and differences were considered significant at P ≤ .05. Graft and patient survival rates and time to CMV infection were summarized using life table methods and Kaplan-Meier curves and tested for significance using the 2-sided log-rank test.

Results

Our intent-to-treat population included 201 patients. Of these, 196 were included in the final analysis as intermediate-risk patients (98 in each group) after exclusion of high-risk patients (n = 5 patients). Detailed demographics of this study group have been described previously and were comparable between the 2 groups (Table 1).4 During year 2 of follow up, there was only 1 case of CMV syndrome in each group (P > .05) (Table 2 and Figure 1). There were no significant differences in acute rejection episodes and in the incidence of PTDM between groups. Only 1 graft failure occurred in each group (P > .05) (Table 2 and Figure 2). Two patients died in group 2 during year 2 of follow up, one due to septicemia and the other due to acute myocardial infarction (Table 2 and Figure 3).

Discussion

Our previous study demonstrated the safety, efficacy, and cost effectiveness of 6 months of low-dose (450 mg daily) valganciclovir anti-CMV prophylaxis posttransplant compared with the standard dose (900 mg daily).4,5 Although most CMV infections occur during the first 6 months after discontinuation of prophylaxis, there are fewer data on later outcomes. In this study, we evaluated the extended effect of this anti-CMV prophylaxis protocol to avoid late-onset CMV infection. Similar to other studies, we showed that prolongation of prophylaxis up to 6 months with either low-dose or standard-dose valganciclovir resulted in a sustained benefit for CMV disease prevention that was maintained up to 2 years posttransplant.12,15-18

The low number of cases of CMV infection beyond 12 months posttransplant may be due to the fact that the overall net immunosuppression state may be lower by the second year, which may allow recovery of CMV-specific immunity.18 Because serology assessment was of limited clinical utility for prediction of CMV disease after discontinuation of prophylaxis, we continued monitoring our patients with CMV PCR up to 2 years to check for presence of viremia and start adequate treatment accordingly.18,23 This was done to make sure we were not missing any case of CMV infection and to intervene early with full treatment to avoid CMV resistance and to have the best outcome. Although there was only 1 case of CMV syndrome in each treatment group, the overall incidence of CMV infections over 2 years was numerically better in the low-dose group (Table 2, Figure 1).

As explained in our previous study, the main difference was in the valganciclovir prophylactic dose and duration, with more incidences of leukopenia in group 2 (P = .033) and subsequent interruptions of the prophylactic course (< 3 months; P = .002). This led to early development of CMV disease in the standard-dose valganciclovir group (group 2) during the treatment phase (P = .004).4 A longer duration of a steady course of low-dose valganciclovir prophylaxis for 6 months resulted in the occurrence of numerically less CMV infections, supporting the use of this regimen in moderate-risk kidney transplant recipients.4

We also examined a number of other outcomes that could be related to indirect effects of CMV disease. By 2 years posttransplant, there were no significant differences seen in rates of graft loss, biopsy-proven acute rejection, or PTDM between the 2 groups. These outcomes were again numerically better in group 1, which confirmed our previous 1-year results showing that low-dose valganciclovir was as effective as a standard-dose regimen with a better safety profile and less cost.4,5

Our study showed a low incidence of CMV infections and no resistant cases among both groups over 2 years. This was possibly due to the strict monitoring of viremia for 24 months, universal prophylaxis, and early management of positive CMV PCR cases with high titers even when asymptomatic. Data on outcomes beyond 1 year posttransplant after anti-CMV prophylaxis in moderate-risk patients are scarce. However, a benefit has been shown regarding patient and graft outcomes.14 In a large retrospective study that included kidney, lung, and heart recipients, anti-CMV prophylaxis showed a positive effect on patient and graft survival up to 3 years posttransplant.1 The lack of data in the literature identifies the need for randomized controlled trials powered to detect differences in long-term outcomes of moderate-risk patients. To our knowledge, this is the first head to-head randomized trial designed to show differences between 2 doses of valganciclovir for anti-CMV prophylaxis in an intermediate-risk group of kidney transplant recipients.

In summary, low dose valganciclovir prophylaxis for 6 months significantly reduced the incidence of CMV infections up to 2 years posttransplant in moderate-risk (D-/R+ or D+/R+) kidney transplant recipients with better safety profile compared with standard-dose valganciclovir.


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Volume : 17
Issue : 3
Pages : 339 - 343
DOI : 10.6002/ect.2018.0020


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From the 1Department of Medicine, Hamed Al-Essa Organ Transplantation Centre, Ibn Sina Hospital, Kuwait; the 2Urology and Nephrology Center, Mansoura University, Egypt; and the 3Department of Medicine, Ain Shams University, Cairo, Egypt
Acknowledgements: The authors have no sources of funding and have no conflicts of interest to report for this study.
Corresponding author: Medhat Mohamed Abdel Halim, Department of Medicine, Hamed Al-Essa Organ Transplantation Centre, Ibn Sina Hospital, PO Box 25427, Code 13115 Safat, Kuwait
Phone: +96 599796203
E-mail: medhatmohamed2000@yahoo.com