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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 19  |  Issue : 3  |  Page : 68-74

Universal prophylaxis with valganciclovir versus preemptive therapy in minimizing the risk of cytomegalovirus infection and disease in high-risk and intermediate-risk kidney transplant recipients: a single-center experience


Renal Transplant Unit, National Institute of Solid Organ and Tissue Transplantation, Dow University of Health Sciences, Karachi, Pakistan

Date of Submission03-May-2019
Date of Acceptance24-Jun-2019
Date of Web Publication2-Aug-2019

Correspondence Address:
MBBS, MRCP (UK), FCPS Muhammad Tassaduq Khan
Renal Transplant Unit, National Institute of Solid Organ and Tissue Transplantation, Dow University of Health Sciences, Ojha Campus, Karachi
Pakistan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jesnt.jesnt_18_19

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  Abstract 


Objective Cytomegalovirus (CMV) is one of the most frequent viral pathogens that results in post-transplantation infection. Universal prophylaxis and preemptive therapy have long been used to prevent and treat CMV infection, respectively, in post-transplantation cases. The aim of this study was to compare the universal prophylaxis with valganciclovir versus preemptive therapy in minimizing the risk of CMV infection and disease in high-risk and intermediate-risk kidney transplant recipients.
Patients and methods This single-center, retrospective cohort study enrolled 63 kidney transplant recipients between March 2017 and January 2018. The outcome variables were occurrence of CMV infection and CMV disease, 1-year estimated glomerular filtration rate (eGFR), allograft rejection, allograft loss, and mortality within the first year after transplantation in high-risk (D+/R−) patients managed with universal prophylaxis of oral valganciclovir and intermediate-risk (D+/R+ or D−/R+) patients receiving preemptive treatment.
Results Of the 63 kidney transplant recipients, 19 (30.2%) were grouped as high risk for CMV infection/disease and 44 (69.8%) were intermediate risk for CMV infection/disease. The average duration of post-transplantation follow-up was 349 (SD 136) days in the high-risk cohort and 335 (SD 112) days in the intermediate-risk cohort (P=0.56). CMV infection was found in 15 (34.1%) of the 44 intermediate-risk patients receiving preemptive therapy and in four (21.1%) of the 19 high-risk patients receiving universal prophylaxis (P<0.01). CMV disease developed in seven (15.9%) of the 44 intermediate-risk patients and in one (5.3%) of the 19 high-risk patients (P<0.01). Allograft rejection was found to be higher in intermediate-risk group than in high-risk group (18.2 vs. 15.8%, P=0.44). Allograft loss and mortality were also comparable between the intermediate-risk and high-risk cohorts (13.6 vs. 10.5%, P=0.54 and 0 vs. 0%, P=0.15, respectively). The mean eGFR at 1 year after transplantation was similar in both the cohorts: intermediate-risk (52.5±21.8) and high-risk (54.3±23.2) (P=0.68) cohorts.
Conclusion Intermediate-risk (D+/R+ or D−/R+) kidney transplant recipients receiving preemptive therapy had significantly higher frequency of CMV infection/disease than high-risk (D+/R−) kidney transplant recipients receiving oral valganciclovir universal prophylaxis during early post-transplantation period. No statistically significant differences were found in relation to allograft rejection, allograft loss, eGFR, and mortality at 1 year in both the cohorts.

Keywords: cytomegalovirus infection/disease, kidney transplant recipients, preemptive therapy, universal prophylaxis


How to cite this article:
Sarfaraz S, Khan MT, bin Hamid R, Lal N, Javaid S, Luxmi S. Universal prophylaxis with valganciclovir versus preemptive therapy in minimizing the risk of cytomegalovirus infection and disease in high-risk and intermediate-risk kidney transplant recipients: a single-center experience. J Egypt Soc Nephrol Transplant 2019;19:68-74

How to cite this URL:
Sarfaraz S, Khan MT, bin Hamid R, Lal N, Javaid S, Luxmi S. Universal prophylaxis with valganciclovir versus preemptive therapy in minimizing the risk of cytomegalovirus infection and disease in high-risk and intermediate-risk kidney transplant recipients: a single-center experience. J Egypt Soc Nephrol Transplant [serial online] 2019 [cited 2019 Oct 17];19:68-74. Available from: http://www.jesnt.eg.net/text.asp?2019/19/3/68/263898




  Introduction Top


Infection is the second major cause of post-transplant deaths in kidney transplant recipients and is linked with reduced allograft survival [1]. Human cytomegalovirus (CMV) is one of the most prevalent opportunistic microorganisms in kidney transplant recipients, especially within the first year of transplantation, and is linked with substantial morbidity and mortality [2],[3]. In almost 60–90% of the kidney transplant recipients, CMV manifests as latent infection. In the absence of CMV prophylaxis with antiviral drugs, 20–60% of the kidney transplant recipients can present with symptomatic CMV infection, generally within the first 3 months after transplantation.

The early course of infection is commonly asymptomatic in immunocompetent hosts; nonetheless, infection can be evidenced as pyrexia of unknown origin, flu-like symptoms, or mononucleosis-like syndrome. The post-transplant CMV infection often ensues owing to transmission from the transplanted organ, because of reactivation of dormant CMV infection. Likewise, the probability of harboring CMV infection is exponentially high in cases where CMV sero-positive donors donate kidneys to CMV sero-negative recipients and in recipients who are given lymphocyte-reducing drugs, for example, polyclonal antithymocyte globulin or monoclonal alemtuzumab, which inhibits and defers reconstitution of CMV-triggered T-cell responses. In addition, besides acute allograft rejection and poor allograft and patient survival, CMV infection is an established risk factor for renal artery stenosis, tubular atrophy, interstitial fibrosis, and opportunistic infections. The percentage of death associated with untreated organ-invasive CMV infection is greater than 60%. Moreover, the financial burden related with the CMV infection, such as hospitalization, diagnostic tests, and therapy with antiviral agents, is indeed devastating [3],[4],[5].

Recent guidelines recommend two potential approaches for prevention of CMV infection after transplantation: universal prophylaxis and preemptive therapy [6]. Universal prophylaxis involves the administration of antiviral drugs to all transplant recipients, regardless of the risk of CMV infection, for a duration of 3–6 months after transplantation. In preemptive therapy, treatment is usually focused only toward high-risk kidney transplant recipients (patients with active CMV replication, detected by CMV DNA monitoring or pp65 antigen detection), irrespective of clinical symptoms, to avoid the advancement of asymptomatic CMV infection into disease [7]. Earlier research studies have shown that both the approaches are effective in terms of thwarting symptomatic CMV disease and long-term allograft and patient survival in kidney recipients after transplantation [8],[9],[10]. However, debatable results have also been published [3],[11],[12],[13],[14].

Unfortunately, data regarding the efficacy of universal prophylaxis and preemptive therapy are still sparse and controversial. To the best of our knowledge, no study has been carried out in this regard in Pakistan. The objective of this study was to evaluate the reduction in CMV infection in the first year of kidney transplantation in patients managed with universal prophylaxis of oral valganciclovir and preemptive therapy at Renal Transplant Unit, National Institute of Solid Organ and Tissue Transplantation, Dow University of Health Sciences, Karachi, Pakistan. Post-transplant outcomes such as 1-year estimated glomerular filtration rate (eGFR), allograft rejection, and allograft and patient survival were also assessed.


  Patients and methods Top


Study design, setting, and population

This was a single-center, retrospective cohort study. Adult patients who underwent kidney transplantation between March 2017 and January 2018 from the Renal Transplant Unit, National Institute of Solid Organ and Tissue Transplantation, Dow University of Health Sciences, Karachi, Pakistan, were enrolled. All the kidney transplants were performed from living kidney donors and received tacrolimus, mycophenolate mofetil, and corticosteroids as part of immunosuppressive therapy. Patients receiving universal prophylaxis or preemptive treatment to prevent CMV infection/disease were recruited; however, kidney recipients with less than 180 days of follow-up period after transplant were excluded from the study. The study stringently conformed to the research ethics standards established by the Declaration of Helsinki and Good Clinical Practice guidelines.

Definition of high-risk and intermediate-risk cytomegalovirus cohort

The kidney transplant recipients were grouped into two cohorts, high risk and intermediate risk, on the basis of the donor/recipient CMV sero-status. The high-risk cohort included CMV sero-status positive donors and CMV sero-status negative recipients (D+/R−). The intermediate-risk cohort consisted of CMV sero-status positive or negative donors and CMV sero-status positive recipients (D+/R+ or D−/R+) [7].

Description of cytomegalovirus infection and cytomegalovirus disease

According to American Transplantation guidelines, CMV infection was described as the presence of active CMV replication (not in dormancy), that is, CMV viremia, irrespective of clinical symptoms [6],[15]. CMV disease was defined as the active CMV DNA replication along with clinically evident signs and symptoms, which includes a viral syndrome (fever and/or fatigue, leukocytopenia or thrombocytopenia, and organ involvement, for instance, nephritis, hepatitis, pneumonitis, adrenalitis, myocarditis, pancreatitis, retinitis, or gastrointestinal disease) [7].

Identification of cytomegalovirus infection events

A medical record review was conducted for demographic and clinical characteristics of study participants. CMV infection events were assessed for CMV DNA in the plasma through qPCR.

Universal prophylaxis with oral valganciclovir and preemptive therapy

Kidney transplant recipients at high risk of CMV infection/disease were given universal prophylaxis with oral antiviral valganciclovir 450 mg twice a day, starting from seventh day till 3 months after transplantation. Recipients were carefully monitored for CMV DNA in the plasma through qPCR. The qPCR was done at 1-week intervals for the first 3 months and at 4, 5, 6, 9 and 12 months afterward. On the contrary, recipients with intermediate risk of CMV infection were monitored for CMV DNA through qPCR, and if found positive (≥400 CMV copies/ml), they received preemptive treatment of oral valganciclovir 900 mg twice a day irrespective of symptoms. The treatment continued for 14 days till qPCR results were negative on two repeated occasions within 1 week (<400 copies/ml). The qPCR was performed at 1-week intervals for the first 3 months after transplantation and then matching to the protocol in universal prophylaxis cohort for detection of relapse of CMV infection.

Outcome variables

The outcome variables were the development of CMV infection and CMV disease, 1-year eGFR, allograft rejection, allograft loss, and mortality within the first year after transplantation. The primary outcome variable was the development of CMV infection and/or CMV disease within first year of transplantation. Secondary outcomes were 1-year eGFR, allograft rejection, allograft loss, and mortality within 1 year of kidney transplantation. The definitions underneath were used for the aforementioned variables:

1-year eGFR: The 1-year eGFR was computed through modification of diet in renal disease formula.

Kidney allograft rejection: Biopsy-confirmed kidney allograft rejection within 12 months after transplantation as per criteria comprehensively defined in Banff 2013 meeting report [16].

Kidney allograft loss: Kidney allograft failure needing dialysis or new transplant within 12 months after transplantation.

Mortality: All-cause mortality identified within 12 months after transplantation [3].

Statistical analysis

The data were entered, tabulated, and analyzed using statistical package for the social sciences (SPSS) software version 20.0 (SPSS Inc., Chicago, Illinois, USA). Mean and SD were used to describe normally distributed data, and where applicable, median and interquartile range were used to describe non-normally distributed data in the same population. t-Test was used to compare the continuous data between the two groups and summarized as mean and SD, whereas noncontinuous data were compared using the Mann–Whitney U-test. Categorical data were compared using χ2-test and presented as proportions and percentages. The P value of less than 0.05 was considered statistically significant.


  Results Top


Demographic and clinical characteristics of kidney transplant recipients

A total of 65 patients undergoing kidney transplantation were enrolled in this retrospective cohort study. Of these 65 kidney transplant recipients, two were excluded from the study owing to inadequate post-transplantation follow-up (<180 days; 123 and 136 days). Of the remaining 63 kidney transplant recipients incorporated in the final analysis, 19 (30.2%) were grouped as high risk for CMV infection/disease (D+/R−) and 44 (69.8%) were grouped as intermediate risk for CMV infection/disease (four patients D−/R+; 40 patients D+/R+; [Figure 1]).
Figure 1 Flow diagram of the kidney transplant recipients enrolled in the study.

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The demographic and clinical characteristics of the kidney transplant recipients are demonstrated in [Table 1]. We found no statistically significant relationship between baseline characteristics of the high risk and intermediate risk for CMV infection/disease patient’s cohort in relation to age, sex, diabetes mellitus, hypertension, sensitization, mean panel-reactive antibodies, nephropathy, dialysis, immunosuppressive therapy, and duration of follow-up. The primary reason for kidney transplantation in both the groups (high risk; 78.9% and intermediate risk; 81.8%) was kidney disease of glomerular origin (glomerulonephritis). For immunosuppressive treatment, 78.9% of patients in high-risk cohort and 88.6% of patients in intermediate-risk cohort received tacrolimus (P=1.00) and 100% of high-risk patients and 95.5% of intermediate-risk patients were given mycophenolate mofetil (P=0.65). All high-risk and intermediate-risk patients received corticosteroids (P=0.23). The average duration of post-transplantation follow-up was 349 (SD 136) days in the high risk for CMV cohort and 335 (SD 112) days in the intermediate risk for CMV cohort (P=0.56).
Table 1 Clinical and demographic characteristics of kidney transplant recipients

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Post-transplantation cytomegalovirus infection and cytomegalovirus disease

Overall, the frequency of CMV infection and CMV disease was considerably higher in the intermediate-risk (preemptive therapy) cohort than the high-risk (universal prophylaxis) cohort after kidney transplantation. CMV infection was found in 15 (34.1%) of the 44 intermediate-risk patients receiving preemptive therapy and in four (21.1%) of the 19 high-risk patients receiving universal prophylaxis (P<0.01). Similarly, CMV disease developed in seven (15.9%) of the 44 intermediate-risk patients receiving preemptive therapy and in one (5.3%) of the 19 high-risk patients receiving universal prophylaxis (P<0.01). The onset of CMV infection in high-risk group patients receiving universal prophylaxis was more than 120 days after transplantation. Conversely, patients in intermediate-risk group receiving preemptive therapy evidenced CMV infection 60 days following kidney transplantation. Similarly, one patient in high-risk cohort developed CMV disease at 6 months. For intermediate-risk cohort, three patients manifested CMV disease at 3 months, one at 4 months, two at 5 months, and one at 6 months. Supplementary table has been added to depict the levels of viral load found at different time intervals in patients with CMV infection and those with CMV disease.

Oral valganciclovir and intravenous ganciclovir were used to treat CMV infection and CMV disease, respectively. The treatment was well-tolerated among all the patients. No significant differences were found regarding the treatment of CMV infection and CMV disease. Interestingly, episode of leukocytopenia was found to be higher in high-risk patients (52.6%) than intermediate-risk patients (27.3%); however, no statistical relationship was observed (P=0.10; [Table 2]).
Table 2 Cytomegalovirus infection and cytomegalovirus disease post-transplantation

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Post-transplantation allograft rejection, allograft loss, mortality, and estimated glomerular filtration rate at 1 year

The number of biopsy-guided allograft rejection was found to be higher in intermediate-risk group receiving preemptive therapy than in high-risk group receiving universal prophylaxis (18.2 vs. 15.8%), and no significant differences were found between the two cohorts (P=0.44). Likewise, allograft loss and mortality were also comparable between the intermediate-risk and high-risk cohorts (13.6 vs. 10.5%, P=0.54 and 0 vs. 0%, P=0.15, respectively). Lastly, the mean eGFR at 1 year after transplantation was similar in both the cohorts: 52.5±21.8 in intermediate-risk (preemptive therapy) group and 54.3±23.2 in high-risk (universal prophylaxis) group (P=0.68; [Table 3]).
Table 3 Allograft rejection, allograft loss, mortality, and estimated glomerular filtration rate at 1 year after transplantation

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  Discussion Top


In this retrospective cohort study, our findings demonstrated that intermediate-risk (D+/R+ or D−/R+) kidney transplant recipients managed with preemptive therapy had a higher rate of CMV infection/disease than high-risk (D+/R−) kidney transplant recipients managed with universal prophylaxis with oral valganciclovir. Despite valganciclovir universal prophylaxis significantly minimizing the early risk of CMV infection and disease, high risk of late-onset CMV infection and disease is a concern. Published data suggest that late-onset CMV infection and disease frequently develops after termination of valganciclovir prophylaxis and is linked with increased allograft loss and/or mortality in high-risk (especially in D+/R−) transplant recipients [9],[17],[18],[19],[20]. Similarly, a case of very late-onset (12 years after kidney transplantation) CMV disease has also been reported recently, however, in D−/R− patient [21].

Research studies have also communicated the advantage of universal prophylaxis over preemptive therapy in reducing the burden of CMV infection and CMV disease in post-transplant patients. Meije et al. [22] reported that late-onset CMV disease was not a fatal condition when they matched universal prophylaxis with preemptive therapy in high-risk (D+/R−) kidney and liver transplant patients. Kliem et al. [11] also testified significantly low frequency of CMV infection and allograft rejection in D+/R+ patients who were receiving universal prophylaxis in contrast to those receiving preemptive therapy. A study by Witzke et al. [12] demonstrated high rate of CMV disease in D+/R+ patients who were managed with preemptive therapy in comparison with patients on universal prophylaxis. Similarly, a meta-analysis also suggested that universal prophylaxis is superior in averting CMV infection within the first year of kidney transplantation than preemptive therapy. The review mentioned that the risk of acute allograft rejection is low with universal prophylaxis [3]. Our study also found that intermediate-risk (D+/R+ or D−/R+) patients receiving preemptive therapy developed CMV infection/disease within first 6 months after kidney transplantation. This finding may also suggest the importance of giving oral valganciclovir universal prophylaxis in early periods (first 3–6 months) after transplantation, the peak vulnerable window for CMV infection. It might have a positive influence on minimizing the risk of late-onset CMV disease. A study suggested decreased risk of late-onset CMV disease in D+/R− patients who received universal prophylaxis for 6 months [23].

Contrasting results have also been reported in the literature. Florescu et al. [13], in their meta-analysis, suggested similar effectiveness for both universal prophylaxis and preemptive therapy in solid organ transplant recipients in inhibiting CMV infection/disease. In addition, they reported no difference in frequency of allograft rejection, allograft loss, and mortality. However, universal prophylaxis was found to be associated with fewer occurrences of very prompt CMV viremia after transplant, more late-onset CMV infections, and higher incidence of leukocytopenia. Another meta-analysis more recently published by Caskurlu et al. [14] reported results significantly different from the aforementioned literature findings. They found universal prophylaxis as superior option to prevent CMV disease; however, high value of number needed to treat patients to prevent CMV disease occurrence through universal prophylaxis in their study suggested the best treatment strategy otherwise. Moreover, they reported no differences in both the treatment strategies regarding acute allograft rejection and allograft.Indirect effects of CMV infection in solid organ transplant recipients have been reported in literature which involves acute allograft rejection, allograft failure, and mortality [24]. Our findings also suggested that the allograft rejection, allograft loss, and mortality rate did not statistically differ between high-risk patients receiving universal prophylaxis and intermediate-risk patients managed with preemptive treatment. However, allograft rejection and allograft loss were frequent in intermediate-risk patients in contrast to high-risk patients (P=0.44 and 0.54, respectively). Despite being intermediate-risk patients, high rates of indirect effects of CMV infection (allograft rejection and allograft loss) could be conceivably owing to CMV DNA replication during early periods after transplantation who were subject to preemptive treatment only when their qPCR was positive for CMV (≥400 CMV copies/ml). A study by Meije et al. [22] supports the superiority of universal prophylaxis with oral valganciclovir over preemptive treatment in reducing the frequency of allograft rejection and allograft loss, as valganciclovir prophylaxis competently inhibits CMV replication during the first 3 months of the post-transplantation period, especially in high-risk (D+/R−) kidney transplant patients.

Following were the research study limitations: (a) this was a retrospective cohort study; (b) the study data collected are from a single center and hence the number of patients recruited is quite small; and (c) the follow-up duration period was very small, that is, 1 year, so we were unable to estimate the long-term consequences of CMV infection/disease on kidney allograft and survival of patients.


  Conclusion Top


Intermediate-risk (D+/R+ or D−/R+) kidney transplant recipients receiving preemptive therapy had significantly higher frequency of CMV infection/disease than high-risk (D+/R−) kidney transplant recipients receiving oral valganciclovir universal prophylaxis during early periods following transplantation. No statistically significant differences were found in relation to allograft rejection, allograft loss, eGFR, and mortality at 1 year in both the cohorts. Nevertheless, allograft rejection and allograft loss were evidenced more often in intermediate-risk patients than in high-risk patients. eGFR at 1 year was also low in intermediate-risk patients compared with high-risk patients, though without any statistical significance. We would highly recommend future prospective studies to assess which approach, universal prophylaxis with oral valganciclovir or preemptive treatment is optimal in averting not only CMV infection and disease but also the indirect effects of CMV infection and disease in high-risk and intermediate-risk kidney transplant patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Cowan J, Bennett A, Fergusson N, McLean C, Mallick R, Cameron DW et al. Incidence Rate of Post-Kidney Transplant Infection: A Retrospective Cohort Study Examining Infection Rates at a Large Canadian Multicenter Tertiary-Care Facility. Can J Kidney Health Dis. 2018; 5:1–8.  Back to cited text no. 1
    
2.
Chitasombat MN, Watcharananan SP. Burden of cytomegalovirus reactivation post kidney transplant with antithymocyte globulin use in Thailand: a retrospective cohort study. F1000Res 2018; 7:1568.  Back to cited text no. 2
    
3.
Rawal BB, Shadrou S, Abubacker F, Ghahramani N. A systematic review and meta-analysis of prophylactic versus pre-emptive strategies for preventing cytomegalovirus infection in renal transplant recipients. Int J Organ Transplant Med 2012; 3:10–17.  Back to cited text no. 3
    
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Azevedo LS, Pierrotti LC, Abdala E, Costa SF, Strabelli TMV, Campos SV et al. Cytomegalovirus infection in transplant recipients. Clinics 2015; 70:515–523.  Back to cited text no. 4
    
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Couzi L, Helou S, Bachelet T, Martin S, Moreau K, Morel D et al. Preemptive therapy versus valgancyclovir prophylaxis in cytomegalovirus-positive kidney transplant recipients receiving antithymocyte globulin induction. Transplant Proc 2012; 44:2809–2813.  Back to cited text no. 5
    
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11.
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14.
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17.
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21.
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22.
Meije Y, Fortun J, Len O, Aguado JM, Moreno A, Cisneros JM et al. Prevention strategies for cytomegalovirus disease and long-term outcomes in the high-risk transplant patient (D+/R−): experience from the RESITRA-REIPI cohort. Transpl Infect Dis 2014; 16:387–396.  Back to cited text no. 22
    
23.
Humar A, Lebranchu Y, Vincenti F, Blumberg EA, Punch JD, Limaye AP et al. The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Am J Transplant 2010; 10:1228–1237.  Back to cited text no. 23
    
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