Impact of antiviral prophylaxis on EBV viremia and posttransplant lymphoproliferative disorders in solid organ transplant recipients: a systematic review and meta-analysis

Abstract

Introduction

Organ transplant recipients face a substantial risk of developing posttransplant lymphoproliferative disorders (PTLD). In over 90% of cases with B‐cell PTLD following solid organ transplantation, the Epstein‐Barr virus (EBV) genome is promptly identified, usually within the initial year. A continuing discussion revolves around the efficacy of antiviral prophylaxis in mitigating the incidence of PTLD in solid organ transplant (SOT) patients. This study aimed to conduct a systematic review and meta-analysis to investigate this issue.

Method

A comprehensive search was conducted up to December 31, 2023, in databases including PubMed, Embase, and the Cochrane Library for retrospective and prospective studies comparing antiviral prophylaxis effects on EVB viremia and PTLD incidence in SOT recipients. Fixed or random effect models were applied based on the heterogeneity assessed via the I² statistic, using Stata 16.0 software for data analysis.

Results

In total, 22 eligible studies involving 13,498 patients were analyzed. Antiviral prophylaxis was associated with a significant reduction in EBV viremia incidence in SOT recipients, as demonstrated in 10 studies (relative risk (RR) 0.69, 95% CI 0.54 to 0.88). The rate of PTLD was significantly lower among those who received antiviral prophylaxis compared to those who did not, as reported in 18 studies (RR 0.77, 95% CI 0.63 to 0.94). No significant difference was observed in the subgroup of high-risk recipients based on EBV serology (RR 1.13, 95% CI 0.72 to 1.78). Additionally, a notable reduction in PTLD incidence was seen in the pediatric subgroup (RR 0.58, 95% CI 0.43 to 0.79) using antiviral prophylaxis, while no significant differences were observed in the subgroup of adults (RR 0.88, 95% CI 0.64 to 1.21). Administration of antiviral prophylaxis can significantly reduce the incidence of PTLD among kidney (RR 0.63, 95% CI 0.46 to 0.87) and heart transplant patients (RR 0.61, 95% CI 0.39 to 0.96). PTLD incidence was significantly reduced among recipients of T-cell depletion or steroid-based immunosuppression using antiviral prophylaxis (RR 0.54, 95% CI 0.39–0.74 and RR 0.55, 95% CI 0.41–0.73, respectively).

Conclusion

This meta-analysis revealed that administering antiviral prophylaxis to patients after solid organ transplantation reduces PTLD and EBV viremia occurrences, especially among pediatric recipients, individuals undergoing kidney or heart transplantation, and those receiving high-intensity immunosuppression regimens.

Key Summary Points

• Post-transplant lymphoproliferative disorders (PTLD) and other EBV syndromes are among the most serious complications following solid organ transplantation (SOT), primarily due to the necessity for prolonged immunosuppressive therapy.

• Among the strategies for preventing EBV-related complications, the use of antiviral prophylaxis is a subject of ongoing debate.

• This systematic review and meta-analysis found that antiviral prophylaxis significantly reduced EBV viremia incidence (risk ratio (RR) 0.69, 95% confidence interval (CI) 0.54 to 0.88) compared to those without prophylaxis.

• In the sub-analysis related to high-risk EBV serologically mismatched SOT recipients (EBV D+/R-), the result did not show a significant difference in terms of PTLD incidence (RR 1.13, 95% CI 0.72 to 1.78).

• Antiviral prophylaxis significantly impacted the occurrence of PTLD events among pediatric SOT patients (RR 0.58, 95% CI 0.43 to 0.79), but not among adult patients (RR 0.88, 95% CI 0.64 to 1.21).

• Antiviral prophylaxis significantly impacted the occurrence of PTLD events among kidney/simultaneous pancreas and kidney (RR 0.63, 95% CI 0.46 to 0.87) and heart (RR 0.61, 95% CI 0.39 to 0.96) transplant patients but not liver  (RR 0.5, 95% CI 0.23 to 1.08) transplant recipients.

Introduction

Epstein–Barr virus (EBV) syndrome can present with a wide spectrum of clinical manifestations, ranging from asymptomatic infection to EBV viremia, EBV disease, and various malignancies including lymphoma [1]. Post-transplant lymphoproliferative disorders (PTLD) and other EBV syndromes are among the most serious complications following solid organ transplantation (SOT), primarily due to the necessity for prolonged immunosuppressive therapy [2].

The incidence of EBV-associated PTLD varies from 1.2% in adults to 8.4% in pediatric patients [3], and is influenced by factors such as the post-transplant period, type of allograft, induction therapy, intensity of immunosuppression, and the recipient’s EBV serological status [4]. The increased incidence of EBV-induced PTLD in younger patients is likely due to their limited prior exposure to EBV, and consequently, lower immunity [5].

Among the strategies for preventing EBV-related complications, the use of antiviral prophylaxis is a subject of ongoing debate. Although this notion is supported by many studies [6,7,8], others have found no significant benefit [9,10,11]. Some of the observations reported in the mentioned studies are provided below for better clarification.

For instance, the correlation between prophylactic antiviral administration and PTLD reduction incidence was estimated about 83% by Funch et al. [6]. This finding was confirmed by Ville et al. [7] indicating that antiviral prophylaxis may serve to avert the occurrence of late-onset PTLD. In addition to PTLD prevention, antiviral utilization has indicated its role in EBV viremia prohibition. The study by Höcker et al. [8] revealed that (val-)ganciclovir use was associated with lower EBV viral load in pediatric kidney allograft recipients.

In contrast to the discussed findings, other research studies have questioned the antiviral therapies efficacy in prevention of EBV-associated complications in transplantation. Due to the results of a Switzerland cohort study published in 2021 [10], no significant correlation was found between the use of antiviral prophylaxis and early or late EBV and PTLD occurrence. Accordingly, two years later, Cheyssac et al. [9] stated that irrespective of EBV status, valganciclovir prophylaxis has no effect for EBV infection prevention in organ transplant recipients.

Although a systematic review and meta-analysis on this topic was conducted in 2016 [3], numerous studies with substantial sample sizes have been published since then (2016–2023). The previous review focused exclusively on high-risk SOT recipients that is seropositive donors and seronegative recipients (D+/R−), leaving the role of antiviral prophylaxis in other EBV serological statuses unclear. Given the importance of this issue and the potential for new insights, we aimed to conduct the present study to further elucidate the role of antiviral prophylaxis in preventing post-transplant EBV viremia, disease and PTLD in patients across different age ranges, both pediatric and adults.

Method

Study design

To guarantee a comprehensive and systematic analysis of the data, we adhered completely to the Preferred Reports for Systematic Reviews and Meta-Analyses (PRISMA) standards throughout our research procedure [12].

Data source and search strategy

A complete search of electronic databases, including PubMed, Cochrane, and Embase, was carried out until December 31, 2023. The search adopted MeSH terms, Emtree terms and related keywords. In addition, the references of included articles and previous relevant systematic reviews were screened to thoroughly identify relevant studies [13]. We followed the PICO (population, intervention, comparison, and outcome) structure to frame our research questions [14, 15]. Solid organ recipients were identified as the population could be studied. The use of antiviral prophylaxis or preventive therapy made up the intervention studied. The outcomes of interest were EBV infection or viremia, EBV disease, and PTLD. No particular group was used for comparison in this framework.

Study selection and data extraction

Two researchers independently screened the titles and abstracts of identified records and resolved any disagreements through discussion. Randomized controlled trials (RCTs) and observational studies that investigated the effects of antiviral prophylaxis or preemptive treatment in preventing EBV-related diseases and complications were included. Researches involving nonhuman subjects, abstracts for conferences, reviews without original data, case reports, and studies published in languages other than English were excluded. The studies that compared the efficacy of two antivirals were also excluded from the meta-analysis. Full-text articles meeting the inclusion criteria were retrieved and the data were extracted using a specific custom Microsoft Excel form. The key data extracted were study details, population demographics, baseline EBV serology, intervention features, and patients’ outcomes. If a study utilized two or more different antivirals or reported outcomes separately across different time frames, it was included in the meta-analysis separately, provided that the populations did not overlap and the results were distinctly separated.

Statistical analysis

The Cochran Q test and the I² statistic were applied for the heterogeneity investigation of the studies [16]. I² statistics of 25%, 50%, and 75% are determined as low, medium, and high heterogeneity levels of studies, respectively. The Q test was supported statistically to be significant with a P-value of less than 0.1. The choice of fixed and random models was depended on the level of heterogeneity. A random model was used when the heterogeneity was significantly different (P < 0.1 for Q test or I² ≥ 50%). On the other hand, if heterogeneity of studies was not significant, a fixed effect model was used [17].

Univariate meta-regressions using random-effects models were performed to explore potential sources of heterogeneity for both EBV viremia and PTLD outcomes. The following categorical variables were assessed as potential moderators: patient age (adult, pediatric, mixed); transplant type (kidney, heart, liver, other); serostatus (high risk, non-high risk, mixed); antiviral agent ((val-)ganciclovir, (val-)acyclovir, (val-)ganciclovir or (val-)acyclovir, mixed); intervention duration (0–1 month, 1–6 months, > 6 months); induction immunosuppression (T-cell depleting, T-cell non-depleting, none, mixed); maintenance immunosuppression (excluding calcineurin inhibitors and antimetabolites: with mTOR inhibitor, with steroids, without steroids); and publication decade (before 2010, 2010 or later).

Funnel plots and Egger’s test were the methods used for assessing publication bias. Sensitivity analysis was done to check the consistency of the results. All analyses were performed using Stata version 16, and a P value of ≤ 0.05 was accepted as statistically significant for the primary outcomes.

Quality assessment

Two reviewers independently evaluated the methodological quality and risk of bias of the included studies using the Revised Cochrane risk-of-bias tool for randomized trials (RoB 2) tool for RCTs [18] and the Risk of Bias in Non-randomized Studies—of Interventions (ROBINS-I) tool for observational studies [19]. Any disagreements were solved by discussion.

Result

Study identification

Researchers retrieved a total of 1,868 publications, including 1,150 from Embase, 715 from PubMed, and three studies from Cochrane database. Also references from recovered articles and related reviews were evaluated. After excluding duplicate articles and filtering based on title and abstract, a total of 142 full text articles underwent review. Ultimately, 120 articles were excluded due to reasons such as unavailability of full text, case reports, overlapping data, the absence of a control group, and the comparison of different antivirals within each study arm. Finally, 22 articles with 13,498 patients were identified based on inclusion and exclusion criteria for further analysis (Fig. 1).

Fig. 1

PRISMA diagram showing study selection process. Legend: The flowchart shows the number of studies that were found, reviewed, and excluded, and the reasons for exclusion at each step of the process

Study characteristics

The studies included in this analysis spanned publication years from 1993 to 2023. The USA [6, 20, 21] and France [7, 9, 22] each conducted three studies, and Australia [23, 24], Canada [25, 26], Germany [8, 11], and Switzerland [10, 27] each conducted two. Additional studies were carried out in Belgium [28], Denmark [29], England [30], Iran [31], Italy [32], Korea [33], and Spain [34]. One study had multicenter populations across continents [35]. Participant numbers varied, ranging from 16 to 4,765 participants in multicenter nationwide observational prospective study from Switzerland [10]. Only one study was RCT [22]. Pediatric patients [6, 8, 9, 25, 26, 29, 31,32,33] and adults (7, 10, 11, 20, 22,23,24, 28, 30, 34) were evaluated in 8 and 10 studies, respectively, with three studies involving both children and adults [35]. In one study, the population remained unidentified [21]. Kidney or liver transplants were the focus of eight [6, 8, 9, 11, 20, 22, 27, 29] and four studies [30,31,32,33], respectively. Heart transplant patients were investigated in three studies [26, 28, 34] and pancreas or simultaneous pancreas and kidney transplantation (SPK) recipients in one study [7]. Furthermore, six studies included a broader population covering various types of solid organ transplantation [21, 23,24,25, 35]. Antivirals such as ganciclovir, valganciclovir, acyclovir, and valacyclovir were used in studies, with durations ranging from two weeks to up to two years post-transplantation [33]. The evaluated primary outcomes included the incidence of EBV infection or viremia, EBV disease, and PTLD across 10 [7,8,9, 11, 20, 24, 25, 28,29,30], 3 [8, 9, 22], and 17 studies [6,7,8,9,10, 20,21,22,23,24, 26,27,28, 31,32,33,34], respectively (Table 1). The median follow-up period varied from two weeks to nine years.

Table 1 Summary of studies included in the analysis

Risk of bias

The risk of bias for primary outcomes was assessed using the ROBINS-I tool for 20 studies [1, 2, 5, 8, 12, 13, 16,17,18, 20, 21, 24, 27,28,29, 33,34,35, 38, 43] the RoB 2 tool for one RCT [22]. The results of bias are reported in Fig. 2 and Fig. 3, respectively.

Fig. 2

Traffic light plot for risk of bias assessment using the ROBINS-I tool for non-randomized studies. Legend: ROBINS-I tool for the assessment of risk of bias in non-randomized studies presented in the form of a traffic light plot. Studies are presented with color-coded assessments indicating their risk levels, allowing for easy visualization of their internal validity

Fig. 3

Traffic light plot for risk of bias assessment using ROB 2.0 for randomized controlled studies. Legend: Traffic light plot for risk of bias assessment using the ROB 2.0 tool for randomized controlled trials. Studies are presented with color-coded assessments indicating their risk levels, allowing for easy visualization of their internal validity

Publication bias

Publication bias was not detected in studies evaluating PTLD (Egger’s test P = 0.355); however, it was detected in studies evaluating EBV viremia (Egger’s test P = 0.018). The funnel plots are displayed in Fig. 4.

Fig. 4

Funnel plot illustrating the effect of antiviral prophylaxis on the incidence of PTLD (left) and EBV viremia (right). Legend: The funnel plot of the log risk ratio against the standard error for antiviral prophylaxis on the incidence of PTLD (left) and EBV viremia (right). The asymmetry of the plots observed indicates the possibility of publication bias

Data analysis

Due to the small number of articles for EBV disease (3 articles) and the different definitions of EBV disease, we performed meta-analysis only for two outcomes: EBV-viremia and PTLD.

Effect of antiviral prophylaxis on the incidence of EBV viremia

As mentioned above, different antivirals were used with varying duration across the included studies. Figure 5 shows that in 10 studies consisting a total of 1,521 patients, regardless of the prophylactic agent and type of SOT, antiviral prophylaxis significantly reduced EBV viremia incidence (risk ratio (RR) 0.69, 95% confidence interval (CI) 0.54–0.88) compared to those without prophylaxis. It should be mentioned that in Ville et al.’s study, the analysis was conducted separately for early EBV viremia incidence (within the first 100 days of transplantation) and late EBV viremia incidence (after one year of transplantation) [7]. Similarly, regarding the study of Halliday et al., that patients received two different antivirals, each group was analyzed separately [30].

Fig. 5

Effect of antiviral prophylaxis on the incidence of EBV viremia. Legend: Forest plot showing the impact of antiviral prophylaxis on the occurrence of EBV viremia. The plot summarizes effect estimates and confidence intervals, demonstrating the protective effect of prophylaxis

Effect of antiviral prophylaxis on the incidence of PTLD

Excluding the prophylactic agent and type of SOT, there was a notable difference in the rate of PTLD as indicated by Fig. 6 among 12,227 patients of 18 studies (RR 0.77, 95% CI 0.63–0.94).

Fig. 6

Effect of antiviral prophylaxis on the incidence of PTLD and subgroup of high-risk EBV serology. Legend: Forest plot showing the effect of antiviral prophylaxis on the incidence of PTLD, including a subgroup analysis for patients with high-risk EBV serology. Results indicate how prophylaxis impacts different risk categories

Subgroup analysis

In the sub-analysis related to 2,327 high-risk EBV serologically mismatched SOT recipients (EBV D + /R−), the result of the analysis of five studies did not show a significant difference in terms of PTLD (RR 1.13, 95% CI 0.72–1.78) (Fig. 6).

All eight studies on pediatric patients, comprising a total of 1,215 SOT recipients, evaluated the antiviral efficacy in preventing PTLD. In this subgroup, antiviral prophylaxis significantly impacted the occurrence of PTLD events (RR 0.58, 95% CI 0.43–0.79) (Fig. 7). However, the analysis of 8 studies encompassing 8,732 adults did not show this effectiveness (RR 0.88, 95% CI 0.64–1.21) (Fig. 7).

Fig. 7

Effect of antiviral prophylaxis on the incidence of PTLD by subgroups of age. Legend: Forest plot presenting the effect of antiviral prophylaxis on the incidence of PTLD by age subgroups. This analysis highlights age-related differences in prophylaxis efficacy, providing insights into tailored approaches

The studies were also analyzed for the effect of antiviral prophylaxis on the occurrence of PTLD, based on the type of solid organ transplanted. The analysis of seven studies conducted on 952 kidney or SPK transplant patients showed that the use of antiviral prophylaxis regimen can significantly reduce the incidence of PTLD with RR of 0.63 (95% CI 0.46–0.87) (Fig. 8). Additionally, based on data from three studies involving 3,806 heart transplant patients, administration of antiviral prophylaxis regimens demonstrated significant effectiveness in reducing the incidence of PTLD (RR 0.61, 95% CI 0.39–0.96) (Fig. 8). The occurrence of PTLD remained unchanged in 358 liver transplant recipients, as the PTLD rate was comparable regardless of whether prophylaxis was administered or not (RR 0.50, 95% CI 0.23–1.08) (Fig. 8).

Fig. 8

Effect of antiviral prophylaxis on the incidence of PTLD by subgroups of organ transplantation. Legend: Forest plot illustrating the effect of antiviral prophylaxis on the incidence of PTLD across various organ transplantation subgroups. Results indicate variations in protective effects based on the type of organ transplanted

The impact of antivirals on the incidence of PTLD, considering the induction regimen, was evaluated as follows: six studies used T-cell depleting agents [6, 21, 22, 26, 28, 29], four studies used T-cell non-depleting agents [8, 20, 30, 33], six studies utilized both types of agents [9, 10, 25, 27, 34, 35], and four studies did not involve any induction regimen [23, 24, 31, 32]. Two studies also did not mention the type of induction regimen [7, 11]. Analysis of these studies indicated that administering antivirals to patients on induction regimens with depleting agents like Anti-thymocyte globulin (ATG) and OKT3 significantly lowered the incidence of PTLD (RR 0.54, 95% CI 0.39–0.74). However, this effect was not significant in other groups. (Fig. 9).

Fig. 9

Effect of antiviral prophylaxis on the incidence of PTLD by subgroups of induction immunosuppression Legend: Forest plot illustrating the effect of antiviral prophylaxis on the incidence of PTLD across different subgroups of induction immunosuppression. Results suggest varying levels of protection offered by antiviral prophylaxis depending on the specific induction immunosuppression regimen

When examining maintenance regimens, studies were categorized based on the use of steroids. An analysis of 12 studies, including 1939 individuals receiving steroids, indicated that antiviral treatment was significantly linked to a lower incidence of PTLD (RR 0.55, 95% CI 0.41–0.73). Conversely, this significant association was not observed in patients on maintenance regimens without steroids. (Fig. 10).

Fig. 10

Effect of antiviral prophylaxis on the incidence of PTLD by subgroups of maintenance immunosuppression Legend: Forest plot illustrating the effect of antiviral prophylaxis on the incidence of PTLD across different subgroups of maintenance immunosuppression. Results suggest varying levels of protection offered by antiviral prophylaxis depending on the specific maintenance immunosuppression regimen

The analysis of patients in two subgroups, categorized by the antiviral therapy they received (either acyclovir and valacyclovir, or ganciclovir and valganciclovir), showed a significant reduction in the incidence of EBV-associated PTLD in both groups (RR 0.65, 95% CI 0.45–0.95 and RR 0.51, 95% CI 0.35–0.74, respectively). However, the RR was found to be lower in the group receiving ganciclovir and valganciclovir.

Meta-regression analysis

For the PTLD outcome, univariate meta-regression analyses identified transplant type, induction immunosuppression, and maintenance immunosuppression as significant moderators of the observed heterogeneity (P < 0.05). In contrast, patient age, serostatus, antiviral agent, intervention duration, and publication decade did not significantly explain the observed heterogeneity (P > 0.05). For the EBV viremia outcome, none of the tested moderators significantly explained the observed heterogeneity (P > 0.05) (Table 2).

Table 2 The result of meta-regression

Discussion

This meta-analysis indicates that antiviral prophylaxis strategies can effectively reduce the incidence of EBV viremia and PTLD. The EBV life cycle consists of two distinct phases: lytic and latent. During the lytic phase, EBV actively replicates and produces infectious virions, a process crucial for initial infection or viral reactivation [36, 37]. Nucleoside analogues such as acyclovir and ganciclovir inhibit lytic EBV replication by targeting key viral and cellular enzymes. Nucleoside analogues acyclovir and ganciclovir undergo initial phosphorylation by the viral protein kinase during the lytic phase, subsequently receiving additional phosphorylation from cellular enzymes guanosine monophosphate (GMP) and nucleoside diphosphate (NDP) kinase, which transform them into their active triphosphate forms. These active forms inhibit EBV DNA polymerase by acting as competitive inhibitors or alternative substrates, halting DNA replication [38]. As a result, antiviral prophylaxis during the lytic phase effectively decreases episodes of EBV viremia [39]. On the other hand, the latent phase of EBV enables the virus to remain undetected within B lymphocytes by expressing a limited number of viral genes, thereby evading immune surveillance. Latent EBV proteins exhibit diverse functions that facilitate cell proliferation, immune evasion, and resistance to apoptosis, thereby contributing to the development of lymphoproliferative diseases [40]. The viral enzyme, porin kinase, which is targeted by nucleoside analogs such as ganciclovir and acyclovir, is expressed solely during the lytic phase of the virus. Consequently, Prophylactic antiviral therapy, is unable to directly target latently infected cells or prevent EBV-driven B-cell transformation linked to PTLD [41]. Nevertheless, Antiviral prophylaxis during the lytic phase of EBV may significantly diminish the viral load and impede the latency transition of infected cells, thereby reducing the reservoir of latently infected B cells and decreasing the risk of sequelae from EBV, particularly in immunocompromised individuals. Furthermore, recent evidence indicates that EBV lytic reactivation is pivotal in oncogenesis by facilitating immune evasion, genomic instability, apoptosis resistance, and enhancing tumorigenesis and invasiveness. Therefore, despite the limited efficacy of antiviral drugs in treating EBV-associated malignancies, preliminary studies have shown promise in combining these agents with histone deacetylase inhibitors, such as arginine butyrate. This approach aims to stimulate lytic gene expression and enhance tumor sensitivity to treatment [38, 41].

PTLD represents a heterogeneous spectrum of predominantly B-cell disorders and is a life-threatening complication after SOT. In most cases, PTLD is associated with active replication of EBV following either primary infection or reactivation [2, 4]. The American Society of Transplantation guideline does not recommend the use of chemoprophylaxis for the early prevention of PTLD in patients with high-risk EBV serology [2]. This recommendation is supported by the findings of a prior meta-analysis [3]. Our systematic review and meta-analysis may change this recommendation and provide important information on the use of antiviral prophylaxis or pre-emptive therapy in preventing PTLD in solid organ transplant recipients. We included all studies that used antiviral drugs, regardless of EBV serology. In the subgroup analysis of patients with high-risk serology, antiviral prophylaxis did not lower the risk of PTLD. This finding aligns with previous meta-analyses that included only studies with high-risk serology patients, concluding that the evidence is insufficient to support the routine use of antivirals in solid organ transplant recipients to decrease the incidence of PTLD [3]. Recipient’s EBV seronegativity is one of the known risk factors for early PTLD, which is typically associated with EBV-positive PTLD [36, 37]. However, this finding is not consistent with our results. This could be due to the limited number of studies and patients included in this sub-analysis, as most of the included studies analyzed mixed serology status of the patients. Therefore, larger and stronger studies are required to make conclusions in this patient population. It should be noted that one of the studies included in the previous meta-analysis was not included in our study because the full text of the publication was not available to the authors of the present work [38]. Additionally, three studies from the previous meta-analysis did not meet our inclusion criteria [42,43,44].

When pediatric patients were separated from the adult SOT recipients, it was observed that antiviral prophylaxis did not lower the risk of PTLD in adults, while, the risk reduction in pediatric patients became more significant. This finding is expected because EBV DNA is detected in the majority of B-cell PTLD developing within the first year after solid organ transplantation [45]. However, in adult populations, PTLD that occurs later after transplantation is increasingly reported to be EBV-negative [46].

In the analysis by induction and maintenance immunosuppression regimen, a significant reduction in the risk of PTLD is observed in patients receiving T-cell-depleting agents and in patients receiving steroids in maintenance immunosuppression other than CNIs and antimetabolites. The use of T-cell-depleting agents in the induction regimen is a significant risk factor for early PTLD [2]. Therefore, in these patients, antiviral prophylaxis may be particularly beneficial in reducing the risk of PTLD.

In the analysis by organ transplant type, a notable reduction in the risk of PTLD is observed in the kidney and heart transplant subgroups; while, this reduction is not significant for liver transplantation. This may be attributable to more potent immunosuppressive regimens employed in heart and kidney transplantation. The limited number of studies on liver transplantation with the small total patient population make it difficult to draw reliable conclusion.

Antiviral prophylaxis significantly reduced the incidence of EBV-associated PTLD in both patient subgroups, regardless of whether they received (val-) acyclovir or (val-) ganciclovir. Notably, a more pronounced reduction in PTLD risk was observed in the (val-) ganciclovir group, suggesting a potential advantage of this antiviral class. However, significant variability existed in antiviral regimens, including drug choice, dosage, and prophylaxis duration, across the study population. This heterogeneity limits our ability to draw definitive conclusions regarding the most effective antiviral drug, dose, or prophylaxis duration for preventing EBV-related post-transplant complications. To address this limitation, head-to-head randomized controlled trials are needed to directly compare the efficacy and safety of different antiviral agents. Notably few studies comparing two antiviral regimens were excluded from the final analysis. In the research conducted by Razonable and colleagues, the rates of EBV DNAemia were found to be quite similar among patients taking oral ganciclovir and those on oral valganciclovir. However, high-level EBV DNAemia was detected in 6.3% of patients receiving oral ganciclovir compared to only 1.2% of those receiving oral valganciclovir. Notably, there was no reported case of PTLD in either group during 12 months after transplantation [47]. An older RCT compared the sequential use of 2 weeks of intravenous ganciclovir followed by 50 weeks of high-dose oral acyclovir with 2 weeks of intravenous ganciclovir alone as prophylaxis for CMV and EBV disease after pediatric liver transplantation. The rate of EBV disease among patients treated with the combination regimen was similar to that of patients receiving ganciclovir alone [48]. In another study, researchers compared two groups of patients, one group receiving intravenous ganciclovir for 100 days (group 1: high-risk serology) and the other group receiving intravenous ganciclovir for 2 weeks (group 2: low-risk serology). Both groups were then transitioned to oral acyclovir. No cases of PTLD and only one case of EBV disease which resolved later were reported in group 1. In contrast, in group 2 two cases of PTLD were reported [49]. Overall, it appears that more comprehensive, controlled clinical trials with adequate sample sizes are needed to determine the optimal prophylaxis regimen.

There are several limitations to this meta-analysis. The majority of the studies included were cohort and observational in design, with only one RCT in the final analysis. A high risk of bias was observed in some of the studies and there was notable clinical heterogeneity among them due to the variations in study methodologies. Some studies focused on CMV prophylaxis and reported its effects on the incidence of PTLD as side findings. The follow-up periods were also different and ranged from several weeks to several years. Moreover, data regarding specific antiviral agents and their duration of administration were insufficient to make specific recommendations regarding the best prophylactic strategy. Furthermore, the induction and maintenance immunosuppression, as well as other concurrent medications, showed significant variations across studies, which may directly influence the incidence of PTLD.

In addition, EBV serology varied among the studies, with most studies were not restricted to the high-risk patients. The definitions of EBV viremia and the methods of EBV viral load detection also varied among studies. Finally, we could not distinguish between early PTLD (within the first year after transplantation) and late PTLD (after the first year of transplantation) as our analysis focused on the overall incidence of PTLD.

Conclusion

This meta-analysis demonstrates that antiviral prophylaxis has a beneficial effect on the prevention of EBV viremia and PTLD after SOT. Notably, pediatric recipients, those undergoing kidney or heart transplantation, and patients receiving T-cell depletion or steroid-based immunosuppression appear to benefit significantly from universal antiviral strategies. While the effectiveness of prophylaxis in adults remains debated, these findings underscore the importance of personalized approaches considering patient age and the unique characteristics of PTLD in different populations. However, further randomized clinical trials with standardized protocols in different populations are needed to clarify several gray areas, such as identifying which populations would benefit most from prophylaxis, the most effective antiviral regimen, and the optimal dose and duration of antiviral therapy.