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

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. 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. 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). 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. 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.

Moghadamnia M ，Delroba K ，Heidari S ，Rezaie Z ，Dashti-Khavidaki S ... -  《Virology Journal》

Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients.

Vernooij RW ，Michael M ，Ladhani M ，Webster AC ，Strippoli GF ，Craig JC ，Hodson EM ... -  《Cochrane Database of Systematic Reviews》

Pre-emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients.

Cytomegalovirus (CMV) is a significant cause of morbidity and death in solid organ transplant recipients. Pre-emptive treatment of patients with CMV viraemia using antiviral agents has been suggested as an alternative to routine prophylaxis to prevent CMV disease. This is an update of a Cochrane review first published in 2006 and updated in 2013. To determine the benefits and harms of pre-emptive treatment of CMV viraemia to prevent CMV disease and death (any cause) and the indirect effects of CMV infection (acute rejection, graft loss, opportunistic infections) in solid organ transplant recipients. The Cochrane Kidney and Transplant Register of Studies was searched up to 17 December 2024 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. We included randomised controlled trials (RCTs) and quasi-RCTs comparing pre-emptive treatment with placebo, no specific treatment, or antiviral prophylaxis in solid organ transplant recipients. Two authors independently assessed the eligibility of the identified studies, assessed the risk of bias, and extracted all data. Results were expressed as risk ratio (RR) and 95% confidence intervals (CI) for dichotomous outcomes. Statistical analyses were performed using a random-effects model. The certainty of evidence was assessed per outcome using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. In this update, we have included seven new studies, bringing the total number of included studies to 22 (1883 participants). Of these, seven investigated pre-emptive treatment versus placebo or standard care, 12 looked at pre-emptive treatment versus antiviral prophylaxis, one study investigated oral versus intravenous pre-emptive treatment, one investigated pre-emptive valganciclovir versus pre-emptive ganciclovir, and one investigated letermovir 40 mg twice/day versus 80 mg once/day. Studies were conducted in Australia, Brazil, the Czech Republic, Germany, Italy, Japan, Norway, Spain, South Korea, and the USA. Organ transplant recipients included kidney, liver, heart, lung, and kidney-pancreas. Thirteen studies were single-centre studies, six were multicentre, and three were unknown. The number of participants ranged from 12 to 296. Overall, selection bias was unclear (55%); performance, detection and attrition bias were high (91%, 63% and 95%, respectively), and reporting bias was low (55%). Compared with placebo or standard care, pre-emptive treatment probably reduces the risk of CMV disease (7 studies, 315 participants: RR 0.29, 95% CI 0.11 to 0.80; I2 = 54%; moderate-certainty evidence) but may result in little or no difference in death (any cause) (3 studies, 176 participants: RR 1.23, 95% CI 0.35 to 4.30; I2 = 0%; low-certainty evidence). Pre-emptive treatment may result in little or no difference in CMV organ involvement, CMV-associated symptoms, acute rejection, graft loss, other infections or leucopenia. Compared to prophylaxis, pre-emptive treatment may make little or no difference to the risk of developing CMV disease (11 studies, 1322 participants: RR 0.97, 95% CI 0.47 to 2.01; I2 = 54%; low-certainty evidence) and probably makes little or no difference to death (any cause) (9 studies, 1098 participants: RR 0.95, 95% CI 0.60 to 1.52; I2 = 0%; moderate-certainty evidence). Pre-emptive treatment may increase the risk of CMV infection (8 studies, 867 participants: RR 1.97, 95% CI 1.48 to 2.61; I2 = 66%; low-certainty evidence). The risk of leucopenia (7 studies, 869 participants: RR 0.57, 95% CI 0.38 to 0.87; I2 = 33%; moderate-certainty evidence) and neutropenia (5 studies, 859 participants: RR 0.63, 95% CI 0.44 to 0.90; I2 = 0% moderate certainty evidence) probably decreases with pre-emptive therapy. There may be little or no difference in the risks of acute rejection, graft loss, and infections other than CMV. Single studies were identified for comparisons between different pre-emptive treatments: 1) oral ganciclovir versus IV ganciclovir; 2) valganciclovir versus ganciclovir; 3) 40 mg twice/day versus 80 mg once/day. No differences between these treatment modalities in terms of CMV disease, death (any cause), or adverse events were identified. In this review, we have included seven new studies, yet the available evidence is overall of low certainty and the conclusions remain similar to the previous version of this review. Pre-emptive treatment probably reduces the risk of CMV disease compared with placebo or standard care. There were no clear differences between pre-emptive treatment and prophylaxis to prevent CMV disease or reduce the risk of death (any cause). The risk of CMV infection may be higher for patients receiving pre-emptive therapy, but the risk of adverse events, such as leucopenia, is probably lower.

Vernooij RW ，Michael M ，Colombijn JM ，Owers DS ，Webster AC ，Strippoli GF ，Hodson EM ... -  《Cochrane Database of Systematic Reviews》

Sex and gender as predictors for allograft and patient-relevant outcomes after kidney transplantation.

Sex, as a biological construct, and gender, defined as the cultural attitudes and behaviours attributed by society, may be associated with allograft loss, death, cancer, and rejection. Other factors, such as recipient age and donor sex, may modify the association between sex/gender and post-transplant outcomes. We sought to evaluate the prognostic effects of recipient sex and, separately, gender as independent predictors of graft loss, death, cancer, and allograft rejection following kidney or simultaneous pancreas-kidney (SPK) transplantation. We aimed to evaluate this prognostic effect by defining the relationship between recipient sex or gender and post-transplantation outcomes identifying reasons for variations between sexes and genders, and then quantifying the magnitude of this relationship. We searched MEDLINE and EMBASE databases from inception up to 12 April 2023, through contact with the Cochrane Kidney and Transplant Information Specialist, using search terms relevant to this review and no language restrictions. Cohort, case-control, or cross-sectional studies were included if sex or gender were the primary exposure and clearly defined. Studies needed to focus on our defined outcomes post-transplantation. Sex was defined as the chromosomal, gonadal, and anatomical characteristics associated with the biological sex, and we used the terms "males" and "females". Gender was defined as the attitudes and behaviours that a given culture associates with a person's biological sex, and we used the terms "men" and "women". Two authors independently assessed the references for eligibility, extracted the data and assessed the risk of bias using the Quality in Prognosis Studies (QUIPS) tool. Whenever appropriate, we performed random-effects meta-analyses to estimate the mean difference in outcomes. The outcomes of interest included the Standardised Outcomes in Nephrology-Kidney Transplant (SONG-Tx) core outcomes, allograft loss, death, cancer (overall incidence and site-specific) and acute or chronic graft rejection. Fifty-three studies (2,144,613 patients; range 59 to 407,963) conducted between 1990 and 2023 were included. Sixteen studies were conducted in the Americas, 12 in Europe, 11 in the Western Pacific, four in the Eastern Mediterranean, three in Africa, two in Southeast Asia, and five across multiple regions. All but one study focused on sex rather than gender as the primary exposure of interest. The number identified as male was 54%; 49 studies included kidney transplant recipients, and four studies included SPK transplant recipients. Twenty-four studies included adults and children, 25 studies included only adults, and four studies included only children. Data from 33 studies were included in the meta-analyses. Among these, six studies presented unadjusted hazard ratios (HRs) that assessed the effect of recipient sex on kidney allograft loss. The other studies reported risk ratios (RRs) for the pre-defined outcomes. Notably, the decision to restrict the meta-analyses to unadjusted estimates arose from the variation in covariate adjustment methods across studies, lacking a common set of adjusted variables. Only three studies considered the modifying effect of recipient age on graft loss or death, which is likely crucial to evaluating sex differences in post-transplant outcomes. No studies considered the modifying effect of recipient age on cancer incidence or allograft rejection risk. In low certainty evidence, compared with male recipients, being female may make little or no difference in kidney allograft loss post-transplantation (7 studies, 5843 patients: RR 0.91, 95% CI 0.73 to 1.12; I2 = 73%). This was also observed in studies that included time-to-event analyses (6 studies, 238,937 patients; HR 1.07, 95% CI, 0.95 to 1.20; I2 = 44%). Two recent large registry-based cohort studies that considered the modifying effects of donor sex and recipient age showed that female recipients under 45 years of age had significantly higher graft loss rates than age-matched male recipients in the setting of a male donor. In contrast, female recipients 60 years and older had lower graft loss rates than age-matched male recipients, regardless of donor sex. Compared with male recipients, being female may make little or no difference in death up to 30 years post-transplantation; however, the evidence is very uncertain (13 studies, 60,818 patients: RR 0.94, 95% CI 0.81 to 1.09; I2 = 92%). Studies that considered the modifying effect of recipient age and donor sex showed that female recipients had a higher excess death risk than males under 45 years of age in the setting of a male donor. Compared with male recipients, being female may make little or no difference in cancer incidence up to 20 years post-transplantation; however, the evidence is very uncertain (7 studies, 25,076 patients; RR 0.84, 95% CI 0.70 to 1.01; I2 = 60%). Compared with male recipients, being female may make little or no difference in the incidence of acute and chronic kidney allograft rejection up to 15 years post-transplantation (9 studies, 6158 patients: RR 0.89, 95% CI 0.75 to 1.05; I2 =54%; low certainty evidence). One study assessed gender and reported that when compared with men, women experienced better five-year survival in high (HR 0.71, 95% CI 0.59 to 0.87) and middle-income areas (HR 0.82, 95% CI 0.74 to 0.92), with no difference in low-income areas (HR 0.85, 95% CI 0.72 to 1.01). There was considerable uncertainty regarding any association between sex or gender and post-transplant patient-relevant outcomes. This was primarily due to clinical and methodological heterogeneity. The observed clinical heterogeneity between studies could be attributed to diverse patient characteristics within sample populations. As a result of limited sex-stratified demographic data being provided, further investigation of this heterogeneity was constrained. However, factors contributing to this finding may include recipient age, donor age, types, and sex. Methodological heterogeneity was noted with the interchangeable use of sex and gender, outcome misclassification, the use of different measures of effects, inconsistent covariate profiles, and disregard for important effect modification. There is very low to low certainty evidence to suggest there are no differences in kidney and pancreas allograft survival, patient survival, cancer, and acute and chronic allograft rejection between male and female kidney and SPK transplant recipients.

Jayanti S ，Beruni NA ，Chui JN ，Deng D ，Liang A ，Chong AS ，Craig JC ，Foster B ，Howell M ，Kim S ，Mannon RB ，Sapir-Pichhadze R ，Scholes-Robertson NJ ，Strauss AT ，Jaure A ，West L ，Cooper TE ，Wong G ... -  《Cochrane Database of Systematic Reviews》

Pre-emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients.

Owers DS ，Webster AC ，Strippoli GF ，Kable K ，Hodson EM ... -  《Cochrane Database of Systematic Reviews》