A Systematic Review and Meta-analysis of Optimized CMV Preemptive Therapy and Antiviral Prophylaxis for CMV Disease Prevention in CMV High-Risk (D+R-) Kidney Transplant Recipients

Abstract

Background. The optimal strategy for cytomegalovirus (CMV) disease prevention in CMV donor/recipient kidney transplant recipients remains uncertain. Conclusions of prior meta-analyses that CMV disease rates with preemptive therapy (PET) and universal prophylaxis (UP) were comparable may have been affected by inclusion of studies lacking key determinants of efficacy of the respective strategies. Methods. We conducted a systematic review and meta-analysis of PET with weekly CMV polymerase chain reaction monitoring for ≥3 mo and UP with 6 mo of valganciclovir. PubMed and Embase databases were reviewed from January 1, 2010, to April 1, 2022. Risk of bias was assessed with 3 instruments (Cochrane RoB, Cochrane RoBINS-I, and an instrument for assessing risk in observational studies). The primary outcome was CMV disease incidence by 1-y posttransplant. Secondary outcomes by 1-y were graft loss, acute allograft rejection, and mortality. Results were synthesized using generalized linear mixed model meta-analysis. PET studies were stratified into low-threshold (LT) and high-threshold (HT) PET based on the viral load threshold for initiation of antiviral therapy. Results. Twenty-five studies met inclusion criteria (6 PET, 19 UP). CMV disease incidence was significantly higher in HT (0.30 [95% confidence interval (CI), 0.22-0.39]) versus LT PET (0.06 [95% CI, 0.03-0.12]). LT PET was associated with a significantly lower CMV disease incidence (0.06 [95% CI, 0.03-0.12]) versus UP (0.21 [95% CI, 0.17-0.27]). Incidence of graft loss, acute allograft rejection, or mortality was not significantly different between LT PET and UP (P > 0.05 for all comparisons). Receipt of lymphocyte-depleting antibodies was not associated with a significant difference in CMV disease incidence (odds ratio = 1.34 [95% CI, 0.80-2.25]). Conclusions. LT PET is associated with a significantly lower incidence of CMV disease compared to UP with similar rates of other clinical outcomes. These findings provide rationale and preliminary data for a randomized superiority trial of optimized LT-PET versus UP in donor seropositive recipient seronegative kidney transplant recipients.

A practical guide to real‐world implementation of pre‐emptive therapy for Cytomegalovirus disease prevention in high‐risk seronegative liver transplant recipients with seropositive donors

“…A recent meta-analysis suggests that PET might be associated with a lower incidence of CMV disease than with 6 months of prophylaxis following kidney transplant, and current guidelines state that PET can be used for CMV disease prevention in CMV D + R − kidney transplant recipients (KTRs). 1,2,21 Despite the promise of PET in CMV D + R − KTRs, the superiority of PET over prophylaxis has not been demonstrated in randomized clinical trials for CMV D + R − non-liver organ transplant recipients. Until the effectiveness of PET in D + R − KTRs is defined in randomized, direct head-to-head studies, liver/KTRs may receive their transplant center's standard CMV prevention strategy for kidney-alone transplant recipients.…”

“…any result ranging from 35 to 49 IU/mL as "detected less than 50 IU/mL" to avert potential confusion regarding the significance of a very low, yet quantifiable CMV DNA load. While the LLOD and reported LLOQ vary between laboratories and individual CMV PCR assays, this PET protocol is likely to be effective using any sensitive CMV quantitative PCR assay on plasma specimens in any clinical laboratory.While low viral load thresholds for AVT initiation during PET may reduce the risk of progression to CMV disease in CMV D + R − solid organ transplant recipients,21 the precise viral load threshold for AVT initiation may not impact the total duration of AVT. In a study of CMV D + R − liver and kidney recipients undergoing PET at low F I G U R E 2 Protocol for pre-emptive therapy in CMV D + /R − liver transplant recipients at the University of Washington.…”

The devil is in the details: Nuances of pre‐emptive therapy for cytomegalovirus disease prevention in high‐risk seropositive donors liver transplant recipients

“…[1][2][3] A low viral load threshold for AVT initiation has been shown to be a key determinant of PET efficacy. 5 Given the rapid kinetics of CMV replication in CMV D+R-LTRs during primary infection and the relatively long delay between first DNAemia detection and AVT initiation, the CMV viral loads on the day that AVT was actually started were likely even higher than the reported "initial" CMV viral loads in the Camus study. 7 High viral loads before AVT initiation may have resulted in progression to CMV disease during PET surveillance in the early post-transplant period, although the timing of CMV disease onset post-transplant was not reported.…”

“…Incidence of CMV DNAemia does not provide a meaningful measurement of CMV-related morbidity when comparing PET and PRO strategies, since the DNAemia that occurs during well-managed PET is planned, expected, and may induce durable protection against late CMV infection and disease that ultimately improves long-term outcomes. 2,[4][5][6] CMV disease is a more clinically relevant outcome than CMV DNAemia, and there are several potential reasons why the incidence of CMV disease in LTRs managed with PET was higher in the Camus study than in the CAPSIL and Doss studies. Key determinants of the efficacy of PET were missing in the Camus study, which was conducted over a decade before these important aspects of PET became defined (Table 1).…”