Immune Monitoring-Guided Versus Fixed Duration of Antiviral Prophylaxis Against Cytomegalovirus in Solid-Organ Transplant Recipients: A Multicenter, Randomized Clinical Trial

Abstract

Background: The use of assays detecting cytomegalovirus (CMV)-specific T cell-mediated immunity may individualize the duration of antiviral prophylaxis after transplantation.

Methods: In this randomized trial, kidney and liver transplant recipients from 6 centers in Switzerland were enrolled if they were CMV-seronegative with seropositive donors or CMV-seropositive receiving antithymocyte globulins. Patients were randomized to a duration of antiviral prophylaxis based on immune monitoring (intervention) or a fixed duration (control). Patients in the control group were planned to receive 180 days (CMV-seronegative) or 90 days (CMV-seropositive) of valganciclovir. Patients were assessed monthly with a CMV ELISpot assay (T-Track CMV); prophylaxis in the intervention group was stopped if the assay was positive. The co-primary outcomes were the proportion of patients with clinically significant CMV infection and reduction in days of prophylaxis. Between-group differences were adjusted for CMV serostatus.

Results: Overall, 193 patients were randomized (92 in the immune-monitoring group and 101 in the control group), of whom 185 had evaluation of the primary outcome (87 and 98 patients). CMV infection occurred in 26 of 87 (adjusted percentage, 30.9%) in the immune-monitoring group and in 32 of 98 (adjusted percentage, 31.1%) in the control group (adjusted risk difference, -0.1; 95% confidence interval [CI], -13.0% to 12.7%; P = .064). The duration of prophylaxis was shorter in the immune-monitoring group (adjusted difference, -26.0 days; 95%, CI, -41.1 to -10.8 days; P < .001).

Conclusions: Immune monitoring resulted in a significant reduction of antiviral prophylaxis, but we were unable to establish noninferiority of this approach on the co-primary outcome of CMV infection.

Clinical trials registration: NCT02538172.

Keywords: cell-mediated immunity; personalized medicine; prevention; transplant; viral infection.

Graphical Abstract

This graphical abstract is also available at Tidbit: https://tidbitapp.io/tidbits/immune-monitoring-guided-vs-fixed-duration-of-antiviral-prophylaxis-against-cytomegalovirus-in-solid-organ-transplant-recipients-a-multicenter-randomized-clinical-trial-1cd729ef-d7a6-4dca-a470-d73a1f6a3b41

Figure 1.

Trial profile.

Figure 2.

Primary outcomes overall and by CMV serostatus. A, Difference in proportion of patients with at least 1 clinically significant CMV infection. Noninferiority would be established if the upper limit of the 2-sided 95% CI was less than 12% (noninferiority margin, dashed line). The P value for noninferiority is 1-sided with α set at 0.025. B, Difference in mean prophylaxis duration. The P value for superiority is 2-sided from a stratified Wilcoxon test with α set at 0.025. Analyses were done in the modified intention-to-treat population. Overall estimates were adjusted for CMV serostatus using stratified analyses with Mantel–Haenszel weights for the risk difference of clinically significant CMV infection (A) and inverse variance weights for the difference in mean prophylaxis duration (B). The P values for interaction between intervention and CMV serostatus were 0.226 for CMV infection (A) and 0.361 for mean prophylaxis duration (B). Abbreviations: CI, confidence interval; CMV, cytomegalovirus.

Figure 3.

Kaplan–Meier estimates of the probability of clinically significant CMV infection: overall (A), CMV-seronegative patients (B), CMV-seropositive patients (C). Overall Kaplan–Meier estimates and corresponding IRRs are unadjusted for CMV serostatus. Abbreviations: CI, confidence interval; CMV, cytomegalovirus; IRR, incidence rate ratio.

Figure 4.

Results of the CMV immune assay: pp65 CMV antigen (A) and IE1 CMV antigen (B). Box plot of results from the T-Track assays in the immune-monitoring and control groups according to CMV risk status (CMV-seronegative and CMV-seropositive). Results of the T-track assays in the control group were not communicated to the treating physicians. The boxes indicate the lower and upper quartiles, and the lines inside the boxes indicate the median. The whiskers extend to the furthest observations from the lower and upper quartiles that are still within 1.5× the interquartile range. Observations beyond that range are shown as circles. The dashed line indicates the primary cutoff of the -Track CMV assay. Abbreviations: CMV, cytomegalovirus; SFC, spot-forming cells.

Figure 4.

Results of the CMV immune assay: pp65 CMV antigen (A) and IE1 CMV antigen (B). Box plot of results from the T-Track assays in the immune-monitoring and control groups according to CMV risk status (CMV-seronegative and CMV-seropositive). Results of the T-track assays in the control group were not communicated to the treating physicians. The boxes indicate the lower and upper quartiles, and the lines inside the boxes indicate the median. The whiskers extend to the furthest observations from the lower and upper quartiles that are still within 1.5× the interquartile range. Observations beyond that range are shown as circles. The dashed line indicates the primary cutoff of the -Track CMV assay. Abbreviations: CMV, cytomegalovirus; SFC, spot-forming cells.