Dataset Information

Cytomegalovirus and Epstein-Barr virus infections among pediatric kidney transplant recipients at a center using universal Valganciclovir Prophylaxis.

ABSTRACT: BACKGROUND:CMV is associated with adverse effects in renal transplant recipients. The objective of this study was to characterize the incidence and timing of CMV and EBV infections in relation to valGCV prophylaxis in a pediatric renal transplant cohort. METHODS:Retrospective cohort of pediatric renal transplant patients given universal valGCV prophylaxis and universal viral surveillance was evaluated. Demographics, prophylaxis, acute rejection, and CMV and EBV infections were abstracted. RESULTS:A total of 92 pediatric renal allograft recipients, 2008-2013, were included. One or more viral infections developed in 77/92 (83.7%) of the patients. EBV was the most common in 62/92 (67%) patients, irrespective of valGCV (82% of episodes occurring on valGCV). CMV DNAemia occurred in 30/92 (33%) patients, 14 episodes (47%) occurring on valGCV. Incidence of breakthrough CMV on prophylaxis was 15% and was associated with persistent DNAemia (OR 7.8, CI:1.6-32.9, P < 0.02). CMV tissue-invasive disease was not seen. CMV syndrome occurred in 10% of the cohort, only in CMV D+ patients, and only one symptomatic breakthrough infection required treatment. Out of 92, 21 (23%) had simultaneous co-infections with 2-3 viruses. CONCLUSIONS:Viral infections in pediatric renal transplant recipients receiving universal valGCV prophylaxis were common. EBV infections were not reduced by valGCV prophylaxis, and nearly half of CMV infections occurred on valGCV. Symptomatic CMV infection while on prophylaxis was rare. valGCV prophylaxis may prevent symptomatic CMV infection but not EBV infection, and frequent CMV surveillance in pediatric renal transplant recipients on prophylaxis may not be necessary.

SUBMITTER: Paulsen G

PROVIDER: S-EPMC6650320 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Cytomegalovirus and Epstein-Barr virus infections among pediatric kidney transplant recipients at a center using universal Valganciclovir Prophylaxis.

Paulsen Grant G Cumagun Pia P Mixon Emily E Fowler Karen K Feig Daniel D Shimamura Masako M

Pediatric transplantation 20190220 3

<h4>Background</h4>CMV is associated with adverse effects in renal transplant recipients. The objective of this study was to characterize the incidence and timing of CMV and EBV infections in relation to valGCV prophylaxis in a pediatric renal transplant cohort.<h4>Methods</h4>Retrospective cohort of pediatric renal transplant patients given universal valGCV prophylaxis and universal viral surveillance was evaluated. Demographics, prophylaxis, acute rejection, and CMV and EBV infections were abs ...[more]

PMID: 30786115

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Project description:To examine the risk of late-onset post-transplant lymphoproliferative disorder (PTLD) in the presence of persisting high Epstein-Barr virus (EBV) in EBV naïve pediatric heart transplant (HT) recipients.A retrospective review of the medical records of the 145 pediatric HT recipients who had serial EBV viral load monitoring at our center was performed. We defined EBV naive patients whose EBV serology either IgM or IgG in the blood were negative at the time of HT and excluded passive transmission from mother to child in subjects less than 6 mo of age.PTLD was diagnosed in 8 out of 145 patients (5.5%); 6/91 (6.5%) in those who were EBV seropositive and 2/54 (3.7%) in the EBV naïve group at the time of HT (P = 0.71). We found 32/145 (22%) patients with persistently high EBV load during continuing follow-up; 20/91 (22%) in EBV seropositive group vs 12/54 (22%) in EBV naïve group (P = 0.97). There was no significant association between pre-HT serostatus and EBV load after transplant (P > 0.05). In the EBV seropositive group, PTLD was diagnosed in 15% (3/20) of patients with high EBV vs 4.2% (3/71) of patients with low or undetectable EBV load (P = 0.14) whereas in EBV naïve patients 8.3% (1/12) of those with high EBV load and 2.3% (1/42) with low or undetectable EBV load (P = 0.41). There was a highly significant association between occurrence of PTLD in those with high EBV load and duration of follow up (4.3 ± 3.9 years) after HT by Cochran-Armitage test for the entire cohort (P = 0.005). At least one episode of acute rejection occurred in 72% (23/32) of patients with high EBV vs 36% (41/113) patients with low or undetectable EBV after HT (P < 0.05).There is an association between persistently high EBV load during post-HT follow up and the occurrence of late-onset PTLD in pediatric HT recipients irrespective of serostatus at the time of transplant. The occurrence of allograft rejection increased in patients with high EBV load presumably due to reduction in immunosuppression.

Project description:Cytomegalovirus infection during antiviral prophylaxis occurs in transplant recipients despite individualized regimens based on renal function. Fifty kidney transplant recipients were assessed between 2016 and 2019 for valganciclovir dosing, ganciclovir exposure, cytomegalovirus infection, and genotypic resistance markers during the first year posttransplant. Ganciclovir plasma concentrations were measured using mass spectrometry. Population pharmacokinetics was used to determine individual ganciclovir exposure and to evaluate the ability of manufacturer dosing guidelines to meet therapeutic target daily area under the curve (AUC24) of 40 to 50 μg·h/mL. Full-length UL54 and UL97 were assessed using high-throughput sequencing in cytomegalovirus DNA-positive patient specimens. Valganciclovir doses administered to recipients with creatinine clearance of <40 mL/min were higher than specified by guidelines, and they were lower for recipients with creatinine clearance of ≥40 mL/min. The mean ganciclovir AUC24 was 33 ± 13 μg·h/mL, and 82% of subjects did not attain the therapeutic target. Pharmacokinetic simulations showed that the guidelines similarly could not attain the therapeutic target in 79% of individuals. Cytomegalovirus breakthrough occurred in 6% (3/50) of recipients, while 12% (6/50) developed late-onset infection. The mean AUC24s of recipients with (n = 3) and without (n = 47) infection were not significantly different (P = 0.528). However, one recipient with an AUC24 of 20 μg·h/mL acquired two UL97 ganciclovir resistance mutations. Current prophylaxis guidelines resulted in subtherapeutic ganciclovir exposure in several study recipients, including the emergence of resistance genotypes. IMPORTANCE This study examined the pharmacokinetics and viral genomic data from a prospective cohort of kidney transplant recipients undergoing valganciclovir prophylaxis for cytomegalovirus (CMV) prevention. We showed for the first time using high-throughput sequencing the detection of ganciclovir resistance mutations in breakthrough CMV infection during subtherapeutic plasma ganciclovir as indicated by the pharmacokinetic parameter daily area under the curve (AUC24). In addition, we found that current valganciclovir dosing guidelines for CMV prophylaxis are predicted to attain therapeutic targets in only 21% of recipients, which is consistent with previous pharmacokinetic studies. The novel findings of resistance mutations during subtherapeutic ganciclovir exposure presented here can inform future studies investigating the dynamics of drug selection pressure and the emergence of resistance mutations in vivo.

Project description:ImportanceValganciclovir for 200 days is standard care for cytomegalovirus (CMV) prophylaxis in high-risk CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor, but its use is limited by myelosuppression.ObjectiveTo compare the efficacy and safety of letermovir with valganciclovir for prevention of CMV disease in CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor.Design, setting, and participantsRandomized, double-masked, double-dummy, noninferiority, phase 3 trial in adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor at 94 participating sites between May 2018 and April 2021 (final follow-up in April 2022).InterventionsParticipants were randomized in a 1:1 ratio (stratified by receipt of lymphocyte-depleting induction immunosuppression) to receive letermovir, 480 mg, orally daily (with acyclovir) or valganciclovir, 900 mg, orally daily (adjusted for kidney function) for up to 200 days after transplant, with matching placebos.Main outcomes and measuresThe primary outcome was CMV disease, confirmed by an independent masked adjudication committee, through posttransplant week 52 (prespecified noninferiority margin, 10%). CMV disease through week 28 and time to onset of CMV disease through week 52 were secondary outcomes. Exploratory outcomes included quantifiable CMV DNAemia and resistance. The rate of leukopenia or neutropenia through week 28 was a prespecified safety outcome.ResultsAmong 601 participants randomized, 589 received at least 1 dose of the study drug (mean age, 49.6 years; 422 [71.6%] men). Letermovir (n = 289) was noninferior to valganciclovir (n = 297) for prevention of CMV disease through week 52 (10.4% vs 11.8% of participants with committee-confirmed CMV disease; stratum-adjusted difference -1.4% [95% CI, -6.5% to 3.8%]). No participants who received letermovir vs 5 participants (1.7%) who received valganciclovir developed CMV disease through week 28. Time to onset of CMV disease was comparable between the groups (hazard ratio, 0.90 [95% CI, 0.56-1.47]). Quantifiable CMV DNAemia was detected in 2.1% of participants in the letermovir group vs 8.8% in the valganciclovir group by week 28. Of participants evaluated for suspected CMV disease or CMV DNAemia, none (0/52) who received letermovir and 12.1% (8/66) who received valganciclovir had resistance-associated substitutions. The rate of leukopenia or neutropenia through week 28 was lower with letermovir vs valganciclovir (26% vs 64%; difference, -37.9% [95% CI, -45.1% to -30.3%]; P < .001). Fewer participants in the letermovir group than the valganciclovir group discontinued prophylaxis due to adverse events (4.1% vs 13.5%) or drug-related adverse events (2.7% vs 8.8%).Conclusion and relevanceAmong adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor, letermovir was noninferior to valganciclovir for prophylaxis of CMV disease over 52 weeks, with lower rates of leukopenia or neutropenia, supporting its use for this indication.Trial registrationClinicalTrials.gov Identifier: NCT03443869; EudraCT: 2017-001055-30.

Dataset Information

Cytomegalovirus and Epstein-Barr virus infections among pediatric kidney transplant recipients at a center using universal Valganciclovir Prophylaxis.

Publications

Cytomegalovirus and Epstein-Barr virus infections among pediatric kidney transplant recipients at a center using universal Valganciclovir Prophylaxis.

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