Reduction in late onset cytomegalovirus primary disease after discontinuation of antiviral prophylaxis in kidney transplant recipients treated with de novo everolimus

Devresse, Arnaud; Leruez‐Ville, Marianne; Scemla, Anne; Avettand-Fènoël, Véronique; Morin, Lise; Lebreton, Xavier; Tinel, Claire; Amrouche, Lucile; Lamhaut, Lionel; Timsit, Marc Olivier; Legendre, Christophe; Anglicheau, Dany

doi:10.1111/tid.12846

Cited by 7 publications

(8 citation statements)

References 35 publications

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“…In multiple randomized controlled trials, the mammalian target of rapamycin inhibitor (mTORi) everolimus (EVR) in combination with reduced‐exposure CNI (cyclosporine [CsA] or tacrolimus [TAC]) was found to be noninferior to standard CNI regimens for antirejection efficacy, with comparable, if not better, allograft function up to 2 years after transplantation . Additional benefits in terms of suppression of viral infections, especially CMV infections, have been reported with early EVR initiation …”

Section: Introductionsupporting

confidence: 75%

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Two-year outcomes in de novo renal transplant recipients receiving everolimus-facilitated calcineurin inhibitor reduction regimen from the TRANSFORM study

Berger

Sommerer

Witzke

et al. 2019

American Journal of Transplantation

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113

117

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TRANSFORM (TRANSplant eFficacy and safety Outcomes with an eveRolimus‐based regiMen) was a 24‐month, prospective, open‐label trial in 2037 de novo renal transplant recipients randomized (1:1) within 24 hours of transplantation to receive everolimus (EVR) with reduced‐exposure calcineurin inhibitor (EVR + rCNI) or mycophenolate with standard‐exposure CNI. Consistent with previously reported 12‐month findings, noninferiority of the EVR + rCNI regimen for the primary endpoint of treated biopsy‐proven acute rejection (tBPAR) or estimated glomerular filtration rate (eGFR) <50 mL/min per 1.73 m2 was achieved at month 24 (47.9% vs 43.7%; difference = 4.2%; 95% confidence interval = −0.3, 8.7; P = .006). Mean eGFR was stable up to month 24 (52.6 vs 54.9 mL/min per 1.73 m2) in both arms. The incidence of de novo donor‐specific antibodies (dnDSA) was lower in the EVR + rCNI arm (12.3% vs 17.6%) among on‐treatment patients. Although discontinuation rates due to adverse events were higher with EVR + rCNI (27.2% vs 15.0%), rates of cytomegalovirus (2.8% vs 13.5%) and BK virus (5.8% vs 10.3%) infections were lower. Cytomegalovirus infection rates were significantly lower with EVR + rCNI even in the D+/R− high‐risk group (P < .0001). In conclusion, the EVR + rCNI regimen offers comparable efficacy and graft function with low tBPAR and dnDSA rates and significantly lower incidence of viral infections relative to standard‐of‐care up to 24 months. Clinicaltrials.gov number: NCT01950819.

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Section: Introductionsupporting

confidence: 75%

“…Consistent with previous studies, the EVR + rCNI regimen offered significant protection from viral infections up to 24 months, thereby confirming the antiviral effect of EVR even in the presence of TAC levels above target range. Of interest, the CMV incidence was also significantly lower with EVR + rCNI in high‐risk (D+/R−) patients.…”

Section: Discussionsupporting

confidence: 55%

Two-year outcomes in de novo renal transplant recipients receiving everolimus-facilitated calcineurin inhibitor reduction regimen from the TRANSFORM study

Berger

Sommerer

Witzke

et al. 2019

American Journal of Transplantation

Self Cite

113

117

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“…In our study, the majority of clinically apparent infections in patients who switched from EVR treatment occurred after switching, which further indicates that discontinuation of EVR may increase the susceptibility of patients to develop CMV infections. In line with our observation, a single-center retrospective study found that the 1-year incidence of late-onset CMV-disease among D+/R-patients after withdrawal of antiviral prophylaxis was significantly lower in patients receiving de novo EVR with reduced-dose CNI compared with patients on MPA in combination with standard dose CNI [20]. As in our study, the vast majority of CMV-disease cases in the EVR arm occurred after discontinuation of EVR [20].…”

Section: Discussionsupporting

confidence: 91%

“…In line with our observation, a single-center retrospective study found that the 1-year incidence of late-onset CMV-disease among D+/R-patients after withdrawal of antiviral prophylaxis was significantly lower in patients receiving de novo EVR with reduced-dose CNI compared with patients on MPA in combination with standard dose CNI [20]. As in our study, the vast majority of CMV-disease cases in the EVR arm occurred after discontinuation of EVR [20]. This is in line with findings from the main ATHENA study cohort, where fewer treatment-emergent CMV infections occurred in the EVR-receiving patients compared with the MPA + TAC group, which held true for both seroconversions and reactivations [26].…”

Section: Discussionsupporting

confidence: 89%

Effect of everolimus‐based drug regimens on CMV‐specific T‐cell functionality after renal transplantation: 12‐month ATHENA subcohort‐study results

et al. 2020

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Post‐transplant cytomegalovirus (CMV) infections and increased viral replication are associated with CMV‐specific T‐cell anergy. In the ATHENA‐study, de‐novo everolimus (EVR) with reduced‐exposure tacrolimus (TAC) or cyclosporine (CyA) showed significant benefit in preventing CMV infections in renal transplant recipients as compared to standard TAC + mycophenolic acid (MPA). However, immunomodulatory mechanisms for this effect remain largely unknown. Ninety patients from the ATHENA‐study completing the 12‐month visit on‐treatment (EVR + TAC n = 28; EVR + CyA n = 19; MPA + TAC n = 43) were included in a posthoc analysis. Total lymphocyte subpopulations were quantified. CMV‐specific CD4 T cells were determined after stimulation with CMV‐antigen, and cytokine‐profiles and various T‐cell anergy markers were analyzed using flow cytometry. While 25.6% of MPA + TAC‐treated patients had CMV‐infections, no such events were reported in EVR‐treated patients. Absolute numbers of lymphocyte subpopulations were comparable between arms, whereas the percentage of regulatory T cells was significantly higher with EVR + CyA versus MPA + TAC (p = 0.019). Despite similar percentages of CMV‐specific T cells, their median expression of CTLA‐4 and PD‐1 was lower with EVR + TAC (p < 0.05 for both) or EVR + CyA (p = 0.045 for CTLA‐4) compared with MPA + TAC. Moreover, mean percentages of multifunctional CMV‐specific T cells were higher with EVR + TAC (27.2%) and EVR + CyA (29.4%) than with MPA + TAC (19.0%). In conclusion, EVR‐treated patients retained CMV‐specific T‐cell functionality, which may contribute to enhanced protection against CMV infections.

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“…An additional eight studies meeting inclusion criteria were identified from the manual review of bibliographies of published SLRs. Ultimately, 86 5,6,14‐97 citations representing 81 unique studies 5,6,14‐92 including 69 803 participants met the inclusion criteria.…”

Section: Resultsmentioning

confidence: 99%

Epidemiology, risk factors, and outcomes associated with cytomegalovirus in adult kidney transplant recipients: A systematic literature review of real‐world evidence

Raval

Kistler

Tang

et al. 2020

Transplant Infectious Dis

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Kidney transplant recipients (KTRs) have increased risk for cytomegalovirus (CMV) infection/disease given the necessity of drug‐induced immunosuppression. A comprehensive review of published literature reporting real‐world data on prevention strategies utilized and associated CMV burden outcomes is limited. Such data could help inform future clinical practice and identify unmet needs in CMV management. We conducted a systematic review of observational studies published in Medline or EMBASE from January 2008 to November 2018 to identify current real‐world CMV management approaches, CMV infection/disease risk factors, and outcomes associated with CMV infection. Descriptive statistics and pooled quantitative analyses were conducted. From 1608 records screened, 86 citations, including 69 803 adult KTR, were included. Prophylaxis and preemptive therapy (PET) were predominant approaches among D+/R‐ and R + CMV serostatus transplants, respectively. Valganciclovir and ganciclovir were frequently utilized across CMV risk strata. Despite prevention approaches, approximately one‐fourth of KTR developed CMV infection. Age and D+/R‐ CMV serostatus were consistent risk factors for CMV infection/disease. CMV infection/disease was associated with increased mortality and graft loss. CMV was similarly associated with acute rejection (AR) risk, but with high heterogeneity among studies. Limited data were available on CMV and opportunistic infections (OIs) risk. CMV remains a significant issue. New strategies may be needed to optimize CMV management.

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Reduction in late onset cytomegalovirus primary disease after discontinuation of antiviral prophylaxis in kidney transplant recipients treated with de novo everolimus

Abstract: Our data suggest that de novo use of EVL may reduce late onset CMV primary disease after the withdrawal of antiviral prophylaxis in kidney transplantation patients.

Cited by 7 publications

References 35 publications

Two-year outcomes in de novo renal transplant recipients receiving everolimus-facilitated calcineurin inhibitor reduction regimen from the TRANSFORM study

Two-year outcomes in de novo renal transplant recipients receiving everolimus-facilitated calcineurin inhibitor reduction regimen from the TRANSFORM study

Effect of everolimus‐based drug regimens on CMV‐specific T‐cell functionality after renal transplantation: 12‐month ATHENA subcohort‐study results

Epidemiology, risk factors, and outcomes associated with cytomegalovirus in adult kidney transplant recipients: A systematic literature review of real‐world evidence

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