The influence of <scp>mTOR</scp> inhibitors on the incidence of <scp>CMV</scp> infection in high‐risk donor positive–recipient negative (D+/R−) kidney transplant recipients

Cristelli, Marina Pontello; Esmeraldo, Ronaldo M.; Pinto, C.; Sandes‐Freitas, Tainá Veras de; Felipe, Cláudia Rosso; Lobo, Clarissa Ferreira; Viana, Laila Almeida; Mansur, Juliana; Stopa, Suelen; Santos, Daniel Wagner; Grenzi, Patricia C.; Aguiar, Wilson; Tedesco‐Silva, Hélio; Pestana, José Osmar Medina

doi:10.1111/tid.12907

Cited by 10 publications

(24 citation statements)

References 27 publications

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“…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: Discussionmentioning

confidence: 98%

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

120

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: Discussionmentioning

confidence: 98%

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

120

117

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“…Among the D+/R− combination, the overall incidence of CMV infection was 46% using only preemptive treatment. The lower efficacy of mTORi for the prevention of CMV infection/disease in this high‐risk group has been previously reported even in patients receiving mTORi, and the lack of specific anti‐CMV cellular immunity appears to be involved . A comprehensive and elegant study showed that sirolimus significantly improved CMV‐specific effector memory T‐cell function and negatively influenced naïve T cells …”

Section: Discussionmentioning

confidence: 85%

Use of mTOR inhibitor as prophylaxis for cytomegalovirus disease after kidney transplantation: A natural experiment

Cristelli

Felipe

Prizmic

et al. 2019

Clinical Transplantation

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Objectives To describe the incidence of cytomegalovirus (CMV) infection/disease in kidney transplant recipients receiving an mTOR‐inhibitor‐containing immunosuppressive regimen without prophylactic CMV treatment. Methods This single‐center retrospective cohort analysis included all de novo kidney transplant recipients (09/15/2015‐07/31/2017) receiving 3 mg/kg single dose of rabbit antithymocyte globulin induction, tacrolimus, everolimus, and prednisone. Preemptive therapy was initiated only in patients deemed at higher risk for CMV infection: (a) D+/R− CMV patients; (b) after treatment for acute rejection (ARt); and (c) after everolimus discontinuation (EVRd). Results Of 230 patients, there were no episodes of CMV disease among 217 (94%) without criteria to initiate preemptive therapy. Of 77 (33.5%) patients initiating preemptive therapy, 13 were D+/R−, 30 were ARt, and 34 were EVRd. The overall incidence of first CMV infection/disease was 6% (46.1% in D+/R−, 13.3% ARt [all patients had also discontinued everolimus], and 11.8% after early [<90 days] EVRd). The incidence of biopsy‐proven acute rejection was 5.6%, and median glomerular filtration rate at month 12 was 47 mL/min/1.73m2. One‐year patient and death‐censored graft survivals were 97.4% and 98.1%. Conclusion This study suggests that everolimus‐containing immunosuppressive regimen reduces the need for preventive strategies for CMV infection in the majority of kidney transplant recipients, reducing antiviral drug‐associated toxicities and healthcare‐related expenditures.

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“…However, in an intermediate risk situation, these drugs might shift the balance toward the control. The magnitude of the mTORi effect may be associated with the presence of CMV‐specific memory cells . To note, the small sample size does not allow us to drawn definitive conclusions about it.…”

Section: Discussionmentioning

confidence: 94%

The impact of everolimus in reducing cytomegalovirus events in kidney transplant recipients on steroid-avoidance strategy: 3-year follow-up of a randomized clinical trial

et al. 2018

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There is no evidence of whether everolimus (EVR) reduces cytomegalovirus (CMV) events in patients receiving steroid-free regimens. Besides, studies evaluating a tacrolimus (TAC) and EVR regimen are limited to 1-year follow-up. In this single-center prospective randomized trial, the incidence of CMV and 3-year efficacy and safety outcomes of EVR were compared to those of mycophenolate sodium (MPS) in a steroid-free regimen based on low-exposure TAC. Both groups received rabbit anti-thymocyte globulin (r-ATG) induction (6 mg/kg) and the steroids were withdrawn at day 7. Maintenance immunosuppression consisted of TAC (4-7 ng/ml until month 3 and 2-4 ng/ml thereafter) plus EVR (3-8 ng/ml) in the EVR group (n = 59); and TAC (4-7 ng/ml during all follow-up) plus MPS (1440 mg) in the MPS group (n = 56). The EVR group presented with a lower incidence of CMV events (18.6% vs. 50%, P = 0.001). No differences were observed in biopsy-proven acute rejection (6.8% vs. 3.6%, P = 0.680),graft loss (0.0% vs. 1.8%, P = 0.487),death (6.8% vs. 1.8%, P = 0.365), or estimated glomerular filtration rate at 36 months (61.1 ± 25.4 vs. 66.3 ± 24 ml/min/1.73 m , P = 0.369). A higher proportion of patients discontinued MPS treatment (8.5% vs. 26.8%, P = 0.013) for safety issues. In conclusion, EVR was associated with lower rates of CMV events in patients induced with standard dose r-ATG and a maintenance steroid-free regimen based on TAC. This regimen effectively prevented acute rejection and demonstrated a more favorable safety profile. (ClinicalTrials.gov:NCT02084446).

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The influence of mTOR inhibitors on the incidence of CMV infection in high‐risk donor positive–recipient negative (D+/R−) kidney transplant recipients

Abstract: In this cohort of high-risk CMV D+/R- kidney transplant recipients receiving rATG induction and tacrolimus, the use of mTOR inhibitors could only show a tendency towards but not a significant difference on the incidence of CMV events, when compared to antimetabolites.

Cited by 10 publications

References 27 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

Use of mTOR inhibitor as prophylaxis for cytomegalovirus disease after kidney transplantation: A natural experiment

The impact of everolimus in reducing cytomegalovirus events in kidney transplant recipients on steroid-avoidance strategy: 3-year follow-up of a randomized clinical trial

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