Valganciclovir prophylaxis extension from 3 to 6 months in high‐risk pancreas‐transplant recipients does not impact incidence of cytomegalovirus infection at 12 months

Leverson

et al. 2022

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Purpose: To evaluate epidemiology, risk-factors, and outcomes of high-level (HL) cytomegalovirus (CMV) viremia in liver transplant recipients.Methods: Adult patients receiving a liver transplant between 1/1/2017 and 9/30/2020 were evaluated. Viral loads at University of Wisconsin Health Clinical Laboratories were required to allow for numerical comparison. Primary objective was incidence and outcomes of HL CMV viremia (viral-load > 100 000 IU/ml). Secondary objective was to elucidate risk factors to allow targeted interventions.Results: Two hundred nine patients met inclusion criteria; 175 kept their graft for at least 240 days. Of these nine patients developed HL CMV, 28 developed low-level (LL CMV, viral-load 250-100 000 IU/ml), and 138 did not develop CMV viremia. When comparing these three groups via classic statistical methods time from transplant to viremia was similar (HL 158 ± 77 days, LL 150 ± 76 days). Clinical factors were also similar with the exception of donor seropositivity (HL 87.5%, LL 70.4%, No CMV 49.6%, p = 0.025). HL CMV was significantly associated with graft loss (p < 0.0001) on Kaplan-Meier analysis; graft loss in the LL CMV group did not differ from the no CMV group (p = 0.96).To allow valid assessment of risk factors in the total study population (n = 209), models of time-varying covariates were used, and Cox proportional hazards ratios were calculated. In this analysis, HL CMV was associated with a significantly increased risk of graft loss (HR 5.6, p = 0.0016). When investigating risk factors associated with HL CMV, donor seropositivity significantly increased risk (HR 8.85, 95% CI 1.13-71.43, p = 0.038). Pretransplant total bilirubin (HR 1.04, 95% CI 0.998-1.07, p = 0.06) trended toward significance. Recipient seronegativity, liver disease, clinical and allocation model for end-stage liver disease (MELD), transplant surgery duration, age, sex, induction immunosuppression, and maintenance immunosuppression were not significantly associated with development of HL CMV. Conclusion:HL CMV after liver transplant is uncommon but is associated with a significantly increased risk of graft loss that is not present in those patients who develop LL CMV or do not develop CMV viremia. Given these negative graft effects, CMV stewardship interventions targeting recipients of CMV seropositive allografts

Section: Discussioncontrasting

confidence: 50%

Risk factors for high level cytomegalovirus viremia in liver transplant recipients and associated outcomes

Leverson

et al. 2022

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“…23 However, when evaluated in other allograft subtypes extension appears to only delay the onset and does not reduce incidence. 24,25 This is thought to be due to the inability to mount CMV-specific cell-mediated immunity while receiving valganciclovir…”

Section: Discussionmentioning

confidence: 99%

Letermovir conversion after valganciclovir treatment in cytomegalovirus high‐risk abdominal solid organ transplant recipients may promote development of cytomegalovirus‐specific cell mediated immunity

Garg

et al. 2021

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Purpose: To evaluate the association of conversion from valganciclovir to letermovir on cytomegalovirus-specific cellular immunity.Methods: Adult patients were included if they received a kidney or liver transplant between 8/1/2018-12/31/20, developed symptomatic, high-level CMV viremia and were converted to letermovir 480 mg daily as monotherapy after treatment with ganciclovir-derivatives for a minimum of 4 weeks and had subsequent CMV cellmediated immunity (CMI) testing via ICS assay by flow cytometry (Viracor Eurofins T Cell Immunity Panel).Results: Seven patients met inclusion criteria; 87.5% were male and recipients of a kidney transplant. All patients were CMV high risk (D+/R-). Mean time from transplant to CMV disease was 200 ± 91 days. Peak viral load (VL) during CMV treatment was 540,341 ± 391,211 IU/mL. Patients received a mean of 30 ± 24 weeks (range: 4-78 weeks) of therapy with ganciclovir-derivatives at induction doses prior to letermovir introduction. The median absolute lymphocyte count (ALC) at letermovir initiation was 400/μL (IQR 575) and the median VL was 51.6 (range: ND-490) IU/mL. Most patients (n = 5/7, 71.4%) experienced an increase in VL 1 and/or 2 weeks after conversion to letermovir. All patients had positive CMI per ICS assay after conversion.Patients received a mean of 10.3 ± 6.9 weeks of letermovir prior to having a positive result. Median ALC at positivity was 900/μL. Immunosuppression was not further reduced from initiation of letermovir to demonstration of CMV CMI. No patient had progressive replication or breakthrough disease while maintained on letermovir and three patients (42.9%) underwent antiviral withdrawal without recurrence at the last follow-up. Conclusion:In this case series of abdominal transplant recipients with severe or persistent CMV infection, patients developed CMV-specific CMI after conversion to letermovir monotherapy. These data suggest that using letermovir in place of valganciclovir for secondary prophylaxis may address the lack of efficacy previously seen with this

“…Again, the duration of surveillance is based on literature suggesting a significant reduction in CMV disease after 1 year 20 . Center specific data in pancreas transplant recipients that demonstrated prophylaxis extension only delayed onset and did not reduce incidence of CMV further corroborated this and was the basis for our surveillance initiative 18 . Pancreas recipients are followed for an additional 6 months after prophylaxis termination.…”

Section: Background and Introductionmentioning

confidence: 94%

“…16 This is mostly attributed to symptomatic late-onset postprophylaxis CMV due to a lack of pretransplant learned immunity. While prophylaxis extension may reduce incidence in kidney transplant recipients, this has not been successfully demonstrated in other allograft subtypes 17,18 and remains an issue in kidney transplant patients with reported rates of late onset infection up to 48% despite 6 months of VGC prophylaxis. 19 However, CMV infection >1 year after transplant is uncommon, with literature reported rates of <5%.…”

Section: High Risk CMV Monitoringmentioning

confidence: 99%

Cytomegalovirus antiviral stewardship in solid organ transplant recipients: A new gold standard

Descourouez

et al. 2022

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Purpose Antimicrobial stewardship programs (ASPs) are essential entities that promote the appropriate use of antimicrobials, leading to improved patient outcomes and reduced resistance. Application to the immunocompromised host is a natural progression for expansion. Cytomegalovirus (CMV) infection is a common complication following solid organ transplant with significant implications on graft survival, making it an attractive ASP target. The aim of this piece is to review our center‐specific experience with the development, implementation, and maintenance of a CMV stewardship initiative at a large transplant center. Methods Our CMV stewardship initiative began in 2018. Herein, we review 3 years’ experience and quality‐related improvement that occurred from initiation to present state and share our stewardship algorithms. Special attention is paid to the impact of the program as well as our increased understanding of the complex interplay between prevention, treatment, and host development of CMV‐specific cell‐mediated immunity (CMI). Results We found our stewardship initiative not only reduced the incidence of ganciclovir resistance but also streamlined care via a centralized and structured approach. This objective, protocolized program has resulted in a significant shift away from a reactive to a proactive state and in turn, reduced CMV treatment rates (26% at initiation to 12% in the current state, p = .012). Conclusion A dedicated multidisciplinary team focused on CMV stewardship is imperative in providing a patient‐centered approach focused on development of CMV‐specific CMI, and as a result prevention of CMV disease. We believe these programs will be the new gold standard for CMV management.