Real world experience with conversion from valganciclovir to letermovir for cytomegalovirus prophylaxis: Letermovir reverses leukopenia and avoids mycophenolate dose reduction.

PURPOSE: Valganciclovir (VGC) is the gold-standard for cytomegalovirus (CMV) prophylaxis (PPX) after solid organ transplant (SOT). Letermovir (LTV) was recently approved in high-risk kidney transplant and has reduced myelosuppressive toxicity. Conversion from VGC to LTV may be pursued in the setting of leukopenia. It is unknown if this strategy is effective. METHODS: Adult patients receiving abdominal SOT were included if converted from VGC to LTV between January 1, 2018 and January 31, 2023. Primary objective was to describe the impact of LTV conversion as measured by WBC recovery, mycophenolate modification, and use of GCSF, and prophylaxis efficacy assessed by course completion and breakthrough DNAemia. Secondary objective was to evaluate rates of post-prophylaxis CMV. RESULTS: Seventy five SOT recipients met inclusion criteria. Mean change in WBC in response to LTV conversion by day 14 was +2.02 ± 2.52 k/uL. 75%(56/75) of the population did not require mycophenolate adjustment or had their dose increased after conversion. GCSF was required in 38.7%(29/75) prior to conversion; only 21.3%(16/75) of patients required GCSF after conversion. Early termination was uncommon, 14.7%(11/75) stopped due to lack of ongoing insurance approval, only one patient stopped due to adverse effects (1.3%). One patient had clinically significant breakthrough (1.3%) that was successfully managed with VGC. Incidence of post prophylaxis CMV was 40%. CONCLUSION: Withholding of VGC with LTV conversion may improve leukopenia without need for additional supportive measures. Most importantly, this strategy avoided additional mycophenolate modifications. In our study, LTV was associated with low rates of breakthrough. Post-prophylaxis CMV was similar to VGC prophylaxis.

Real-World Experience With CMV inSIGHT T Cell Immunity Testing in High-Risk Kidney and Pancreas Transplant Recipients.

BACKGROUND: Cytomegalovirus (CMV)-specific cell-mediated immunity is important for control of CMV after transplant. Assays exist to measure this, but their place in therapy is unclear, particularly in CMV high-risk recipients, without pretransplant exposure. OBJECTIVE: The objective of this study was to evaluate predictive potential of a positive assay to determine freedom from DNAemia and describe subsequent 3-month CMV outcomes. METHODS: Adult CMV high-risk kidney and/or pancreas transplant recipients were included if a CMV inSIGHT T Cell Immunity Panel (TCIP, Eurofins Viracor) was ordered and resulted between 1 August, 2019 and 30 July, 2022. RESULTS: Seventy-six patients were included in our study; 49 tested during prophylaxis and 27 during treatment. Most TCIP assays obtained in the prophylaxis cohort were negative (n = 46, 93.9%). Rate of post-TCIP CMV infection was 10.2%. In those tested during treatment, 33.3% were positive and rate of post-TCIP CMV recurrence was 22.2%. The positive predictive value of the assay to successfully predict immunity was 66.7% during both prophylaxis and treatment. There were 4 cases of TCIP predictive failure with progressive CMV replication. At time of replication, 2 patients had concomitant clinical confounders thought to influence immune control of viral replication. All patients had intensification of immunosuppression prior to recurrent replication, but after TCIP was collected. CONCLUSION AND RELEVANCE: The data obtained from the TCIP are not static, immune control of CMV in latency can change and must be evaluated in clinical context. Timing of TCIP after transplant is significant, and patient-specific factors remain important to assess the likelihood of CMV in each unique patient-specific scenario. A CMV stewardship program can aid in application and interpretation of results.

Maribavir for the Management of Cytomegalovirus in Adult Transplant Recipients: A Review of the Literature and Practical Considerations.

OBJECTIVE: To review the efficacy and safety of maribavir for management of cytomegalovirus (CMV) in solid organ transplant recipients. DATA SOURCES: A literature search of PubMed and the Cochrane Controlled Trials Register (1960 to early July 2022) was performed using the following search terms: maribavir, 1263W94, and cytomegalovirus. STUDY SELECTION AND DATA EXTRACTION: All relevant English-language studies were reviewed and considered, with a focus on phase 3 trials. DATA SYNTHESIS: Maribavir, an orally available benzimidazole riboside with minimal adverse effects, was originally studied for universal prophylaxis in phase 3 trials but failed to demonstrate noninferiority over placebo and oral ganciclovir. It was effective for preemptive treatment in a dose-finding Phase 2 study. Maribavir is FDA approved for treatment of refractory/resistant CMV infection based on improved response rate at 8 weeks compared with investigator-assigned therapy (IAT) when initiated at median viral loads less than approximately 10 000 IU/mL (55.7% vs 23.9%, P < 0.001). Recurrence after 8-week treatment for refractory/resistant CMV was high (maribavir 50% vs IAT 39%). Significant drug interactions exist and must be managed by a pharmacotherapy expert to prevent harm. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: The addition of maribavir to the antiviral armamentarium should improve the management of refractory/resistant CMV, allowing early transition from toxic, high-cost, intravenous agents such as foscarnet and outpatient management. Optimal timing of initiation, duration, and potential alternative uses are unclear. CONCLUSION: Future studies are needed to fully elucidate the role of maribavir in the management of CMV after transplant.

CMV antiviral stewardship: navigating obstacles to facilitate target attainment.

PURPOSE OF REVIEW: Despite the availability of potent antivirals, consensus guidelines and decades of research, cytomegalovirus (CMV) continues to be associated with negative outcomes after solid organ transplant. This has been attributed to postprophylaxis CMV infection and a lack of development of CMV-specific cell mediated immunity (CMI). A shift from a focus on antiviral prevention to a focus on CMI target attainment is needed to improve CMV outcomes after transplantation. RECENT FINDINGS: There are many obstacles to CMI target attainment. Antiviral stewardship programs (AVS) have been employed to improve patient outcomes through appropriate antiviral use, reduction of unnecessary exposure and resistance mitigation. By focusing on the patient's unique substrate of conglomerate risk factors and addressing these factors specifically with evidenced based methodology, the AVS can address these obstacles, increasing rates of CMI and subsequently reducing risk of future CMV infection and negative outcomes. SUMMARY: With its multidisciplinary composition utilizing decades of experience from antimicrobial stewardship principles and practices, the AVS is uniquely poised to facilitate the shift from a focus on prevention to CMI target attainment and be the supporting pillar for the frontline transplant clinician caring for transplant patients with CMV.

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

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.

A pilot study of an intensified ganciclovir dosing strategy for treatment of cytomegalovirus disease in kidney and/or pancreas transplant recipients.

PROBLEM: Mathematical modeling suggests aggressive ganciclovir dosing in the first week of cytomegalovirus disease (CMV) treatment may improve response. This has not been evaluated clinically. METHODS: Adult kidney and/or pancreas transplant recipients admitted with CMV (4/29/19-7/15/20) received IV ganciclovir(10 mg/kg Q12 h × 7 days) with step-down to standard-of-care (SOC) dosing thereafter (5 mg/kg Q12). A SOC cohort admitted before implementation of the dosing strategy (10/20/16-3/2/19) served as a comparator. PRIMARY OBJECTIVE: rate of viral clearance (delta log CMV) at therapy day 7. SECONDARY OBJECTIVE: safety/short term efficacy. RESULTS: Fifty-four patients met inclusion criteria; 22 high-dose, 32 SOC. Demographics were similar with the exception of more women (45.4% vs. 15.6%,P = .03) and higher presenting viral-load in the high-dose group (log 6.0±.7 vs. log 5.2±1.2, P = .02). High-dose resulted in significantly greater response to therapy at day 7 (log -.92±.51 vs. log -.56±.79, P = .04). Change in WBC at day 7 was not different (-.49±1.92 vs. -.45±5.1, P = .97). Short-term clinical outcomes were similar between groups including mean hospital length-of-stay (P = .52), readmission rates (30 d: P = .38; 90 d: P = .5) and achievement of CMV viral-load less-than-lower-limit-of-quantification by day 90 (73% vs. 84%, P = .06). Rejection after CMV as well as graft/patient survival were similar between groups (P = .56, P > .99, P > .99). CONCLUSION: A high-dose IV ganciclovir strategy results in improved viral clearance kinetics without safety concerns and similar short term clinical outcomes.

A call for transplant stewardship: The need for expanded evidence-based evaluation of induction and biologic-based cost-saving strategies in kidney transplantation and beyond.

Rising expenditures threaten healthcare sustainability. While transplant programs are typically considered profitable, transplant medications are expensive and frequently targeted for cost savings. This review aims to summarize available literature supporting cost-containment strategies used in solid organ transplant. Despite widespread use of these tactics, we found the available evidence to be fairly low quality. Strategies mainly focus on induction, particularly rabbit antithymocyte globulin (rATG), given its significant cost and the lack of consensus surrounding dosing. While there is higher-quality evidence for high single-dose rATG, and dose-rounding protocols to reduce waste are likely low risk, more aggressive strategies, such as dosing rATG by CD3+ target-attainment or on ideal-body-weight, have less robust support and did not always attain similar efficacy outcomes. Extrapolation of induction dosing strategies to rejection treatment is not supported by any currently available literature. Cost-saving strategies for supportive therapies, such as IVIG and rituximab also have minimal literature support. Deferral of high-cost agents to the outpatient arena is associated with minimal risk and increases reimbursement, although may increase complexity and cost-burden for patients and infusion centers. The available evidence highlights the need for evaluation of unique patient-specific clinical scenarios and optimization of therapies, rather than simple blanket application of cost-saving initiatives in the transplant population.

Conversion from cytomegalovirus universal prophylaxis with valganciclovir to the preemptive monitoring approach to manage leukopenia after kidney or pancreas transplantation.

PURPOSE: In clinical practice, conversion from universal cytomegalovirus prophylaxis (CMV PPX) with valganciclovir (VGC) to targeted therapy (preemptive monitoring, PEM) is often pursued in the setting of leukopenia. It is unknown if this is an effective strategy. METHODS: Adult patients receiving a kidney and/or pancreas transplant were included if converted from PPX to PEM between 9/1/19 and 3/1/20 due to leukopenia. A positive CMV viral load (VL) was defined as CMV PCR greater than the lower limit of quantification (LLOQ) based on local lab testing. A CMV VL of >500 IU/mL was chosen as the preemptive treatment (PET) threshold. Primary objective was to describe the impact of conversion on resolution of leukopenia. Secondary objectives were to assess PEM associated outcomes. RESULTS: There were 49 patients converted from PPX to PEM due to leukopenia in the study period; 88% were KTRs and 96% received lymphocyte-depleting induction; 84% were seropositive at transplant (R+) and 16% were high-risk (D+/R-). Mean WBC at time of enrollment was 1.4 ± 0.4. After PEM conversion, WBC recovered to >3 in 87.8% of the population in a mean of 26.8 ± 24.5 days. Immunosuppression was modified in 96% of the population and GCSF was required in 46.9% of patients. CMV viremia occurred in 36.7% of the population; 78% were KTRs and 94% were R+. Time from PEM enrollment to PET was 64 ± 34 days. Median VL at first detection was 587 IU/mL, median peak was 1920 IU/mL. Five patients (27.8%) presented with symptoms consistent with CMV syndrome, none had end organ disease. Six patients (33%) presented with a VL <500 IU/mL at first detection, but all subsequently surpassed the threshold and required PET. Mean duration of PET was 25 ± 11 days. Mean change in WBC in response to PET was -0.4 ± 1.3. Immunosuppression required further adjustment in 61% of patients. There were no deaths or graft loss due to CMV at last follow-up. CONCLUSION: In kidney and pancreas transplant recipients who undergo PEM conversion due to leukopenia, withholding of VGC can improve leukopenia, but other concomitant measures are necessary. This population should be considered fairly high risk, with a threshold of treatment of first quantifiable replication. Our findings suggest lack of harm from this approach but highlight the importance of close monitoring to prevent symptomatic replication. Larger studies with longer follow-up are needed to better evaluate the impact of PEM conversion on late-onset CMV and patient and graft outcomes.

The addition of adjunctive letermovir to valganciclovir for refractory cytomegalovirus viremia in kidney transplant recipients.

PURPOSE: Persistent viral replication resulting in ongoing cytomegalovirus (CMV) viremia despite adequate therapy is difficult to manage and associated with negative outcomes. We report a case series of kidney transplant recipients receiving adjunctive letermovir in combination with valganciclovir for refractory CMV. METHODS: Adult patients receiving a kidney or kidney-pancreas transplant were included if they developed CMV viremia and initiated letermovir 480 mg daily as part of a dual therapy regimen with valganciclovir 900 mg twice daily between 1/9/2020 and 31/12/2020. Included patients received ≥90 days of valganciclovir and had a detectable viral load less than 1000 Iu/ml (log10  < 3) at the time of letermovir initiation. The primary objective was to evaluate the impact of adjunctive letermovir on viral clearance to negativity. We also evaluated effect of letermovir on tacrolimus levels. RESULTS: Eight patients were included. Letermovir was added 223 ± 105 days after initiation of CMV treatment with ganciclovir derivatives. Median viral load at initiation was 139.7 (range: 73-355) IU/ml and did not clear or change significantly after 2, 4 and 12 weeks of adjunctive letermovir (132.5 [range: 34.5-513] IU/ml vs. 68.7 [range: 34.5-574] IU/ml vs. 78.3 [range: 34.5-347] IU/ml, p > 0.05). Tacrolimus was reduced by ∼30% in anticipation of a letermovir-tacrolimus drug interaction. Despite this reduction, mean tacrolimus serum levels two weeks after adjunctive letermovir increased by 43% (5.6 ± 1.6 ng/ml vs 8.0 ± 4.6 ng/ml). CONCLUSION: In kidney and kidney-pancreas recipients with refractory CMV, the use of adjunctive letermovir did not result in viral clearance. Additionally, despite a mean tacrolimus dose reduction of 30% at letermovir initiation, serum concentrations increased by over 40%. Further investigation into the optimal approach to refractory CMV is needed.

Impact and outcomes of primary cytomegalovirus disease in seronegative abdominal solid organ transplant recipients of cytomegalovirus unexposed donors (D-/R-).

BACKGROUND: Primary cytomegalovirus (CMV) disease in high-risk (D+/R-) abdominal solid organ transplant recipients (aSOTRs) is well described, however, little is known of primary CMV disease in low-risk (D-/R-) patients. METHODS: Observational study of adult aSOTRs between 1/1/2009 and 9/1/2019 screened based on serostatus at transplant; D-/R- and D+/R- patients were included. PRIMARY OBJECTIVE: Describe epidemiology of primary CMV in D-/R- aSOTRs. SECONDARY OBJECTIVE: Compare infectious and transplant-related outcomes of primary CMV disease in the first 90 days (early CMV) between D-/R- and D+/R-. RESULTS: Of 782 D-/R- aSOTRs in the study period, 13 developed CMV at any time after transplant to last follow-up. Of 671 D+/R- patients, 186 developed CMV. Early CMV disease was significantly more common in the D-/R- group (54% vs 15.6%, P = .0005) despite populations being similar demographically, including allograft subtype. D-/R- patients with early CMV disease had median viral load >100 000 IU/mL and 42.9% had end-organ manifestations; 71.4% required hospital admission. Immunosuppressive therapy was adjusted in 100% of patients, there was an approximately 14.3% rate of antiviral resistance and 28.6% had concomitant opportunistic infection. These findings were similar to D+/R- patients. There was no difference in risk of rejection or all-cause mortality associated with early CMV disease, however, graft loss was significantly higher in D-/R-. CONCLUSION: D-/R- aSOTRs infrequently develop CMV, however, when it occurs, they present with disease manifestations similar to and graft outcomes inferior to D+/R- with CMV. Additionally, the majority of CMV disease in D-/R- occurs in the first 90 days after transplant, suggesting possible donor subclinical infection or transfusion source. The complicated course in D-/R- is likely caused by low clinical suspicion. Awareness of disease severity and aggressive upfront management may promote positive outcomes.

Cytomegalovirus antiviral stewardship in the COVID-19 Era: Increasing complexity of prophylaxis and treatment and potential mitigation strategies.

Cytomegalovirus (CMV) infection is one of the most common and significant complications after solid organ transplant (SOT). Severe acute respiratory coronavirus 2 (SARS-CoV-2), which causes the novel betacoronavirus 2019 disease (COVID-19), has become the first global pandemic in 100 years. The world's attention has turned to address this unanticipated development; however, the viral infection that has long plagued outcomes after solid organ transplantation still requires vigilance. With physical distancing as the key intervention to reduce the healthcare burden, and the unease related to healthcare contact within the transplant population given the associated morbidity and mortality of COVID-19 in transplant recipients, providers have struggled to evaluate and streamline essential in-person healthcare contact, including laboratory visits. Owing to this, the COVID-19 pandemic has placed a significant strain on the delivery of CMV prophylaxis and treatment after solid organ transplantation. In this piece, we will describe issues our CMV antiviral stewardship service has encountered in the care of the transplant recipient with CMV during the this unprecedented time and share our expert opinion to approaches to providing optimal, evidenced based care during a pandemic associated with a seemingly unrelated viral infection.

Management of BK viremia is associated with a lower risk of subsequent cytomegalovirus infection in kidney transplant recipients.

The risk of subsequent cytomegalovirus infection (CMV) in kidney transplant recipients (KTR) after diagnosis of BK polyomavirus viremia (BKV) is unclear, and current evidence is conflicting. We reviewed all KTR transplanted at our institution between 1/1/2005 and 12/31/2015. Follow-up began 3 months after transplantation to avoid confounding effects of prophylaxis. Clinically significant BKV, defined as detectable BK viremia >1000 copies/mL via molecular diagnostic testing (PCR), was treated as a time-varying exposure with 1-year follow-up. This viral load cutoff was chosen to ensure a more homogenous population that would be considered to have clinically significant BK viremia that necessitated management via immunosuppressive modification. Patients were then screened for subsequent CMV infection. 2435 RTX recipients met inclusion criteria; of these, 314 developed BKV during follow-up (BK+). Lymphocyte depletion, tacrolimus maintenance, and biopsy-proven rejection were significantly higher in the BK+ group. BK+ was associated with lower risk of subsequent CMV infection (BK+ HR 0.45, 95% CI 0.22-0.94, P = .03, relative risk reduction 55%). When adjusted for significant confounding factors, CMV incidence remained reduced in the BK+ population (HR 0.47, 95% CI 0.22-0.98, P = .04). This large series of KTR demonstrates that BKV is associated with lower risk of subsequent CMV infection.

Alternatives to immediate release tacrolimus in solid organ transplant recipients: When the gold standard is in short supply.

Given the current climate of drug shortages in the United States, this review summarizes available comparative literature on the use of alternative immunosuppressive agents in adult solid organ transplant recipients including kidney, pancreas, liver, lung, and heart, when immediate-release tacrolimus (IR-TAC) is not available. Alternative options explored include extended-release tacrolimus (ER-TAC) formulations, cyclosporine, belatacept, mammalian target of rapamycin inhibitors, and novel uses of induction therapy for maintenance immunosuppression. Of available alternatives, only ER-TAC formulations are of non-inferior efficacy compared to IR-TAC when used de novo or after conversion in stable kidney transplant recipients (KTRs). All other alternatives were associated with higher rates of biopsy-proven rejection, but improved tolerance from classic adverse effects of IR-TAC including nephrotoxicity and development of diabetes. While most alternative therapies are approved in KTRs, access via third-party payors is an obstacle in non-KTRs. In the setting of IR-TAC shortage, alternate therapeutic options may be plausible depending on the organ population and individual patient situation to ensure appropriate, effective immunosuppression for each patient.

Alemtuzumab induction for retransplantation after primary transplant with alemtuzumab induction
.

BACKGROUND: Lymphocyte-depleting induction with alemtuzumab (ALEM) or rabbit antithymocyte-globulin (rATG) is commonly used at retransplantation. It is unknown which agent is preferable, particularly when ALEM was used at primary transplant. OBJECTIVE: Evaluate outcomes after ALEM at retransplant following primary transplant with ALEM induction (ALEM-ALEM) as compared to retransplant with rATG (ALEM-rATG). MATERIALS AND METHODS: Single-center, observational cohort study of adult patients receiving kidney or pancreas transplant between January 1, 2001 and December 12, 2016. RESULTS: 45 patients (16 ALEM-ALEM and 29 ALEM-rATG) met inclusion criteria. The ALEM-ALEM group had fewer days between transplants (621.0 ± 821.8 vs. 2,024.4 ± 1,285.8, p = 0.049), lower panel-reactive-antibodies (PRA) prior to transplant 2 (15.7 ± 31.5 vs. 53.2 ± 37.8; p = 0.0003), and more pancreas secondary transplants, although this was not statistically significant (ALEM-ALEM 37.5% vs. ALEM-rATG 10.3%, p = 0.05). The ALEM-ALEM group experienced a significantly higher rate of fungal infection (ALEM-ALEM 46.8% vs. ALEM-rATG 11.3%, p = 0.02). When adjusted in a multivariate model, this trend persisted (HR 3.97, CI 0.95 - 16.5, p = 0.05). A subgroup analysis of patients receiving a kidney for both transplant 1 and 2 to remove the possible confounding effect of pancreas allografts also found incidence of fungal infection at 1 year to be significantly higher in the ALEM-ALEM group (ALEM-ALEM 25% vs. ALEM-rATG 9.3%, p = 0.025). Rejection rates were not different between groups at 1 year (ALEM-ALEM 25% vs. ALEM-rATG 24.2%). Rates of cytomegalovirus (CMV) infection, BK polyomavirus infection, patient and graft survival were also similar. CONCLUSION: Patients with repeat courses of ALEM induction across multiple transplants may have a higher incidence of fungal infection. Future studies are needed to explore this risk, particularly in light of current drug manufacturer allocation practices and potential increased utilization by transplant centers.

The risk of cytomegalovirus infection after treatment of acute rejection in renal transplant recipients.

The risk of cytomegalovirus infection (CMV) after rejection treatment is poorly understood. To investigate this, we conducted a case/control (1:2) analysis of adult renal transplant recipients between January 1, 2005 and December 31, 2015, via incidence density sampling and survival analysis. Our objective was to evaluate the association of prior acute rejection with subsequent CMV, including epidemiology and outcomes. There were 2481 eligible renal transplants within the study period and 251 distinct CMV infections. Despite the use of antiviral prophylaxis rejection was a significant risk factor for CMV on unadjusted (HR 1.73 [1.34, 2.24] P < 0.05) and adjusted analysis (HR 1.46 [1.06, 2.04] P < 0.05). When matching cases to controls patients with CMV had significantly more rejection prior to CMV diagnosis (26.7% vs 14.2%, P < 0.01). CMV was associated with a twofold increased risk of prior rejection on unadjusted (OR 1.94, 95%CI: 1.28-2.96, P < 0.01) and adjusted analysis (OR 2.16, 95% CI: 1.31-3.58, P < 0.01). Patients with rejection preceding CMV had significantly increased graft loss (HR 2.89, 95% CI: 1.65-5.09, P < 0.01) and mortality (HR 1.82, 95% CI: 1.12-4.24, P = 0.03) as compared to those CMV cases without rejection. In conclusion, rejection is a risk factor for CMV infection that appears to persist for 1 year. Preceding rejection events increased risk of graft loss and mortality in CMV patients. Given this, prolonged surveillance monitoring for CMV after rejection may be warranted. Studies are needed investigating optimal monitoring strategies.

Safety of Antithymocyte Globulin in Patients Undergoing Liver Transplantation With Livers From Donation After Circulatory Death Donors.

Background: Studies suggest that rabbit-antithymocyte globulin (rATG) decreases biliary complications (BCs) after donation-after-circulatory-death-donor liver transplantation (DCD LTx), but safety data are lacking. Objective: Our aim was to assess the safety of rATG for this indication. The secondary end point was efficacy of rATG for this indication. Methods: Adult recipients of DCD LTx were divided into 2 cohorts: protocolized use of rATG in the modern era (July 1, 2013, to December 31, 2016) and a historical control without rATG (January 1, 2005, to June 30, 2013). Incidence of infection, leukopenia, and thrombocytopenia were compared for the safety assessment, incidence of BCs, ischemic cholangiopathy (IC), and transplant outcomes for the efficacy assessment. Results: A total of 83 patients met inclusion criteria: 42 in the historical cohort and 41 in the modern cohort. The modern cohort had significantly fewer bacterial infections at 3 months (historical 54.8% vs modern 23%; P = 0.004) and 1 year (historical 62.1% vs modern 34.2%, P = 0.004). The modern cohort also had fewer fungal infections at these time points (historical 33.3% and 47.9% vs modern 15% and 15%; P = 0.001). There were no significant differences in platelet or white blood cell reduction between groups. There was a nonsignificant, but numerical, trend toward reduced IC/BC in the modern cohort at 1 year (IC: historical 30.1% vs modern 13.2%, P = 0.08; BC: historical 51% vs modern 37.5%, P = 0.13). There was no difference in graft/patient survival. Conclusion and Relevance: Our data suggest no major safety issues with rATG in DCD LTx. Our study should ease clinical apprehension surrounding rATG use for this indication. Future prospective studies are needed to further evaluate the role of rATG and its impact on efficacy end points.

Management of Tumor Necrosis Factor α Inhibitor Therapy After Renal Transplantation: A Comparative Analysis and Associated Outcomes.

BACKGROUND: Biologic agents inhibiting the tumor necrosis factor α pathway (TNFα-Is) are used to treat systemic inflammatory diseases. The best management of these agents after renal transplantation is unknown. OBJECTIVE: Evaluate peritransplant use of TNFα-Is and associated outcomes. METHODS: Retrospective, single-center study of adult renal-transplant-recipients (RTRs) transplanted between 1/1/1998-12/31/2017, who received TNFα-Is for inflammatory disease prior to transplant. Qualifying patients were divided into 2 cohorts: patients who resumed TNFα-Is after transplant and those who did not. Outcomes were evaluated. RESULTS: A total of 5256 renal transplants occurred in the study window; 14 patients met inclusion criteria. Primary indication for TNFα-I was Crohn's-disease (CD; 57.1%). Infliximab was utilized most frequently (50%). Seven RTRs resumed TNFα-I posttransplant; mean time to resumption of 10.6±4.35 months (median=6 months), 85.7% for CD. Immunosuppression was modified in 2 patients (28.6%) in response to restarting TNFα-I therapy. Seven RTRs did not resume TNFα-Is following transplant; the majority of these had rheumatic diseases. There was no significant difference in time to first bacterial or fungal infection, rejection, or patient survival between the 2 groups. Last measured estimated glomerular-filtration-rate was similar between groups (TNFα-I: 41 ± 14.2 vs 48.6 ± 8.6, P = 0.25). No patient had cytomegalovirus infection; however, 42.8% of each cohort had documented BK virus infection. Malignancy occurred more frequently in the cohort that resumed TNFα-Is (42.8% vs 14.3%, P = 0.24); however, this was not statistically significant. Conclusion and Relevance: TNFα-I therapy prior to renal-transplant is relatively uncommon. The decision to continue therapy after transplant must balance risks of infection and malignancy against inflammatory disease recurrence. A multidisciplinary treatment approach is necessary as use of TNFα-I affects immunosuppressive management and appears to affect transplant outcomes. Future studies are needed to further clarify the role of TNFα-I therapy use in RTRs with inflammatory disorders focusing on its correlation with both BK and malignancy.

Epidemiology, Risk Factors, and Outcomes After Early Posttransplant Clostridiodes difficile Infection in Renal Transplant Recipients.

BACKGROUND: Modifiable risk-factors associated with Clostridioides difficile infection (CDI) in renal-transplant (RTX) have not been clearly established and peri-transplant risk has not been described. OBJECTIVE: Evaluate epidemiology, risk-factors and outcomes after CDI occurring in the first 90 days after RTX (CDI-90).Methods: Observational cohort study/survival analysis of adult RTX recipients from 1/1/2012-12/31/2015. Primary outcome was CDI-90 incidence/risk-factors. Secondary outcome was evaluation of post-90 day transplant outcomes. RESULTS: 982 patients met inclusion criteria; 46 with CDI-90 and 936 without (comparator). CDI incidence in the total population was 4.7% at 90 days, 6.3% at 1 year, and 6.4% at 3 years. Incidence of CDI-90 was 5%; time to diagnosis was 19.4±25 days (median 7). Risk-factors for CDI-90 were alemtuzumab induction (Hazard ratio [HR] 1.5, 95% CI(1.1-2.0), p = 0.005) and age at transplant (HR 1.007/year, 95% CI (1.002-1.012), p= 0.007). However, risk-factors for CDI at any time were different; donation-after-circulatory-death (DCD) donor (HR 2.5 95% CI (1.3-4.9), p = 0.008) and female gender (HR 1.6 95% CI (1.0-2.7), p = 0.049). On Kaplan-Meier, CDI-90 appeared to have an impact on patient/graft survival, however when analyzed in a multivariable stepwise Cox proportional hazards model, only age was significantly associated with survival (p = 0.002). CONCLUSION AND RELEVANCE: Incidence of CDI-90 is low, mostly occurring in the first post-operative month. Risk-factors vary temporally based on time from transplant. In the early post-op period induction agent and age at transplant are significant, but not after. Associations between CDI and negative graft outcomes appear to be largely driven by age. Future studies validating these risk-factors as well as targeted prophylaxis strategies and their effect on long term graft outcomes and the host microbiome are needed.

Evaluation of infectious risk and outcomes in the hmong renal transplant population.

BACKGROUND: Hmong ethnicity has been associated with infection, particularly fungal. The risk of infection after transplant in the Hmong population is unknown. METHODS: Observational study of adult renal transplant (RTX) recipients between 1/1/1994 and 12/31/2015. Primary objective was to identify infectious risk in the Hmong RTX population as compared to non-Hispanic whites (NHW). Secondary objective was to evaluate transplant outcomes. RESULTS: There was a total of 2599 patients in the study window; 95 Hmong, 2504 NHW. The Hmong population had significantly fewer bacterial and fungal infections at 1 and 3 years (Bacterial: Hmong 21.7%, 32.4% vs NHW 36.9%, 46.7%, P = .004; Fungal: Hmong 3.3%, 5.7% vs NHW 12.7%, 16.6%, P = .0005) and improved graft and patient survival at 1, 5, and 10 years (Graft: Hmong 92.6%, 78.4%, 61.9% vs NHW 90.7%, 72.2%, 48.5%, P = .006; Patient: Hmong 97.8%, 94.5%, 83.3% vs NHW 95.3%, 82.1%, 62.1% P < .001). Spectrum of bacterial infection was similar, but with significantly more Staphylococcal infection in the NHW population. Blastomycoses were the major fungal pathogen in Hmong (2/3, 67%) vs Candida in NWH (77%). When minimally adjusted for PRA and age, rates of bacterial infection (HR 0.69, 95% CI 0.48-0.99, P = .047), fungal infection (HR 0.39, 95% CI 0.17-0.87, P = .02), and mortality (HR 0.5, 95% CI 0.28-0.88, P = .02) were more favorable in the Hmong population. When analyzed in a stepwise Cox proportional hazards model; Hmong ethnicity was not a significant risk factor for graft failure, rejection, CMV, BK, or fungal infection after RTX and was associated with reduced risk of bacterial infection (HR 0.61, 95% CI 0.4-0.9, P = .02) and mortality (HR 0.51, 95% CI 0.27-0.96, P = .04). CONCLUSIONS: Despite concern regarding infective risk in the Hmong population, infection after RTX is no higher than NHW comparator. In all analyses, the Hmong population has equal or better outcomes. It does not appear variance in standard infection prophylaxis is necessary for the Hmong population after RTX.

A targeted fungal prophylaxis protocol with static dosed fluconazole significantly reduces invasive fungal infection after liver transplantation.

BACKGROUND: Invasive fungal infection (IFI) after liver transplant (LTx) is associated with extensive morbidity and mortality. Targeted prophylaxis reduces risk, but qualifying criteria, drug of choice and regimen are unclear and compliance is inconsistent. OBJECTIVE: Assess the impact of a risk factor-based fungal prophylaxis protocol (FPP) after LTx on fungal infection rates, fungal epidemiology, and transplant outcomes. METHODS: Observational cohort study of adult LTx recipients between July 1, 2009, and June 30, 2017. Patients in the FPP group were given a set dose of 400 mg fluconazole without renal adjustment on POD 1-14 via pharmacist delegation protocol. RESULTS: One hundred and eighty-nine patients met inclusion criteria; 50 in the FPP and 139 in the pre-implementation comparator group. Of those who would be considered high-risk, 22.3% received antifungal prophylaxis prior to FPP implementation vs 92% after implementation (P < .0001). There were significantly fewer fungal infections in the FPP group at 1 year (12.5% vs 26.6%, P = .03). IFI in the pre-implementation control group was due to Candida species in 95% of cases; 30% were species with reduced fluconazole susceptibility. IFI in the FPP group was due to Candida species in all cases, and no isolates had reduced fluconazole susceptibility. Aspergillus did not account for any IFI between the groups. One-year patient and graft survival were similar between groups. In a multivariable model accounting for patient and donor age, donor type, MELD, and cold ischemic time, FPP was protective against fungal infection (HR 0.3, P = .015). FPP did not significantly impact graft survival (HR 0.4, P = .14), but trended toward improved patient survival. (HR 0.18, P = .06). CONCLUSION: Implementation of a targeted FPP utilizing static dosing of fluconazole 400 mg × 14 days to those that meet high-risk criteria significantly reduces invasive fungal infection after liver transplant. Use of this protocol did not adversely affect fungal epidemiology and may have a positive impact on allograft and patient survival. Future large prospective studies are needed to better evaluate survival impact.