Early Everolimus-Facilitated Reduced Tacrolimus in Liver Transplantation: Results From the Randomized HEPHAISTOS Trial.

Everolimus-facilitated reduced-exposure tacrolimus (EVR + rTAC) at 30 days after liver transplantation (LT) has shown advantages in renal preservation. This study evaluated the effects of early initiation of EVR + rTAC in de novo LT recipients (LTRs). In HEPHAISTOS (NCT01551212, EudraCT 2011-003118-17), a 12-month, multicenter, controlled study, LTRs were randomly assigned at 7 to 21 days after LT to receive EVR + rTAC or standard-exposure tacrolimus (sTAC) with steroids. The primary objective was to demonstrate superior renal function (assessed by estimated glomerular filtration rate [eGFR]) with EVR + rTAC versus sTAC at month 12 in the full analysis set (FAS). Other assessments at month 12 included the evaluation of renal function in compliance set and on-treatment (OT) patients, efficacy (composite endpoint of graft loss, death, or treated biopsy-proven acute rejection [tBPAR] and individual components) in FAS, and safety. In total, 333 patients (EVR + rTAC, 169; sTAC, 164) were included in the FAS. A high proportion of patients was nonadherent in maintaining tacrolimus trough levels (EVR + rTAC, 36.1%; sTAC, 34.7%). At month 12, the adjusted least square mean eGFR was numerically higher with EVR + rTAC versus sTAC (76.2 versus 72.1 mL/minute/1.73 m2 , difference: 4.1 mL/minute/1.73 m2 ; P = 0.097). A significant difference of 8.3 mL/minute/1.73 m2 (P = 0.03) favoring EVR + rTAC was noted in the compliance set. Incidence of composite efficacy endpoint (7.7% versus 7.9%) and tBPAR (7.1% versus 5.5%) at month 12 as well as incidence of treatment-emergent adverse events (AEs) and serious AEs were comparable between groups. A lower proportion of patients discontinued EVR + rTAC than sTAC treatment (27.2% versus 34.1%). Early use of everolimus in combination with rTAC showed comparable efficacy, safety, and well-preserved renal function versus sTAC therapy at month 12. Of note, renal function was significantly enhanced in the compliance set.

Frailty as a predictive factor for survival after liver transplantation, especially for patients with MELD≤15-a prospective study.

INTRODUCTION: Frailty has been discussed as a predictor of morbidity and mortality for liver cirrhosis. The aim of our study is to evaluate the role of frailty in liver transplantation, particularly for patients with MELD scores < 15. METHODS: All patients listed for liver transplantation between September 2015 and November 2018 were prospectively included in the study. Frailty was assessed by Fried's frailty classification. Pre-, intra-, and postoperative data were prospectively recorded. Univariate and multivariate regression analyses were performed. The ethical approval of the institutional board review was obtained for the study. RESULTS: There were 114 patients included in the study, and their median MELD score was 16. Of these, 86 patients were defined as frail (75.4%). A total of 62 patients (54.4%) underwent liver transplantation, 11 (17.7%) died postoperatively, and 24 patients (21.0%) died while on the waitlist. All postoperative mortality cases were frail, and only 3 patients (12.5%) were non-frail in the waitlist mortality group. There were 14 patients who had MELD scores of <15 (58.3%). The overall survival of non-frail patients was significantly better than that of frail patients. The multivariate regression analyses identified frailty criteria, including unintended weight loss and low hand grip strength, and platelet count and being married or living in a solid partnership were prognostic factors for survival in all patients. CONCLUSION: The addition of frailty assessment can be beneficial for predicting mortality after liver transplantation, especially in patients with low MELD score. Frail patients on the waitlist have significant risk for mortality even with low MELD score.

mTOR Inhibition Is Most Beneficial After Liver Transplantation for Hepatocellular Carcinoma in Patients With Active Tumors.

OBJECTIVE: The aim of this study was to evaluate the survival benefit of sirolimus in patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) (exploratory analysis of the SiLVER-trial). SUMMARY AND BACKGROUND DATA: Patients receiving LT) for HCC are at a high risk for tumor recurrence. Calcineurin inhibitors have shown evidence to promote cancer growth, whereas mammalian target of rapamycin (mTOR) inhibitors like sirolimus have anticancer effects. In the SiLVER-trial (Clinicaltrials.gov: NCT00355862), the effect of sirolimus on the recurrence of HCC after LT was investigated in a prospective randomized trial. Although the primary endpoint of improved disease-free survival (DFS) with sirolimus was not met, outcomes were improved for patients in the sirolimus-treatment arm in the first 3 to 5 years. To learn more about the key variables, a multivariate analysis was performed on the SiLVER-trial data. PATIENTS AND METHODS: Data from 508 patients of the intention-to-treat analysis were included in exploratory univariate and multivariate models for overall survival (OS), DFS and a competing risk analysis for HCC recurrence. RESULTS: Sirolimus use for ≥3 months after LT for HCC independently reduced the hazard for death in the multivariate analysis [hazard ratio (HR): 0.7 (95% confidence interval, CI: 0.52-0.96, P = 0.02). Most strikingly, patients with an alpha-fetoprotein (AFP) ≥10 ng/mL and having used sirolimus for ≥3 months, benefited most with regard to OS, DFS, and HCC-recurrence (HR: 0.49-0.59, P = 0.0079-0.0245). CONCLUSIONS: mTOR-inhibitor treatment with sirolimus for ≥3 months improves outcomes in LT for HCC, especially in patients with AFP-evidence of higher tumor activity, advocating particularly for mTOR inhibitor use in this subgroup of patients. CLINICAL TRIAL REGISTRATION: EudraCT: 2005-005362-36 CLINICALTRIALS.GOV:: NCT00355862.

Long-term follow-up of five yr shows superior renal function with everolimus plus early calcineurin inhibitor withdrawal in the PROTECT randomized liver transplantation study.

BACKGROUND: The 12-month (M) PROTECT study showed that de novo liver transplant recipients (LTxR) who switched from a calcineurin inhibitor (CNI)-based immunosuppression to a CNI-free everolimus (EVR)-based regimen showed numerically better renal function. Here, we present the five-yr follow-up data. METHODS: PROTECT was a randomized controlled study in which LTxR received basiliximab and CNI-based immunosuppression ± corticosteroids. Patients were randomized 1:1 to receive EVR or continue CNI. Patients completing the core study could enter the extension study on their randomized treatment. RESULTS: A total of 81 patients entered the extension study (41, EVR; 40, CNI). At M59 post-randomization, the adjusted mean eGFR was significantly higher in the EVR group, with a benefit of 12.4 mL/min using Cockcroft-Gault (95% CI: 1.2; 23.6; p = 0.0301). Also, there was a significant benefit for adjusted and unadjusted eGFR using the four-variable Modification of Diet in Renal Disease (MDRD4) or Nankivell formula. During the extension period, treatment failure rates were similar. SAEs occurred in 26 (63.4%) and 28 (70.0%) of the patients in EVR and CNI groups, respectively. CONCLUSION: Compared with the CNI-based treatment, EVR-based CNI-free immunosuppression resulted in significantly better renal function and comparable patient and graft outcomes after five-yr follow-up.

Liver transplantation with donors over the expected lifespan in the model for end-staged liver disease era: is Mother Nature punishing us?

BACKGROUND: The lack of sufficient donors to satisfy the waiting list requirements has prompted many to expand the acceptance criteria. The purpose of this study was to evaluate our liver transplantation (LT) experience with donors beyond the average lifespan. PATIENTS AND METHODS: From January 2008 to December 2009, we received 75 liver offers involving donors ≥ 75 years of age. Donor and recipient data were analysed by both uni- and multivariate Cox proportional hazard model analyses. RESULTS: We performed 32 adult liver transplants (43%). Half of the patients received organs through rescue allocations. Seven recipients (22%) developed initial poor function. Two had primary graft non-function (PNF). Four recipients were re-transplanted (two PNF and two ischaemic-type bile lesions). One- and 3-year cumulative survival was 62 and 51% respectively. PNF, lab model for end-staged liver disease (MELD), post-LT haemodialysis, post-LT re-operations and post-LT sepsis were significant predictors by univariate analysis. Only PNF reached multivariate significance (P = 0.0307). Rescue offer allocation reached significance as a predictor of PNF by general linear model forward analysis. One- and 3-year 'MELD based allocation' (n = 16) vs 'rescue allocation' (n = 16) survival rates were 44 and 29% vs 82 and 76% respectively (P = 0.0197). CONCLUSIONS: Although grafts from donors ≥ 75 years allow for an expansion of the donor pool, long-term recipient survival is inferior to that encountered with younger donors. Acceptable results could be obtained by identifying 'preferred' recipients for rescue allocations.

Efficacy, safety, and immunosuppressant adherence in stable liver transplant patients converted from a twice-daily tacrolimus-based regimen to once-daily tacrolimus extended-release formulation.

The aim of this study was to determine the efficacy, safety, and immunosuppressant adherence in 125 stable liver transplant (LT) patients converted from twice-daily tacrolimus (TAC BID) to once-daily TAC (TAC OD). Tacrolimus trough levels, laboratory parameters, metabolic disorders, selected patient reported outcomes, and adverse events were assessed. Mean TAC trough level concentration was 6.1 ± 2.3 ng/ml at study entry, decreased to 5.5 ± 2.1 ng/ml (P = 0.016) and 5.5 ± 2.2 ng/ml (P = 0.019) after 1 and 2 weeks, respectively, and tended to equal the baseline value during further follow-up. At week 1, TAC concentrations were lower in 62.4% of patients and higher in 36.0% when compared with baseline. Renal and cardiovascular risk factors remained stable and no rejection episodes occurred over 12 months. Adverse events were consistent with the safety profile known from previous studies with TAC BID. Nonadherence measured by the "Basel Assessment of Adherence Scale to Immunosuppressives" was evident in 66.4% at study entry and decreased to 30.9% postconversion (P < 0.0001). Prevalence of nonadherence at baseline was significantly higher in patients converted >2 years after LT and in those ≤60 years of age. Conversion to TAC OD is safe, enhances immunosuppressant adherence and should be accompanied by a close TAC level monitoring during the initial period.

Assessment of allograft fibrosis by transient elastography and noninvasive biomarker scoring systems in liver transplant patients.

BACKGROUND: This prospective, monocentric study was designed to assess the efficacy of transient elastography (TE), biochemical tests, and more complex scores in determining fibrosis stage in 157 patients transplanted for hepatitis C virus (HCV) infection or non-HCV-related liver diseases. METHODS AND RESULTS: The optimal TE cutoff values for HCV patients and non-HCV patients were 4.7 and 5.0 kPa for F> or =1, 7.1 and 7.3 kPa for F> or =2, 10.9 kPa and 9.9 kPa for F> or =3, and 17.3 and 12.6 kPa for F=4, respectively. The corresponding area under the receiver operating characteristic (AUROC) curves for F> or =1, F> or =2, F> or =3, and F=4 were 0.95 and 0.86, 0.89 and 0.85, 0.97 and 0.88, and 0.99 and 0.97 for HCV and non-HCV patients, respectively. On the basis of the logistic regression equation, we created a model (FibroTransplant score) to identify advanced fibrosis (F> or =3). The accuracy of this model was tested in a validation group (n=74). AUROCs for diagnosis of F> or =3 in HCV patients and non-HCV patients of the training group were 0.89 and 0.83 (FibroTransplant score), 0.86 and 0.66 (Benlloch score), 0.81 and 0.71 (aspartate aminotransferase-to-platelet ratio index), 0.80 and 0.77 (Hepascore), 0.79 and 0.70 (FibroTest), 0.78 and 0.71 (FIB-4), 0.75 and 0.60 (Forns index), 0.73 and 0.69 (FibroIndex), and 0.70 and 0.59 (Lok score). Among the validation group, AUROCs of the FibroTransplant score for F> or =3 were 0.90 and 0.91, respectively. CONCLUSIONS: TE and the FibroTransplant score can be reliably used for diagnosing advanced fibrosis in transplanted patients.

Predictive factors of outcome in patients transplanted for hepatitis B.

BACKGROUND: This study aimed to (1) identify the variables that affect graft and patient survival in recipients transplanted for hepatitis B virus (HBV) disease; and (2) assess factors associated with an increased risk of graft cirrhosis at 5 years after liver transplantation (LT). METHODS AND RESULTS: A total of 104 chronically infected HBV patients were considered for this study and all received tacrolimus- or cyclosporine A (CSA)-based immunosuppressive regimens. The overall 5-year patient and graft survival rates were 80% and 73%, respectively. Univariate Cox proportional hazards regression analysis indicated that older recipient age and higher body mass index (BMI) at LT, LT more than or equal to 1998, arterial hypertension, hyperlipidemia, and CSA-based immunosuppression correlated with decreased patient survival. In the multivariate model, advanced recipient age, higher BMI, CSA-based immunosuppressive therapy, and increasing cold ischemia time were associated with worse patient survival. Recipient age and BMI at time of LT and posttransplant hypertriglyceridemia also affected graft survival. Log-rank analysis showed that a viral load of more than 10 copies/mL and antiviral therapy at LT, post-LT biliary complications, HBV recurrence, nucleos(t)ide analogue monoprophylaxis (without hepatitis B immunoglobulin), and short-term (< or = 1 year) mycophenolate mofetil therapy were significant risk factors for graft cirrhosis within 5 years of LT. CONCLUSION: Various recipient factors at the time of LT and post-LT virological status, antiviral prophylaxis, cholestasis, cardiovascular risk profile, and immunosuppressive regimen affect the outcome of HBV patients after LT. Prospective studies are warranted to define optimal immunosuppression for recipients transplanted for hepatitis B.