Effects of everolimus plus minimized tacrolimus on kidney function in liver transplantation: REDUCE, a prospective, randomized controlled study.

BACKGROUND AND AIM: reduction in calcineurin inhibitor levels is considered crucial to decrease the incidence of kidney dysfunction in liver transplant (LT) recipients. The aim of this study was to evaluate the safety and impact of everolimus plus reduced tacrolimus (EVR + rTAC) vs. mycophenolate mofetil plus tacrolimus (MMF + TAC) on kidney function in LT recipients from Spain. METHODS: the REDUCE study was a 52-week, multicenter, randomized, controlled, open-label, phase 3b study in de novo LT recipients. Eligible patients were randomized (1:1) 28 days post-transplantation to receive EVR + rTAC (TAC levels ≤ 5 ng/mL) or to continue with MMF + TAC (TAC levels = 6-10 ng/mL). Mean estimated glomerular filtration rate (eGFR), clinical benefit in renal function, and safety were evaluated. RESULTS: in the EVR + rTAC group (n = 105), eGFR increased from randomization to week 52 (82.2 [28.5] mL/min/1.73 m2 to 86.1 [27.9] mL/min/1.73 m2) whereas it decreased in the MMF + TAC (n = 106) group (88.4 [34.3] mL/min/1.73 m2 to 83.2 [25.2] mL/min/1.73 m2), with significant (p < 0.05) differences in eGFR throughout the study. However, both groups had a similar clinical benefit regarding renal function (improvement in 18.6 % vs. 19.1 %, and stabilization in 81.4 % vs. 80.9 % of patients in the EVR + rTAC vs. MMF + TAC groups, respectively). There were no significant differences in the incidence of acute rejection (5.7 % vs. 3.8 %), deaths (5.7 % vs. 2.8 %), and serious adverse events (51.9 % vs. 44.0 %) between the 2 groups. CONCLUSION: EVR + rTAC allows a safe reduction in tacrolimus exposure in de novo liver transplant recipients, with a significant improvement in eGFR but without significant differences in renal clinical benefit 1 year after liver transplantation.

Post-transplantation outcome in non-alcoholic steatohepatitis cirrhosis: Comparison with alcoholic cirrhosis.

INTRODUCTION AND OBJECTIVES: Non-alcoholic steatohepatitis (NASH) indication of liver transplant (LT) has increased recently, whereas alcoholic cirrhosis remains a major indication for LT. To characterize NASH-related cases and to compare the post-transplant outcome of these two conditions represents our major objective. MATERIAL AND METHODS: Patients undergoing LT for NASH between 1997 and 2016 were retrieved. Those transplanted between 1997 and 2006 were compared to an "age and LT date" matched group of patients transplanted for alcoholic cirrhosis (ratio 1:2). Baseline features and medium-term outcome measures were compared. RESULTS: Of 1986 LT performed between 1997 and 2016, 40 (2%) were labeled as NASH-related indications. NASH-related cases increased initially (from 0.8% in 1997-2001 to 2.7% in 2002-2006) but remained stable in subsequent years (2.3%). Hepatocellular carcinoma (HCC) prevalence was greater in NASH-vs alcohol-related cirrhosis (40% vs 3%, p=0.001). The incidence of overweight, obesity, arterial hypertension, dyslipidemia, diabetes, hyperuricemia, renal insufficiency and cardiovascular (CV) disease was similar in both groups at 5 years post-LT. Five-year survival was higher in NASH but without reaching statistical significance (83% vs 72%, p=0.21). The main cause of mortality in NASH-LT patients was HCC recurrence. CONCLUSION: Most previously considered cryptogenic cases are actually NASH-cirrhosis. While the incidence of this indication is increasing in many countries, it has remained relatively stable in our Unit, the largest LT center in Spain. HCC is common in these patients and represents a main cause of post-transplant mortality. Metabolic complications, CV-related disease and 5-yr survival do not differ in patients transplanted for NASH vs alcohol.

Impact of hepatitis C virus (HCV) antiviral treatment on the need for liver transplantation (LT).

BACKGROUND: Therapies for hepatitis C virus (HCV) infection have revolutionized the treatment of patients with chronic HCV infection. The effect of these therapies on the epidemiology of liver transplantation (LT) has yet to be elucidated. AIM: To establish whether the indications for LT have changed as a result of the introduction of new therapies for HCV. MATERIALS AND METHODS: We conducted a retrospective study based on a prospectively maintained registry of patients who undergo LT at La Fe Hospital in Valencia from 1997 to 2016. An analysis of outcome measures over time stratified by LT indications was performed. RESULTS: From January 1997 to December 2016, 2379 patients were listed for LT. Of these, 1113 (47%) were listed for HCV cirrhosis±hepatocellular carcinoma (HCC). This percentage varied significantly over time declining from 48.8% in the 1997-2009 initial period (IFN-based regimens) to 33% in the 2014-2016 final period (DAAs regimens) (P = .03). However, during that period, the proportion of those included in the waiting list (WL) due to HCV-HCC increased significantly (P = .001). In addition, among HCV-positive waitlisted patients with decompensated cirrhosis without HCC, the proportion of those with an HCV-alcohol mixed etiology also increased significantly over time (P = .001). Of all HCV-positive waitlisted patients, 203 were eventually removed from the WL due to either clinical improvement (n = 77) or more frequently worsening/death (n = 126). CONCLUSIONS: The proportion of patients wait-listed for LT for decompensated HCV cirrhosis has significantly decreased over time. These changes are possibly related to the large-scale use of direct-acting antivirals.

Remnant vital tissue following locoregional therapy for hepatocellular carcinoma: another player in the game.

The applicability of liver transplantation (LT) as a curative option for patients with hepatocellular carcinoma (HCC) is limited by organ shortage. In addition to tumor size and number, other variables, particularly those that are surrogates of tumor biology should be incorporated into the allocation policies to improve the estimation of post-LT benefit. In this issue of Transplant International, Manzia et al. analyze the role of remnant vital tissue (RVT) of the target lesion after locoregional therapies (LRT) in predicting post-LT HCC recurrence This article is protected by copyright. All rights reserved.

Cytomegalovirus reactivation in liver transplant recipients due to hepatitis C cirrhosis is associated with higher cardiovascular risk - an observational, retrospective study.

The association between cytomegalovirus (CMV) reactivation and cardiovascular risk has been reported in solid organ transplant populations; however, it has yet to be assessed in liver transplantation (LT). We aim to evaluate whether CMV reactivation is associated with cardiovascular events (CVE) in HCV-LT patients. LT patients (2010 and 2014) due to HCV cirrhosis were included. Clinically significant CMV (CS-CMV) was defined as viral load (VL) >5000 copies/ml, need of therapy or CMV disease. Baseline variables and endpoint measures (CVE, survival, severe recurrent hepatitis C, de novo tumors, and diabetes) were collected. One hundred and forty patients were included. At LT, a history of AHT was present in 23%, diabetes 22%, tobacco use 45%, obesity 20%, and renal impairment (eGFR < 60 ml/min) in 26.5%. CS-CMV reactivation occurred in 25% of patients. Twenty-six patients (18.5%) developed a CVE. Cox regression analysis revealed two factors significantly associated with CVE: Pre-LT DM [HR = 4.6 95% CI (1.6, 13), P = 0.004] and CS-CMV [HR = 4.7 95% CI (1.8, 12.5), P = 0.002]. CS-CMV was not independently associated with the remaining endpoints except for survival (P = 0.03). In our series, CS-CMV reactivation was associated with a greater risk of developing CVE, thus confirming data from other solid organ transplant populations and emphasizing the need for adequate CMV control.

Clinical outcomes of patients undergoing antiviral therapy while awaiting liver transplantation.

BACKGROUND & AIMS: Antiviral therapy for the treatment of hepatitis C (HCV) infection has proved to be safe and efficacious in patients with cirrhosis awaiting liver transplantation (LT). However, the information regarding the clinical impact of viral eradication in patients on the waiting list is still limited. The aim of the study was to investigate the probability of delisting in patients who underwent antiviral therapy, and the clinical outcomes of these delisted patients. METHODS: Observational, multicenter and retrospective analysis was carried out on prospectively collected data from patients positive for HCV, treated with an interferon-free regimen, while awaiting LT in 18 hospitals in Spain. RESULTS: In total, 238 patients were enrolled in the study. The indication for LT was decompensated cirrhosis (with or without hepatocellular carcinoma [HCC]) in 171 (72%) patients, and HCC in 67 (28%) patients. Sustained virologic response (SVR) rate was significantly higher in patients with compensated cirrhosis and HCC (92% vs. 83% in patients with decompensated cirrhosis with or without HCC, p=0.042). Among 122 patients with decompensated cirrhosis without HCC, 29 (24%) were delisted due to improvement. No patient with baseline MELD score >20 was delisted. After delisting (median follow-up of 88weeks), three patients had clinical decompensations and three had de novo HCC. Only two of the patients with HCC had to be re-admitted onto the waiting list. The remaining 23 patients remained stable, with no indication for LT. CONCLUSIONS: Antiviral therapy is safe and efficacious in patients awaiting LT. A quarter of patients with decompensated cirrhosis can be delisted asa result of clinical improvement, which appears to be remain stable in most patients. Thus, delisting is a safe strategy that could spare organs and benefit other patients with a more urgent need. LAY SUMMARY: Antiviral therapy in patients awaiting liver transplantation is safe and efficacious. Viral eradication allows removal from the waiting list of a quarter of treated patients. Delisting because of clinical improvement is a safe strategy that can spare organs for patients in urgent need.

An objective definition for clinical suspicion of T-cell-mediated rejection after liver transplantation.

A uniform definition of clinical suspicion of T-cell-mediated rejection (TCMR) in liver transplantation (LT) is needed to homogenize clinical decisions, especially within randomized trials. This multicenter study included a total of 470 primary LT recipients. The derivation cohort consisted of 142 patients who had clinically driven liver biopsies at any time after LT. The external validation cohort included 328 patients who underwent protocol biopsies at day 7-10 after LT. The rates of moderate-severe histological TCMR were 33.8% in the derivation cohort and 43.6% in the validation cohort. Independent predictors (ie, risk factors) of moderate-severe TCMR in the derivation cohort were as follows: serum bilirubin >4 mg/dL (OR=5.83; P<.001), rising bilirubin within the 4 days prior to liver biopsy (OR=4.57; P=.003), and blood eosinophils count >0.1×109 /L (OR=3.81; P=.004). In the validation cohort, the number of risk factors was an independent predictor of moderate-severe TCMR (OR=1.74; P=.001), after controlling for hepatitis C status. The number of risk factors paralleled the rates of moderate-severe TCMR in the derivation and validation cohorts (P<.001 in both comparisons). In conclusion, increased serum bilirubin, rising bilirubin and eosinophilia are validated risk factors for moderate-severe histological TCMR and could be used as objective criteria to select candidates for liver biopsy.

Framingham score, renal dysfunction, and cardiovascular risk in liver transplant patients.

Cardiovascular (CV) events represent major impediments to the long-term survival of liver transplantation (LT) patients. The aim of this study was to assess whether the Framingham risk score (FRS) at transplantation can predict the development of post-LT cardiovascular events (CVEs). Patients transplanted between 2006 and 2008 were included. Baseline features, CV risk factors, and CVEs occurring after LT (ischemic heart disease, stroke, heart failure, de novo arrhythmias, and peripheral arterial disease) were recorded. In total, 250 patients (69.6% men) with a median age of 56 years (range, 18-68 years) were included. At transplantation, 34.4%, 34.4%, and 33.2% of patients, respectively, had a low, moderate, and high FRS with a median FRS of 14.9 (range, 0.09-30); 14.4% of LT recipients developed at least 1 CVE at a median of 2.619 years (range, 0.006-6.945 years). In the univariate analysis, factors associated with the development of CVEs were the continuous FRS at LT (P = 0.003), age (P = 0.007), creatinine clearance [estimated glomerular filtration rate (eGFR); P = 0.020], and mycophenolate mofetil use at discharge (P = 0.011). In the multivariate analysis, only the eGFR [hazard ratio (HR), 0.98; 95% confidence interval (CI), 0.97-1.00; P = 0.009] and FRS (HR, 1.06; 95% CI, 1.02-1.10; P = 0.002) remained in the model. Moreover, an association was also found between the FRS and overall survival (P = 0.004) with 5-year survival rates of 82.5%, 77.8%, and 61.4% for the low-, moderate-, and high-risk groups, respectively. Continuous FRS, eGFR, and hepatitis C virus infection were independent risk factors for overall mortality. In our series, the FRS and eGFR at LT were able to predict the development of post-LT CVEs and poor outcomes. Liver Transpl 21:812-822, 2015. © 2015 AASLD.

Renal function improvement in liver transplant recipients after early everolimus conversion: A clinical practice cohort study in Spain.

A national, multicenter, retrospective study was conducted to assess the results obtained for liver transplant recipients with conversion to everolimus in daily practice. The study included 477 recipients (481 transplantations). Indications for conversion to everolimus were renal dysfunction (32.6% of cases), hepatocellular carcinoma (HCC; 30.2%; prophylactic treatment for 68.9%), and de novo malignancy (29.7%). The median time from transplantation to conversion to everolimus was 68.7 months for de novo malignancy, 23.8 months for renal dysfunction, and 7.1 months for HCC and other indications. During the first year of treatment, mean everolimus trough levels were 5.4 (standard deviation [SD], 2.7) ng/mL and doses remained stable (1.5 mg/day) from the first month after conversion. An everolimus monotherapy regimen was followed by 28.5% of patients at 12 months. Patients with renal dysfunction showed a glomerular filtration rate (4-variable Modification of Diet in Renal Disease) increase of 10.9 mL (baseline mean, 45.8 [SD, 25.3] versus 57.6 [SD, 27.6] mL/minute/1.73 m(2) ) at 3 months after everolimus initiation (P < 0.001), and 6.8 mL at 12 months. Improvement in renal function was higher in patients with early conversion (<1 year). Adverse events were the primary reason for discontinuation in 11.2% of cases. The probability of survival at 3 years after conversion to everolimus was 83.0%, 71.1%, and 59.5% for the renal dysfunction, de novo malignancy, and HCC groups, respectively. Everolimus is a viable option for the treatment of renal dysfunction, and earlier conversion is associated with better recovery of renal function. Prospective studies are needed to confirm advantages in patients with malignancy.

Use of artificial intelligence as an innovative donor-recipient matching model for liver transplantation: results from a multicenter Spanish study.

BACKGROUND & AIMS: There is an increasing discrepancy between the number of potential liver graft recipients and the number of organs available. Organ allocation should follow the concept of benefit of survival, avoiding human-innate subjectivity. The aim of this study is to use artificial-neural-networks (ANNs) for donor-recipient (D-R) matching in liver transplantation (LT) and to compare its accuracy with validated scores (MELD, D-MELD, DRI, P-SOFT, SOFT, and BAR) of graft survival. METHODS: 64 donor and recipient variables from a set of 1003 LTs from a multicenter study including 11 Spanish centres were included. For each D-R pair, common statistics (simple and multiple regression models) and ANN formulae for two non-complementary probability-models of 3-month graft-survival and -loss were calculated: a positive-survival (NN-CCR) and a negative-loss (NN-MS) model. The NN models were obtained by using the Neural Net Evolutionary Programming (NNEP) algorithm. Additionally, receiver-operating-curves (ROC) were performed to validate ANNs against other scores. RESULTS: Optimal results for NN-CCR and NN-MS models were obtained, with the best performance in predicting the probability of graft-survival (90.79%) and -loss (71.42%) for each D-R pair, significantly improving results from multiple regressions. ROC curves for 3-months graft-survival and -loss predictions were significantly more accurate for ANN than for other scores in both NN-CCR (AUROC-ANN=0.80 vs. -MELD=0.50; -D-MELD=0.54; -P-SOFT=0.54; -SOFT=0.55; -BAR=0.67 and -DRI=0.42) and NN-MS (AUROC-ANN=0.82 vs. -MELD=0.41; -D-MELD=0.47; -P-SOFT=0.43; -SOFT=0.57, -BAR=0.61 and -DRI=0.48). CONCLUSIONS: ANNs may be considered a powerful decision-making technology for this dataset, optimizing the principles of justice, efficiency and equity. This may be a useful tool for predicting the 3-month outcome and a potential research area for future D-R matching models.

Improved renal function in liver transplant recipients treated for hepatitis C virus with a sustained virological response and mild chronic kidney disease.

Hepatitis C virus (HCV) is associated with renal complications. We aimed to determine whether a sustained virological response (SVR) was associated with improvements in renal function (RF) in liver transplant (LT) recipients treated for HCV. Changes in RF were compared 1, 3, and 5 years after therapy as a function of the stage of chronic kidney disease (CKD) before treatment (BT). Variables associated with renal dysfunction [RD; 4-variable Modification of Diet in Renal Disease (MDRD-4) value 60 mL/minute] at the last follow-up (LFU) were evaluated for all treated LT patients with a minimum follow-up of at least 1 year since the end of treatment (EOT; n = 175). There were 99 patients with stage 2 CKD BT (MDRD-4 value 60-89 mL/minute/1.73 m(2) ), and an improvement in RF was observed more frequently among SVR patients versus nonresponders (NRs). The median changes in the MDRD-4 values BT to 1, 3, and 5 years after treatment were -0.5, 4.5, and 9.4 mL/minute for the SVR patients and -1, -0.3, and -1.5 mL/minute for the NRs (P = 0.61, P = 0.06, and P = 0.004, respectively). RD was present in 31% of the patients at the LFU at a median of 3.8 years after EOT (range 1-9 years). The follow-up did not differ between SVR patients and NRs. RD was present at the LFU in 19% of SVR patients versus 40% of NRs (P = 0.002). In the multivariate analysis, RD at the LFU was associated with NRs [relative risk (RR) 3.8, 95% confidence interval (CI) = 1.3-11.23, P = 0.01], EOT MDRD-4 values (RR = 1.022, 95% CI = 1.001-1.04, P = 0.04), and female sex (RR = 5.6, 95% CI = 1.84-17.5, P = 0.002). In conclusion, SVR leads to improved RF in HCV-infected LT recipients with stage 2 CKD BT.

Efficacy of the retreatment of hepatitis C virus infections after liver transplantation: role of an aggressive approach.

A sustained virological response (SVR) is achieved by 30% of naive liver transplantation (LT) recipients treated with pegylated interferon (PEG-IFN) and ribavirin (RBV). Almost no data are available about retreatment. The aim of this study was to assess the efficacy, tolerability, and SVR predictors of retreatment. Data were collected from 4 centers on the retreatment of prior nonresponders to standard therapy or PEG-IFN (with or without RBV) and relapsers. Seventy-nine of 301 treatment-experienced LT patients (26%), who had a median age of 59 years (range = 35-77 years) and were mostly male (72%) and infected with genotype 1 (87%), were retreated with PEG-IFN and RBV at a median of 6.9 years after LT. During the first course of therapy, 35% were treated with interferon, 49% received tacrolimus, 52% received steroids, and 49.5% were relapsers. Retreatment was started at a median of 1.9 years (range = 45 days to 8.2 years) after the end of the first course. The proportion of patients with cirrhosis increased from 10% to 37% (P < 0.001). In addition, in retreated patients, full initial RBV doses (P = 0.03), growth factors [erythropoietin (P < 0.001) and granulocyte colony-stimulating factor (P = 0.048)], and transfusions (P = 0.03) were used more frequently, and the treatment duration was longer (P = 0.03). An end-of-treatment response was achieved in 61%, whereas SVR, which was associated with improved survival, occurred in 28 (35%). The variables predicting SVR were age (P = 0.04), disease severity [fibrosis (50% with F0-F2 versus 26% with F3-4), P = 0.03; bilirubin, P = 0.006; platelet count, P = 0.03], adherence, and viral kinetics. None of the patients without an early virological response achieved SVR. There was a trend of prior relapsers achieving higher SVR rates than prior nonresponders. In conclusion, SVR, which was achieved by approximately one-third of the retreated patients, can be predicted with the same variables used for naive LT recipients (age, disease severity, adherence, and viral kinetics) and is associated with enhanced survival.

Long-term outcome of 'long-term liver transplant survivors'.

There are few studies focusing on long-term complications in liver transplant (LT) recipients. The aim of this study was to define the outcome of LT recipients having survived at least 10 years from LT. Of 323 adult LT done between 1991 and 1997, the 167(52%) alive >10 years post-LT (baseline time) formed the study population. Long-term outcome measures included the following: immunosuppression, metabolic complications [obesity, arterial hypertension (AH), diabetes, dislypidemia], cardiovascular events (CVE), chronic renal dysfunction-CRD, and de novo tumors. Median age at LT was 50 years. Most common indication was postnecrotic cirrhosis (89%), mostly because of HCV (46%). At study-baseline (10 years post-LT), 29% were obese and AH, diabetes, dislypidemia, and CRD were present in 75%, 30%, 42%, and 36%, respectively. In most cases, these complications were already present 1 year post-LT; less than one quarter developed them onward. The 6 year cumulative survival since baseline reached 84% (n = 24 deaths), with most deaths related to recurrent graft diseases (mostly HCV) followed by de novo tumors or CVE. 1, 3, 5 and 10 years cumulative rates of CVE and de novo tumors since baseline were 2%, 5%, 10% and 17%, and 1%, 3%, 6% and 13%, respectively. Chronic renal impairment was independently associated with survival and development of CVE since baseline. The medium-term survival of 'long-term survivors', i.e. patients alive 10 years after LT is good, but metabolic complications and CRD are common and continue to increase afterwards. Cardiovascular events and de novo tumors increase gradually over time and represent a major cause of late mortality.

Haemophagocytic syndrome in a liver transplant patient during treatment with Telaprevir.

Haemophagocytic syndrome (HS) is a rare disease that is often fatal despite treatment. HS is characterized by fevers, lymphadenopathy, hepatosplenomegaly, cytopenias and hyperferritinaemia due to deregulated activation and proliferation of macrophages, leading to uncontrolled phagocytosis of platelets, erythrocytes, lymphocytes, and their hematopoietic precursors throughout the reticuloendothelial system. Mycobacterium tuberculosis-associated HS is a rare and underdiagnosed association with only 39 cases reported. We describe a case of HS associated with disseminated Mycobacterium tuberculosis in the setting of post-liver transplantation anti-hepatitis C therapy with pegylated interferon (pegIFN), ribavirin (RBV) and telaprevir (TVR). Despite the delay in the etiologic diagnosis, the patient was treated properly with corticosteroids, cyclosporine and tuberculostatic agents. It is unknown whether telaprevir, a drug that only recently has been started off-label in liver transplant recipients, may have contributed to the development of the HS. Unfortunately, as in many reported cases of HS, the outcome was unfavourable resulting in the death of the patient.

Comparison of results of combined liver-kidney transplantation vs. isolated liver transplantation.

INTRODUCTION: Combined liver-kidney transplantation (LKT) is the best therapeutic option for patients with end-stage liver and kidney disease. OBJECTIVES: To analyze baseline characteristics and clinical outcome of LKT compared to isolated liver transplantation (LT). MATERIAL AND METHODS: The study included 16 LKT performed between 1998 and 2006 and 32 LT matched by age, sex, date and indication for transplantation. Demographic, pretransplant, post-transplant and survival variables were analyzed. RESULTS: As planned by the study design, mean age, distribution by sex and indication for LT were similar between groups. The most common indication for LT was HCV- and/or alcohol-induced cirrhosis. The most common indication for KT was renal failure, in most cases secondary to glomerulonephritis. Twelve patients (69%) were on dialysis before LKT. Hepatocellular carcinoma and diabetes mellitus pre-transplantation were similar between groups. However pretransplant arterial hypertension (AHT) was higher in LKT than LT (50% vs. 19%; p = 0.02). In the post-transplant: reoperation due to bleeding, bacterial infections, liver rejection, AHT and median creatinine levels at 1st and 3rd years were similar in LKT and LT. In contrast, early post-transplant dialysis was higher in LKT than LT (31% vs. 3%; p = 0.01). Survival rates at 1st, 3rd, 5th and 7th years were similar in both groups (87.5%, 74%, 74% and 66% vs. 81%, 75%, 75% and 75% in LT and LKT, respectively). CONCLUSIONS: LKT is an effective therapeutic option in patients with end-stage liver and kidney disease. Most early and late complications and long-term survival are similar to those observed with LT.

[Liver transplantation: personalized immunosuppression in patients with hepatitis C virus infection and hepatocellular carcinoma]. / Trasplante hepático: inmunosupresión personalizada en pacientes con hepatitis C y carcinoma hepatocelular.

Transplantation has become the treatment of choice in end-stage liver disease, with 5-year survival rates of around 68-74% in European and North-American registries (www.unos.org, www.eltr.org, www.ont.es). These results are largely due to the development of powerful immunosuppressive agents, mainly calcineurin inhibitors. However, these immunosuppressive drugs are not free of adverse effects, especially nephrotoxicity. Moreover, two of the most frequent indications for transplantation, cirrhosis due to hepatitis C virus and hepatocellular carcinoma, can recur in the transplanted graft. Whether specific immunosuppression could be less harmful in these conditions is the subject of debate. With the greater use of suboptimal donors and of expanded criteria for liver transplantation in patients with hepatocellular carcinoma, aggressive recurrences can be expected to increase. The present review attempts to elucidate whether there is an immunosuppression strategy that could minimize the risk of aggressive tumoral recurrence or recurrence of hepatitis C.

Comparison of two non-contemporaneous HCV-liver transplant cohorts: strategies to improve the efficacy of antiviral therapy.

BACKGROUND & AIMS: In a previous study, advanced fibrosis was associated with worsening efficacy of antiviral therapy in HCV-transplant patients. We aimed at assessing whether changes in treatment policy, that is starting therapy at lesser stages of fibrosis, have resulted in improved efficacy. METHODS: Efficacy (rapid, early, end-of-treatment, and sustained viral response (SVR)) and tolerability (peginterferon (pIFN)/ribavirin (RBV) doses, premature discontinuation, dose reductions, anemia, growth factors, transfusions) were compared between two non-contemporaneous cohorts of post-LT naïve patients treated with pIFN-RBV: Group 1 (n=44), a historical cohort of patients treated during the period 2005-2007 and Group 2 (n=70), patients treated more recently (2007-2010), where treatment was started once there was evidence of fibrosis. RESULTS: SVR increased from 25% to 54% (p=0.002) due to a reduction in relapse rate. Comparing both cohorts, a decrease in the number of cirrhotic patients together with an increase in platelet count was observed in recent years. Additional non-intentional changes included: (i) an increase of patients treated under cyclosporine immunosuppression, (ii) treatment-related factors with an increase in patients treated with initial full pIFN and RBV doses, who developed anemia and hence required dose modifications and erythropoietin. Baseline factors associated with SVR were younger donor age, lack of cirrhosis or severe necroinflammation and the use of RBV at full doses at initiation while on-treatment variables were adherence and viral kinetics. CONCLUSIONS: Treatment in the absence of cirrhosis is associated with higher SVR warranting strict disease progression monitoring. A more aggressive approach, particularly regarding RBV dosage, is also associated with improved efficacy. Further studies are required to assess whether switching to cyclosporine will result in improved SVR.

Anemia is not predictive of sustained virological response in liver transplant recipients with hepatitis C virus who are treated with pegylated interferon and ribavirin.

In the immunocompetent setting, antiviral therapy-related anemia has recently been shown to be associated with a sustained virological response (SVR). Our goal was to assess whether this is also true for liver transplantation (LT). We included 160 LT patients with recurrent hepatitis C virus (HCV) who were treated with pegylated interferon and ribavirin (RBV) between 2002 and 2010; 76% of the patients were men, the median age of the patients was 56 years (range = 33-75 years), 63% had advanced fibrosis, and 86% were infected with HCV genotype 1a or 1b. The baseline immunosuppression was tacrolimus in 56% of the patients. Mycophenolate mofetil (MMF) was used in 15%. Anemia was defined as a hemoglobin (Hb) level < 10 g/dL. Significant anemia was present when the Hb decline was >5 g/dL. Anemia and significant anemia developed in 67% and 41% of the patients, respectively. Erythropoietin was used in 60%. Factors independently associated with significant anemia included low estimated creatinine clearance [relative risk (RR) = 0.951, 95% confidence interval (CI) = 0.925-0.978, P = 0.0001], a longer time from LT to therapy (RR = 1.001, 95% CI = 1.000-1.001, P = 0.002), high baseline viremia (RR = 3.2, 95% CI = 1.3-8.1, P = 0.01), cyclosporine A (CSA)-based immunosuppression (RR: 3.472, 95% CI: 1.386-8.695; P = 0.008), and the use of MMF (RR: 5.346, 95% CI: 1.398-20.447; P = 0.014). An SVR occurred in 43% of the patients; the factors associated with an SVR included baseline variables (younger recipient age, younger donor age, infections with non-1 HCV genotypes, body mass index, and mild fibrosis) and on-treatment factors related to adherence or viral kinetics. Anemia resulted in RBV dose reductions but was not associated with the virological response at any time. In conclusion, anemia is a very frequent complication in LT patients during antiviral therapy and is associated with increased RBV dose reduction but not with an SVR. Predictors of anemia include MMF or CSA immunosuppression, high viremia, and renal insufficiency.

The Impact of Direct-acting Antivirals on Overall Mortality and Tumoral Recurrence in Patients With Hepatocellular Carcinoma Listed for Liver Transplantation: An International Multicenter Study.

BACKGROUND: There is a lack of data on the use of direct-acting antivirals (DAA) on the risk of death and tumoral recurrence in patients with hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) listed for liver transplantation (LT). We aimed to assess the impact of antiviral treatment on mortality and HCC recurrence patients with HCC-HCV. METHODS: This was a retrospective multicenter study of patients with HCC-HCV listed for LT from 2005 to 2015. Patients were divided according to the antiviral treatment received after HCC diagnosis: DAA, interferon (IFN), or no antiviral. Intention-to-treat overall survival and HCC recurrence incidence were compared by the Kaplan-Meier method. Multivariable regression analysis was performed to identify risk factors for outcomes. RESULTS: A total of 1012 HCV-HCC patients were listed for LT during the study period. The median follow-up was 4.0 (interquartile range = 2.3-6.7) years. Mortality was 5.6 (95% confidence interval [CI], 4.3-7.2), 13.1 (95% CI, 11.0-15.7), and 6.2 (95% CI, 5.4-7.2) deaths per 100 person-year among patients treated with DAA, IFN, and antiviral naïve, respectively (P < 0.001). Of the 875 HCV-HCC transplant recipients, the 5-year recurrence-free survival was 93.4%, 84.8%, 73.9% for the pre-LT DAA, pre-LT IFN, and antiviral naïve groups, respectively (P < 0.001). After multivariable regression, the use of pre-LT DAA was not associated to risk of recurrence (hazard ratio = 0.44 [95% CI, 0.19-1.00]). Post-LT DAA was not related to increased risk of recurrence (hazard ratio = 0.62 [95% CI, 0.33-1.16]). CONCLUSIONS: In this multicenter intent-to-treat study, DAA therapy was not found to be a risk factor for mortality or HCC recurrence after adjusting for potential confounders.

Deep-sequencing reveals broad subtype-specific HCV resistance mutations associated with treatment failure.

A percentage of hepatitis C virus (HCV)-infected patients fail direct acting antiviral (DAA)-based treatment regimens, often because of drug resistance-associated substitutions (RAS). The aim of this study was to characterize the resistance profile of a large cohort of patients failing DAA-based treatments, and investigate the relationship between HCV subtype and failure, as an aid to optimizing management of these patients. A new, standardized HCV-RAS testing protocol based on deep sequencing was designed and applied to 220 previously subtyped samples from patients failing DAA treatment, collected in 39 Spanish hospitals. The majority had received DAA-based interferon (IFN) α-free regimens; 79% had failed sofosbuvir-containing therapy. Genomic regions encoding the nonstructural protein (NS) 3, NS5A, and NS5B (DAA target regions) were analyzed using subtype-specific primers. Viral subtype distribution was as follows: genotype (G) 1, 62.7%; G3a, 21.4%; G4d, 12.3%; G2, 1.8%; and mixed infections 1.8%. Overall, 88.6% of patients carried at least 1 RAS, and 19% carried RAS at frequencies below 20% in the mutant spectrum. There were no differences in RAS selection between treatments with and without ribavirin. Regardless of the treatment received, each HCV subtype showed specific types of RAS. Of note, no RAS were detected in the target proteins of 18.6% of patients failing treatment, and 30.4% of patients had RAS in proteins that were not targets of the inhibitors they received. HCV patients failing DAA therapy showed a high diversity of RAS. Ribavirin use did not influence the type or number of RAS at failure. The subtype-specific pattern of RAS emergence underscores the importance of accurate HCV subtyping. The frequency of "extra-target" RAS suggests the need for RAS screening in all three DAA target regions.