Reply to: Renal impairment and anemia during triple therapy

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 yea…

Genetic similarity of hepatitis C virus and fibrosis progression in chronic and recurrent infection after liver transplantation

SUMMARY. The effect of hepatitis C virus (HCV) genetic heterogeneity on clinical features of post-transplantation hepatitis C is controversial. Different regions of the HCV genome have been associated with apoptosis, fibrosis, and other pathways leading to liver damage in chronic HCV infection. Besides, differences in immunodominant regions, such as NS3, may influence HCV-specific immune responses and disease outcome. In the liver transplant setting, a recent study has reported a positive association between HCV-1b Core region genetic relatedness 5-year post-transplantation and histological severity of recurrent hepatitis C. We have compared nucleotide sequences of HCV Core, NS3 and NS5b re…

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

Abstract 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 (…

Boceprevir in the treatment of chronic hepatitis C virus infection

1Hepatology-Liver Transplantation Unit, Digestive Medicine Service, Hospital Universitari La Fe, and National Network Center for Hepatology and Gastroenterology Research, instituto de Salud Carlos iii, CiBeReHD Spain; 2CSiSP, Center for Public Health Research, Public Health Department, Generalitat Valenciana and Microbioloy Department/ institut Cavanilles, University of Valencia, Valencia, Spain; 3National Network Center for Biomedical Research in epidemiology and Public Health, instituto de Salud Carlos iii, CiBeReSP Spain

Characteristics, Trends, and Outcomes of Liver Transplantation for Primary Sclerosing Cholangitis in Female Versus Male Patients

Background. The influence of sex on primary sclerosing cholangitis (PSC), pre- and postliver transplantation (LT) is unclear. Aims are to assess whether there have been changes in incidence, profile, and outcome in LT-PSC patients in Europe with specific emphasis on sex. Methods. Analysis of the European Liver Transplant Registry database (PSC patients registered before 2018), including baseline demographics, donor, biochemical, and clinical data at LT, immunosuppression, and outcome. Results. European Liver Transplant Registry analysis (n = 6463, 32% female individuals) demonstrated an increasing number by cohort (1980-1989, n = 159; 1990-1999, n = 1282; 2000-2009, n = 2316; 2010-2017, n =…

Rabbit anti-thymocyte globulin in liver transplantation: All that glitters is not gold, but 1000 patients are so many to dazzle

Management of anemia induced by triple therapy in patients with chronic hepatitis C: Challenges, opportunities and recommendations

SummaryThe addition of protease inhibitors, boceprevir or telaprevir, to peginterferon+ribavirin (PegIFN/RBV) increases the frequency as well as the severity, and hence, clinical relevance of anemia, which has now become one of the major complications associated with triple therapy. Most significant factors associated with anemia in patients receiving triple therapy include older age, lower body mass index (BMI), advanced fibrosis, and lower baseline hemoglobin. The variability in inosine triphosphate pyrophosphatase (ITPA) gene, which encodes a protein that hydrolyses inosine triphosphate (ITP), has been identified as an essential genetic factor for anemia both in dual and triple therapy. …

Long-term outcome after living donor liver transplantation compared to donation after brain death in autoimmune liver diseases: Experience from the European Liver Transplant Registry.

Knowledge of living donor liver transplantation (LDLT) for autoimmune liver diseases (AILDs) is scarce. This study analyzed survival in LDLT recipients registered in the European Liver Transplant Registry with autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis (PSC) and the non-autoimmune disorder alcohol-related cirrhosis. In total, 29 902 individuals enrolled between 1998 and 2017 were analyzed, including 1003 with LDLT. Survival from >90 days after LDLT for AILDs in adults was 85.5%, 74.2%, and 58.0% after 5, 10, and 15 years. Adjusted for recipient age, sex, and liver transplantation era, adult PSC patients receiving LDLT showed increased mortality compare…

The ILTS Consensus Conference on NAFLD/NASH and Liver Transplantation: Setting the Stage

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 (p…

Combined resistance and endurance training at a moderate-to-high intensity improves physical condition and quality of life in liver transplant patients.

Background: Although currently, moderate and high intensity concurrent physical exercise is prescribed in populations with special needs due to its greater effect on physical condition and health-related quality of life (HRQOL), there are no data in the liver transplantation (LT) setting. Aim: To evaluate changes in maximal strength, aerobic capacity, body composition, liver function, and HRQOL in LT patients after a moderate to high intensity combined resistance-endurance training. Material and methods: 6 months after LT, 54 patients were randomized into two groups: intervention group (IG) and control group (CG). 50 patients completed the study with repeat testing at 6 and 12 months after …

Posttransplant Management of Recipients Undergoing Liver Transplantation for Hepatocellular Carcinoma. Working Group Report From the ILTS Transplant Oncology Consensus Conference

Although liver transplantation (LT) is the best treatment for patients with localized hepatocellular carcinoma (HCC), recurrence occurs in 6%-18% of patients. Several factors, particularly morphological criteria combined with dynamic parameters, known before LT modify this risk and combined in prediction models may be used to stratify patients at need of variable surveillance strategies. Additional variables though likely explain differences in recurrence rates in patients with the same pre-LT HCC status. One of these variables is possibly immunosuppression (IS). Once recurrence takes place, management is highly heterogenous. Within the International Liver Transplantation Society Consensus …

Worse recent efficacy of antiviral therapy in liver transplant recipients with recurrent hepatitis C: Impact of donor age and baseline cirrhosis

We hypothesized that antiviral efficacy [sustained virologic response (SVR)] has improved in recent years in the transplant setting. Our aim was to assess whether the efficacy of pegylated interferon (PegIFN)–ribavirin (Rbv) has improved over time. One hundred seven liver transplant patients [74% men, 55.5 years old (range: 37.5–69.5), 86% genotype 1a or 1b] were treated with PegIFN-Rbv for 355 (16–623) days at 20.1 (1.7–132.6) months after transplantation. Tacrolimus was used in 61%. Sixty-seven percent had baseline F3–F4 (cirrhosis: 20.5%). Donor age was 49 (12–78) years. SVR was achieved in 39 (36.5%) patients, with worse results achieved in recent years (2001–2003: n = 27, 46.5%; 2004: …

International Liver Transplantation Consensus Statement on End-stage Liver Disease Due to Nonalcoholic Steatohepatitis and Liver Transplantation.

Nonalcoholic steatohepatitis (NASH)-related cirrhosis has become one of the most common indications for liver transplantation (LT), particularly in candidates older than 65 years. Typically, NASH candidates have concurrent obesity, metabolic, and cardiovascular risks, which directly impact patient evaluation and selection, waitlist morbidity and mortality, and eventually posttransplant outcomes. The purpose of these guidelines is to highlight specific features commonly observed in NASH candidates and strategies to optimize pretransplant evaluation and waitlist survival. More specifically, the working group addressed the following clinically relevant questions providing recommendations based…

New developments in the management of hepatitis C virus infection: focus on boceprevir

Chronic hepatitis C virus infection is an important public health problem, and the standard treatment (combination of pegylated interferon-α and ribavirin) has an effectiveness rate of only 40%-50%. Novel virus-specific drugs have recently been designed, and multiple compounds are under development. The approval for the clinical use of direct-acting antivirals in 2011 (boceprevir [BOC] and telaprevir, viral NS3 protease inhibitors) has increased recovery rates by up to 70%. Therefore, a highly effective treatment has been envisioned for the first time. This paper focuses on BOC and the implementation of new BOC-based treatment regimes.

Changing delta hepatitis patient profile: A single center experience in Valencia region, Spain

Background Delta hepatitis is a rare infection with an aggressive disease course. For almost three decades, however, there have been no epidemiological studies in our traditionally endemic area. Aim To investigate the prevalence of delta hepatitis in a sample of patients with chronic hepatitis B virus (HBV) infection followed at a Hepatology Unit in Valencia, Spain. Methods Retrospective evaluation of anti-hepatitis D virus-immunoglobulin G seroprevalence among patients with chronic HBV infection (n = 605) followed at a reference Hepatology Unit in Spain. Results The prevalence of anti-hepatitis D virus-immunoglobulin G among HBV-infected patients was 11.5%: Male (63%) and median age of 52 …

Tratamiento de la hepatitis C en grupos de pacientes especiales

Resumen El plan de tratamiento de la hepatitis cronica C en las poblaciones especiales varia en funcion de la comorbilidad y las evidencias de tratamiento existentes. En los pacientes con coinfeccion por virus de la hepatitis C y virus de la inmunodeficiencia humana, los resultados del tratamiento con biterapia (interferon pegilado mas ribavirina) son pobres. En los pacientes infectados por virus de genotipo 1, la terapia triple (biterapia mas boceprevir o telaprevir) ha duplicado la tasa de respuesta, pero los inhibidores de la proteasa pueden interactuar con algunos farmacos antirretrovirales y provocan mas efectos adversos. Estos inconvenientes no los presentan los nuevos antivirales dir…

Progression of liver fibrosis in post-transplant hepatitis C: mechanisms, assessment and treatment.

SummaryLiver fibrosis results from an excessive wound healing response in most chronic liver diseases, such as hepatitis C. Despite great advances in antiviral therapy in recent years, progressive liver fibrosis remains a major problem for patients with recurrent hepatitis C after liver transplantation. Liver biopsy remains a central tool in the management of HCV-positive liver transplant recipients, but reliable non-invasive methods for the assessment of liver fibrosis, such as ultrasound elastography, are increasingly being incorporated in the management of post-transplant patients, helping predict prognosis, guide treatment decisions, and stratify patients for emerging antifibrotic thera…

The changing face of hepatology.

Wilson’s Disease: Facing the Challenge of Diagnosing a Rare Disease

Wilson disease (WD) is a rare disorder caused by mutations in ATP7B, which leads to the defective biliary excretion of copper. The subsequent gradual accumulation of copper in different organs produces an extremely variable clinical picture, which comprises hepatic, neurological psychiatric, ophthalmological, and other disturbances. WD has a specific treatment, so that early diagnosis is crucial to avoid disease progression and its devastating consequences. The clinical diagnosis is based on the Leipzig score, which considers clinical, histological, biochemical, and genetic data. However, even patients with an initial WD diagnosis based on a high Leipzig score may harbor other conditions th…

Obeticholic Acid and Fibrates in Primary Biliary Cholangitis: Comparative Effects in a Multicentric Observational Study

INTRODUCTION: Obeticholic acid (OCA) and fibrates therapy results in biochemical improvement in placebo-controlled trials in patients with primary biliary cholangitis and insufficient response to ursodeoxycholic acid. There is scarce information outside of clinical trials. Therefore, we have assessed the effectiveness and adverse events of these treatments. METHODS: Data from patients included in the ColHai registry treated with OCA, fibrates, or both were recorded during a year, as well as adverse events and treatment discontinuation. RESULTS: Eighty-six patients were treated with OCA, 250 with fibrates (81% bezafibrate; 19% fenofibrate), and 15 with OCA plus fibrates. OCA group had baseli…

Milan-out Criteria and Worse Intention-to-Treat Outcome Postliver Transplantation

Background. Milan criteria are widely used for liver transplantation selection in hepatocellular carcinoma but have been recognized to be too restrictive. Milan-out criteria are increasingly being adopted. Our aim was to analyze if liver transplantation waitlisted Milan-out hepatocellular carcinoma patients have different outcome than Milan patients. Methods. Retrospective study including all consecutive patients with hepatocellular carcinoma admitted in the waiting list for liver transplantation between January 2012 and January 2015. We included 177 patients, 146 of which eventually transplanted. Downstaging was achieved in the Milan-out cases (n = 29) before waitlisting. Results. From dia…

Peritransplant Antiviral Treatment of Human Immunodeficiency Virus/Hepatitis C Virus–Coinfected Patients

Should organs from hepatitis C-positive donors be used in hepatitis C-negative recipients for liver transplantation?

Given the scarcity of donated organs and the frequency of death on the waiting list, strategies that could improve the available supply of high-quality liver grafts are much needed. Direct-acting antiviral agent (DAA) regimens have proved to be highly effective to treat hepatitis C virus (HCV), even in the setting of posttransplantation. The question arises as to whether transplant communities should consider the utilization of HCV-positive donors into HCV-negative recipients. This review summarizes risk of transmission, treatment options with success rate, and ethical considerations for usage of HCV-positive donors. Liver Transplantation 24 831-840 2018 AASLD.

Frailty and Sarcopenia in Acute‐on‐Chronic Liver Failure

In patients with cirrhosis, sarcopenia is a critical reduction in skeletal muscle mass and frailty represents a status of global physical dysfunction caused by under nutrition, muscle wasting, and functional impairment. Both are prevalent conditions in liver transplant candidates and have shown to be independent predictors of adverse outcome. Evidence supports their incorporation into clinical practice both as a prognostic factor guiding clinical decision making and as a tool to identify candidates for physical and nutritional interventions. The wide heterogeneity of instruments used for sarcopenia and frailty measurement, the absence of a single suitable instrument for sarcopenia and frail…

Fat, cancer, the gut-liver axis and rare liver diseases

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-baselin…

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 h…

Controlling Diabetes After Liver Transplantation: Room for Improvement.

BACKGROUND Diabetes mellitus is a chronic illness with great impact on long-term outcome after liver transplantation (LT). Despite this, the current level of glycemic control and quality of screening strategies for diabetes-associated conditions that are being provided to liver transplant recipients with diabetes have not yet been assessed. METHODS We performed a cross-sectional, multicenter study that included 344 liver transplant recipients and examined the level of glycemic control and its associated factors, as well as the quality of screening strategies for diabetes-associated conditions. RESULTS Seventy-five patients (21.8%) suffered from diabetes before transplantation, and 82 (23.8%…

Alcoholic and Nonalcoholic Liver Disease: Diagnostic Assessment and Therapeutic Perspectives

Long-term Challenges After Solid Organ Transplantation

Presentation and Outcomes of Pregnancy in Patients With Autoimmune Hepatitis

Autoimmune hepatitis (AIH) frequently affects women of childbearing age in whom the desire to have a family raises the question regarding the potential risks for the fetus and the mother. The information on AIH in pregnant patients is scarce.1 The aims of this study were (1) to identify the risk factors associated with flares in pregnant patients diagnosed with AIH, (2) to determine the course of AIH in patients with pregnancy-related flares, and (3) to describe the outcome of AIH diagnosed in the postpartum period.

A population-based screening for hepatitis C antibodies and active infection using a point-of-care test in a low prevalence area

Background Data on the true prevalence of hepatitis C virus (HCV) infection in the general population is essential. We evaluated a program implementing free universal HCV screening using a non-invasive point-of-care test (POCT) (OraQuick-HCV rapid test) in oral fluid in an urban area in Valencia, South-Eastern Spain. Methods A cross-sectional study was performed during 2015–2017. Free HCV screening was offered by regular mail to 11,500 individuals aged 18 and over, randomly selected from all census residents in the Health Department. All responding participants filled in a questionnaire about HCV infection risk factors and were tested in their tertiary Hospital. In those with a positive POC…

High efficacy and safety of triple therapy in HCV genotype 1 and moderate fibrosis: a multicenter study of clinical practice in Spain.

Background and rational. Telaprevir-based therapy (TBT) has been extensively evaluated in clinical trials. So we designed a study to compare the efficacy and safety of TBT between patients with moderate fibrosis and those suffering from advanced fibrosis in clinical practice. A multicenter observational and ambispective study was conducted. It included 582 patients with chronic hepatitis C genotype 1, 214 with fibrosis F2, and 368 with F3/F4 (F3: 148; F4: 220). Results. The mean patient age was 55 years, 67% male. Type of prior response was 22% naive, 57% relapsers, and 21% partial/null responders, 69% had high viral load (> 800,000 IU/mL). HCV genotypes were 1a (19%), 1b (69%), and 1 (12%)…

Eliminación de la hepatitis C. Documento de posicionamiento de la Asociación Española para el Estudio del Hígado (AEEH)

La Asociación Española para el Estudio del Hígado (AEEH) está convencida de que la eliminación de la hepatitis C en España es posible siempre y cuando seamos capaces de emplear los recursos y las herramientas necesarias para la misma. Este documento refleja la posición de la AEEH respecto a la eliminación del virus de la hepatitis C (VHC), estableciendo una amplia serie de recomendaciones que se pueden agrupar en cinco categorías: 1) cribado del VHC en función de la edad, de la existencia de factores de riesgo clásicos de adquisición de la infección, búsqueda activa de pacientes diagnosticados con anterioridad y desarrollo de estrategias de microeliminación en poblaciones vulnerables; 2) si…

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.

© 2019 Elsevier Ltd. All rights reserved.

Overcoming drug resistance in HSV, CMV, HBV and HCV infection.

Although vaccination has provided as a very efficient preventive tool, antiviral therapy is still needed to control viral infections not avoidable by prophylaxis with vaccines; those caused by viruses for which a vaccine is available, but vaccination is not universally implemented or does not result in complete, long-term protection; and in immunocompromised individuals with reduced immune control of viral replication. After more than 50 years of the first licensing for an antiherpetic drug, novel compounds for herpes-simplex viruses and human cytomegalovirus will open new strategies for better control and management of these two recurrent viral infections. Besides, the development and use…

ELITA consensus statements on the use of DAAs in liver transplant candidates and recipients

International audience; The advent of safe and highly effective direct-acting antiviral agents (DAAs) has had huge implications for the hepatitis C virus (HCV) transplant field, and changed our management of both patients on the waiting list and those with HCV graft re-infection after liver transplantation (LT). When treating HCV infection before LT, HCV re-infection of the graft can be prevented in nearly all patients. In addition, some candidates show a remarkable clinical improvement and may be delisted. Alternatively, HCV infection can be treated post-LT either soon after the transplant, taking advantage of the removal of the infected native liver, or at the time of disease recurrence, …

Primary biliary cholangitis in Spain. Results of a Delphi study of epidemiology, diagnosis, follow-up and treatment.

RESUMEN Introducción: la colangitis biliar primaria (CBP) es una enfermedad rara, de la que existe información limitada en España sobre su epidemiología y manejo en la práctica clínica habitual. Objetivos: conocer la epidemiología, flujo del paciente, diagnóstico, seguimiento y tratamiento de la CBP en España. Métodos: revisión de la literatura y estudio siguiendo la metodología Delphi con participación de 28 especialistas en dos rondas de consulta y un taller de validación de resultados presencial. Resultados: existen, aproximadamente, 9.400 pacientes con CBP en España, con una incidencia anual de entre 0,51 y 3,86 casos/100.000 habitantes, aunque el margen de error se presupone alto dada …

Longterm Survival After Liver Transplantation for Autoimmune Hepatitis : Results From the European Liver Transplant Registry

The aim of this study was to analyze longterm patient and graft survival after liver transplantation for autoimmune hepatitis (AIH-LT) from the prospective multicenter European Liver Transplant Registry. Patient and liver graft survival between 1998 and 2017 were analyzed. Patients after AIH-LT (n = 2515) were compared with patients receiving LT for primary biliary cholangitis (PBC-LT; n = 3733), primary sclerosing cholangitis (PSC-LT; n = 5155), and alcohol-related cirrhosis (AC-LT; n = 19,567). After AIH-LT, patient survival was 79.4%, 70.8%, and 60.3% and graft survival was 73.2%, 63.4%, and 50.9% after 5, 10, and 15 years of follow-up. Overall patient survival was similar to patients af…

Genetic variability of hepatitis C virus non-structural protein 3 and virus-specific CD8+ response in patients with chronic hepatitis C.

Hepatitis C virus (HCV) variation in specific T-cell epitopes may represent a mechanism of viral persistence in chronic infection. We examined the HCV non-structural protein 3 (NS3), including the immunologically relevant epitopes HCV NS3-2 KLVALGINAV (human leukocyte antigen [HLA]-A2-restricted) and HCV NS3-1391 LIFCHSKKK (HLA-A3-restricted), in 22 HLA-A2+ patients with chronic infection. Significant amino acid variation was found in HCV NS3-2 epitope sequences when compared to the HCV-1 prototype virus. Six of the nine different HCV NS3-2 peptide variants were identified in patients with HCV NS3-2-specific CD8+ cells, detected with an HLA-A2 tetramer made with the HCV-1 prototype peptide.…

Expanded criteria for liver transplantation in patients with cirrhosis and hepatocellular carcinoma

Orthotopic liver transplantation (OLT) selection for patients with hepatocellular carcinoma (HCC) is a matter of debate. The Milan criteria (MC) have been largely adopted by the international community. The main aim of this study was to evaluate the survival rates and recurrence probabilities of a new proposal for criteria (up to 3 tumors, each no larger than 5 cm, and a cumulative tumor burden </= 10 cm). Patients with cirrhosis and HCC included on the waiting list (WL) from 1991 to 2006 were retrospectively analyzed. Outcomes in patients who had tumors within and beyond the MC were compared. The survival analysis was done (1) with the intention-to-treat principle and (2) among transplante…

Equally Interchangeable? How Sex and Gender Affect Transplantation

Organ transplantation as an option to overcome end-stage diseases is common in countries with advanced healthcare systems and is increasingly provided in emerging and developing countries. A review of the literature points to sex- and gender-based inequity in the field with differences reported at each step of the transplant process, including access to a transplantation waiting list, access to transplantation once waitlisted, as well as outcome after transplantation. In this review, we summarize the data regarding sex- and gender-based disparity in adult and pediatric kidney, liver, lung, heart, and hematopoietic stem cell transplantation and argue that there are not only biological but al…

Iberogast-Induced Severe Hepatotoxicity Leading to Liver Transplantation

Cardiovascular risk and liver transplantation in HIV patients. Are HIV infected liver transplant recipients at higher risk?

Abstract Background Cardiovascular (CV) diseases are currently one of the main causes of morbimortality in HIV-infected patients. Similarly, LT recipients have increased prevalence of CV risk factors. Our aim was to assess whether HIV infected LT patients have an increased prevalence of CV risk factors and events (CVE) as compared to non-HIV LT patients. Methods We included LT recipients from 2004 to 2016 from a single center. HIV-infected patients were matched to 2 non-HIV controls each by sex, liver disease etiology, and date of LT. Results A total of 138 LT recipients were included (46 HIV-infected and 92 HIV-uninfected). HCV was the main etiology (85% of HIV-infected and 83% of HIV-unin…

The road map toward an hepatitis C virus-free transplant population

Antiviral therapy to eradicate hepatitis C virus (HCV) infection improves outcomes in patients undergoing liver transplantation (LT) for advanced chronic HCV with or without hepatocellular carcinoma. Traditionally, antiviral therapy focused on the use of interferon (IFN)-based regimens, with antiviral treatment initiated in the posttransplant period once recurrent HCV disease with fibrosis in the allograft was identified. The use of IFN-based therapy was limited in pretransplant patients with advanced liver disease. Earlier intervention, either before transplantation or early after LT, is now feasible with the advent of second-generation direct-acting antiviral agents (DAAs) with superior t…

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…

Fat and liver transplantation: clinical implications

Nonalcoholic steatohepatitis (NASH), with or without hepatocellular carcinoma, is a growing indication for liver transplantation (LT) worldwide, particularly in the Western world. Patients with NASH typically combine features of metabolic syndrome with cardiovascular comorbidities, which challenge pre-LT evaluation, surgical approaches, post-LT management, and outcomes. Post-LT survival in NASH patients is excellent, similar to that achieved with other indications, particularly in the absence of cardiovascular comorbidities. Although disease recurrence on the liver allograft is common, progression to advanced disease is uncommon, at least in the short term. Whether this holds true with long…

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.

Итоговое резюме KDIGO 2018 по гепатиту С для рекомендаций по ХБП: достижения в оценке и менеджменте

Infection with the hepatitis C virus (HCV) has adverse liver, kidney, and cardiovascular consequences in patients with chronic kidney disease (CKD), including those on dialysis therapy and in those with a kidney transplant. Since the publication of the original Kidney Disease: Improving Global Outcomes (KDIGO) HCV Guideline in 2008, major advances in HCV management, particularly with the advent of direct-acting antiviral therapies, have now made the cure of HCV possible in CKD patients. In addition, diagnostic techniques have evolved to enable the noninvasive diagnosis of liver fibrosis. Therefore, the Work Group undertook a comprehensive review and update of the KDIGO HCV in CKD Guideline.…

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…

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. Wi…

Genetics of Wilson disease and Wilson-like phenotype in a clinical series from eastern Spain.

Wilson's disease (WD) is an autosomal recessive disorder caused by ATP7B mutations. Subjects with only one mutation may show clinical signs and individuals with biallelic changes may remain asymptomatic. We aimed to achieve a conclusive genetic diagnosis for 34 patients clinically diagnosed of WD. Genetic analysis comprised from analysis of exons to WES (whole exome sequencing), including promoter, introns, UTRs (untranslated regions), besides of study of large deletions/duplications by MLPA (multiplex ligation-dependent probe amplification). Biallelic ATP7B mutations were identified in 30 patients, so that four patients were analyzed using WES. Two affected siblings resulted to be compound…

Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial

Summary Background Hepatitis C virus (HCV) genotype 4 accounts for about 13% of global HCV infections. Because interferon-containing treatments for genotype 4 infection have low efficacy and poor tolerability, an unmet need exists for effective all-oral regimens. We examined the efficacy and safety of an all-oral interferon-free regimen of ombitasvir, an NS5A inhibitor, and paritaprevir (ABT-450), an NS3/4A protease inhibitor dosed with ritonavir (ombitasvir plus paritaprevir plus ritonavir), given with or without ribavirin. Methods In this multicentre ongoing phase 2b, randomised, open-label combination trial (PEARL-I), patients were recruited from academic, public, and private hospitals a…

Hepatitis C virus viral kinetics during α-2a or α-2b pegylated interferon plus ribavirin therapy in liver transplant recipients with different immunosuppression regimes

Abstract Background Predictors of sustained virological response (SVR) to antiviral therapy post-liver transplantation (LT) for chronic hepatitis C are needed. In non-transplanted patients, viral kinetics can predict SVR. Objectives To determine the early viral kinetics in LT recipients with different immunosuppression (tacrolimus – Tac- vs. cyclosporine – CsA-) during treatment with peg-IFN + RBV. Study design Prospective pilot study in HCV-1b infected patients: (LT CsA n = 8; Tac n = 8; non-LT n = 4), treated with IFN α-2a vs. α-2b (180 μg or 1.5 μg/kg, respectively) once weekly plus weight-based RBV. Median CsA or Tac baseline trough levels were 141 and 7.70 ng/mL, respectively. HCV-RNA …

The New Era of Hepatitis C

Hepatitis C virus (HCV) is the leading cause of end-stage liver disease in both Europe and the United States and is the most common reason for liver transplant. In the absence of antiviral therapy, recurrent infection is the norm with subsequent graft hepatitis and impaired survival. Whether it may be better to postpone therapy in patients in whom higher risk of failure and toxicity is coupled with lower chance of liver function improvement likely depends on several factors, including waiting time, center allocation policy, presence of hepatocellular carcinoma and local prevalence of anti-HCV-positive donors.

Executive summary of the 2018 KDIGO Hepatitis C in CKD Guideline: welcoming advances in evaluation and management

Infection with the hepatitis C virus (HCV) has adverse liver, kidney, and cardiovascular consequences in patients with chronic kidney disease (CKD), including those on dialysis therapy and in those with a kidney transplant. Since the publication of the original Kidney Disease: Improving Global Outcomes (KDIGO) HCV Guideline in 2008, major advances in HCV management, particularly with the advent of direct-acting antiviral therapies, have now made the cure of HCV possible in CKD patients. In addition, diagnostic techniques have evolved to enable the noninvasive diagnosis of liver fibrosis. Therefore, the Work Group undertook a comprehensive review and update of the KDIGO HCV in CKD Guideline.…

Hepatitis C-related cirrhosis. Current status.

Chronic hepatitis C virus (HCV) infection affects around 150 million people. It is a leading cause of liver related morbidity and mortality through its predisposition to liver fibrosis, cirrhosis and end-stage liver complications. New treatments based on direct-acting antivirals have opened a new era in the management of HCV cirrhosis. They allow for HCV eradication without substantial side effects in almost all cirrhotic patients, reducing the risk of hepatocellular carcinoma, liver decompensation and mortality. This review provides an update on HCV cirrhosis. The paper focuses on the disease burden and major progresses in the diagnosis, follow-up and treatment of this patient subgroup.

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 naive patients treated with pIFN-RBV: Group 1 (n=44), a historical cohort of patients treated during the peri…

Last gasps of the hepatitis C virus dragon: Direct acting antiviral failures and hepatitis C virus-positive donors.

Stretching the boundaries for liver transplant in the 21st century.

Given the high waiting list mortality, there is a clear need to identify strategies to increase the number of livers for transplantation. Some strategies require policy changes, whereas others depend on a better understanding of available opportunities. We divided the strategies to increase the number of livers for transplantation into two categories-those aiming to increase the use of organs considered to be of suboptimal quality, and those aiming to increase the use of organs considered to be of suboptimal size. Enough evidence suggests that, if considered in the context of other donor and recipient variables, grafts from elderly donors are a safe option. The severity of steatosis, and no…

HCV-induced immune responses influence the development of operational tolerance after liver transplantation in humans.

Pathogen-induced immune responses prevent the establishment of transplantation tolerance in experimental animal models. Whether this occurs in humans as well remains unclear. The development of operational tolerance in liver transplant recipients with chronic hepatitis C virus (HCV) infection allows us to address this question. We conducted a clinical trial of immunosuppression withdrawal in HCV-infected adult liver recipients to elucidate (i) the mechanisms through which allograft tolerance can be established in the presence of an ongoing inflammatory response and (ii) whether anti-HCV heterologous immune responses influence this phenomenon. Of 34 enrolled liver recipients, drug withdrawal…

Trends for genetic variation of Hepatitis C Virus quasispecies in Human Immunodeficiency virus-1 coinfected patients

Chronic infection by Hepatitis C Virus (HCV) causes liver fibrosis, which is accelerated by unknown mechanisms in patients with HIV-1 coinfection. The evolution of HCV quasispecies in this setting of coinfection is not fully understood. To compare HCV quasispecies between HIV-HCV coinfection and HCV monoinfection, we sequenced 340 HCV clones from the HVR-1 and NS3 regions at two different time points in two groups of treatment-naive patients with HCV-1a infection: (1) HIV-HCV positive (n=6); and (2) HIV negative-HCV positive (n=3). In HCV/HIV coinfection, we found a trend for reduced HCV genetic complexity and diversity, and a trend towards reduced dN/dS ratios in the HVR-1 region, especial…

Guía de tratamiento de la infección por virus de la hepatitis C. Asociación Española para el Estudio del Hígado (AEEH)

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. Multiva…

Beyond cure

PURPOSE OF REVIEW The aim of this review was to define the implication of hepatitis C virus (HCV) eradication in patients with cirrhosis. RECENT FINDINGS Sustained virologic response (SVR) is associated with a favourable outcome in patients with cirrhosis especially in the presence of regression of cirrhosis but also with extrahepatic outcomes regarding health-related quality of life, risk of diabetes, risk of cardiovascular diseases and control of HIV replication by antiretroviral therapy. In patients with decompensated cirrhosis identifying the point of no return where viral eradication is not followed by clinical improvement is extremely relevant. A strict follow-up is needed in order to…

Delisting of liver transplant candidates with chronic hepatitis C after viral eradication: A European study

Background &amp; Aims: All oral direct acting antivirals (DAA) have been shown to improve the liver function of patients with decompensated cirrhosis but it is presently unknown whether this clinical improvement may lead to the delisting of some patients. The aim of this study was to assess if and which patients can be first inactivated due to clinically improvement and subsequently delisted in a real life setting. Methods: 103 consecutive listed patients without hepatocellular carcinoma were treated with different DAA combinations in 11 European centres between February 2014 and February 2015. Results: The cumulative incidence of inactivated and delisted patients by competing risk analysis…

Delisting HCV-infected liver transplant candidates who improved after viral eradication: Outcome 2 years after delisting

International audience; BACKGROUNDS & AIMS: Treating patients with decompensated cirrhosis with direct-acting antiviral (DAA) therapy while on the waiting list for liver transplantation results in substantial improvement of liver function allowing 1 in 4 patients to be removed from the waiting list or delisted, as reported in a previous study promoted by the European Liver and Intestine Transplant Association (ELITA). The aim of this study was to report on clinical outcomes of delisted patients, including mortality risk, hepatocellular carcinoma development and clinical decompensation requiring relisting. METHODS: One hundred and forty-two HCV-positive patients on the liver transplant waiti…

Treatment of chronic hepatitis C in hemodialysis patients

Hepatitis C virus (HCV) infection is especially problematic in patients with end-stage renal disease (ESRD) who are undergoing hemodialysis. Rates of HCV infection are higher among hemodialysis patients than in the general population, and several routes of transmission are thought to stem from the dialysis unit. Management of chronic hepatitis C is also more complicated in hemodialysis patients because of altered pharmacokinetics and a predisposition for drug-related toxicity, particularly ribavirin-induced anemia. Clinical trials of patients with chronic hepatitis C and healthy, functioning kidney grafts are rare because of the inherent dangers of graft rejection. As a result, most studies…

Introduction to hepatitis C virus infection: Overview and history of hepatitis C virus therapies

Chronic hepatitis C virus (HCV) infection is an infection that affects over 71 million people worldwide that primarily leads to significant morbidity and mortality through its predisposition to liver fibrosis, cirrhosis, and liver cancer. In addition, extrahepatic manifestations, such as mixed cryoglobulinaemia-associated vasculitis including renal disease, or type II diabetes are frequently encountered in chronically infected individuals. HCV treatment aims to permanently eradicate the virus in order to prevent both liver and extra-hepatic manifestations. Over two decades after the HCV discovery, treatments have evolved from nonspecific immune modulating therapies based on interferon to sp…

Significant impact of new oral therapies against HCV on the waiting list for liver transplantation in Spain.

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, ha…

Genomic medicine reaches HCV-related liver transplantation: Hopes and clinical and public health implications

Prospective validation of a noninvasive index for predicting liver fibrosis in hepatitis C virus-infected liver transplant recipients

We previously developed a mathematical model, the Hospital Universitario La Fe (HULF) index, as an alternative to protocol liver biopsy (PLB) to estimate significant fibrosis (SF) in patients who underwent liver transplantation (LT) for liver damage caused by chronic HCV infection. In the present study, we sought to validate this noninvasive index. The commonly derived clinical and laboratory data for calculating the HULF index were prospectively collected over 2.7 years from patients undergoing LT and PLB. The sensitivity, specificity, positive and negative predictive values, and diagnostic capacity were evaluated with receiver operating characteristic curve analysis. Biopsy was performed …

Transplantation for Hepatitis C

Cirrhosis of mixed etiology (hepatitis C virus and alcohol): Posttransplantation outcome-Comparison with hepatitis C virus-related cirrhosis and alcoholic-related cirrhosis

Hepatitis C virus (HCV)-related liver disease is enhanced by alcohol consumption. Of HCV-related liver transplantation (LT) recipients, 25% have a history of alcohol intake. The purpose of this research was to determine whether LT outcome differs between patients with cirrhosis of mixed etiology compared to HCV or alcohol alone. Of 494 LT (1997-2001), recipient/donor features, post-LT histological, metabolic complications [hypertension, diabetes-diabetes mellitus (DM)], and de novo tumors were compared in 3 groups [HCV-related cirrhosis = 170 (HCV group), alcohol-related cirrhosis (alcohol group) = 107, and cirrhosis of mixed etiology (mixed group) = 60]. Protocol biopsies were done in HCV …