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Background and objectives Since June 2016, there have been outbreaks of hepatitis A in various European countries, mainly affecting men who have sex with men (MSM). The aim of this study was to assess their clinical and epidemiological impact in Cantabria, Spain. Material and methods We retrospectively collected all cases of hepatitis A diagnosed in Cantabria between January 2013 and September 2018. We compared 2 periods: January 2013–May 2016 and June 2016–September 2018. Results A total of 156 cases were diagnosed, observing an increase in the incidence starting in October 2016. With regard to 2013–2016, we observed a higher proportion of men (50.0% vs. 84.5%; p = .012) with a predominance of the homosexual orientation (80.6%) and a higher rate of sexual transmission (0% vs. 48.3%; p = .061) for the patients in the 2016–2018 period. From the clinical standpoint, all cases of severe hepatitis occurred during this latter period. Conclusions Our results reaffirm the high clinical and epidemiological impact of the epidemic outbreak in Cantabria and emphasises the need for optimising the current prevention measures against hepatitis A.

Resumen La cirrosis hepatica es una enfermedad con alta morbilidad y mortalidad. En su fase de cirrosis descompensada, puede presentar numerosas complicaciones derivadas de una insuficiencia hepatica avanzada y el desarrollo de hipertension portal. La ascitis es la complicacion mas frecuente que encontramos en el 80% de los casos de cirrosis descompensada. Sin embargo, en esta actualizacion, desarrollaremos las otras tres complicaciones mas frecuentes: la hemorragia digestiva secundaria a hipertension portal, la peritonitis bacteriana espontanea y la encefalopatia hepatica. Estas tres complicaciones constituyen urgencias medicas en el paciente cirrotico que pueden ser potencialmente mortales. El manejo de estas complicaciones consta de un tratamiento especifico y de la prevencion de nuevos episodios y complicaciones directamente relacionadas, teniendo siempre en cuenta la posible indicacion de un trasplante hepatico en estos pacientes.

Resumen La progresion de la enfermedad hepatica a fases avanzadas, como la cirrosis, provoca el desarrollo de complicaciones derivadas de la hipertension portal. En el paciente cirrotico que se presenta con alteraciones de la conducta, neurocognitivas o del nivel de conciencia, nos debe hacer pensar en el desarrollo de encefalopatia hepatica. En la mayoria de los casos, encontraremos un factor precipitante que sera clave en el manejo, asi como medidas generales que pasan por la descontaminacion intestinal mediante laxantes y antibioticos no absorbibles. Por otro lado, se debe hacer una evaluacion pormenorizada de otras causas no relacionadas con la cirrosis o relacionadas con la etiologia de la enfermedad hepatica.

In this review, the peculiarities of infection and treatment of HCV in the prison population are detailed. In addition, the barriers to HCV treatment and possible solutions are highlighted. Several previous experiences of HCV treatment in prisons have been successful. In this manuscript, we detail the most relevant. We think that incarceration should be considered an opportunity to engage this population in health care. Therefore, we should encourage systematic screening of these patients and promote the access to treatment by supporting equity with the general population. Thus, inmates’ care must involve a multidisciplinary team. To solve this matter, we propose telehealth to bring together all these services and overcome the geographical barrier(s) and improve costs. Then, to go further in hepatitis C elimination, harm-reduction programs should be added to treat with direct-acting antivirals.

Background Knowledge of haematological abnormalities in cirrhosis has greatly improved in recent years. Aims To evaluate how Spanish Digestive Disease specialists manage haemostatic alterations and associated disorders in patients with cirrhosis. Methods All members of the Spanish Association for the Study of the Liver and Spanish Society of Digestive Pathology were invited to fill in a web-based questionnaire. Results 135 professionals, 93 hepatologists and 42 non-hepatologists responded to the survey. The concept of rebalanced haemostasis was known by 74.8% of them. Most specialists corrected the INR and thrombocytopenia before invasive procedures with moderate risk of bleeding or major surgery and in severe gastrointestinal bleeding. The threshold of platelets and, especially, INR used to administer blood products varied greatly. Pharmacological prophylaxis of venous thromboembolism prevailed, but it was highly dependent on the INR and platelet figures. Most participants initiated anticoagulation regardless of the degree of portal vein thrombosis, even in patients ineligible for transplantation. In potential candidates, only 56% maintained it indefinitely or until liver transplantation. No major differences between hepatologists and non-hepatologists were found. Conclusions A significant variability and certain deviation from current guidelines was observed among Spanish Digestive Disease specialists regarding management of haemostatic alterations and associated disorders in cirrhosis.

Background and Aims: The Spanish prison population includes two groups: people in prison and those who are serving non-custodial sentences. The latter has not yet been studied. This study aims to describe this population and the results of a test-and-treat strategy for hepatitis C including a holistic health assessment. Method: This prospective study included all subjects serving non-custodial sentences at the Center for Social Integration. It was assisted by the medical team, a navigator, and a systematic screening of HCV (Hepatitis C Virus) performed by point-of-care tests. All cases with active infection are evaluated using telemedicine by a specialist to prescribe antiviral treatment. The navigator facilitates continuity for medical and social assistance. Results: The screening rate reached 92.8% (548/590). HCV seroprevalence and viraemia prevalence were 8% (44) and 2.9% (16), respectively. Regarding comorbidities: problems related to drug dependence were detected in 264 (48.2%), suspected serious mental disorder in 44 (8.3%), and previous stay in prison in 122 cases (22.2%). The navigator monitored 59 (15.2%) patients regarding HCV treatment or comorbidities. All patients (10/10) completing 12 weeks follow-up achieved sustained virological response. Conclusions: The population serving non-custodial sentences is a challenging group with a high prevalence of HCV infection. Micro-elimination programs using point of care diagnostic tests, telemedicine, and a navigator are necessary in this underserved vulnerable population.

Hepatitis C (HCV) management has dramatically changed with the advent of direct-acting antivirals. Their high efficacy and safety are changing the paradigm of detection and treatment of patients with an active HCV infection. Following the latest guidelines, the path to elimination of hepatitis C will be achieved by simplifying management.

Hepatitis C (HCV) management has dramatically changed with the advent of direct-acting antivirals. Their high efficacy and safety are changing the paradigm of detection and treatment of patients with an active HCV infection. Following the latest guidelines, the path to elimination of hepatitis C will be achieved by simplifying management.

Introduction Linkage to care for hepatitis C includes a new tool: teleconsultation. Micro-elimination in prison is a recommendation and is feasible. An economic evaluation of telemedicine for hepatitis C virus (HCV) treatment in prisons has not yet been performed. This study aimed to provide a cost-minimization analysis comparing two strategies of HCV treatment in a prison: telemedicine clinical practice (TCP) and the usual clinical practice (UCP). Methods An observational cost-minimization study was carried out on a cohort of inmates who received anti-HCV treatment in El Dueso prison (May 2016–November 2017). A decision tree was constructed, incorporating different clinical profiles according to the severity of the disease, the results of diagnostic tests, and treatment outcomes as well as the costs of each profile. Satisfaction with telemedicine was evaluated through an 11-question questionnaire with a 5-point Likert scale. Results Seventy-five inmates were treated and underwent TCP with a follow-up of one year. The average cost per patient with the TCP strategy was €1,172 (€1,151 direct costs). Had UCP been carried out, the cost would have been €1,687 (€1,630 direct). Telemedicine consultation practice produced savings of €516 (30.6%) per patient, with total savings of €38,677. The transfer costs from prison to hospital represented the most important saving item, accounting for 99.3% of the TCP-related savings. The questionnaire revealed high levels of satisfaction with TCP, with a median score of 5 in each question. Sustained virological response rates were 94.7% after the first treatment and 100% after retreatment of the four relapses. Conclusion Telemedicine consultation practice is a more efficient strategy than UCP, mainly due to the reduction of transfer costs while preserving effectiveness and user satisfaction.

Introduccion: nuestro objetivo fue determinar la prevalencia de infeccion por virus de la hepatitis C (VHC) en pacientes con trastornos psicoticos no afectivos y compararla con los datos poblacionales. Material y metodos: se realizo un estudio observacional mediante la determinacion de anti-VHC (RNA-VHC en los seropositivos) sobre 425 muestras sericas de pacientes con psicosis no afectiva. Resultados: ocho pacientes presentaron anti-VHC positivo (1,9 %) y cinco, RNA-VHC detectable (1,2 %). La prevalencia de viremia fue significativamente mayor que la de la poblacion general (OR 5,4; IC 95 %: 1,9-14,6). Conclusiones: los pacientes con trastorno psicotico no afectivo presentan una prevalencia de infeccion activa superior a la poblacion general y deberian ser objeto de un cribado sistematico.

The latest epidemiological data in Spain were obtained a decade ago and revealed a prevalence of hepatitis B surface antigen (HBsAg) of 0.7%; hence, updated epidemiological data are necessary. Our aim was to determine the prevalence of hepatitis B virus (HBV) infection, and to analyse associated factors and characterize chronic infection. A population-based, cross-sectional study was performed in Spain between July 2015 and April 2017. Participants from three regions were selected using two-stage conglomerate sampling and stratified by age. Anthropometric and demographic data were collected, and blood samples were taken to detect serological markers of HBV infection and to quantify HBV-DNA. The characterization of chronic HBV infection was based on ALT (alanine aminotransferase) values, HBV-DNA levels, and results of transient elastography. The overall prevalence rates of HBsAg and antibody to hepatitis B core antigen (anti-HBc) among 12 246 participants aged 20-74 years (58.4% females) were 0.6% (95% CI [0.4-0.7]) and 8.2% (7.7-8.7), respectively. The risk factors for HBV infection identified in the multivariate analysis were age, nosocomial risk, and non-Spanish nationality. Moreover, most patients HBsAg positive (76.6%) presented as hepatitis B e antigen (HBeAg)?negative chronic infection (formerly ?inactive carriers?) and only 6 (9.4%) HBsAg carriers fulfilled current criteria for treatment. The current HBV burden in Spain remains low but virtually unchanged over the past 15 years. Increased efforts are still needed to reach the goal set forth by the World Health Organization (WHO) for HBV elimination by 2030.

El virus de la hepatitis C (VHC) es una de las principales causas de morbilidad y mortalidad relacionadas con el higado en todo el mundo, con mas de 70 millones de personas afectadas. Aproximadamente, entre el 55 % y el 85 % de las personas infectadas desarrollaran infeccion cronica por VHC y entre el 15 % y 30 % de este grupo desarrollaran cirrosis hepatica y complicaciones asociadas en los 20-30 anos siguientes. En nuestro pais, la seroprevalencia de anti-VHC oscila entre el 0,8 y el 1,2 % de la poblacion adulta, mientras que entre el 0,2 y el 0,4 % muestran una infeccion activa por el VHC. En los ultimos anos, gracias a la aparicion de los agentes antivirales de accion directa (AAD), que alcanzan tasas de curacion superiores al 95 %, la eliminacion del VHC es una posibilidad real y, de hecho, la Organizacion Mundial de la Salud (OMS) establecio en el ano 2016 una estrategia global con el objetivo de conseguir su eliminacion para el ano 2030.

Background & Aims: Patients with advanced liver fibrosis remain at risk of cirrhosis-related outcomes and those with severe comorbidities may not benefit from hepatitis C (HCV) eradication. We aimed to collect data on all-cause mortality and relevant clinical events within the first two years of directacting antiviral therapy, whilst determining the prognostic capability of a comorbidity-based model. Methods: This was a prospective non-interventional study, from the beginning of direct-acting antiviral therapy to the event of interest (mortality) or up to two years of follow-up, including 14 Spanish University Hospitals. Patients with HCV infection, irrespective of liver fibrosis stage, who received direct-acting antiviral therapy were used to build an estimation and a validation cohort. Comorbidity was assessed according to Charlson comorbidity and CirCom indexes. Results: A total of 3.4% (65/1,891) of individuals died within the first year, while 5.4% (102/1,891) died during the study. After adjusting for cirrhosis, platelet count, alanine aminotransferase and sex, the following factors were independently associated with one-year mortality: Charlson index (hazard ratio [HR] 1.55; 95% CI 1.29-1.86; p = 0.0001), bilirubin (HR 1.39; 95% CI 1.11-1.75; p = 0.004), age (HR 1.06 95% CI 1.02-1.11; p = 0.005), international normalized ratio (HR 3.49; 95% CI 1.36-8.97; p = 0.010), and albumin (HR 0.18; 95% CI 0.09-0.37; p = 0.0001). HepCom score showed a good calibration and discrimination (C-statistics 0.90), and was superior to the other prognostic scores (model for end-stage liver disease 0.81, ChildPugh 0.72, CirCom 0.68) regarding one-and two-year mortality. HepCom score identified low- (= 25 points: 56%-59%) mortality groups, both in the estimation and validation cohorts. The distribution of clinical events was similar between groups. Conclusions: The HepCom score, a combination of Charlson comorbidity index, age, and liver function (international normalized ratio, albumin, and bilirubin) enables detection of a group at high risk of one-and two-year mortality, and relevant clinical events, after starting direct-acting antiviral therapy. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

OBJECTIVES: Interferon-free therapies have an improved safety and efficacy profile. However, data in elderly patients, who have frequently advanced liver disease, associated comorbidities, and use concomitant medications are scarce. The im of this study was to assess the effectiveness and tolerability of all-oral regimens in elderly patients in real-life clinical practice. METHODS: Retrospective analysis of hepatitis C virus (HCV) patients aged >= 65 years receiving interferon-free regimens within the Spanish National Registry (Hepa-C). RESULTS: Data of 1,252 patients were recorded. Of these, 955 (76%) were aged 65-74 years, 211 (17%) were aged 75-79 years, and 86 (7%) were aged >= 80 years at the start of antiviral therapy. HCV genotype-1b was predominant (88%) and 48% were previous non-responders. A significant proportion of patients had cirrhosis (922; 74%), of whom 11% presented decompensated liver disease. The most used regimens were SOF/LDV (33%), 3D (28%), and SOF/SMV (26%). Ribavirin was added in 49% of patients. Overall, the sustained virological response (SVR12) rate was 94% without differences among the three age categories. Albumin = 75 years (2.59 (1.16-5.83); P = 0.02) and albumin = 75 years) or those with advanced liver disease (albumin

We are currently living in an unprecedented era of hepatitis C treatment with the availability of highly effective drugs yielding minimal side effects. The problem we currently face is the retreatment of patients refractory to these drugs. Although several factors can influence treatment failure, this review focuses on antiviral resistance. Resistance-associated substitutions may be identified at baseline or be treatment-emergent. The latter seem to be more clinically relevant and must be studied in the event of treatment failure (no virological response). In this article, we present the latest data from clinical trials and studies in real-life clinical practice. Finally, based on this current evidence, we propose some recommendations for the management and retreatment of these patients.

We are currently living in an unprecedented era of hepatitis C treatment with the availability of highly effective drugs yielding minimal side effects. The problem we currently face is the retreatment of patients refractory to these drugs. Although several factors can influence treatment failure, this review focuses on antiviral resistance. Resistance-associated substitutions may be identified at baseline or be treatment-emergent. The latter seem to be more clinically relevant and must be studied in the event of treatment failure (no virological response). In this article, we present the latest data from clinical trials and studies in real-life clinical practice. Finally, based on this current evidence, we propose some recommendations for the management and retreatment of these patients.

Background & Aims: Clinical trials evaluating second-generation direct-acting antiviral agents (DAAs) have shown excellent rates of sustained virologic response (SVR) and good safety profiles in patients with chronic hepatitis C virus (HCV) genotype 1 infection. We aimed to investigate the effectiveness and safety of two oral DAA combination regimens, ombitasvir/paritaprevir/rito navir plus dasabuvir (OMV/PTV/r + DSV) and ledipasvir/sofosbuvir (LDV/SOF), in a real-world clinical practice. Methods: Data from HCV genotype 1 patients treated with either OMV/PTV/r + DSV +/- ribavirin (RBV) (n = 1567) or LDV/SOF +/- RBV (n = 1758) in 35 centers across Spain between April 1, 2015 and February 28, 2016 were recorded in a large national database. Demographic, clinical and virological data were analyzed. Details of serious adverse events (SAEs) were recorded. Results: The two cohorts were not matched with respect to baseline characteristics and could not be compared directly. The SVR12 rate was 96.8% with OMV/PTVr/DSV +/- RBV and 95.8% with LDV/SOF +/- RBV. No significant differences were observed in SVR according to HCV subgenotype (p = 0.321 [OMV/PTV/r + DSV +/- RBV] and p = 0.174 [LDV/SOF]) or degree of fibrosis (c0.548 [OMV/PTV/r/DSV +/- RBV] and p = 0.085 [LDV/SOF]). Only baseline albumin level was significantly associated with failure to achieve SVR (p < 0.05) on multivariate analysis. Rates of SAEs and SAE-associated treatment discontinuation were 5.4% and 1.7%, in the OMV/PTV/r + DSV subcohort and 5.5% and 1.5% in the LDV/SOF subcohort, respectively. Hepatocellular carcinoma (HCC) recurred in 30% of patients with a complete response to therapy for previous HCC. Incident HCC was reported in 0.93%. Conclusions: In this large cohort of patients managed in the real-world setting in Spain, OMV/PTV/r + DSV and LDV/SOF achieved high rates of SVR12, comparable to those observed in randomized controlled trials, with similarly good safety profiles. Lay summary: In clinical trials, second-generation direct-acting antiviral agents (DAAs) have been shown to cure over 90% of patients chronically infected with the genotype 1 hepatitis C virus and have been better tolerated than previous treatment regimens. However, patients enrolled in clinical trials do not reflect the real patient population encountered in routine practice. The current study, which includes almost 4,000 patients, demonstrates comparable rates of cure with two increasingly used DAA combinations as those observed in the clinical trial environment, confirming that clinical trial findings with DAAs translate into the real-world setting, where patient populations are more diverse and complex. (c) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Hepatitis C virus (HCV) is 15 times more prevalent among persons in Spain’s prisons than in the community. Recently, Spain initiated a pilot program, JAILFREE-C, to treat HCV in prisons using direct-acting antivirals (DAAs). Our aim was to identify a cost-effective strategy to scale-up HCV treatment in all prisons. Using a validated agent-based model, we simulated the HCV landscape in Spain’s prisons considering disease transmission, screening, treatment, and prison-community dynamics. Costs and disease outcomes under status quo were compared with strategies to scale-up treatment in prisons considering prioritization (HCV fibrosis stage vs. HCV prevalence of prisons), treatment capacity (2,000/year vs. unlimited) and treatment initiation based on sentence lengths (>6 months vs. any). Scaling-up treatment by treating all incarcerated persons irrespective of their sentence length provided maximum health benefits–preventing 10,200 new cases of HCV, and 8,300 HCV-related deaths between 2019–2050; 90% deaths prevented would have occurred in the community. Compared with status quo, this strategy increased quality-adjusted life year (QALYs) by 69,700 and costs by €670 million, yielding an incremental cost-effectiveness ratio of €9,600/QALY. Scaling-up HCV treatment with DAAs for the entire Spanish prison population, irrespective of sentence length, is cost-effective and would reduce HCV burden.

Accurate HCV prevalence estimates are necessary for guiding elimination policies. Our aim was to determine the HCV prevalence and assess the cost-effectiveness of a screen-and-treat strategy in the Spanish population. A population-based, cross-sectional study (PREVHEP-ETHON Cohort, Epidemiological sTudy of Hepatic infectiONs; NCT02749864) was performed from July 2015-April 2017. Participants from three Spanish regions were selected using two-stage conglomerate sampling, and stratified by age, with randomized subject selection. Anthropometric and demographic data were collected, and blood samples were taken to detect anti-HCV antibodies/quantify HCV RNA. The cost-effectiveness of the screening strategies and treatment were analysed using a Markov model. Among 12 246 participants aged 20-74 (58.4% females), the overall anti-HCV prevalence was 1.2% (95% CI 1.0-1.4), whereas the detectable HCV-RNA prevalence was 0.3% (0.2-0.4). Infection rates were highest in subjects aged 50-74 years [anti-HCV 1.6% (1.3-1.9), HCV RNA 0.4% (0.3-0.6]. Among the 147 anti-HCV + subjects, 38 (25.9%) had active infections while 109 (74.1%) had been cleared of infection; 44 (40.4%) had cleared after antiviral treatment, whereas 65 (59.6%) had cleared spontaneously. Overall, 59.8% of the anti-HCV + participants were aware of their serological status. Considering a cost of treatment of €7000/patient, implementing screening programmes is cost-effective across all age cohorts, particularly in patients aged 50-54 (negative incremental cost-effectiveness ratio which indicates a cost-saving strategy). The current HCV burden is lower than previously estimated, with approximately 25% of anti-HCV + individuals having an active infection. A strategy of screening and treatment at current treatment prices in Spain is cost-effective across all age cohorts.

Background: we aimed to assess the influence of metabolic syndrome on fibrosis regression (using liver-stiffness measurement (LSM) and serological scores) and the relationship with the expression of lysyl oxidase-like-2 as a potential goal of antifibrotic therapy. Methods: We included 271 patients treated with Direct Antiviral Therapy (DAAs) in our hospital who achieved a sustained virological response (SVR), physical examination, blood tests, and LSM were made at baseline (B) and 24 months (24 M) after SVR. Hemodynamic studies and transjugular liver biopsies were performed on 13 patients. Results: At B, 68 patients were F1 (25.1%), F2 n = 59 (21.7%), F3 n = 44 (16.05%), and 100 were F4 (36.9%). Although the LSM (absolute value) improved in 82% of patients (n = 222), it progressed in 17.5% of patients (n = 48). At 24 M, 48 patients met the metabolic syndrome (MetS) criteria and there was an increase in patients with a BMI of &gt, 25 kg/m2 (p &lt, 0.001). At B and 24 M, a BMI of &gt, 25 kg/m2 is a risk factor for significant fibrosis or steatosis at 24 M (p &lt, 0.05) and progression on LSM (p &lt, 0.001), as well as MetS at B and 24 M (OR 4.1 IC (1.4&ndash, 11.7), p = 0.008, and OR 5.4 IC (1.9&ndash, 15.4), p = 0.001, respectively). Regarding the correlation between LSM and the liver biopsy, we found that only six out of 13 patients had a matching LSM and biopsy. We found a statistically significant decrease in LOXL2 levels at 24 M with respect to B (p &lt, 0.001) with higher serological value in patients with elastography of &gt, 9 kPa vs. &lt, 9 kPa (p = 0.046). Conclusion: Regression of LSM was reached in 82% of patients. Downregulated LOXL2 was demonstrated post-SVR, with overexpression in cirrhotic patients being a potential therapy goal in selected patients.

In randomized controlled trials of patients with chronic HCV infection, elbasvir/grazoprevir (EBR/GZR) demonstrated high cure rates and a good safety profile. This study assessed the effectiveness and safety of EBR/GZR, with and without ribavirin, in a real‐world HCV patient cohort. HEPA‐C is a collaborative, monitored national registry of HCV patients directed by the Spanish Association for the Study of the Liver and the Networked Biomedical Research Centre for Hepatic and Digestive Diseases. Patients entered into HEPA‐C between December 2016 and May 2017, and treated with EBR/GZR with at least end‐of‐treatment response data, were included. Demographic, clinical and virologic data were analysed, and adverse events (AEs) recorded. A total of 804 patients were included in the study. The majority were male (57.9%), with a mean age of 60 (range, 19‐92) years. Genotype (GT) distribution was GT 1, 86.8% (1a, 14.3%; 1b, 72.5%); GT 4, 13.2% and 176 patients (21.9%) were cirrhotic. Overall, among 588 patients with available data, 570 (96.9%) achieved sustained virologic response at 12 weeks post‐treatment (SVR12). SVR12 rates by genotype were GT 1a, 97.7%; GT 1b, 98.6%; and GT 4, 98.1%. No significant differences in SVR12 according to fibrosis stage were observed. Eighty patients experienced an AE, resulting in treatment discontinuation in three. In this large cohort of patients with chronic HCV managed in a real‐world setting in Spain, EBR/GZR achieved high rates of SVR12, comparable to those observed in randomized controlled trials, with a similarly good safety profile.

Background & Aims: Despite direct-acting antivirals being highly effective at eradicating hepatitis C virus infection, their impact on the development of hepatocellular carcinoma (HCC) remains controversial. We analyzed the clinical and radiological outcome of cirrhotic patients treated with interferon-free regimens to estimate the risk of developing HCC. Methods: This was a retrospective multicenter study focusing on cirrhotic patients treated with direct-acting antivirals until December 2016. Clinical and radiologic characteristics were collected before the start of antiviral therapy, at follow-up and at HCC development. Diagnosis of HCC was centrally validated and its incidence was expressed as HCC/100 person-years. Results: A total of 1,123 patients were included (60.6% males, 83.8% Child-Pugh A) and 95.2% achieved a sustained virologic response. Median time of follow-up was 19.6 months. Seventy-two patients developed HCC within a median of 10.3 months after starting antiviral treatment. HCC incidence was 3.73 HCC/100 person-years (95% CI 2.96-4.70). Baseline liver function, alcohol intake and hepatic decompensation were associated with a higher risk of HCC. The relative risk was significantly increased in patients with non-characterized nodules at baseline 2.83 (95% CI 1.55-5.16) vs. absence of non-characterized nodules. When excluding these patients, the risk remained increased. Conclusion: These data expose a clear-cut time association between interferon-free treatment and HCC. The mechanisms involved in the increased risk of HCC emergence in the short term require further investigation. Lay summary: In this cohort of cirrhotic patients, interferonfree therapies achieved a high rate of sustained virologic response (>95%); however, we reported a risk of de novo hepatocellular carcinoma of 3.73 per 100 person-years and a clearcut time association with antiviral therapy. The time association between starting direct-acting antivirals and developing hepatocellular carcinoma, together with the association with the presence of non-characterized nodules at baseline ultrasound, suggests that antiviral therapy elicits a mechanism (probably immune-related) that primes the growth and clinical recognition of hepatocellular carcinoma early during follow-up. As a result, short-term liver cancer risk is significantly increased. (C) 2019 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

Portal sinusoidal vascular disease is a presinusoidal cause of portal hypertension (PHT) of unknown etiology, characterized by typical manifestations of PHT (esophageal varices, ascites, portosystemic collaterals), plaquetopenia and splenomegaly with a gradient of portal pressure slightly increased, according to the presinusoidal nature of the PHT. A few cases in the literature have shown a relationship between oxaliplatin and the development of presinusoidal portal hypertension, years after the chemotherapy for colorectal cancer (therefore, different to sinusoidal obstruction syndrome). There are three mechanisms through which oxaliplatin can cause sinusoidal damage: 1) damage at the level of endothelial cells and stimulates the release of free radicals and depletion of glutathione transferase, with altering the integrity of the sinusoidal cells. The damage in the endothelial sinusoidal cells allows to erythrocytes to across into the Dissé space and formation of perisinusoidal fibrosis, 2) the appearance of nodular regenerative hyperplasia is favored by the chronic hypoxia of the centrilobular areas and, finally, 3) oxaliplatin can generate an obliteration of the blood capillaries and zones of parenchymal extinction. These three facts can develop, in a minority of cases, the appearance of a presinusoidal increase of portal pressure, which typically appears years after the completion of chemotherapy and sometimes is underdiagnosed until variceal bleeding, ascites or encephalopathy appear. The knowledge of this pathology is essential to be able to perform an early diagnostic and consult to the hepatologist. Funding: This research received an external funding of CI18/67/02 Acuerdo de cooperación en el programa de becas de investigación científica de IDIVAL de JANSSEN-CILAG, S.A.

The concept of liver fibrosis and cirrhosis being static and therefore irreversible is outdated. Indeed, both human and animal studies have shown that fibrogenesis is a dynamic and potentially reversible process that can be modulated either by stopping its progression and/or by promoting its resolution. Therefore, the study of the molecular mechanisms involved in the pathogenesis of liver fibrosis is critical for the development of future antifibrotic therapies. The fibrogenesis process, common to all forms of liver injury, is characterized by the increased deposition of extracellular matrix components (EMCs), including collagen, proteoglycans, and glycoproteins (laminin and fibronectin 2). These changes in the composition of the extracellular matrix components alter their interaction with cell adhesion molecules, influencing the modulation of cell functions (growth, migration, and gene expression). Hepatic stellate cells and Kupffer cells (liver macrophages) are the key fibrogenic effectors. The antifibrogenic mechanism starts with the activation of Ly6Chigh macrophages, which can differentiate into macrophages with antifibrogenic action. The research of biochemical changes affecting fibrosis irreversibility has identified lysyl oxidase-like 2 (LOXL2), an enzyme that promotes the network of collagen fibers of the extracellular matrix. LOXL2 inhibition can decrease cell numbers, proliferation, colony formations, and cell growth, and it can induce cell cycle arrest and increase apoptosis. The development of a new humanized IgG4 monoclonal antibody against LOXL2 could open the window of a new antifibrogenic treatment. The current therapeutic target in patients with liver cirrhosis should focus (after the eradication of the causal agent) on the development of new antifibrogenic drugs. The development of these drugs must meet three premises: Patient safety, in non-cirrhotic phases, down-staging or at least stabilization and slowing the progression to cirrhosis must be achieved; whereas in the cirrhotic stage, the objective should be to reduce fibrosis and portal pressure. Funding: This research was funded by NEXT-VAL grant 15/12 from Health Research Institute Marques de Valdecilla (IDIVAL).

Background & Aims: Around 5% of patients with chronic hepatitis C virus (HCV) infection treated with direct-acting antiviral (DAA) agents do not achieve sustained virological response (SVR). The currently approved retreatment regimen for prior DAA failure is a combination of sofosbuvir, velpatasvir, and voxilaprevir (SOF/VEL/VOX), although there is little data on its use in clinical practice. The aim of this study was to analyse the effectiveness and safety of SOF/VEL/VOX in the real-world setting. Methods: This was a prospective multicentre study assessing the efficacy of retreatment with SOF/VEL/VOX in patients who had experienced a prior DAA treatment failure. The primary endpoint was SVR 12 weeks after the completion of treatment (SVR12). Data on safety and tolerability were also recorded. Results: A total of 137 patients were included: 75% men, 35% with liver cirrhosis. Most were infected with HCV genotype (GT) 1 or 3. The most common prior DAA combinations were sofosbuvir plus an NS5A inhibitor or ombitasvir/paritaprevirtr +dasabuvir. A total of 136 (99%) patients achieved undetectable HCV RNA at the end of treatment. Overall SVR12 was 95% in the 135 patients reaching this point. SVR12 was lower in patients with cirrhosis (89%, p = 0.05) and those with GT3 infection (80%, p

Chronic hepatitis C infection (HCV) activates a systemic cell-mediated immune response characterized by the production of IFN? and an innate immune response addressed by the activation of TLR signaling. We aimed to investigate whether HCV eradication by direct acting antivirals (DAA) leads to a recovery in cell-mediated immune response and TLR expression and functionality. Blood samples were obtained in HCV infected patients before DAA treatment and at week +48 after the end of treatment. Results were compared to healthy controls. Cell surface expression of TLR8 was assessed on peripheral blood mononuclear cells (PBMCs) by flow cytometry. Freshly isolated PBMCs were cultured with specific TLR8 agonists and intracellular production of cytokines was determined by flow-cytometry after ex vivo TLR8 activation with ssRNA 40. Production of IFN?, IL2 and IL17 was assessed by flow cytometry in T cells after polyclonal activation. Included were 50 HCV-infected patients and 15 controls. TLR8 expression in PBMCs was significantly increased before treatment and recovered normal levels at week +48. Production of IL1b, IL6 and TNF? dependent on the activation of TLR8 in PBMCs was also increased in patients before DAA treatment, with a significant reduction at week +48. Combined expression of IFN? and IL2 in CD4+ T cells in HCV-infected patients was significantly increased compared to controls and recovered normal levels at week +48. DAA-mediated clearance of HCV is associated with a decreased expression and activation of TLR8 in PBMCs until healthy control levels which is accompanied by a reduction in the Th1 response. This research was funded by the Instituto de Salud Carlos III (ISCIII), grant number PIE15/00079.

Marino, Z., Darnell, A., Lens, S., Sapena, V., Diaz, A., Belmonte, E., Perello, C., Calleja, J.L., Varela, M., Rodriguez, M., Rodriguez de Lope, C., Llerena, S., Torras, X., Gallego, A., Sala, M., Morillas, R.M., Minguez, B., Llaneras, J., Coll, S., Carrion, J.A., Inarrairaegui, M., Sangro, B., Vilana, R., Sole, M., Ayuso, C., Rios, J., Forns, X., Bruix, J., Reig, M.

Resumen Epidemiologia La hepatitis C es una infeccion virica que afecta a unos 180 millones de personas en el mundo. Se trata de la primera causa de trasplante hepatico en nuestro pais. Historia natural La evolucion natural de la enfermedad es la aparicion de cirrosis y el aumento del riesgo de desarrollo de cancer hepatocelular. Manifestaciones clinicas Es una enfermedad silente, cuyo diagnostico mediante signos clinicos supone detectarla en fases avanzadas, es por ello de gran importancia el desarrollo de programas de cribado. Diagnostico El diagnostico inicial se realiza mediante anticuerpos anti-VHC y se confirma demostrando la replicacion virica. Indicacion de tratamiento Se establece tras la evaluacion del grado de fibrosis. Las nuevas tecnicas de evaluacion no invasiva de la fibrosis y la ecografia de ultima generacion permiten una estadificacion precisa y rapida de la enfermedad. Antiviricos de accion directa La incorporacion de los agentes antiviricos de accion directa al arsenal terapeutico frente al VHC ha supuesto un gran avance que permite obtener elevadas tasas de curacion, evitando el empleo de interferon y ribavirina.

Resumen Concepto La hepatitis es una enfermedad del higado de etiologia multifactorial que se caracteriza por la existencia de necrosis hepatocelular e inflamacion. Clasificacion Segun su curso evolutivo pueden ser agudas, cronicas o fulminantes. En esta actualizacion nos centraremos fundamentalmente en las producidas por agentes viricos, que son la causa mas frecuente de hepatitis. Hepatitis B Describiremos con detalle la etiopatogenia, epidemiologia, la historia natural, las manifestaciones clinicas, el diagnostico, el tratamiento y las estrategias de prevencion de la infeccion por el virus de la hepatitis B. Otras hepatitis viricas Posteriormente se destacaran los aspectos mas relevantes de otras hepatitis viricas (hepatitis A, D y E).

AIM To evaluate the long-term outcome of an acute hemodynamic response-guided protocol in which acute responders to intravenous propranolol received traditional nonselective beta-blockers (NSBBs) and acute nonresponders received carvedilol. METHODS Retrospective review of a protocol for primary prophylaxis of variceal bleeding guided by the acute hemodynamic response to intravenous propranolol. Fifty-two acute responders treated with traditional NSBB (i.e. propranolol or nadolol) were compared with 24 acute nonresponders receiving carvedilol. A second hemodynamic study was performed in 27 and 13 patients, respectively. The primary endpoint was development of first or further decompensation. Secondary endpoints included death from any cause, association between acute and chronic hemodynamic response, and baseline clinical and laboratory variables related to the acute hemodynamic response. RESULTS Acute responders and acute nonresponders presented similar 1, 2, and 3-year probabilities of first decompensation (NSBB: 0%, 13.7%, 26.1% vs carvedilol: 0%, 20%, 20%, P = 0.968) or further decompensation (21.2%, 26.1%, 40.9% vs 21.2%, 50.0%, 50.0%, P = 0.525). A previous episode of hepatic encephalopathy was the only independent predictor of decompensation [hazard ratio (95% confidence interval): 8.03 (2.76-23.37)]. Mortality rates were similar in acute responders and acute nonresponders with compensated (P = 0.428) or decompensated cirrhosis (P = 0.429). No clinical, laboratory, endoscopic or hemodynamic parameter predicted the acute hemodynamic response. In patients receiving traditional NSBB, the acute and chronic changes of hepatic venous pressure gradient were correlated (r = 0.59, P = 0.001). Up to 69.2% of acute nonresponders gained chronic response with carvedilol. CONCLUSION Early identification and treatment with carvedilol of acute nonresponders to intravenous propranolol improves the clinical outcome of this high-risk group of patients, probably due to its greater effects for reducing portal pressure.

Epigenetic modifications such as DNA and histone methylation functionally cooperate in fostering tumor growth, including that of hepatocellular carcinoma (HCC). Pharmacological targeting of these mechanisms may open new therapeutic avenues. We aimed to determine the therapeutic efficacy and potential mechanism of action of our dual G9a histone-methyltransferase and DNA-methyltransferase 1 (DNMT1) inhibitor in human HCC cells and their crosstalk with fibrogenic cells. The expression of G9a and DNMT1, along with that of their molecular adaptor ubiquitin-like with PHD and RING finger domains-1 (UHRF1), was measured in human HCCs (n = 268), peritumoral tissues (n = 154), and HCC cell lines (n = 32). We evaluated the effect of individual and combined inhibition of G9a and DNMT1 on HCC cell growth by pharmacological and genetic approaches. The activity of our lead compound, CM-272, was examined in HCC cells under normoxia and hypoxia, human hepatic stellate cells and LX2 cells, and xenograft tumors formed by HCC or combined HCC+LX2 cells. We found a significant and correlative overexpression of G9a, DNMT1, and UHRF1 in HCCs in association with poor prognosis. Independent G9a and DNMT1 pharmacological targeting synergistically inhibited HCC cell growth. CM-272 potently reduced HCC and LX2 cells proliferation and quelled tumor growth, particularly in HCC+LX2 xenografts. Mechanistically, CM-272 inhibited the metabolic adaptation of HCC cells to hypoxia and induced a differentiated phenotype in HCC and fibrogenic cells. The expression of the metabolic tumor suppressor gene fructose-1,6-bisphosphatase (FBP1), epigenetically repressed in HCC, was restored by CM-272. Conclusion: Combined targeting of G9a/DNMT1 with compounds such as CM-272 is a promising strategy for HCC treatment. Our findings also underscore the potential of differentiation therapy in HCC.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. There is increasing interest in developing specific markers to serve as predictors of response to sorafenib and to guide targeted therapy. Using a sequencing platform designed to study somatic mutations in a selection of 112 genes (HepatoExome), we aimed to characterize lesions from HCC patients and cell lines, and to use the data to study the biological and mechanistic effects of case-specific targeted therapies used alone or in combination with sorafenib. We characterized 331 HCC cases in silico and 32 paired samples obtained prospectively from primary tumors of HCC patients. Each case was analyzed in a time compatible with the requirements of the clinic (within 15 days). In 53% of the discovery cohort cases, we detected unique mutational signatures, with up to 34% of them carrying mutated genes with the potential to guide therapy. In a panel of HCC cell lines, each characterized by a specific mutational signature, sorafenib elicited heterogeneous mechanistic and biological responses, whereas targeted therapy provoked the robust inhibition of cell proliferation and DNA synthesis along with the blockage of AKT/mTOR signaling. The combination of sorafenib with targeted therapies exhibited synergistic anti-HCC biological activity concomitantly with highly effective inhibition of MAPK and AKT/mTOR signaling. Thus, somatic mutations may lead to identify case-specific mechanisms of disease in HCC lesions arising from multiple etiologies. Moreover, targeted therapies guided by molecular characterization, used alone or in combination with sorafenib, can effectively block important HCC disease mechanisms. FUNDING: Grants from ISCIII, co-financed by the European Union (FEDER) (PI16/00156), Ramón and Cajal research program from MINECO (RYC-2013-14097) and FUNDACIÓN LUCHAMOS POR LA VIDA to JPV. Grants from ISCIII (RD06/0020/0107-RD012/0036/0060) to MAP. Grant from ISCIII (Ref. PIE15/00079) to JC & JPV. NGD is a recipient of a UC-IDIVAL pre-doctoral fellow. I.V. was also supported by the Ramón and Cajal research program.

Introduction The achievement of a state of tolerance and minimization of the immunosuppressive load form part of the “Holy Grail” in solid organ transplantation. Galectin-1 recently has been described to be involved in the maintenance of a tolerant environment, but there is no evidence of its role in human liver transplantation. The aim of our study was to measure the serum levels of galectin-1 in stable liver transplant recipients. Methods Serum levels of galectin-1 were determined in 30 stable liver transplant recipients who had been free of rejection episodes for at least 8 years. Fifteen patients with an acute rejection episode and 34 healthy subjects were used as the control group. Results The concentrations of galectin-1 were significantly higher in stable liver transplant recipients compared with healthy subjects and with the acute rejection group. Conclusions These preliminary results indicate that galectin-1 is upregulated in stable liver transplant recipients. Thus, our results extend the recent findings that galectin-1 may play an immune-suppressive role in liver transplantation. It remains to be established whether it might help to induce tolerance in liver transplantation.

OBJECTIVES: Prisons are major reservoirs of hepatitis C virus (HCV) in which a therapeutic approach has been particularly difficult so far. Our aim was to create a permanent program of HCV elimination in a prison based on a "test and treat" strategy. METHODS: This open-label clinical trial was conducted in the Spanish prison "El Dueso" between May 2016 and July 2017. Viremic patients were treated with a ledipasvir-sofosbuvir regimen (8-12 weeks) according to the 2015 Spanish Guidelines. A teleconsultation program was established to follow-up patients from the hospital. Non-responders were submitted for a phylogenetic analysis and offered retreatment. An evaluation of new cases of HCV infection was performed every 6 months and upon release in all inmates. RESULTS: 847 (99.5%) inmates accepted to participate. HCV antibodies were present in 110 (13.0%) and 86 (10.2%) had detectable viremia. Most of them were genotype 1 or 3 (82.6%) and had

Patients with HCV genotype 3 (GT3) infection and cirrhosis are currently the most difficult to cure. We report our experience with sofosbuvir+daclatasvir (SOF+DCV) or sofosbuvir/ledipasvir (SOF/LDV), with or without ribavirin (RBV) in clinical practice in this population. This was a multicenter observational study including cirrhotic patients infected by HCV GT3, treated with sofosbuvir plus an NS5A inhibitor (May 2014-October 2015). In total, 208 patients were included: 98 (47%) treatment-experienced, 42 (20%) decompensated and 55 (27%) MELD score >10. In 131 (63%), treatment was SOF+DCV and in 77 (37%), SOF/LDV. Overall, 86% received RBV. RBV addition and extension to 24 weeks was higher in the SOF/LDV group (95% vs 80%, P=.002 and 83% vs 72%, P=.044, respectively). A higher percentage of decompensated patients were treated with DCV than LDV (25% vs 12%, P=.013). Overall, SVR12 was 93.8% (195/208): 94% with SOF+DCV and 93.5% with SOF/LDV. SVR12 was achieved in 90.5% of decompensated patients. Eleven treatment failures: 10 relapses and one breakthrough. RBV addition did not improve SVR (RR: 1.08; P=.919). The single factor associated with failure to achieve SVR was platelet count 10. In 131 (63%), treatment was SOF+DCV and in 77 (37%), SOF/LDV. Overall, 86% received RBV. RBV addition and extension to 24 weeks was higher in the SOF/LDV group (95% vs 80%, P=.002 and 83% vs 72%, P=.044, respectively). A higher percentage of decompensated patients were treated with DCV than LDV (25% vs 12%, P=.013). Overall, SVR12 was 93.8% (195/208): 94% with SOF+DCV and 93.5% with SOF/LDV. SVR12 was achieved in 90.5% of decompensated patients. Eleven treatment failures: 10 relapses and one breakthrough. RBV addition did not improve SVR (RR: 1.08; P=.919). The single factor associated with failure to achieve SVR was platelet count

Treatments with interferon-free direct-acting antiviral agents have high efficacy, with sustained virological response rates of more than 90%. Nevertheless, they fail to eliminate the infection in 1-7% of patients. The majority of virological failures are due to relapse following treatment discontinuation, while virological rebound during therapy is rare. Although not the only factor, the presence of resistance-associated variants is one of the major causes for said failure. Resistance-associated variants affect the sequence involved in protein synthesis on which different direct-acting antiviral agents act (NS3/4A, NS5A, NS5B). Of all these variants, the ones with the greatest impact are resistance-associated variants that affect the NS5A region due to their long-term persistence. In this article we will describe the most significant NS5A resistance-associated variants, the clinical relevance of their detection both before and after treatment, their persistence over time, and lastly, we will devote particular attention to discussing what approach to adopt when dealing with treatment failure to an antiviral regimen that includes NS5A inhibitors.

We performed a case-series analysis of reactivation of herpesvirus in patients with hepatitis C virus (HCV) infection treated with direct-acting antiviral (DAA) agents. We collected data from 576 patients with HCV infection treated with DAA combinations at 3 hospitals in Spain, from November 2014 through November 2015. We also collected data from a control population (230 HCV-infected patients, matched for sex and age; 23 untreated and 213 treated with interferon-based regimens). Herpesvirus was reactivated in 10 patients who received DAA therapy (7 patients had cirrhosis and 3 patients had received liver transplants), a median of 8 weeks after the therapy was initiated. None of the controls had herpesvirus reactivation. Patients with herpesvirus reactivation were receiving the DAA agents sofosbuvir with ledipasvir (with or without ribavirin, 7/10), ombitasvir with paritaprevir and ritonavir plus dasabuvir (with or without ribavirin, 2/10), or sofosbuvir with simeprevir plus ribavirin (1/10). Two of the 10 patients developed postherpetic neuralgia and 1 patient developed kerato-uveitis. All 10 patients with herpesvirus reactivation achieved a sustained virologic response. Immune changes that follow clearance of HCV might lead to reactivation of other viruses, such as herpesvirus. Patients with HCV infection suspected of having herpesvirus infection should be treated immediately. Some groups also might be screened for herpesvirus infection.

Hepatitis C therapy in the era of the newer direct-acting antiviral agents has radically changed our treatment schemes by achieving very high rates of sustained virological response. However, treatment with direct antiviral agents fails in a subgroup of patients. This group of so-called difficult-to-treat individuals is the subject of this paper, which reviews the causes of virological failure, their clinical implications, and some final recommendations.