Search

Introduction and Objectives: The treatment of vulnerable populations must be prioritized to accomplish the WHO HCV elimination goals by 2030, including patients with mental health disorders, incarcerated patients or homeless patients. Simplifying the treatment cascade and rapid treatment start is key to achieving this goal, even more so in the COVID-19 era. Sofosbuvir/velpatasvir (SOF/VEL) is a protease inhibitor-free, pangenotypic, panfibrotic, single duration, single tablet regimen, to be taken without regards to food and with limited drug-drug interactions, allowing treatment simplification. Purpose: This real world data (RWD) analysis evaluates the effectiveness and safety of SOF/VEL for 12 weeks in a heterogeneous HCV population who suffer a mental health disorder, are incarcerated, or homeless. Materials and Methods: 33 clinical cohorts across Australia, Canada, Europe & USA included 1,888 patients, 280 of them (from 6 clinical cohorts) were treated in Canada and overall managed following local standards of care. Adults were included if SOF/VEL for 12 weeks was started before November 2019 and completed while suffering a mental health disorder, being incarcerated or homeless, irrespective of genotype (GT), presence of compensated cirrhosis (CC) or treatment experience. Exclusion criteria were history of decompensation, prior NS5A-inhibitor exposure, treatment duration >12 weeks or addition of ribavirin. Sustained virological response (SVR; ≥12 weeks after end-of-treatment) and time to treatment initiation were assessed. Results: Overall analysis includes 1,888 (71.3% male) patients (1,422 with a mental health disorder, 526 incarcerated, 153 homeless) aged 50 years, 24.4% were taking antipsychotic drugs and 52.2% of patients had former or current intravenous drug use. 43.2% patients had HCV GT1, 11.6% GT2, 36.3% GT3, 5.9% GT4-6, and 3.0% mixed/unknown GT. 19.0% patients had CC and 12.4% were treatment-experienced. In 257 patients (13.6%), SVR was not evaluated due to non-virological or unknown reasons; 79.9% of those were lost to follow-up (LTFU). When SVR was measured, 98.0% (n=1598/1631) achieved SVR, with 97.6%, 98.9% and 100% in patients with a mental health disorder, incarcerated or homeless patients, respectively. SVR was 98.5% in non-cirrhotic and 95.4% in CC patients. SVR remained >95% under antipsychotic use or coexistence of two negative factors of non-response such as GT3 plus active drug use or psychiatric disorder. SVR was similar, irrespective of time from diagnosis to treatment. Detailed analysis of the Canadian cohort data will be presented at the conference. Conclusion: A test-and-treat strategy, easily implemented with SOF/VEL, and supported by the AASLD/ALEH/APASL/EASL joint call to action, could further enhance the population-level efficacy of HCV therapy by reducing the rate of non-virologic failure due to LTFU and related factors.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD), emerges as major cause of morbidity and mortality globally, with chronic patients facing increased risk. Guidelines on MASLD management in primary care (PC) are limited. This study aimed to develop and evaluate a clinical care pathway for use in PC to improve MASLD screening and management, including early detection, communication and treatment, in three European countries (Greece, Spain, the Netherlands)., Methods: An international multidisciplinary panel of experts oversaw pathway development, which was designed as a two-step algorithm with defined and sequenced tasks. To evaluate algorithm implementation, a controlled pilot study was conducted. Patients at risk of MASLD were assigned to general practitioners (GPs) trained in algorithm implementation (active group) or usual care (control group) and followed for 4-8 weeks. Primary outcomes were the number of patients screened for MASLD, managed in PC and referred to specialists., Results: In this algorithm, patients with metabolic or liver dysfunction, confirmed MASLD or cardiovascular disease are screened with FIB-4 and classified as having risk of low-level (FIB-4 < 1.3), intermediate-level (1.3 ≤ FIB-4 < 2.67) or high-level MASLD (FIB-4 ≥ 2.67). The algorithm provides evidence-based tools to support GPs manage patients with risk of low-level MASLD in PC, coordinate linkage of patients with risk of high-level MASLD to specialists and refer patients with risk of intermediate-level MASLD for elastography (low-risk if <7.9 kPa or intermediate/high-risk if ≥7.9 kPa). During pilot evaluation, N  = 37 participants were recruited in Spain (54.1% women, median age: 63 years). Significantly higher rates of patients in the active group ( n  = 17) than the control group ( n  = 20) were screened with FIB-4 (94.1% vs. 5.5%, p  = 0.004). Patients in the active group received significantly more frequently a PC intervention for weight loss (70.6% vs. 10.0%, p  < 0.001), alcohol regulation (52.9% vs. 0%, p  < 0.001) and smoking cessation (29.4% vs. 0%, p  = 0.005). In Greece no algorithm implementation was observed in either the active or control group, while the evaluation was not conducted in the Netherlands for logistic reasons., Conclusion: This study provides evidence on the development and implementation of a new PC algorithm for MASLD screening and management. Variations among participating settings in algorithm implementation are indicative of context-specific particularities. Further research is necessary for integrating such pathways in tailored interventions to tackle this emerging public health issue., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Anastasaki, Papadakis, Gergianaki, Papastamatiou, Aligizakis, Grillaki, Boutzoukaki, Sivaropoulos, Anastasiou, Mendive, de Juan-Asenjo, Hernández-Ibáñez, Martínez-Escudé, Garcia-Retortillo, Koek, Heyens, Muris and Lionis.)

Background: Liver cirrhosis is a major cause of death worldwide. Cirrhosis develops after a long asymptomatic period of fibrosis progression, with the diagnosis frequently occurring late, when major complications or cancer develop. Few reliable tools exist for timely identification of individuals at risk of cirrhosis to allow for early intervention. We aimed to develop a novel score to identify individuals at risk for future liver-related outcomes., Methods: We derived the LiverRisk score from an international prospective cohort of individuals from six countries without known liver disease from the general population, who underwent liver fibrosis assessment by transient elastography. The score included age, sex, and six standard laboratory variables. We created four groups: minimal risk, low risk, medium risk, and high risk according to selected cutoff values of the LiverRisk score (6, 10, and 15). The model's discriminatory accuracy and calibration were externally validated in two prospective cohorts from the general population. Moreover, we ascertained the prognostic value of the score in the prediction of liver-related outcomes in participants without known liver disease with median follow-up of 12 years (UK Biobank cohort)., Findings: We included 14 726 participants: 6357 (43·2%) in the derivation cohort, 4370 (29·7%) in the first external validation cohort, and 3999 (27·2%) in the second external validation cohort. The score accurately predicted liver stiffness in the development and external validation cohorts, and was superior to conventional serum biomarkers of fibrosis, as measured by area under the receiver-operating characteristics curve (AUC; 0·83 [95% CI [0·78-0·89]) versus the fibrosis-4 index (FIB-4; 0·68 [0·61-0·75] at 10 kPa). The score was effective in identifying individuals at risk of liver-related mortality, liver-related hospitalisation, and liver cancer, thereby allowing stratification to different risk groups for liver-related outcomes. The hazard ratio for liver-related mortality in the high-risk group was 471 (95% CI 347-641) compared with the minimal risk group, and the overall AUC of the score in predicting 10-year liver-related mortality was 0·90 (0·88-0·91) versus 0.84 (0·82-0·86) for FIB-4., Interpretation: The LiverRisk score, based on simple parameters, predicted liver fibrosis and future development of liver-related outcomes in the general population. The score might allow for stratification of individuals according to liver risk and thus guide preventive care., Funding: European Commission under the H20/20 programme; Fondo de Investigación Sanitaria de Salud; Instituto de Salud Carlos III; Spanish Ministry of Economy, Industry, and Competitiveness; the European Regional Development Fund; and the German Ministry of Education and Research (BMBF)., Competing Interests: Declaration of interests PN reports grants from Novo Nordisk and has received consulting fees from Novo Nordisk, Boehringer Ingelheim, Gilead, Intercept, Poxel Pharmaceuticals, Bristol Myers Squibb (BMS), Pfizer, Sun Pharma, Madrigal and GSK. He also reports honoraria as a speaker for Novo Nordisk and AiCME; upport for attending meetings from for Novo Nordisk; and participation on an advisory board for Novo Nordisk, Boehringer Ingelheim, Gilead, Intercept, Poxel Pharmaceuticals, BMS, Pfizer, Sun Pharma, Madrigal, and GSK. AK reports grants from EU Horizon 2020, Novo Nordisk Foundation, Danish National Research Foundation, Region of Southern Denmark; royalties or licenses from Gyldendal; has served as speaker for Norgine, Siemens and Nordic Bioscience; patents from Region of Southern Denmark and University of Southern Denmark; has participated in advisory boards for Norgine and Siemens; has been Vice Secretary European Association for the Study of The Liver (EASL); and received other services from Norgine, Siemens and Echosens. LC has served as speaker for Echosens and Nordic Bioscience; and received consulting fees from Echosens, Madrigal, MSD, Novo Nordisk, Pfizer and Sagimet. LaC reports a grant from Gilead, has received consulting fees from Echosens, Madrigal, MSD, Novo Nordisk, Pfizer and Sagimet; and payment as a speaker for Echosens and Novo Nordisk. AMA reports a grant from Novo Nordisk, Pfizer, and Target Pharma; and has received consulting fees from Novo Nordisk. RJdK reports a grant from GSK, Gilead, Janssen, Inventiva, and Echosens; has served as speaker for Abbvie, Gilead, and Echosens; and has received consulting fees from Abbvie and Gilead. NF has received consulting fees from Gilead. PGa has served as speaker for Bayer, Adaptimmune, Sirtex, Lilly, Roche and Ipsen; and received consulting fees from Bayer, Boston Scientific, AstraZeneca, Adaptimmune, BMS, Eisai, MSD, Sirtex, Lilly, Roche, Guerbet, and Ipsen. IGr participated in advisory boards for GE healthcare; and has served as speaker for Roche and Siemens. ING reports a grant from Gilead. RuH served as speaker for the American Gastroenterological Association and was a manuscript reviewer for GUT; reports support for lectures at the University of Navarra, Pamplona, Spain; and was an external advisor for LiverHope 2020. He also participated in the Steering committee of AASLD-ACLF Special interest Group and Practice Guidelines Committee of AGA. PK reports a grant from Sequana; royalty for UpToDate; honorarium as an Associate Editor for Gastroenterology; and support for attending meeting of EASL and INASL. TK served as speaker for Gilead; has received consulting fees from Albireo and MSD; was a board member at Biomed Alliance; and reports a relationship of stock or stock option with Ultimovacs. JMP reports grants from the European Commission (EFPIA IMI2 853966-2 ISCIII PI19/01898, EFPIA IMI2 777377 ISCIII PI22/01770, and H2020 847989) and Ajuntament de Barcelona-Fundació La Caixa; served as speaker for Novartis, Novo Nordisk, and FLS; and received consulting fees from Boehringer-Ingelheim, MSD, and Novo Nordisk. He also received support from Rubió and NovoNordisk. SP reports a grant from the European Association for the Study of the Liver and the Italian Ministry of Health; received consulting fees from Protein Plasma Therapeutics Assocation and Resolution Therapeutics; and served as speaker for Grifols. He participated in an advisory board of Mallinckrodt. JS reports grants from Gilead Sciences, Boehringer Ingelheim, and Siemens Healthcare; served as speaker for Boehringer Ingelheim, Echosens, MedPublico GmbH, Novo Nordisk, Madrigal Pharmaceuticals, Histoindex, and MedPublico; received consulting fees from Apollo Endosurgery, Bayer, Boehringer Ingelheim, BMS, Gilead Sciences, GSK, Intercept Pharmaceuticals, Ipsen, Inventiva Pharma, Madrigal, MSD, Northsea Therapeutics, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, and Siemens Healthineers; and reports stock or stock options with AGED diagnostics and Hepta Bio. MSB reports a grant from LiverRisk score. MTh is supported by a grant from the Novo Nordisk Foundation (NNF20OC0059393); and served as speaker for Echosens, Siemens Healthcare, Tillotts Pharma, and Norgine; received consulting fees from Ge Healthcare; reports scientific advisory board membership for ID-LIVER (research project); and is a board member of Alcohol & Society (non-governmental organisation, Denmark). VW-SW reports a grant from Gilead Sciences served as speaker for Abbott, AbbVie, Gilead Sciences, Novo Nordisk, and Unilab; reports support from Gilead Sciences; has stock options from Illuminatio Medical Technology; and has received consulting fees from AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Inventiva, Novo Nordisk, Pfizer, Sagimet Biosciences, TARGET PharmaSolutions. MGR reports a grant from Gliead Sciences; served as speaker for Gilead, Abbvie, and Advanz; and reports support from Gilead and Abbvie. DR received honoraria as speaker from Gilead and Abbvie; and received support for meetings and travel from Gilead and AbbVie. PG has received research funding from Gilead, Mallinckrodt, Grifols, and Ferring. PG has consulted or attended advisory boards for Grifols SA, Ferring Pharmaceuticals, Gilead, Intercept, Martin Pharmaceuticals, Promethera, Sequana, RallyBio, SeaBeLife Merck Sharp and Dohme (MSD), and Behring; and received speaking fees from Pfizer. RMM has received honoraria as speaker from Gilead, Abbvie, and Advanz; reports support from Gilead, Abbvie, and Advanz and participated in an advisory board of Advanz. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Primary care has a crucial role to play in the prevention, early detection, referral, and risk factor management of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NAFLD/NASH). In 2021, a team of European collaborators developed a continuing medical education (CME) program on NAFLD/NASH that consolidates evidence and clinical best practices tailored to the primary care setting. This article reports on the methodology used to design and develop the CME and the results of a feasibility study., Methods: An expert advisory group representing both European specialists and general practitioners supported the design of the CME to be implemented in three European settings (Greece, Spain, and Netherlands). The CME features four training modules and problem-based learning using clinical case studies. The CME was tested regarding feasibility and acceptability among a sample of primary care providers (PCPs) in Greece ( n  = 28) with measurements occurring before, immediately after, and 1 month following the training. Outcome measures included satisfaction with the CME, changes in PCPs' knowledge, attitudes, confidence, and self-reported clinical practices related to NAFLD/NASH., Results: The CME is available as an open-access e-learning course on the European Society for Primary Care Gastroenterology education platform in English, Greek, Spanish, and Dutch. The feasibility study documented high levels of satisfaction, with 96% of PCPs reporting they were extremely or very satisfied with the overall training. Statistically significant increases in PCPs' confidence in NAFLD/NASH-related clinical practices were documented between the pre- and post-assessments. At the follow-up, 62% of GPs reported that the CME had changed their clinical practices related to NAFLD/NASH to a great extent., Conclusion: This CME intervention developed by experts and tailored to PCPs in European settings may serve as an asset for increasing knowledge, confidence, and practice behaviors related to NAFLD/NASH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Papadakis, Anastasaki, Gergianaki, Koek, Mendive, Anastasiou, Heyens, Garcia-Retortillo, Muris and Lionis.)

Hepatitis C virus (HCV) is prevalent in people with mental health disorders, a priority population to diagnose and cure in order to achieve HCV elimination. This integrated analysis pooled data from 20 cohorts in seven countries to evaluate the real-world effectiveness of the pangenotypic direct-acting antiviral (DAA) sofosbuvir/velpatasvir (SOF/VEL) in people with mental health disorders. HCV-infected patients diagnosed with mental health disorders who were treated with SOF/VEL for 12 weeks without ribavirin as part of routine clinical practice were included. The primary outcome was sustained virological response (SVR) in the effectiveness population (EP), defined as patients with an available SVR assessment. Secondary outcomes were reasons for not achieving SVR, characteristics of patients with non-virological failures, adherence, and time from HCV RNA diagnosis to SOF/VEL treatment initiation. A total of 1209 patients were included; 142 did not achieve an SVR for non-virological reasons ( n = 112; 83 lost to follow-up, 20 early treatment discontinuations) or unknown reasons ( n = 30). Of the 1067 patients in the EP, 97.4% achieved SVR. SVR rates in the EP were ≥95% when stratified by type of mental health disorder and other complicating baseline characteristics, including active injection drug use and antipsychotic drug use. Of 461 patients with data available in the EP, only 2% had an adherence level < 90% and 1% had an adherence level < 80%; all achieved SVR. Patients with mental health disorders can be cured of HCV using a well-tolerated, pangenotypic, protease inhibitor-free SOF/VEL regimen. This DAA allows the implementation of a simple treatment algorithm, with minimal monitoring requirements and fewer interactions with central nervous system drugs compared with protease-inhibitor DAA regimens.

Abnormal liver function tests (A-LFTs) during admission for coronavirus disease-19 (COVID-19) are frequent, but its evolution after COVID-19 resolution remains unexplored. We evaluated factors related to A-LFTs during COVID-19 and assessed the liver outcome after patients' discharge. This is a observational study including: (1) retrospective analysis of variables related to A-LFTs during COVID-19; and (2) follow-up evaluation with blood test, transient elastography and liver biopsy in those with persistent A-LFTs. A-LFTs were defined according to CTCAEv4.0. Among 595 patients, 366 (61.5%) showed A-LFTs. The ratio of partial pressure of oxygen and inspired oxygen fraction (P/F) below 200, ferritin ≥1000 ng/mL, male gender and antibiotic and immunomodulatory treatments were related to A-LFTs. Follow-up evaluation was performed in 153 individuals. Persistent A-LFTs at follow-up was similar in patients with/without A-LFTs during admission (14.1% vs. 4.9%, p = 0.104). Fifteen (93%) and 58 (39%) patients with/without A-LFTs at follow-up showed metabolic fatty liver disease criteria (p < 0.001), which were histologically confirmed. In conclusion, A-LFTs during COVID-19 were related to infection severity. Abnormalities remitted at follow-up in >80% of patients, and no correlation between A-LFTs at admission and at follow-up was found. Most patients with A-LFTs at follow-up had non-invasive and histologically proven fatty liver disease., (© 2022 John Wiley & Sons Ltd.)

Background: Nucleos(t)ide analogues withdrawal may improve HBsAg loss rates. However, conditions to select patients are not well established., Aims: to evaluate the impact of HBsAg kinetics before treatment interruption on post-treatment response., Methods: Longitudinal, ambispective study in non-cirrhotic chronic hepatitis B HBeAg-negative patients, analysing on-treatment and post-treatment HBsAg kinetics. On-treatment HBsAg kinetics diagnostic accuracy (AUROC) to identify HBsAg loss was evaluated., Results: 52 HBeAg-negative patients stopped treatment after 8.2 years, and 6 (11.5%) achieved HBsAg loss one year after withdrawal. Multivariate analysis showed that on-treatment HBsAg kinetics was related to HBsAg loss (OR=0.10; 95%CI=0.016-0.632; p = 0.014) with a high diagnostic accuracy (AUROC=0.935). A significant HBsAg decline ≥1 log10 IU/mL showed a positive and negative predictive value of 50% and of 97.6%, respectively. After treatment interruption, HBsAg decline speed (log10 IU/mL/year) accelerated in patients treated >6 years (from -0.06 to -0.20, p<0.05) and remained stable in treated <6 years (from -0.12 to -0.12 p=ns)., Conclusions: On-treatment HBsAg kinetics can predict post-treatment HBsAg loss rate. Half of patients with a significant HBsAg decline can eliminate HBsAg the first year after withdrawal. Post-treatment HBsAg decline is faster not only in patients who lost the HBsAg but also in those who remain HBsAg-positive., Competing Interests: Conflict of interest None declared., (Copyright © 2022. Published by Elsevier Ltd.)

Background: The development of liver cirrhosis is usually an asymptomatic process until late stages when complications occur. The potential reversibility of the disease is dependent on early diagnosis of liver fibrosis and timely targeted treatment. Recently, the use of non-invasive tools has been suggested for screening of liver fibrosis, especially in subjects with risk factors for chronic liver disease. Nevertheless, large population-based studies with cost-effectiveness analyses are still lacking to support the widespread use of such tools. The aim of this study is to investigate whether non-invasive liver stiffness measurement in the general population is useful to identify subjects with asymptomatic, advanced chronic liver disease., Methods: This study aims to include 30,000 subjects from eight European countries. Subjects from the general population aged ≥ 40 years without known liver disease will be invited to participate in the study either through phone calls/letters or through their primary care center. In the first study visit, subjects will undergo bloodwork as well as hepatic fat quantification and liver stiffness measurement (LSM) by vibration-controlled transient elastography. If LSM is ≥ 8 kPa and/or if ALT levels are ≥1.5 x upper limit of normal, subjects will be referred to hospital for further evaluation and consideration of liver biopsy. The primary outcome is the percentage of subjects with LSM ≥ 8kPa. In addition, a health economic evaluation will be performed to assess the cost-effectiveness and budget impact of such an intervention. The project is funded by the European Commission H2020 program., Discussion: This study comes at an especially important time, as the burden of chronic liver diseases is expected to increase in the coming years. There is consequently an urgent need to change our current approach, from diagnosing the disease late when the impact of interventions may be limited to diagnosing the disease earlier, when the patient is asymptomatic and free of complications, and the disease potentially reversible. Ultimately, the LiverScreen study will serve as a basis from which diagnostic pathways can be developed and adapted to the specific socio-economic and healthcare conditions in each country., Trial Registration: This study is registered on Clinicaltrials.gov ( NCT03789825 )., (© 2022. The Author(s).)

Background & Aims: Alcoholic hepatitis (AH) is associated with a high incidence of infection and mortality. Rifaximin reduces bacterial overgrowth and translocation. We aimed to study whether the administration of rifaximin as an adjuvant treatment to corticosteroids decreases the number of bacterial infections at 90 days in patients with severe AH compared to a control cohort., Methods: This was a multicentre, open, comparative pilot study of the addition of rifaximin (1200 mg/day/90 days) to the standard treatment for severe AH. The results were compared with a carefully matched historical cohort of patients treated with standard therapy and matching by age and model of end-stage liver disease (MELD). We evaluated bacterial infections, liver-related complications, mortality and liver function tests after 90 days., Results: Twenty-one and 42 patients were included in the rifaximin and control groups respectively. No significant baseline differences were found between groups. The mean number of infections per patient was 0.29 and 0.62 in the rifaximin and control groups, respectively (p = .049), with a lower incidence of acute-on-chronic liver failure (ACLF) linked to infections within the treatment group. Liver-related complications were lower within the rifaximin group (0.43 vs. 1.26 complications/patient respectively) (p = .01). Mortality was lower in the treated versus the control groups (14.2% vs. 30.9, p = .15) without significant differences. No serious adverse events were associated with rifaximin treatment., Conclusions: Rifaximin is safe in severe AH with a significant reduction in clinical complications. A lower number of infections and a trend towards a lower ACLF and mortality favours its use in these patients., (© 2022 The Authors. Liver International published by John Wiley & Sons Ltd.)

Microwave (MWA) and radiofrequency ablation (RFA) are main ablative techniques for hepatocellular carcinoma (HCC) and colorectal liver metastasis (MT). This randomized phase 2 clinical trial compares the effectiveness of MWA and RFA as well as morphology of corresponding ablation zones. HCC and MT patients with 1.5-4 cm tumors, suitable for ablation, were randomized into MWA or RFA Groups. The primary endpoint was short-to-long diameter ratio of ablation zone (SLR). Primary technical success (TS) and a cumulative local tumor progression (LTP) after a median 2-year follow-up were compared. Between June 2015 and April 2020, 82 patients were randomly assigned (41 patients per group). For the per-protocol analysis, five patients were excluded. MWA created larger ablation zones than RFA (p = 0.036) although without differences in SLR (0.5 for both groups, p = 0.229). The TS was achieved in 98% (46/47) and 90% (45/50) (p = 0.108), and LTP was observed in 21% (10/47) vs. 12% (6/50) (OR 1.9 [95% CI 0.66-5.3], p = 0.238) of tumors in MWA vs. RFA Group, respectively. Major complications were found in 5 cases (11%) vs. 2 cases (4%), without statistical significance. MWA and RFA show similar SLR, effectiveness and safety in liver tumors between 1.5 and 4 cm., (© 2022. The Author(s).)

Cirrhosis, highly prevalent worldwide, develops after years of hepatic inflammation triggering progressive fibrosis. Currently, the main etiologies of cirrhosis are non-alcoholic fatty liver disease and alcohol-related liver disease, although chronic hepatitis B and C infections are still major etiological factors in some areas of the world. Recent studies have shown that liver fibrosis can be assessed with relatively high accuracy noninvasively by serological tests, transient elastography, and radiological methods. These modalities may be utilized for screening for liver fibrosis in at-risk populations. Thus far, a limited number of population-based studies using noninvasive tests in different areas of the world indicate that a significant percentage of subjects without known liver disease (around 5% in general populations and a higher rate -18% to 27%-in populations with risk factors for liver disease) have significant undetected liver fibrosis or established cirrhosis. Larger international studies are required to show the harms and benefits before concluding that screening for liver fibrosis should be applied to populations at risk for chronic liver diseases. Screening for liver fibrosis has the potential for changing the current approach from diagnosing chronic liver diseases late when patients have already developed complications of cirrhosis to diagnosing liver fibrosis in asymptomatic subjects providing the opportunity of preventing disease progression., (© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: Hepatitis B e antigen-negative chronic hepatitis B patients under nucleos(t)ids analogues (NAs) rarely achieve hepatitis B surface antigen (HBsAg) loss., Aim: To evaluate if the addition of pegylated interferon (Peg-IFN) could decrease HBsAg and hepatitis B core-related antigen (HBcrAg) levels and increase HBsAg loss rate in patients under NAs therapy., Methods: Prospective, non-randomized, open-label trial evaluating the combination of Peg-IFN 180 µg/week plus NAs during forty-eight weeks vs NAs in monotherapy. Hepatitis B e antigen-negative non-cirrhotic chronic hepatitis B patients of a tertiary hospital, under NAs therapy for at least 2 years and with undetectable viral load, were eligible. Patients with hepatitis C virus, hepatitis D virus or human immunodeficiency virus co-infection and liver transplanted patients were excluded. HBsAg and HBcrAg levels (log10 U/mL) were measured at baseline and during ninety-six weeks. HBsAg loss rate was evaluated in both groups. Adverse events were recorded in both groups. The kinetic of HBsAg for each treatment group was evaluated from baseline to weeks 24 and 48 by the slope of the HBsAg decline (log10 IU/mL/week) using a linear regression model., Results: Sixty-five patients were enrolled, 61% receiving tenofovir and 33% entecavir. Thirty-six (55%) were included in Peg-IFN-NA group and 29 (44%) in NA group. After matching by age and treatment duration, baseline HBsAg levels were comparable between groups (3.1 vs 3.2) ( P = 0.25). HBsAg levels at weeks 24, 48 and 96 declined in Peg-IFN-NA group (-0.26, -0.40 and -0.44) and remained stable in NA group (-0.10, -0.10 and -0.10) ( P < 0.05). The slope of HBsAg decline in Peg-IFN-NA group (-0.02) was higher than in NA group (-0.00) ( P = 0.015). HBcrAg levels did not change. Eight (22%) patients discontinued Peg-IFN due to adverse events. The HBsAg loss was achieved in 3 (8.3%) patients of the Peg-IFN-NA group and 0 (0%) of the NA group., Conclusion: The addition of Peg-IFN to NAs caused a greater and faster decrease of HBsAg levels compared to NA therapy. Side effects of Peg-IFN can limit its use in clinical practice., Competing Interests: Conflict-of-interest statement: Authors declare no conflict-of-interest., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: HBeAg-negative chronic hepatitis B patients require long-term nucleos(t)ide analogues(NAs) because loss of surface antigen (HBsAg) is unusual. Low quantitative HBsAg (qHBsAg) levels can identify patients with higher probability of seroclearance. The aim of our study was to evaluate qHBsAg in HBeAg-negative patients receiving NAs to predict a reduction of HBsAg levels and seroclearance., Methods: Retrospective analysis of qHBsAg in HBeAg-negative patients before and at years 1, 3, 5, 8 and over of NAs treatment., Results: From 1999 to 2015, HBsAg was quantified in 358 serum samples from 95 HBeAg-negative patients. Low qHBsAg (<120 IU/mL) was identified at baseline or during follow-up in 14% of patients and HBsAg loss in 4%. No baseline variables predicted seroclearance and only treatment duration predicted low qHBsAg. The annual decline of qHBsAg was -0.102 log IU/mL and the median time to HBsAg loss was 6.04 years. The decline was greater in patients achieving low HBsAg levels (-0.257) than in those who did not (-0.057)(p<0.001). The diagnostic accuracy (ROC curve, 95%CI) of qHBsAg delta at year 3 was 0.89 (0.81-0.97), with cut-off >0.3 log IU/mL showing a positive and negative predictive value of 42% and 100% to identify patients achieving low levels of HBsAg., Conclusions: Reduction of qHBsAg is slow in HBeAg-negative patients receiving NAs, although low levels or faster qHBsAg decline may occur in 14%. A qHBsAg reduction >0.3 log IU/mL at year 3 can identify patients with a higher probability of achieving low levels and HBsAg seroclearance.

Background and Aim: Transient elastography is the reference method for liver stiffness measurement (LSM) in the general population, having lower applicability in obese patients. We evaluated the applicability and diagnostic accuracy of the M and XL probes in overweight/obese patients to establish the most appropriate approach., Methods: From May 2013 to March 2015, we evaluated patients with a body mass index (BMI) ≥ 28 kg/m 2 . We constructed an algorithm with variables independently related to unreliable LSM with the M probe., Results: A total of 1084 patients were evaluated. M and XL probe applicability was 88.8% and 98%, respectively. Waist circumference (WC) (OR; 95% CI; P) (0.97; 0.94-0.99; P < 0.001) and skin-capsule distance (SCD) (0.83; 0.79-0.87; P < 0.001) were independently related to unreliable LSM (M probe). The SCD was > 25 mm in 5.5% of individuals with a BMI ≤ 35 kg/m 2 and a WC ≤ 117 cm, with LSM (M probe) applicability rising to 94.3%. In contrast, 36.9% of patients with a BMI > 35 kg/m 2 and/or a WC > 117 cm presented an SCD > 25 mm, with M probe applicability being 73.1%. The diagnostic accuracy (area under the receiver operator characteristic) using the M probe to identify significant steatosis (0.76), fibrosis (0.89), and cirrhosis (0.96) was very high in patients with a BMI ≤ 35 kg/m 2 and a WC ≤ 117 cm., Conclusions: The applicability and accuracy of the FibroScan ® M probe to identify fibrosis and steatosis was excellent in overweight and obesity grade I (BMI ≤ 35 kg/m 2 ) with a WC ≤ 117 cm. The XL probe increased the applicability of transient elastography in obesity grade II-III (BMI > 35 kg/m 2 )., (© 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Introduction & Aims: Cryopreservation of serum samples is a standard procedure for biomedical research in tertiary centers. However, studies evaluating the long-term biological stability of direct liver fibrosis markers using cryopreserved samples are scarce., Methods: We compared the stability of hyaluronic acid (HA), tissue inhibitor of metalloproteinases (TIMP-1) and amino-terminal propeptide of type III procollagen (PIIINP) in 225 frozen serum samples of HCV-infected patients with a paired liver biopsy for up to 25 years (1990-2014). Moreover, we assessed the diagnostic accuracy (AUROC) of the Enhanced Liver Fibrosis (ELF®) score to identify significant fibrosis (F2-4) and its predictive capacity to identify clinical events during follow-up., Results: Seventy-six patients (39,8%) had mild fibrosis (F0-1) and 115 (60,2%) significant fibrosis (F2-4). HA, PIIINP and TIMP-1 values remained stable during the period from 1995 to 2014 while those of 1990-94 were slightly higher. We did not find significant differences in the median ELF® values during the 20-year period from 1995-2014 in patients with mild (from 8,4 to 8,7) and significant fibrosis (from 9,9 to 10,9) (p = ns between periods and fibrosis stages). The AUROCs of ELF® to identify significant fibrosis were high in all the periods (from 0,85 to 0,91). The ELF® score showed a good predictive capability to identify clinical events during follow-up., Conclusions: The biological stability of direct serum markers (HA, PIIINP and TIMP-1) using HCV-infected samples cryopreserved for 20 years is good. Therefore, the diagnostic accuracy of the ELF® score to identify significant fibrosis and clinical events during follow-up is very high., Competing Interests: The authors have declared that no competing interests exist.

Objective: The clinical value of thyrotropin receptor antibodies for the differential diagnosis of thyrotoxicosis induced by pegylated interferon-alpha remains unknown. We analyzed the diagnostic accuracy of thyrotropin receptor antibodies in the differential diagnosis of thyrotoxicosis in patients with chronic hepatitis C (CHC) receiving pegylated interferon-alpha plus ribavirin., Methods: Retrospective analysis of 274 patients with CHC receiving pegylated interferon-alpha plus ribavirin. Interferon-induced thyrotoxicosis was classified according to clinical guidelines as Graves disease, autoimmune and non- autoimmune destructive thyroiditis., Results: 48 (17.5%) patients developed hypothyroidism, 17 (6.2%) thyrotoxicosis (6 non- autoimmune destructive thyroiditis, 8 autoimmune destructive thyroiditis and 3 Graves disease) and 22 "de novo" thyrotropin receptor antibodies (all Graves disease, 2 of the 8 autoimmune destructive thyroiditis and 17 with normal thyroid function). The sensitivity and specificity of thyrotropin receptor antibodies for Graves disease diagnosis in patients with thyrotoxicosis were 100 and 85%, respectively. Patients with destructive thyroiditis developed hypothyroidism in 87.5% of autoimmune cases and in none of those with a non- autoimmune etiology (p<0.001)., Conclusion: Thyrotropin receptor antibodies determination cannot replace thyroid scintigraphy for the differential diagnosis of thyrotoxicosis in CHC patients treated with pegylated interferon., (© Georg Thieme Verlag KG Stuttgart · New York.)

Transient elastography (TE) is the reference method to obtain liver stiffness measurements (LSM), but no results are obtained in 3.1% and unreliable in 15.8%. We assessed the applicability and diagnostic accuracy of TE re-evaluation using M and XL probes. From March 2011 to April 2012 868 LSM were performed with the M probe by trained operators (50-500 studies) (LSM1). Measurements were categorized as inadequate (no values or ratio <60% and/or IQR/LSM >30%) or adequate. Inadequate LSM1 were re-evaluated by experienced operators (>500 explorations) (LSM2) and inadequate LSM2 using XL probe (LSMXL). Inadequate LSM1 were obtained in 187 (21.5%) patients, IQR/LSM >30% in 97 (51%), ratio <60% in 24 (13%) and TE failed to obtain a measurement in 67 (36%). LSM2 achieved adequate registers in 123 (70%) of 175 registers previously considered as inadequate. Independent variables (OR, 95%CI) related to inadequate LSM1 were body mass index (1.11, 1.04-1.18), abdominal circumference (1.03, 1.01-1.06) and age (1.03, 1.01-1.04) and to inadequate LSM2 were skin-capsule distance (1.21, 1.09-1.34) and abdominal circumference (1.05, 1.01-1.10). The diagnostic accuracy (AUROC) to identify significant fibrosis improved from 0.89 (LSM1) to 0.91 (LSM2) (P = 0.046) in 334 patients with liver biopsy or clinically significant portal hypertension. A third evaluation (LSMXL) obtained adequate registers in 41 (93%) of 44 patients with inadequate LSM2. Operator experience increases the applicability and diagnostic accuracy of TE. The XL probe may be recommended for patients with inadequate values obtained by experienced operators using the M probe. http://clinicaltrials.gov (NCT01900808)., (© 2014 John Wiley & Sons Ltd.)

Background/aims: The existence of an extrahepatic hepatitis C virus replication compartment is an important question for optimizing therapy and preventing the infection of liver grafts. An extraheptic replication compartment could be indicated if viral decline during the anhepatic phase is not a single exponential. However, the duration of the anhepatic phase is too short (0.5-2h) to allow such analysis. Here we mathematically analyze viral decline during liver transplantation beyond the period of the anhepatic phase and examine the possibility of viral compartmentalization., Methods: Viral load of 30 patients undergoing liver transplantation was frequently measured. Simulation and non-linear fitting of differential equation models were used to test different compartmentalization hypotheses., Results: In 16 of the patients (56%), a bi-phasic viral decline was observed which is explained by the existence of a second replication compartment. This extrahepatic compartment is responsible for about 3.1% of virus in circulation and the mean half-life of its infected cells is 2.6 days. The remaining patients, with a single exponential decline, have either a second compartment with relatively low contribution or no second compartment., Conclusions: These results provide a first quantitative picture of the extrahepatic hepatitis C viral contribution and may suggest new approaches for viral clearance.

Preliminary reports suggested that hepatitis C virus (HCV) infection has a more aggressive course following living donor liver transplantation (LDLT) compared to cadaveric liver transplantation (CLT). The aim of this prospective study was to establish if HCV disease recurrence differs between LDLT and CLT. A cohort of 116 consecutive HCV-infected patients undergoing 117 LTs in a single center from March 2000 to August 2003 were followed-up, including systematic liver biopsies. Severe recurrence (SR) was defined as biopsy-proven cirrhosis and/or the occurrence of clinical decompensation. After a median follow-up of 22 months (2.6-44 months), 26 (22%) patients developed SR (decompensation in 12), involving 17 (18%) of 95 patients undergoing CLT and 9 (41%) of 22 undergoing LDLT. The 2-year probability of presenting SR was significantly higher in LDLT compared to CLT (45% vs. 22%, P = .019). By univariate analysis LDLT (P = .019) and an ALT higher than 80 IU/L 3 months after LT (P = .022) were predictors of SR. In 93 patients from whom a liver biopsy was available 3 months after LT, a lobular necroinflammatory score >1 (P < .01), LDLT (P < .01), and biliary complications (P = .046) were associated with SR. However, the only variables independently associated with SR were LDLT (odds ratio [OR], = 2.8; 95% CI,1.19-6.6; P = .024) and a lobular necroinflammatory score > 1 (OR, 3.1; 95% CI, 1.2-8; P = .013). In conclusion, HCV recurrence is more severe in LDLT compared to CLT. Although our results were based on a single-center experience, they should be considered in the decision-making process of transplant programs, since severe HCV recurrence may ultimately compromise graft and patient survival., (Copyright 2004 American Association for the Study of Liver Diseases)

The study of hepatitis C virus (HCV) kinetics after liver transplantation (LT) might be important to design strategies to prevent HCV infection of the graft. We analyzed HCV kinetics during and immediately after LT in 20 consecutive patients undergoing LT for HCV-related cirrhosis. HCV RNA was quantified in blood samples obtained at regular intervals before, during, and after transplantation. HCV-RNA concentrations decreased in 18 of 20 patients during the anhepatic phase (mean decay slope -0.92, mean HCV elimination half-life 2.2 hours). We found a significant correlation between the HCV viral load decay and the blood loss during the anhepatic phase, indicating that the observed HCV clearance rates are maximum estimates. In fact, in 1 patient with an unusually long anhepatic phase of 20 hours and with minimum blood loss, the HCV elimination half-life was 10.3 hours. Eight to 24 hours after graft reperfusion a sharp decrease in HCV viral load occurred in 19 patients (mean decay slope -0.34, mean HCV elimination half-life 3.44 hours). HCV RNA became undetectable in only 1 patient. During the following days, HCV-RNA concentrations increased rapidly in 10 patients (mean HCV doubling time 13.8 hours), remained at similar levels in 4, and continued to decrease in 6. The only variable associated with a second-phase viral load decay was the absence of corticosteroids as part of the immunosuppressive regimen. In conclusion, a sharp decrease in HCV viral load occurs during the anhepatic phase and immediately after graft reperfusion, most likely owing to a lack of virion production and hepatic viral clearance. HCV infection of the graft, however, is an extremely dynamic process and viral replication begins a few hours after LT.