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

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Etude prospective des performances diagnostiques de différentes méthodes d'évaluation de la fibrose hépatique dans les hépatites chroniques B et C (élastométrie impulsionnelle (FibroScan®), score biologique APRI, analyse morphométrique d'image et score biologique METAVIR)

L'évaluation de la fibrose hépatique est un élément pronostic et pré-thérapeutique indispensable dans les hépatites chroniques virales B et C. De nouvelles méthodes d'évaluation sont maintenant disponibles, dont la place par rapport à la ponction biopsie hépatique reste à préciser. Le but de cette étude était d'étudier les performances diagnostiques de différentes méthodes d'évaluation de la fibrose hépatique, en comparaison à l'étude anatomo-pathologique du parenchyme hépatique. Méthodes : Les performances diagnostiques du FibroScan®, du score APRI et de l'analyse morphométrique d'image ont été étudiées. Le FibroScanCR, est basé sur la technique d'élastométrie impulsionnelle ultrasonore et mesure l'élasticité du foie. Le score APRI est un score biologique simple. L'analyse morphométrique d'image est une technique de quantification de la fibrose à partir d'une coupe tissulaire de parenchyme. Ces trois méthodes ont été étudiées chez 90 malades atteints d'hépatite chronique virale B ou C, en comparaison avec le score histologique semi-quantitatif METAVIR. Résultats : Les performances diagnostiques (aires sous la courbe ROC) du FibroScan® étaient respectivement, pour les stades de fibrose METAVIR >= F2, >= F3, et le stade de cirrhose F4, 0,936, 0,918 et 0,936. Les valeurs seuils d'élasticité corespondantes pour chaque stade de fibrose étaient > 7,8 kPa, > 10,6 kPa et > 13,6 kPa. Pour la technique de morphométrie, les aires sous la courbe étaient, pour les stades de fibrose METAVIR>=F2, >=F3, et le stade de cirrhose F4, 0,888, 0,871 et 0,902, avec des valeurs seuils respectives >5%, >6,7% et >6,7%. Pour le score biologique APRI, les aires sous la courbe étaient, pour chaque stade de fibrose, 0,763, 0,854 et 0,906 avec des valeurs seuils respectives > 1,094, >1,218 et > 1,218. L'élasticité hépatique était significativement corrélée à la quantité de fibrose hépatique (r = 0,526, p<0,0001). Conclusion : Dans les hépatites chroniques virales C, des trois méthodes étudiées, le FibroScan® est celle qui présente la meilleur performance diagnostique. Cet examen est surtout pertinent pour les malades avec une fibrose extensive (F3 ou F4), dans le cadre du dépistage de la cirrhose, ou pour les malades sans fibrose significative F1. La technique de morphométrie a permis de mettre en évidence une corrélation positive entre élasticité et quantité de fibrose. La combinaison score biologique et FibroScan® améliore la performance diagnostique.ROUEN-BU Médecine-Pharmacie (765402102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Misidentification of recombinant hepatitis C virus leading to treatment failure with direct acting antivirals

International audienceThe use of new Direct Acting Antivirals, specific of HCV, has greatly improved the HCV treatment. Most of the DAA are specific of HCV genotypes. Genotyping methods may target different regions of the HCV genome, though only the whole genome sequencing could confirm the correct genotype. The present study describes the virological investigation of a treatment failure due to the false identification of an unusual 2k/1b recombinant HCV form. It describes the sequencing methods, and the similarity analysis of the sequences to different genotype query sequences, to identify the recombination breakpoint

Adjuvant I-131 Lipiodol After Resection or Radiofrequency Ablation for Hepatocellular Carcinoma.

International audienceHigh rates of recurrence have been observed after curative treatment for hepatocellular carcinoma (HCC). The main aim of this study was to establish the influence of adjuvant transarterial radioembolization-based I-131 lipiodol on survival and recurrence

Transient and etiology-related transcription regulation in cirrhosis prior to hepatocellular carcinoma occurrence

AIM: To search for transcription dysregulation that could (1) differentiate hepatocellular carcinoma (HCC)-free from HCC-related cirrhosis (2) differentiate HCC-free cirrhosis related to HCV from that related to alcohol intake

Antioxidants plus corticosteroids in the treatment of severe acute alcoholic hepatitis: the question is still open.

International audienc

Is ribavirin actually useful for Genotype 1 cirrhotic patients who receive DAAs combination? An updated meta-analysis of randomized controlled trials

66th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD), San Francisco, CA, NOV 13-17, 2015International audienc