A randomized, controlled study of peginterferon lambda-1a/ribavirin +/- daclatasvir for hepatitis C virus genotype 2 or 3

Background and purpose: Peginterferon Lambda was being developed as an alternative to alfa interferon for the treatment of chronic hepatitis C virus (HCV) infection. We compared peginterferon Lambda-1a plus ribavirin (Lambda/RBV) and Lambda/RBV plus daclatasvir (DCV; pangenotypic NS5A inhibitor) with peginterferon alfa-2a plus RBV (alfa/RBV) in treatment-naive patients with HCV genotype 2 or 3 infection. Methods: In this multicenter, double-blind, phase 3 randomized controlled trial, patients were assigned 2:2:1 to receive 24 weeks of Lambda/RBV, 12 weeks of Lambda/RBV + DCV, or 24 weeks of alfa/RBV. The primary outcome measure was sustained virologic response at post-treatment Week 12 (SVR12). Results: Overall, 874 patients were treated: Lambda/RBV, n = 353; Lambda/RBV + DCV, n = 349; alfa/RBV, n = 172. Patients were 65 % white and 33 % Asian, 57 % male, with a mean age of 47 years; 52 % were infected with genotype 2 (6 % cirrhotic) and 48 % with genotype 3 (9 % cirrhotic). In the Lambda/RBV + DCV group, 83 % (95 % confidence interval [CI] 78.5, 86.5) achieved SVR12 (90 % genotype 2, 75 % genotype 3) whereas SVR12 was achieved by 68 % (95 % CI 63.1, 72.9) with Lambda/RBV (72 % genotype 2, 64 % genotype 3) and 73 % (95 % CI 66.6, 79.9) with peginterferon alfa/RBV (74 % genotype 2, 73 % genotype 3). Lambda/RBV + DCV was associated with lower incidences of flu-like symptoms, hematological abnormalities, and discontinuations due to adverse events compared with alfa/RBV. Conclusion: The 12-week regimen of Lambda/RBV + DCV was superior to peginterferon alfa/RBV in the combined population of treatment-naive patients with genotype 2 or 3 infection, with an improved tolerability and safety profile compared with alfa/RBV.Peer reviewe

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

Hépatite chronique C à transaminases normales de façon répétée

Environ un quart des malades atteints d’hépatite chronique C ont des transaminases normales de façon répétée. Le pronostic est dans l’ensemble bon. La vitesse de progression de la fibrose est lente et l’évolution vers la cirrhose est rare dans cette population. En raison d’une faible efficacité des traitements disponibles, l’attitude thérapeutique recommandée était jusqu’à présent l’abstention. Avec l’arrivée de la bithérapie interféron pégylé-ribavirine, beaucoup plus efficace, l’opportunité de traiter ces malades doit être rediscutée, en particulier chez ceux qui ont une forte probabilité de réponse prolongée

Physiopathologie du traitement de l'hépatite chronique C par les interférons, la ribavirine et les inhibiteurs spécifiques

Pas de résumé françaisPas de résumé anglaisPARIS-EST-Université (770839901) / SudocPARIS12-Bib. électronique (940280011) / SudocSudocFranceF

Environmental factors as disease accelerators during chronic hepatitis C.

International audienceProgression of chronic hepatitis is highly variable among individuals, as the result of several host, viral and environmental factors. The latter have been extensively investigated in order to ameliorate hepatitis C outcome, particularly in difficult-to-treat patients. Over the last decade, several studies have shown that a combination of HCV infection and high levels of alcohol abuse results in synergistic acceleration of liver fibrogenesis. In addition, recent data indicate that light alcohol intake may also exacerbate fibrosis progression. It has also been suggested that cigarette smoking may enhance activity grade in patients with chronic hepatitis C, thereby increasing progression of fibrosis. This assumption mostly relies on epidemiological evidences in the absence of pathogenic studies. Finally, cannabis use is increasingly emerging as a novel co-morbidity in patients with chronic hepatitis C. Indeed, regular cannabis smoking is an independent predictor of both fibrosis and steatosis severity in infected patients. In addition, experimental studies have shown that cannabinoid CB1 receptors enhance liver fibrogenesis and steatogenesis by distinct mechanisms, therefore strongly supporting epidemiological findings. Altogether, patients should be informed of the deleterious impact of alcohol, tobacco and cannabis use and should be offered appropriate support to achieve abstinence

: Cannabinoïdes et hépatopathies chroniques

(1er paragraphe) Le cannabis (marijuana, Cannabis sativa) est utilisé depuis l'antiquité comme substance psychoactive récréative, mais également en médecine traditionnelle pour ses effets orexigènes et antalgiques (1, 2). Le principal composé actif du cannabis, le Δ9–tetrahydrocannabinol (THC) n'a cependant a été isolé qu'en 1964. La compréhension des mécanismes d'action des phytocannabinoïdes a connu un essor considérable depuis les années quatre-vingt dix, avec le clonage de deux récepteurs spécifiques, CB1 et CB2, suivi de l'identification de ligands endogènes de ces récepteurs, les endocannabinoïdes. Ce système a depuis été progressivement impliqué dans de très nombreux processus physiopathologiques, ouvrant ainsi de nouvelles perspectives thérapeutiques (1, 2). L'hépatologie n'est pas en reste, avec en l'espace de cinq ans, l'identification d'un rôle clef des cannabinoïdes dans la physiopathologie de l'hypertension portale, de la stéatose et de la fibrogenèse hépatique (3)