The bile acid derivative 6-ethylchenodeoxycholic acid (obeticholic acid) is a potent activator of the farnesoid X nuclear receptor that reduces liver fat and fibrosis in animal models of fatty liver disease. We assessed the efficacy of obeticholic acid in adult patients with non-alcoholic steatohepatitis.
We did a multicentre, double-blind, placebo-controlled, parallel group, randomised clinical trial at medical centres in the USA in patients with non-cirrhotic, non-alcoholic steatohepatitis to assess treatment with obeticholic acid given orally (25 mg daily) or placebo for 72 weeks. Patients were randomly assigned 1:1 using a computer-generated, centrally administered procedure, stratified by clinical centre and diabetes status. The primary outcome measure was improvement in centrally scored liver histology defined as a decrease in non-alcoholic fatty liver disease activity score by at least 2 points without worsening of fibrosis from baseline to the end of treatment. A planned interim analysis of change in alanine aminotransferase at 24 weeks undertaken before end-of-treatment (72 weeks) biopsies supported the decision to continue the trial (relative change in alanine aminotransferase −24%, 95% CI −45 to −3). A planned interim analysis of the primary outcome showed improved efficacy of obeticholic acid (p=0·0024) and supported a decision not to do end-of-treatment biopsies and end treatment early in 64 patients, but to continue the trial to obtain the 24-week post-treatment measures. Analyses were done by intention-to-treat. This trial was registered with ClinicalTrials.gov, number NCT01265498.
Between March 16, 2011, and Dec 3, 2012, 141 patients were randomly assigned to receive obeticholic acid and 142 to placebo. 50 (45%) of 110 patients in the obeticholic acid group who were meant to have biopsies at baseline and 72 weeks had improved liver histology compared with 23 (21%) of 109 such patients in the placebo group (relative risk 1·9, 95% CI 1·3 to 2·8; p=0·0002). 33 (23%) of 141 patients in the obeticholic acid developed pruritus compared with nine (6%) of 142 in the placebo group.
Obeticholic acid improved the histological features of non-alcoholic steatohepatitis, but its long-term benefits and safety need further clarification.
National Institute of Diabetes and Digestive and Kidney Diseases, Intercept Pharmaceuticals.
http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/12-1-reading-terrault a video presentation of this article
http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/12-1-interview-terrault the interview with the author
The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation. ClinTrials.gov: NCT01938430.
In HCV-infected patients in whom initial peginterferon alfa and ribavirin treatment failed, retreatment with telaprevir in combination with peginterferon alfa-2a and ribavirin was more effective than retreatment with peginterferon alfa-2a and ribavirin alone. (ClinicalTrials.gov number, NCT00420784.)
We aimed to determine whether frailty, a validated geriatric construct of increased vulnerability to physiologic stressors, predicts mortality in liver transplant (LT) candidates. Consecutive adult outpatients listed for LT with laboratory MELD≥12 at a single center (97% recruitment rate) underwent 4 frailty assessments: Fried Frailty, Short Physical Performance Battery (SPPB), Activities of Daily Living (ADL), and Instrumental ADL (IADL) scales. Competing risks models associated frailty with wait-list mortality (death/delisting for being too sick for LT). 294 listed LT patients with MELD≥12, median age 60y, and MELD 15 were followed for 12 months. By Fried Frailty score≥3, 17% were frail; 11/51 (22%) of the frail versus 25/243 (10%) of the not frail died/were delisted (p=0.03). Each 1-unit increase in the Fried Frailty score was associated with a 45% (95%CI, 4-202%) increased risk of wait-list mortality adjusted for MELD. Similarly, the adjusted risk of wait-list mortality associated with each 1-unit decrease (i.e., increasing frailty) in the SPPB (HR 1.19, 95%CI 1.07-1.32). Frailty is prevalent in LT candidates. It strongly predicts wait-list mortality, even after adjustment for liver disease severity demonstrating the applicability and importance of the frailty construct in this population.
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