Factors Associated With Histologic Response in Adult Patients With Nonalcoholic Steatohepatitis.

Abstract

BACKGROUND & AIMS:

Nonalcoholic steatohepatitis (NASH) is a leading cause of liver transplantation, and many trials are underway to evaluate potential therapies. The farnesoid X receptor ligand obeticholic acid in the NASH treatment trial evaluated the effects of obeticholic acid vs placebo on histologic response (defined as decrease in nonalcoholic fatty liver disease activity score [NAS] by ≥2, with no worsening of fibrosis); 45% of patients had a histologic response to obeticholic acid (25 mg), and 21% had a response to placebo (P < .01). We performed a secondary analysis of data from this trial to identify clinical parameters associated with a histologic response.

METHODS:

We used a logistic regression model with a stepwise selection procedure to identify baseline and early on-treatment factors associated with a histologic response at 72 weeks. Baseline demographics, liver histology, medical history, concomitant medications, cardiometabolic parameters, and serum biochemistry, as well as the changes over the course of the trial (at weeks 12 and 24), were evaluated as potential predictors of a histologic response. The model was cross-validated by a jackknife method, and performance was evaluated with the area under the receiver operating characteristic curve.

RESULTS:

The logistic regression model found that obeticholic acid treatment, baseline NAS > 5, baseline triglyceride level ≤ 154 mg/dL, baseline international normalized ratio ≤ 1, baseline aspartate aminotransferase level ≤ 49 U/L, and a decrease in alanine aminotransferase level at week 24 by 17 U/L or more, to be significantly associated with histologic response (area under the receiver operating characteristic curve, 0.83; 95% confidence interval, 0.77-0.89; P < .0001).

CONCLUSIONS:

In a secondary analysis of data from a clinical trial of obeticholic acid in patients with NASH, we identified routine clinical and laboratory parameters during the first 24 weeks of treatment (such as baseline NAS, triglyceride levels, and a decrease in alanine aminotransferase level) to significantly associate with histologic markers of response.

• Authors: Rohit Loomba, Arun J Sanyal, Kris V Kowdley, Norah Terrault, Naga P Chalasani, Manal F Abdelmalek, Arthur J McCullough, Reshma Shringarpure, Beatrice Ferguson, Lois Lee, Jianfen Chen, Alexander Liberman, David Shapiro, Brent A Neuschwander-Tetri
• Journal: Gastroenterology (Gastroenterology) Vol. 156 Issue 1 Pg. 88-95.e5 (01 2019) ISSN: 1528-0012 [Electronic] United States
• PMID: 30222962 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers
• Gastrointestinal Agents
• Ligands
• Receptors, Cytoplasmic and Nuclear
• obeticholic acid
• farnesoid X-activated receptor
• Chenodeoxycholic Acid

Topics

• Adult
• Biomarkers (blood)
• Biopsy
• Chenodeoxycholic Acid (analogs & derivatives, therapeutic use)
• Clinical Enzyme Tests
• Decision Support Techniques
• Female
• Gastrointestinal Agents (therapeutic use)
• Humans
• Ligands
• Liver (drug effects, metabolism, pathology)
• Liver Cirrhosis (blood, drug therapy, pathology)
• Male
• Middle Aged
• Non-alcoholic Fatty Liver Disease (blood, drug therapy, pathology)
• Predictive Value of Tests
• Receptors, Cytoplasmic and Nuclear (drug effects, metabolism)
• Time Factors
• Treatment Outcome
• United States