Factors Associated With Histologic Response in Adult Patients With Nonalcoholic Steatohepatitis

Rohit Loomba, Arun J. Sanyal, Kris V. Kowdley, Norah Terrault, Naga Chalasani, Manal F. Abdelmalek, Arthur J. McCullough, Reshma Shringarpure, Beatrice Ferguson, Lois Lee, Jianfen Chen, Alexander Liberman, David Shapiro, Brent A. Neuschwander-Tetri

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)88-95.e5
JournalGastroenterology
Volume156
Issue number1
DOIs
StatePublished - Jan 1 2019

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Alanine Transaminase
Triglycerides
Placebos
International Normalized Ratio
Aspartate Aminotransferases
ROC Curve
Liver Transplantation
Fibrosis
Therapeutics
Clinical Trials
Confidence Intervals
Ligands
6-ethylchenodeoxycholic acid
Non-alcoholic Fatty Liver Disease

Keywords

  • FLINT Trial
  • FXR Agonist
  • NAFLD
  • OCA

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Loomba, R., Sanyal, A. J., Kowdley, K. V., Terrault, N., Chalasani, N., Abdelmalek, M. F., ... Neuschwander-Tetri, B. A. (2019). Factors Associated With Histologic Response in Adult Patients With Nonalcoholic Steatohepatitis. Gastroenterology, 156(1), 88-95.e5. https://doi.org/10.1053/j.gastro.2018.09.021

Factors Associated With Histologic Response in Adult Patients With Nonalcoholic Steatohepatitis. / Loomba, Rohit; Sanyal, Arun J.; Kowdley, Kris V.; Terrault, Norah; Chalasani, Naga; Abdelmalek, Manal F.; McCullough, Arthur J.; Shringarpure, Reshma; Ferguson, Beatrice; Lee, Lois; Chen, Jianfen; Liberman, Alexander; Shapiro, David; Neuschwander-Tetri, Brent A.

In: Gastroenterology, Vol. 156, No. 1, 01.01.2019, p. 88-95.e5.

Research output: Contribution to journalArticle

Loomba, R, Sanyal, AJ, Kowdley, KV, Terrault, N, Chalasani, N, Abdelmalek, MF, McCullough, AJ, Shringarpure, R, Ferguson, B, Lee, L, Chen, J, Liberman, A, Shapiro, D & Neuschwander-Tetri, BA 2019, 'Factors Associated With Histologic Response in Adult Patients With Nonalcoholic Steatohepatitis', Gastroenterology, vol. 156, no. 1, pp. 88-95.e5. https://doi.org/10.1053/j.gastro.2018.09.021
Loomba, Rohit ; Sanyal, Arun J. ; Kowdley, Kris V. ; Terrault, Norah ; Chalasani, Naga ; Abdelmalek, Manal F. ; McCullough, Arthur J. ; Shringarpure, Reshma ; Ferguson, Beatrice ; Lee, Lois ; Chen, Jianfen ; Liberman, Alexander ; Shapiro, David ; Neuschwander-Tetri, Brent A. / Factors Associated With Histologic Response in Adult Patients With Nonalcoholic Steatohepatitis. In: Gastroenterology. 2019 ; Vol. 156, No. 1. pp. 88-95.e5.
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AU - Loomba, Rohit

AU - Sanyal, Arun J.

AU - Kowdley, Kris V.

AU - Terrault, Norah

AU - Chalasani, Naga

AU - Abdelmalek, Manal F.

AU - McCullough, Arthur J.

AU - Shringarpure, Reshma

AU - Ferguson, Beatrice

AU - Lee, Lois

AU - Chen, Jianfen

AU - Liberman, Alexander

AU - Shapiro, David

AU - Neuschwander-Tetri, Brent A.

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N2 - 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.

AB - 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.

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