TY - JOUR
T1 - Improvements in Histologic Features and Diagnosis Associated With Improvement in Fibrosis in Nonalcoholic Steatohepatitis
T2 - Results From the Nonalcoholic Steatohepatitis Clinical Research Network Treatment Trials
AU - for the Nonalcoholic Steatohepatitis Clinical Research Network
AU - Brunt, Elizabeth M.
AU - Kleiner, David E.
AU - Wilson, Laura A.
AU - Sanyal, Arun J.
AU - Neuschwander-Tetri, Brent A.
N1 - Funding Information:
The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK061738, U01DK061730, U01DK061713). Additional support is received from the National Center for Advancing Translational Sciences (UL1TR000439, UL1TR000436, UL1TR000006, UL1TR000448, UL1TR000100, UL1TR000004, UL1TR000423, UL1TR000058). This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute. The PIVENS trial was conducted by the NASH CRN and supported in part by Takeda Pharmaceuticals North America through a Cooperative Research and Development Agreement with the NIDDK. The vitamin E and matching placebo for the PIVENS trial were provided by Pharmavite through a clinical trial agreement with the NIH. The FLINT trial was conducted by the NASH CRN and supported in part by a Collaborative Research and Development Agreement between the NIDDK and Intercept Pharmaceuticals. © 2018 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.30418 Potential conflict of interest: Dr. Brunt consults for Arix, Cymabay, NGM, and Roth Capital Partners. Dr. Neuschwander-Tetri consults for and advises Allergan, Arrowhead, Blade, Boehringer Ingelheim, BMS, Coherus, Consynance, Cymabay, Enanta, Gelesis, Gilead, Intercept, Karos, Lexicon, Madrigal, Medimmune, Merck, Metacrine, NGM, pH-Pharma, and Prometheus. Dr. Sanyal received grants from Conatus, Gilead, Mallinckrodt, Novartis, Galectin, Bristol-Myers Squibb, Merck, Sequana, Hemoshear, and Lilly. He owns stock in Akarna, GenFit, NewCo LLC, Tiziana, and Natural Shield. He also received royalties from UptoDate.
Publisher Copyright:
© 2018 by the American Association for the Study of Liver Diseases.
PY - 2019
Y1 - 2019
N2 - Hepatocellular injury and inflammation are believed to be the primary drivers of fibrogenesis that ultimately lead to cirrhosis in patients with nonalcoholic steatohepatitis (NASH). This study sought associations between observed improvements in fibrosis with improvement in specific histologic features, nonalcoholic fatty liver disease activity score (NAS) ≥2, diagnostic category, and primary histologically based outcomes of two adult NASH treatment trials. The primary outcome for the study was fibrosis improvement from baseline to end of treatment, defined as a 1-point or more improvement in fibrosis stage. This is a retrospective analysis of biopsy data collected from the NASH Clinical Research Network Pathology Committee of Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with NASH Trial (PIVENS) and Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment Trial (FLINT) baseline and final biopsies. Treatment group–adjusted univariable and multivariable logistic regression models related improvement in fibrosis to improvements in other histologic variables, resolution of steatohepatitis, and improvement in the NAS ≥2. In PIVENS 221 subjects had baseline and 96-week biopsies, and in FLINT 200 subjects had baseline and 72-week biopsies. Improvement in fibrosis was found in 38% of PIVENS and 29% of FLINT biopsies; fibrosis improvement was more likely in treated than placebo subjects in both studies. Controlling for treatment group, fibrosis improvement was associated most strongly with resolution of NASH (PIVENS, odds ratio [OR], 3.9; 95% confidence interval [CI] 2.0-7.6; P < 0.001; FLINT, OR, 8.0; 95% CI 3.1-20.9; P < 0.001), and improved NAS by ≥2 (PIVENS, OR, 2.4; 95% CI 1.3-4.3; P = 0.003; FLINT, OR, 4.2; 95% CI 2.1-8.3; P < 0.001). Improvement in histologic features associated with improved fibrosis for both studies included steatosis, ballooning, Mallory-Denk bodies, and portal, but not lobular, inflammation. Conclusion: These findings support a strong link between histologic resolution of steatohepatitis with improvement in fibrosis in NASH.
AB - Hepatocellular injury and inflammation are believed to be the primary drivers of fibrogenesis that ultimately lead to cirrhosis in patients with nonalcoholic steatohepatitis (NASH). This study sought associations between observed improvements in fibrosis with improvement in specific histologic features, nonalcoholic fatty liver disease activity score (NAS) ≥2, diagnostic category, and primary histologically based outcomes of two adult NASH treatment trials. The primary outcome for the study was fibrosis improvement from baseline to end of treatment, defined as a 1-point or more improvement in fibrosis stage. This is a retrospective analysis of biopsy data collected from the NASH Clinical Research Network Pathology Committee of Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with NASH Trial (PIVENS) and Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment Trial (FLINT) baseline and final biopsies. Treatment group–adjusted univariable and multivariable logistic regression models related improvement in fibrosis to improvements in other histologic variables, resolution of steatohepatitis, and improvement in the NAS ≥2. In PIVENS 221 subjects had baseline and 96-week biopsies, and in FLINT 200 subjects had baseline and 72-week biopsies. Improvement in fibrosis was found in 38% of PIVENS and 29% of FLINT biopsies; fibrosis improvement was more likely in treated than placebo subjects in both studies. Controlling for treatment group, fibrosis improvement was associated most strongly with resolution of NASH (PIVENS, odds ratio [OR], 3.9; 95% confidence interval [CI] 2.0-7.6; P < 0.001; FLINT, OR, 8.0; 95% CI 3.1-20.9; P < 0.001), and improved NAS by ≥2 (PIVENS, OR, 2.4; 95% CI 1.3-4.3; P = 0.003; FLINT, OR, 4.2; 95% CI 2.1-8.3; P < 0.001). Improvement in histologic features associated with improved fibrosis for both studies included steatosis, ballooning, Mallory-Denk bodies, and portal, but not lobular, inflammation. Conclusion: These findings support a strong link between histologic resolution of steatohepatitis with improvement in fibrosis in NASH.
UR - http://www.scopus.com/inward/record.url?scp=85062720854&partnerID=8YFLogxK
U2 - 10.1002/hep.30418
DO - 10.1002/hep.30418
M3 - Article
C2 - 30549292
AN - SCOPUS:85062720854
VL - 70
SP - 522
EP - 531
JO - Hepatology
JF - Hepatology
SN - 0270-9139
IS - 2
ER -