Author information
1 Virginia Commonwealth University, Richmond, Virginia.
2 Pinnacle Clinical Research, San Antonio, Texas.
3 Hôpital Universitaire Pitié-Salpêtrière, Paris, France.
4 Duke Clinical Research Institute, Durham, North Carolina.
5 University of Virginia, Charlottesville, Virginia.
6 Liver Institute of Virginia, Richmond, Virginia.
7 Gilead Sciences, Inc, Foster City, California.
8 Inova Fairfax Hospital, Falls Church, Virginia.
9 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
10 Inselspital, Bern University, Switzerland.
11 IDIBAPS, University of Barcelona, Barcelona, Spain.
Abstract
Progression of nonalcoholic steatohepatitis (NASH) is incompletely characterized. We analyzed data on longitudinal changes in liver histology, hepatic venous pressure gradient (HVPG), and serum markers of fibrosis in 475 NASH patients with bridging fibrosis (F3) or compensated cirrhosis (F4) enrolled in 2 phase 2b, placebo-controlled trials of simtuzumab. The trials were terminated after 96 weeks due to lack of efficacy, so data from treatment groups were combined. Liver biopsies and HVPG measurements (only for patients with F4 fibrosis) were collected at screening, and weeks 48 and 96. Patients were assessed for Ishak fibrosis stage, hepatic collagen content and alpha-smooth muscle actin (by morphometry), NAFLD Activity Score (NAS), and serum markers of fibrosis. Associations with progression to cirrhosis (in patients with F3 fibrosis) and liver-related clinical events (in patients with F4 fibrosis) were determined. Progression to cirrhosis occurred in 22% (48/217) of F3 patients and liver-related clinical events occurred in 19% (50/258) of patients with cirrhosis. Factors significantly associated with progression to cirrhosis included higher baseline values of and greater increases in hepatic collagen content, level of alpha-smooth muscle actin, and Enhanced Liver Fibrosis score. Similar factors, plus lack of fibrosis stage improvement (hazard ratio, 9.30; 95% CI, 1.28-67.37), higher HVPG at baseline, and greater increase in HVPG over time, were associated with an increased risk of liver-related clinical events in patients with cirrhosis. Diseaseprogression was not associated with the NAS at baseline or changes in NAS during treatment after adjustment for fibrosis stage. CONCLUSION: In patients with advanced fibrosis due to NASH, the primary determinant of clinical disease progression is fibrosis and its change over time.