The Natural History of Advanced Fibrosis Due to Nonalcoholic Steatohepatitis: Data From the Simtuzumab Trials

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 patients with NASH with bridging fibrosis (F3) or compensated cirrhosis (F4) enrolled in two phase 2b, placebo‐controlled trials of simtuzumab. The trials were terminated after 96 weeks because of 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 at 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% confidence interval, 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. Disease progression 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.

Changes in Hepatic Venous Pressure Gradient Predict Hepatic Decompensation in Patients Who Achieved Sustained Virologic Response to Interferon‐Free Therapy

“…Finally, the prognostic impact of HVPG decreases due to pharmacological therapies for NASH is currently being investigated. The results of a recent randomized controlled trial on simtuzumab, a monoclonal antibody against lysyl oxidase‐like 2, in patients with compensated cirrhosis suggest that an HVPG decrease ≥ 20% is associated with a lower risk of hepatic decompensation . However, simtuzumab has been found to be ineffective in this setting, and one third of patients included in this analysis have been assigned to the placebo group .…”

“…The results of a recent randomized controlled trial on simtuzumab, a monoclonal antibody against lysyl oxidase-like 2, in patients with compensated cirrhosis suggest that an HVPG decrease ≥ 20% is associated with a lower risk of hepatic decompensation. (17) However, simtuzumab has been found to be ineffective in this setting, and one third of patients included in this analysis have been assigned to the placebo group. (36) Thus, this study confirms the prognostic value of HVPG and its changes over time in compensated NASH cirrhosis rather than providing strong evidence for the use of HVPG response as a surrogate outcome for the clinical effectiveness of an etiological treatment.…”

“…(36) Thus, this study confirms the prognostic value of HVPG and its changes over time in compensated NASH cirrhosis rather than providing strong evidence for the use of HVPG response as a surrogate outcome for the clinical effectiveness of an etiological treatment. (17) Accordingly, insights from patients with CHC are of great importance for advancing the understanding of the association between changes in HVPG due to therapies targeting intrahepatic resistance (i.e., etiological treatments) and clinical outcomes. Evidence from such studies is essential for promoting HVPG as a surrogate endpoint accepted by regulatory authorities.…”

“…(15) However, there is also limited evidence from patients with HVPG ≥ 12 mm Hg due to alcoholic liver disease (ALD) who were advised to abstain from alcohol (HVPG decrease cutoff ≥ 15%), (16) or patients with compensated cirrhosis due to nonalcoholic steatohepatitis (NASH) treated with simtuzumab or placebo (HVPG decrease cutoff ≥ 20%). (17) Besides variceal (re-)bleeding, HVPG response to conventional NSBB ± vasoactive drugs has been shown to decrease the risks of occurrence/worsening of ascites and its complications. (15) In addition, some studies even reported (trends toward) a decrease in hepatic encephalopathy (HE), a decompensating event that is less closely linked to PH.…”

The 20% Rule of NASH Progression: The Natural History of Advanced Fibrosis and Cirrhosis Caused by NASH

“…In this context, Sanyal and colleagues explore in this issue of Hepatology the progression of liver disease and predictors of fibrosis progression and decompensation, as well as potential monitoring strategies in 475 patients with nonalcoholic steatohepatitis (NASH) and bridging fibrosis or compensated cirrhosis. (4) Notably, 68% of patients with cirrhosis had a baseline hepatic venous pressure gradient (HPVG) measurement of ≥10 mm Hg, demonstrating that the majority had clinically significant portal hypertension at study entry. The cohort originated from two phase 2 randomized clinical trials of simtuzumab, a humanized monoclonal antibody targeting lysyl oxidaselike 2 (LOXL2), which had negative results.…”