Cirrhosis Regression is Associated with Improved Clinical Outcomes in Patients with Nonalcoholic Steatohepatitis

Background & aims Surrogate endpoints that predict complications are necessary for assessment and approval of NASH therapies. We assessed associations between histologic and noninvasive tests of fibrosis (NITs) with liver-related complications in patients with NASH cirrhosis. Approach & results Patients with compensated cirrhosis due to NASH were enrolled in two placebo-controlled trials of simtuzumab and selonsertib. Liver fibrosis at baseline and week 48 (W48) was staged by NASH CRN and Ishak classifications and a machine learning (ML) approach, hepatic collagen and α-SMA expression were quantified by morphometry, liver stiffness (LS) was measured by transient elastography, and serum NITs (ELF, NAFLD Fibrosis Score [NFS], and FIB-4) were calculated. Cox regression determined associations between these parameters at baseline and their changes over time with adjudicated liver-related clinical events. Among 1135 patients, 709 (62%) had Ishak stage 6 fibrosis, and median ELF and LS were 10.66 and 21.1 kPa, respectively. During a median follow-up of 16.6 months, 71 (6.3%) had a liver-related event; associated baseline factors included Ishak stage 6 fibrosis, and higher hepatic collagen, α-SMA expression, ML-based fibrosis parameters, LS, ELF, NFS, and FIB-4. Cirrhosis regression observed in 16% (176/1135) between BL and W48 was associated with a lower risk of events vs non-regression (1.1% [2/176] vs 7.2% [69/957]; HR: 0.16; 95%CI 0.04,0.65 [p=0.0104]). Conversely, after adjustment for baseline values, increases in hepatic collagen, α-SMA, ML-based fibrosis parameters, NFS, and LS were associated with an increased risk of events. Conclusions In patients with compensated cirrhosis due to NASH, regression of fibrosis is associated with a reduction in liver-related complications. These data support the utility of histologic fibrosis regression and NITs as clinical trial endpoints for NASH cirrhosis.