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Controlled Clinical Trial
. 2022 May;75(5):1235-1246.
doi: 10.1002/hep.32204. Epub 2022 Feb 7.

Cirrhosis regression is associated with improved clinical outcomes in patients with nonalcoholic steatohepatitis

Arun J Sanyal  1 , Quentin M Anstee  2 , Michael Trauner  3 , Eric J Lawitz  4 , Manal F Abdelmalek  5   6 , Dora Ding  7 , Ling Han  7 , Catherine Jia  7 , Ryan S Huss  7 , Chuhan Chung  7 , Vincent Wai-Sun Wong  8 , Takeshi Okanoue  9 , Manuel Romero-Gomez  10 , Andrew J Muir  5   6 , Nezam H Afdhal  11 , Jaime Bosch  12   13 , Zachary Goodman  14 , Stephen A Harrison  15 , Zobair M Younossi  14 , Robert P Myers  7
Affiliations
Controlled Clinical Trial

Cirrhosis regression is associated with improved clinical outcomes in patients with nonalcoholic steatohepatitis

Arun J Sanyal et al. Hepatology. 2022 May.

Abstract

Background and aims: Surrogate endpoints that predict complications are necessary for assessment and approval of NASH therapies. We assessed associations between histologic and noninvasive tests (NITs) of fibrosis with liver-related complications in patients with NASH cirrhosis.

Approach and 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 Clinical Research Network (CRN) and Ishak classifications and a machine learning (ML) approach, hepatic collagen and alpha-smooth muscle actin (α-SMA) expression were quantified by morphometry, liver stiffness (LS) was measured by transient elastography, and serum NITs (enhanced liver fibrosis [ELF], NAFLD fibrosis score [NFS], and Fibrosis-4 index [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 1,135 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% (176/1,135) between BL and W48 was associated with a lower risk of events versus nonregression (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.

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Conflict of interest statement

Dr. Myers is employed by and owns stock in Gilead. Dr. Afdhal advises Gilead and Echosens. Dr. Anstee consults for, is on the speakers’ bureau for, has active research collaborations with, and received grants from Allergan/Tobira. He consults for, has active research collaborations with, and received grants from AstraZeneca, Novartis, and Pfizer. He consults for, is on the speakers’ bureau for, and has active research collaborations with Bristol‐Myers Squibb and Genfit. He consults for and is on the speakers’ bureau for Abbott and Gilead. He consults for and has active research collaborations with Eli Lilly, HistoIndex, Intercept, and Novo Nordisk. He has active research collaborations with and received grants from AbbVie, GlaxoSmithKline, and Glympse Bio. He consults for 89Bio, Acuitas, Altimmune, Axcella, Blade, BNN Cardio, Celgene, Cirius, CymaBay, EcoR1, E3Bio, Galmed, Genentech, Grunthal, Indalo, Imperial Innovations, Inventiva, IQVIA, Janssen, Madrigal, Medimmune, Metacrine, NewGene, NGMBio, North Sea, Poxel, ProSciento, Raptor, Servier, Terns, and Viking. He has active research collaborations with Antaros, Boehringer Ingelheim, Echosens, Ellegaard Gottingen Minipigs AS, Exalenz, iXscient, Nordic Bioscience, One Way Liver Genomics, Perspectum, Resoundant, Sanofi‐Aventis, SomaLogic, and Takeda. He is on the speakers’ bureau for Clinical Care Options, Falk, Fishawack, Integritas, Kenes, and MedScape. He received grants from Vertex. He received royalties from Elsevier. Dr. Sanyal consults and received grants from Conatus, Gilead, Mallinckrodt, Immuron, Boehringer Ingelheim, Novartis, Bristol‐Myers Squibb, Merck, Eli Lilly, Novo Nordisk, Fractyl, Siemens, Madrigal, Inventiva, and Covance. He consults for and owns stock in Genfit. He consults for Intercept, Pfizer, Salix, Galectin, Hemoshear, Terns, Albireo, Sanofi, Janssen, Takeda, NorthSea, AMRA, Perspectum, Poxel, 89 Bio, AstraZeneca, NGM, Amgen, Regeneron, Genentech, Roche, Prosciento, Histoindex, Path AI, and Biocellvia. He received grants from Echosens‐Sandhill, Owl, and Second Genome. He owns stock in Exalenz, Sanyal Bio, Durect, Indalo, Tiziana, and Rivus. He received royalties from Elsevier and UptoDate. Dr. Trauner advises for, is on the speakers’ bureau for, and received grants from Gilead, Intercept, and MSD. He advises and received grants from Falk and Albireo. He advises BiomX, Boehringer Ingelheim, Genfit, Janssen, Novartis, Phenex, Regulus, and Shire. He is on the speakers’ bureau for Falk Foundation. He received grants from AbbVie, Alnylam, Cymabay, Takeda, and UltraGenyx. Dr. Lawitz received grants from 89Bio, Akero, Alnylam, Amgen, AstraZeneca, Axcella, Boehringer Ingelheim, Bristol‐Myers Squibb, Cymabay, CytoDyn, Durect, Eli Lilly, Enanta, Galectin, Galmed, Genentech, Gilead, Hanmi, Intercept, Inventiva, Janssen, Laboratory for Advanced Medicine, Madrigal, Merck, Metacrine, NGM, NorthSea, Novartis, Novo Nordisk, Pfizer, Poxel, Roche, Sagimet, Synlogic, Terns, Valeant, Viking, and Zydus. Dr. Abdelmalek received grants from Gilead. Dr. Ding is employed by and owns stock in Gilead. Dr. Jia is employed by and owns stock in Gilead. Dr. Huss is employed by and owns stock in Gilead. Dr. Chung is employed by and owns stock in Gilead. Dr. Wong consults for and received grants from Gilead. He consults for 3V‐Bio, AbbVie, Allergan, Boehringer Ingelheim, Echosens, Inventiva, Merck, Novartis, Novo Nordisk, Pfizer, ProSciento, Sagimet, TARGET, and Terns. He is cofounder of Illuminatio Medical Technology Limited. Dr. Muir consults for and received grants from Gilead. He received grants from Cymabay. Dr. Bosch consults for Gilead and Actelion. Dr. Younossi consults for Gilead, Intercept, Novo Nordisk, Siemens, and Terns. Dr. Harrison consults for, advises, received grants from, and owns stock in Akero, Galectin, Genfit, Hepion, Metacrine, NGM, and NorthSea. He consults for, advises, and received grants from Axcella, Civi, CymaBay, Gilead, High Tide, Intercept, Madrigal, Novartis, Novo Nordisk, Poxel, and Sagimet. He consults for, advises, and owns stock in HistoIndex and Sonic Incytes. He consults for and advises Altimmune, Echosens, Foresite, Medpace, Prometic, Ridgeline, and Terns. He consults for and received grants from Enyo and Viking. He advises and received grants from Galmed. He advises and owns stock in Chronwell and PathAI. He received grants from and owns stock in Cirius. He consults for AgomAB, Alentis, Alimentiv, Boston Pharmaceuticals, B Riley, BVF, Canfite, Corcept, Fibronostics, Fortress, Inipharm, Ionis, Kowa, Microba, Nutrasource, and Piper Sandler. He advises 89Bio, Arrowhead, Indalo, and Theratechnologies.

Figures

FIGURE 1
FIGURE 1
Associations between fibrosis‐related histological parameters and NITs with time to first liver‐related clinical event. Separate multivariate models run with baseline and change from baseline for each variable. Models for change adjusted for baseline value. Bold indicates significant value (p < 0.05)
FIGURE 2
FIGURE 2
Liver‐related clinical events according to baseline Ishak fibrosis stage
FIGURE 3
FIGURE 3
Association between fibrosis regression and liver‐related clinical events. HR for clinical events with fibrosis regression vs. no fibrosis regression (reference). p values by Fisher’s exact test
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