Objective In retrospective studies, liver stiffness (LS) by vibration-controlled transient elastography (VCTE) is associated with the risk of liver decompensation in patients with non-alcoholic steatohepatitis (NASH), but prospective data in biopsy-confirmed cohorts with advanced fibrosis are limited. We aimed to establish thresholds for LS by VCTE that predict progression to cirrhosis among patients with bridging fibrosis and hepatic decompensation among patients with cirrhosis due to NASH.
Design We used data from four randomised placebo-controlled trials of selonsertib and simtuzumab in participants with advanced fibrosis (F3–F4). The trials were discontinued due to lack of efficacy. Liver fibrosis was staged centrally at baseline and week 48 (selonsertib study) or week 96 (simtuzumab study). Associations between LS by VCTE with disease progression were determined using Cox proportional hazards regression analysis.
Results Progression to cirrhosis occurred in 16% (103/664) of participants with bridging fibrosis and adjudicated liver-related events occurred in 4% (27/734) of participants with baseline cirrhosis. The optimal baseline LS thresholds were ≥16.6 kPa for predicting progression to cirrhosis, and ≥30.7 kPa for predicting liver-related events. Baseline LS ≥16.6 kPa (adjusted HR 3.99; 95% CI 2.66 to 5.98, p<0.0001) and a ≥5 kPa (and ≥20%) increase (adjusted HR 1.98; 95% CI 1.20 to 3.26, p=0.008) were independent predictors of progression to cirrhosis in participants with bridging fibrosis, while baseline LS ≥30.7 kPa (adjusted HR 10.13, 95% CI 4.38 to 23.41, p<0.0001) predicted liver-related events in participants with cirrhosis.
Conclusion The LS thresholds identified in this study may be useful for risk stratification of NASH patients with advanced fibrosis.
- nonalcoholic steatohepatitis
Data availability statement
No data are available.
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Contributors Study design: RL and RPM. Data acquisition: RL, DD, CJ, AB, RSH, CC, ZG and RPM. Data analysis: RL, DH, DD, LM, CJ and RPM. Data interpretation and review/revision of the manuscript: all authors. Study concept and study supervision: RL and RPM. Writing of first draft: DH and RL. All authors approved the final draft of the manuscript as well as the authorship list. Gurantor of article: RL.
Competing interests RL receives funding support from NIAAA (U01AA029019), NIEHS (5P42ES010337), NCATS (5UL1TR001442), NIDDK (U01DK130190, U01DK061734, R01DK106419, P30DK120515, R01DK121378, R01DK124318), NHLBI (P01HL147835), and DOD PRCRP (W81XWH-18-2-0026). RL serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Terns Pharmaceuticals and Viking Therapeutics. In addition his institutions received research grants from Arrowhead Pharmaceuticals, Astrazeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Merck, Pfizer, Sonic Incytes and Terns Pharmaceuticals. Co-founder of LipoNexus Inc. DH receives funding support from Singapore Ministry of Health’s National Medical Research Council under its NMRC Research Training Fellowship (MOH-000595-01). In addition, he has served as an advisory board member for Eisai. MFA receives funding support from NIDDK (U01DK130177, U01DK061713, R01DK12137), NCI (UG1CA242643) and DOD (W81XWH2010514). MFA serves as a consultant/advisor to Bristol-Myer Squibb, CohBar, Inventiva, Madrigal, NGM Biopharmaceuticals, Novo Nordisk, Theratechnologies, 89 Bio, Somologics, and Hanmi Pharmaceuticals. In addition, her institutions received research grants from Allergan, Boehringer-Ingelheim, Bristol-Myers Squibb, Enyo, Enanta, Durect, Galectin Therapeutics, Gilead, Galmed, Intercept, Hanmi, Inventiva, Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Poxel, TARGET PharmaSolutions, Celgene, Genentech. and Viking Pharmaceuticals. QMA is funded by the LITMUS (Liver Investigation: Testing Marker Utility in Steatohepatitis) consortium funded by the Innovative Medicines Initiative (IMI2) Program of the European Union under Grant Agreement 777377; this Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. He reports Research Grant Funding from Allergan/Tobira, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Glympse Bio, Intercept, Novartis Pharma AG, Pfizer Ltd; Consultancy from 89Bio, Abbvie/Allergan, Altimentiv, Altimmune, AstraZeneca, Axcella, Blade, BMS, BNN Cardio, Boehringer Ingelheim, Cirius, CymaBay, EcoR1, E3Bio, Eli Lilly & Company Ltd., Galmed, Genentech, Genfit SA, Gilead, Grunthal, HistoIndex, Indalo, Intercept Pharma Europe Ltd., Inventiva, IQVIA, Janssen, Johnson & Johnson, Madrigal, MedImmune, Medpace, Merck, Metacrine, NGMBio, North Sea Therapeutics, Novartis, Novo Nordisk A/S, PathAI, Pfizer, Poxel, ProSciento, Raptor Pharma, Roche, Servier, Shionogi, Terns, The Medicines Company, Viking Therapeutics; Speaker fees from Abbott Laboratories, Allergan/Tobira, BMS, Clinical Care Options, Falk, Fishawack, Genfit SA, Gilead, Integritas Communications, Kenes, Medscape; and Royalties from Elsevier. DD, LM, CJ, AB, RSH, CC and RPM are employees and shareholders of Gilead Sciences. VW served as a consultant or advisory board member for AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Inventiva, Merck, Novo Nordisk, Pfizer, ProSciento, Sagimet Biosciences, and TARGET PharmaSolutions; and a speaker for Abbott, AbbVie, Echosens, Gilead Sciences, Novo Nordisk. He has received a research grant from Gilead Sciences, and was a co-founder of Illuminatio Medical Technology Limited. JB was a consultant for Gilead Sciences, Actelion and Surrozen.
Provenance and peer review Not commissioned; externally peer reviewed.
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