Fibrosis is an independent predictor of death in nonalcoholic steatohepatitis (NASH). We assessed the associations between histologic and noninvasive tests (NITs) for fibrosis with clinical and ...patient-reported outcomes (PROs) in advanced NASH.
Patients with advanced NASH (NASH Clinical Research Network stage F3 or F4) were enrolled in 4 multinational clinical trials of simtuzumab and selonsertib. Liver biopsy samples, NIT results, and PROs (Short Form-36, Chronic Liver Disease Questionnaire–NASH, EuroQol-5D, and Work Productivity and Activity Impairment) were prospectively collected.
A total of 2154 patients with advanced NASH were included: 52.5% with F4 NASH, 40% male, 72% with type 2 diabetes, baseline liver stiffness of 24.1 ± 14.2 kPa in F4 disease and 14.6 ± 8.0 kPa in F3 disease, baseline mean Enhanced Liver Fibrosis score of 11.4 ± 1.2 in F4 disease and 10.3 ± 1.0 in F3 disease, and a median follow-up of 16 months. Of those with baseline F3 disease, 16.7% experienced disease progression to cirrhosis, whereas for those with F4 disease, 7.3% experienced clinical events (39% ascites, 24% hepatic encephalopathy); patients who progressed had higher baseline NIT scores (all P < .0001). Adjusted for baseline levels, increases in NIT scores were also associated with increased risk of disease progression in both the F3 and F4 groups (P < .01 for all NITs in F3 and for ELF, NAFLD Fibrosis Score, Fibrosis-4 (FIB-4), and liver stiffness in F4). Higher NIT scores were found to be associated with impairment in PROs: ELF, ≥10.43; Nonalcoholic Fatty Liver Disease Fibrosis Score, ≥1.80; Fibrotest score, ≥0.54; liver stiffness, ≥23.4 kPa. During treatment, patients with decreases in NIT scores experienced improvement of their PRO scores, whereas those with increase in NIT scores had their PRO scores worsen (P < .05).
Baseline NIT scores and their changes over time are predictors of adverse clinical and PROs in patients with advanced NASH. (ClinicalTrials.gov, Numbers NCT01672866, NCT01672879, NCT03053050, and NCT03053063)
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•Liver stiffness by magnetic resonance elastography (MRE) correlated with fibrosis.•Reductions in liver stiffness by MRE were associated with improvement of fibrosis.•Assessment of ...liver fat by magnetic resonance imaging (MRI) correlated with severity of liver steatosis.•Reductions in MRI estimates of liver fat were correlated with reductions in liver fat on biopsy.
Non-invasive tools for monitoring treatment response and disease progression in non-alcoholic steatohepatitis (NASH) are needed. Our objective was to evaluate the utility of magnetic resonance (MR)-based hepatic imaging measures for the assessment of liver histology in patients with NASH.
We analyzed data from patients with NASH and stage 2 or 3 fibrosis enrolled in a phase II study of selonsertib. Pre- and post-treatment assessments included centrally read MR elastography (MRE)-estimated liver stiffness, MR imaging-estimated proton density fat fraction (MRI-PDFF), and liver biopsies evaluated according to the NASH Clinical Research Network classification and the non-alcoholic fatty liver disease activity score (NAS).
Among 54 patients with MRE and biopsies at baseline and week 24, 18 (33%) had fibrosis improvement (≥1-stage reduction) after undergoing 24 weeks of treatment with the study drug. The area under the receiver operating characteristic curve (AUROC) of MRE-stiffness to predict fibrosis improvement was 0.62 (95% CI 0.46–0.78) and the optimal threshold was a ≥0% relative reduction. At this threshold, MRE had 67% sensitivity, 64% specificity, 48% positive predictive value, 79% negative predictive value. Among 65 patients with MRI-PDFF and biopsies at baseline and week 24, a ≥1-grade reduction in steatosis was observed in 18 (28%). The AUROC of MRI-PDFF to predict steatosis response was 0.70 (95% CI 0.57–0.83) and the optimal threshold was a ≥0% relative reduction. At this threshold, MRI-PDFF had 89% sensitivity and 47% specificity, 39% positive predictive value, and 92% negative predictive value.
These preliminary data support the further evaluation of MRE-stiffness and MRI-PDFF for the longitudinal assessment of histologic response in patients with NASH.
Liver biopsy is a potentially painful and risky method to assess damage to the liver due to non-alcoholic steatohepatitis (NASH). We analyzed data from a clinical trial to determine if 2 methods of magnetic resonance imaging – 1 to measure liver fat and 1 to measure liver fibrosis (scarring) – could potentially replace liver biopsy in evaluating NASH-related liver injury. Both imaging methods were correlated with biopsy in showing the effects of NASH on the liver.
Background and Aims
Manual histological assessment is currently the accepted standard for diagnosing and monitoring disease progression in NASH, but is limited by variability in interpretation and ...insensitivity to change. Thus, there is a critical need for improved tools to assess liver pathology in order to risk stratify NASH patients and monitor treatment response.
Approach and Results
Here, we describe a machine learning (ML)‐based approach to liver histology assessment, which accurately characterizes disease severity and heterogeneity, and sensitively quantifies treatment response in NASH. We use samples from three randomized controlled trials to build and then validate deep convolutional neural networks to measure key histological features in NASH, including steatosis, inflammation, hepatocellular ballooning, and fibrosis. The ML‐based predictions showed strong correlations with expert pathologists and were prognostic of progression to cirrhosis and liver‐related clinical events. We developed a heterogeneity‐sensitive metric of fibrosis response, the Deep Learning Treatment Assessment Liver Fibrosis score, which measured antifibrotic treatment effects that went undetected by manual pathological staging and was concordant with histological disease progression.
Conclusions
Our ML method has shown reproducibility and sensitivity and was prognostic for disease progression, demonstrating the power of ML to advance our understanding of disease heterogeneity in NASH, risk stratify affected patients, and facilitate the development of therapies.
The multimodal activities of farnesoid X receptor (FXR) agonists make this class an attractive option to treat nonalcoholic steatohepatitis. The safety and efficacy of tropifexor, an FXR agonist, in ...a randomized, multicenter, double-blind, three-part adaptive design, phase 2 study, in patients with nonalcoholic steatohepatitis were therefore assessed. In Parts A + B, 198 patients were randomized to receive tropifexor (10-90 μg) or placebo for 12 weeks. In Part C, 152 patients were randomized to receive tropifexor 140 µg, tropifexor 200 µg or placebo (1:1:1) for 48 weeks. The primary endpoints were safety and tolerability to end-of-study, and dose response on alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hepatic fat fraction (HFF) at week 12. Pruritus was the most common adverse event in all groups, with a higher frequency in the 140- and 200-µg tropifexor groups. Decreases from baseline in ALT and HFF were greater with tropifexor versus placebo at week 12, with a relative decrease in least squares mean from baseline observed with all tropifexor doses for ALT (tropifexor 10-90-μg dose groups ranged from -10.7 to -16.5 U l
versus placebo (-7.8 U l
) and tropifexor 140- and 200-μg groups were -18.0 U l
and -23.0 U l
, respectively, versus placebo (-8.3 U l
)) and % HFF (tropifexor 10-90-μg dose groups ranged from -7.48% to -15.04% versus placebo (-6.19%) and tropifexor 140- and 200-μg groups were -19.07% and -39.41%, respectively, versus placebo (-10.77%)). Decreases in ALT and HFF were sustained up to week 48; however, similar trends in AST with tropifexor at week 12 were not observed. As with other FXR agonists, dose-related pruritus was frequently observed. Clinicaltrials.gov registration: NCT02855164.
Background and Aims
Hepatic fibrosis secondary to HCV infection can lead to cirrhosis and hepatic decompensation. Sustained virologic response (SVR) is possible with direct‐acting antiviral drug ...regimens; however, patients with advanced fibrosis have an increased risk for HCC. Heat shock protein 47 (HSP47), a key collagen chaperone, has been implicated in fibrosis development. We evaluated the efficacy and safety of BMS‐986263, a lipid nanoparticle delivering small interfering RNA designed to degrade HSP47 mRNA, for the treatment of advanced fibrosis.
Approach and Results
NCT03420768 was a Phase 2, randomized (1:1:2), placebo‐controlled trial conducted at a hepatology clinic in the United States. Patients with HCV‐SVR (for ≥ 1 year) and advanced fibrosis received once‐weekly i.v. infusions of placebo or BMS‐986263 (45 or 90 mg) for 12 weeks. The primary endpoint was ≥ 1 METAVIR stage improvement at Week 12; key secondary endpoints included Ishak score improvement, pharmacokinetics, fibrosis biomarkers, and safety. All 61 patients completed treatment, and 2/15 (13%, placebo), 3/18 (17%, 45 mg), and 6/28 (21%, 90 mg) had METAVIR improvements of ≥ 1 stage at Week 12. Five patients in the 90‐mg arm had Ishak improvements by ≥ 2 stages. BMS‐986263 plasma concentrations increased in a generally dose‐proportional fashion between BMS‐986263 doses, with no notable accumulation with weekly dosing. All adverse events (AEs) were mild or moderate in intensity; most treatment‐related AEs were infusion‐related reactions in the BMS‐986263 arms. At baseline, collagen levels were low, indicating low levels of fibrogenesis in these patients.
Conclusions
In patients with HCV‐SVR, BMS‐986263 administration was generally well tolerated through Week 36 and resulted in METAVIR and Ishak score improvements. Further evaluation of BMS‐986263 in patients with active fibrogenesis is warranted.
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.
De novo lipogenesis (DNL) converts carbon substrates to lipids. Increased hepatic DNL could contribute to pathogenic liver triglyceride accumulation in nonalcoholic steatohepatitis (NASH) and ...therefore may be a potential target for pharmacological intervention. Here, we measured hepatic DNL using heavy water in 123 patients with NASH with fibrosis or cirrhosis, calculated the turnover of hepatic triglycerides to allow repeat labeling studies, and determined the associations of hepatic DNL with metabolic, fibrotic, and imaging markers. We found that hepatic DNL was higher in patients with fibrotic NASH median (IQR), 40.7% contribution to palmitate (32.1, 47.5), n=103 than has been previously reported in healthy volunteers and remained elevated median (IQR), 36.8% (31.0, 44.5), n=20 in patients with cirrhosis, despite lower liver fat content. We also showed that turnover of intrahepatic triglyceride pools was slow (t½ >10 days). Furthermore, DNL contribution was determined to be independent of liver stiffness by magnetic resonance imaging but was positively associated with the number of large very low density lipoprotein (VLDL) particles, the size of VLDL, the lipoprotein insulin resistance score, and levels of ApoB100, and trended toward negative associations with the fibrosis markers FIB-4, FibroSure, and APRI. Finally, we found treatment with the acetyl-CoA carboxylase inhibitor firsocostat reduced hepatic DNL at 4 and 12 weeks, using a correction model for residual label that accounts for hepatic triglyceride turnover. Taken together, these data support an important pathophysiological role for elevated hepatic DNL in NASH and demonstrate that response to pharmacological agents targeting DNL can be correlated with pretreatment DNL.
Patient-reported outcomes (PROs) are used to measure patients' experience with their disease. However, there are few PRO data from patients with NASH. We collected data from the STELLAR clinical ...trials to assess PROs for NASH and advanced fibrosis.
We analyzed data from 1667 patients (58 ± 9 years, 40% male, 52% with cirrhosis, 74% with diabetes) with NASH and bridging fibrosis or compensated cirrhosis (metavir scores, F3 or F4) enrolled in the phase 3 STELLAR trials of selonsertib (NCT03053050 and NCT03053063) who completed PRO questionnaires (SF-36, CLDQ-NASH, EQ-5D, or WPAI:SHP) before treatment initiation.
Compared with patients with F3 fibrosis, higher proportions of patients with F4 fibrosis were female, were white, had more hematologic and gastrointestinal comorbidities, and had type 2 diabetes (P ≤ .01). Mean physical health-related PRO scores were significantly lower than those of the general population: patients with F4 fibrosis had score reductions of 4.4% to 12.9% in 6/8 SF-36 domains and patients with F3 fibrosis had score reductions of 3.9% to 11.7% in 4/8 domains (P < .01). Compared to patients with F3 fibrosis, those with F4 fibrosis had lower scores in all but 1 domains of CLDQ-NASH, Role Physical, Bodily Pain, and Social Functioning domains of the SF-36, and EQ-5D (P ≤ 01). In multivariate regression analysis, factors independently associated with lower PRO scores included having cirrhosis, female sex, higher body mass index, history of smoking, and diabetes or other comorbidities (P < .01).
PROs are significantly lower in patients with NASH with advanced fibrosis who participated in the STELLAR clinical trials. Treatment of patients with NASH should focus on improving not only clinical outcomes but also quantifiable symptom burden and health-related quality of life.
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.
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.
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.
The LS thresholds identified in this study may be useful for risk stratification of NASH patients with advanced fibrosis.
Liver biopsy is invasive and associated with complications, sampling errors, and observer variability. Vibration-controlled transient elastography (VCTE) with FibroScan can be used to immediately ...assess liver stiffness. We aimed to define optimal levels of liver stiffness to identify patients with chronic viral hepatitis and significant fibrosis, advanced fibrosis, or cirrhosis.
In a prospective, 2-phase study, patients with chronic hepatitis C or B underwent VCTE followed by liver biopsy analysis from January 2005 through May 2008 at 6 centers in the United States. In phase 1 we identified optimal levels of liver stiffness for identification of patients with stage F2-F4 or F4 fibrosis (the development phase, n = 188). In phase 2 we tested these cutoff values in a separate cohort of patients (the validation phase, n = 560). All biopsies were assessed for METAVIR stage by a single pathologist in the phase 1 analysis and by a different pathologist in the phase 2 analysis. Diagnostic performances of VCTE were assessed by area under the receiver operating characteristic curve (AUROC) analyses.
In phase 1 of the study, liver stiffness measurements identified patients with ≥ F2 fibrosis with AUROC value of 0.89 (95% confidence interval, 0.83-0.92) and identified patients with F4 fibrosis with AUROC value of 0.92 (95% confidence interval, 0.87-0.95). Liver stiffness cutoff values (kPa) in phase 1 were 8.4 for ≥ F2 (82% sensitivity, 79% specificity) and 12.8 for F4 (84% sensitivity, 86% specificity). In the phase 2 analysis, the liver stiffness cutoff values identified patients with ≥ F2 fibrosis with 58% sensitivity (P < .0001 vs phase 1) and 75% specificity (nonsignificant difference vs phase 1); they identified patients with F4 fibrosis with 76% sensitivity (P < .0001 vs phase 1) and 85% specificity (nonsignificant differences vs phase 1). VCTE had an interobserver agreement correlation coefficient of 0.98 (n = 26) and an intraobserver agreement correlation coefficient of 0.95 (n = 34).
In a large U.S. multicenter study, we confirmed that VCTE provides an accurate assessment of liver fibrosis in patients with chronic viral hepatitis. Our findings are similar to those from European and Asian cohorts.
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