Fibrosis progression rate and comparison of paired liver biopsy versus non-invasive tests as surrogate endpoints for clinical trials in MetALD and ALD.
Abstract
BACKGROUND & AIMS
Drug development for metabolic and alcohol-related liver disease (MetALD) and Alcohol-related liver disease (ALD) is emerging, but designing clinical trials remain challenging due to unknown disease progression rates and a lack of validated surrogate endpoints. We studied fibrosis progression rates and determinants of progression using dual liver biopsies and compared the prognostic performance of six non-invasive biomarkers of fibrosis.
METHODS
We included patients from two RCTs and one cohort study with a history of excessive alcohol intake who underwent paired liver biopsies and non-invasive testing. Fibrosis progression rates were calculated, and associations between changes in histological and non-invasive biomarkers were analysed. We used C-statistics to compare how changes in liver biopsy and non-invasive biomarkers after the second liver biopsy predicted hepatic decompensation or death.
RESULTS
164 patients were included with median biopsy interval of 1.9 years and the histological fibrosis progression rate was 0.22 [0.07;0.37] stages per year. The progression rate was over two-fold increased in patients with active alcohol consumption at baseline compared to abstinent individuals (one stage every 3 years vs. every 8 years). During a median 2.1-year follow-up period after the second biopsy, twenty-one patients decompensated or died (13%). The delta value (change from baseline to second biopsy) showed that histological fibrosis stage and non-invasive biomarkers equally predicted adverse outcomes: LiverPRO (0.78), PRO-C3 (0.72), histological fibrosis stage (0.70), FIB-4 (0.68), TE (0.66), Agile 3+ (0.75), and ELF (0.64).
CONCLUSION
Active alcohol consumption determines fibrosis progression in ALD and MetALD. Non-invasive biomarkers are promising surrogate markers for understanding disease dynamics and monitoring in ALD and MetALD clinical trials.
