Fibrosis Progression Rate and Comparison of Paired Liver Biopsy vs Noninvasive Tests as Surrogate Endpoints for Clinical Trials in Metabolic and Alcohol-Associated Liver Disease and Alcohol-Associated Liver Disease.
Abstract
BACKGROUND & AIMS
Drug development for metabolic and alcohol-related liver disease and alcohol-related liver disease is emerging, but designing clinical trials remains 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 6 noninvasive biomarkers of fibrosis.
METHODS
We included patients from 2 randomized controlled trials and 1 cohort study with a history of excessive alcohol intake who underwent paired liver biopsies and noninvasive testing. Fibrosis progression rates were calculated, and associations between changes in histologic and noninvasive biomarkers were analyzed. We used C-statistics to compare how changes in liver biopsy and noninvasive biomarkers after the second liver biopsy predicted hepatic decompensation or death.
RESULTS
A total of 164 patients were included with a median biopsy interval of 1.9 years, and the histologic fibrosis progression rate was 0.22 (95% confidence interval, 0.07-0.37) stages per year. The progression rate was increased over 2-fold in patients with active alcohol consumption at baseline compared with abstinent individuals (1 stage every 3 years vs every 8 years). During a median 2.1-year follow-up period after the second biopsy, 21 patients decompensated or died (13%). The delta value (change from baseline to second biopsy) showed that histologic fibrosis stage and noninvasive biomarkers equally predicted adverse outcomes: LiverPRO (0.78), pro-collagen type III N-terminal propeptide (0.72), histologic fibrosis stage (0.70), Fibrosis-4 index (0.68), transient elastography (0.66), Agile 3+ (0.75), and Enhanced Liver Fibrosis test (0.64).
CONCLUSIONS
Active alcohol consumption determines fibrosis progression in alcohol-related liver disease and metabolic and alcohol-related liver disease. Noninvasive biomarkers are promising surrogate markers for understanding disease dynamics and monitoring in alcohol-related liver disease and metabolic and alcohol-related liver disease clinical trials.
