Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement. METHODS: In the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72 and 96. Liver biopsies were obtained at baseline and 72 weeks. RESULTS: In patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4 and 4% for NFS. Reductions in APRI (P = 0.015) and FIB-4 (P = 0.036), but not NFS (P = 0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (P = 0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (P < 0.0001); NFS (P < 0.05)]. CONCLUSIONS: Readily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate endpoints in NASH clinical trials.

Factors Associated With Histologic Response in Adult Patients With Nonalcoholic Steatohepatitis.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is a leading cause of liver transplantation, and many trials are underway to evaluate potential therapies. The farnesoid X receptor ligand obeticholic acid in the NASH treatment trial evaluated the effects of obeticholic acid vs placebo on histologic response (defined as decrease in nonalcoholic fatty liver disease activity score [NAS] by ≥2, with no worsening of fibrosis); 45% of patients had a histologic response to obeticholic acid (25 mg), and 21% had a response to placebo (P < .01). We performed a secondary analysis of data from this trial to identify clinical parameters associated with a histologic response. METHODS: We used a logistic regression model with a stepwise selection procedure to identify baseline and early on-treatment factors associated with a histologic response at 72 weeks. Baseline demographics, liver histology, medical history, concomitant medications, cardiometabolic parameters, and serum biochemistry, as well as the changes over the course of the trial (at weeks 12 and 24), were evaluated as potential predictors of a histologic response. The model was cross-validated by a jackknife method, and performance was evaluated with the area under the receiver operating characteristic curve. RESULTS: The logistic regression model found that obeticholic acid treatment, baseline NAS > 5, baseline triglyceride level ≤ 154 mg/dL, baseline international normalized ratio ≤ 1, baseline aspartate aminotransferase level ≤ 49 U/L, and a decrease in alanine aminotransferase level at week 24 by 17 U/L or more, to be significantly associated with histologic response (area under the receiver operating characteristic curve, 0.83; 95% confidence interval, 0.77-0.89; P < .0001). CONCLUSIONS: In a secondary analysis of data from a clinical trial of obeticholic acid in patients with NASH, we identified routine clinical and laboratory parameters during the first 24 weeks of treatment (such as baseline NAS, triglyceride levels, and a decrease in alanine aminotransferase level) to significantly associate with histologic markers of response.