Nash Progression Rates Based on Fibrosis and Inflammation (NAS): A Paired Biopsy Analysis from a Natural History Cohort in the US

OBJECTIVES: Disease progression in nonalcoholic steatohepatitis (NASH) is assessed by progression of fibrosis (from F0 to F4 [most severe/cirrhosis]) and inflammation (using the nonalcoholic fatty liver disease activity score [NAS]), which are endpoints in clinical trials evaluating NASH therapeutics. In real-world patients, data supporting state transition probabilities in economic models are limited regarding fibrosis and lacking regarding NAS. This current analysis estimates NASH progression in a natural history cohort stratified by both baseline fibrosis stage and NAS.

METHODS: Data from patients enrolled in a longitudinal observational cohort study (TARGET-NASH [NCT02815891]) with biopsy-confirmed NASH, paired biopsies, and NAS were used to determine the transition probability of NAS and conditional probability of fibrosis progression (from index biopsy to second biopsy given NAS at index). As NAS ≥4 is an inclusion criterion for NASH clinical trials, we examined this categorically. Multinomial logistic regression was adapted to estimate the transition probabilities.

RESULTS: 152 patients were included in this analysis (median age: 57 years; 90% White; 61% female; 66% with BMI ≤ 35; median/mean inter-biopsy times: 31.5/45.8 months); n=71 had NAS scores for both biopsies. In the NAS <4 group (n=27), the annual transition probability to NAS ≥4 was 0.29 (95% confidence interval [CI]: 0.1-0.47); in the NAS ≥4 group (n=44), the probability of transitioning to NAS <4 was 0.37 (95%CI: 0.22-0.53). Regardless of initial NAS, fibrosis stage was more likely to remain the same or increase (59/71 with NAS <4, 64/81 with NAS ≥4).

CONCLUSIONS: Most patients with NASH were unlikely to achieve fibrosis improvement within 1 year regardless of initial NAS (<4 or ≥4). Including NAS in addition to fibrosis was feasible for modeling disease progression; transition of NAS was sensitive to annual change for evaluating NASH progression in the context of fibrosis. This observation should be explored in future research.