J Hepatol. 2023 Nov 15:S0168-8278(23)05270-4. doi: 10.1016/j.jhep.2023.10.038. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Strategies to reduce liver biopsy (LB) screen failures through better patient selection are needed for clinical trials. Standard fibrosis biomarkers were not derived to detect “at-risk” metabolic dysfunction-associated steatohepatitis (MASH; MASH with non-alcoholic fatty liver disease activity score ≥4 and fibrosis stage ≥2). We compared the performance of screening pathways that incorporate NIS2+™, an optimized version of the blood-based NIS4® technology designed to identify at-risk MASH, with those incorporating fibrosis (FIB)-4 within the RESOLVE-IT clinical trial (NCT02704403), aiming for optimal selection of patients for LB.

METHODS: A retrospective simulation analysis was conducted in the RESOLVE-IT screening pathway (RSP) cohort. Liver biopsy failure rate (LBFR), number of patients needed to screen, and overall cost estimations of different pathways were calculated for a range of NIS2+™ and FIB-4 cutoffs and compared with those of the RSP, which relied on investigators’ local practices. Analysis of potential recruitment bias based on histology, sex, age, or comorbidities was performed.

RESULTS: The analysis cohort included 1,929 patients, 765 (40%) with at-risk MASH. The NIS2+™ pathway resulted in a significantly lower LBFR (39%) compared with the FIB-4 (58%) or the RSP (60%) when using cost-optimized cutoffs (NIS2+™, 0.53; FIB-4, 0.58). For every 1,000 inclusions, NIS2+™ significantly reduced unnecessary LBs (632 vs 1,522; -58%) and screening costs (US$12.7 million vs US$15.0 million) vs the RSP, while the number of patients needed to screen increased moderately (3,220 to 4,033). NIS2+™ alone is better than FIB-4 alone or combined with FIB-4.

CONCLUSIONS: This analysis demonstrated that patient selection for LB using NIS2+™ significantly reduced unnecessary biopsies and screening costs, which could greatly improve a major feasibility aspect of MASH clinical trials.

IMPACT AND IMPLICATIONS: Simple and accurate non-invasive strategies for optimizing the selection of patients who should be referred for liver biopsy (LB) for inclusion in MASH clinical trials is critical to reduce the high liver biopsy failure rates (LBFRs). While the use of FIB-4 alone did not lead to a significant improvement of the screening process, selecting patients using NIS2+ ™, a recently developed optimization of the NIS4® technology for the detection of at-risk MASH, showed improved performances by simultaneously reducing LBFRs and the overall cost of the trial, keeping a manageable number of patients needed to screen, without generating any bias in included patients’ characteristics. This makes NIS2+ ™ an accurate and reliable screening tool for improving the recruitment of patients in future MASH clinical trials, and would lead to increased patient comfort and security, ensuring timely and cost-efficient completion of those trials.

PMID:38061448 | DOI:10.1016/j.jhep.2023.10.038