PCA and redundancy analysis supported the AKUSSI as a robust AKU disease severity measure, although some AKUSSI features could be removed for simplicity. For small patient populations and rare diseases, PCA and redundancy analysis together can aid validation of disease severity metrics.

Objectives: NASH is a chronic liver disease characterized by fatty liver, inflammation and fibrosis. NASH fibrosis is considered an indicator of long-term adverse outcomes and is associated with a high economic burden, particularly in patients with advanced fibrosis (Stage F$3). Estimated lifetime costs in this population in the US reportedly exceeded $95 billion in 2017. As there are currently no approved treatments in NASH, the aim of this review was to understand if advanced fibrosis is targeted by available off-label therapies and current investigational treatments. Methods: A structured literature review was conducted across multiple databases. Searches were limited to English language studies published between January 2007 and January 2019, and included clinical, observational and review publications, reporting on available and investigational treatments used in NASH. Additional grey literature searches were conducted. Results: In total, 48 publications were included. Although there are no licensed treatments in NASH, nine currently available treatments were used off-label with reported improvements in steatosis and/or fibrosis. Out of these, only pioglitazone, statins, and vitamin E were studied in patients with advanced fibrosis specifically. However, limited improvements in fibrosis were observed in all cases. Additionally, six investigational treatments were identified in various stages of NASH fibrosis: n=4 in F1-F3; n=1 in F2/F3 and n=1 in F3/F4. Despite this, only half (n=3) reported improvements in fibrosis staging. Conclusions: There is an unmet need for licensed treatments in NASH, specifically treatments in advanced fibrosis -only three off-label treatments and one investigational therapy are being studied in these patients, with limited efficacy reported. NASH patients with advanced fibrosis represent a high-burden population and in the absence of effective treatments, lifetime costs and the impact on healthcare systems are likely to rise. Further clinical research into new treatments is needed in this population.