Abstract

Background: About 30% of patients with PBC have a suboptimal response to ursodeoxycholic acid (UDCA), leading to a worse prognosis. In the phase III POISE trial, response to obeticholic acid (OCA) was assessed by using the POISE score. Recently, complete biochemical normalization (normal ALP and bilirubin ≤ 0.6 ULN) has been proposed as a new therapeutic aim in PBC, as it significantly improves liver-related and overall survival, but the effectiveness of second-line therapy for this new therapeutic target has not been evaluated.

Methods: Prospective, multicentre real-world clinical practice study including PBC patients non-responders to UDCA according to Paris II criteria, from 25 hospitals from Spain and Portugal. All patients received OCA or OCA plus fibrates (19.25%), and the study evaluated the safety and effectiveness of treatment on biochemical and liver function scores, GLOBE-PBC and UK-PBC at 5 years. POISE response rates, biochemical complete response, incidence of decompensation, liver-related survival and safety were also assessed.

Results: The study included 316 patients, with a median follow-up of 26.3 months (IQR: 13.3-43.3). ALP, GGT and aminotransferases decreased (p<0.01), while serum albumin increased (p<0.01) and bilirubin also decreased (p=0.013). Globe-PBC and UK-PBC scores at 5 years improved (p<0.01). At 12 months, 41.7% achieved a POISE response by intention-to-treat (ITT) analysis. Factors associated with POISE response in the univariate analysis were absence of cirrhosis, lower serum bilirubin and lower values of FIB-4, APRI, CPT, Globe and UK-PBC scores, as well as higher serum albumin, higher platelet count and triple therapy. After adjusting for sex, age, cirrhosis, albumin levels, bilirubin, platelet count and baseline OCA dose, triple therapy, serum albumin and bilirubin remained associated with POISE response. Triple therapy was more likely to achieve a complete biochemical response compared to dual therapy (fig. 1). Liver-related survival at 36 months was 97.3% (95% CI 94-98.8). OCA discontinuation occurred in 18.2% of patients. Decompensation, death and liver transplantation occurred in 19, 3 and 4 patients, respectively. Of the 72 patients with cirrhosis, 16 experienced decompensation, all of them with APRI ≥ 0.75 (AUROC: 0.77, CI: 0.65-0.89).

Conclusion: Second-line therapy with OCA or OCA plus fibrates showed long-term positive effects on liver biochemistry and liver function in patients with PBC non-responders to UDCA. Triple therapy was more effective than dual therapy in achieving a POISE response and a complete biochemical response. The treatment appears safe in the early stages of cirrhosis.