Rifaximin Improves Cognitive Performance and Reduces Cirrhosis‐Related Adverse Events in Covert Hepatic Encephalopathy: A Randomized Controlled Trial

BACKGROUND: Covert hepatic encephalopathy (CHE) is associated with cognitive impairment and adverse clinical outcomes; however, randomized evidence supporting therapeutic intervention remains limited. AIM: To evaluate the efficacy of rifaximin (RFX) as a treatment for CHE. METHODS: In this multicentre, open-label randomized controlled trial, patients with CHE associated with liver cirrhosis were randomized (1:1) to receive RFX or no treatment and followed for 12 weeks. The primary endpoint was the change in Stroop test performance. Secondary endpoints included NCT-B scores, serum ammonia levels, cirrhosis-related adverse events, and gut microbiota composition. RESULTS: Fifty patients were randomized and completed follow-up. Stroop test performance improved significantly in the RFX group (p = 0.006) but not in controls (p = 0.400), with a trend toward greater improvement with RFX (Δ Stroop test: -4.45 ± 7.12 vs. -0.98 ± 5.74 s; p = 0.056). Among patients not receiving synthetic disaccharides at baseline, improvement was significantly greater with RFX (Δ Stroop test: -3.73 ± 5.96 vs. -0.80 ± 5.86 s; p = 0.049). No significant changes were observed in NCT-B scores or serum ammonia levels. Cirrhosis-related adverse events were significantly reduced in the RFX group (p = 0.006). Overall, gut microbial diversity did not differ between groups; however, RFX selectively altered specific taxa, including loss of the [Eubacterium] brachy group. CONCLUSIONS: RFX improved cognitive performance assessed by the Stroop test and reduced cirrhosis-related adverse events in patients with CHE. These randomized data support RFX as an effective therapeutic option and highlight the Stroop test as a sensitive endpoint for treatment response.