Abstract
BACKGROUND: Hepatic encephalopathy (HE) is a serious complication of liver cirrhosis, often leading to frequent hospitalizations and reduced quality of life. OBJECTIVE: To prospectively compare the efficacy, safety, and tolerability of lactulose versus rifaximin monotherapy in preventing recurrent HE among patients with cirrhosis across multiple tertiary centers. METHODOLOGY: This prospective, multi-center comparative observational study was conducted between November 2023 and October 2024 across three sites: Capital Hospital (Islamabad, Pakistan), AlBashir Hospital (Amman, Jordan), and Abbas Institute of Medical Sciences (Muzaffarabad, Azad Jammu and Kashmir). A total of 236 patients with cirrhosis with a prior episode of overt HE were randomly assigned to receive either rifaximin 550 mg twice daily or lactulose 30 mL three times daily for six months, followed by an additional six months of follow-up. Data were collected on treatment adherence, adverse effects, HE recurrence, and hospitalizations. Statistical analysis was performed using SPSS v26 (IBM Corp., Armonk, NY), with significance set at P < 0.05. RESULTS: Treatment adherence ≥80% was achieved in 102 (86.4%) patients in the rifaximin group versus 85 (72.0%) in the lactulose group (P = 0.008). Recurrent HE occurred in 19 (16.1%) rifaximin patients compared to 41 (34.8%) lactulose patients (P = 0.001). HE-related hospitalizations were significantly lower in the rifaximin group (15, 12.7%, vs. 36, 30.5%; P < 0.001). Adverse effects such as diarrhea (6.8% vs. 27.1%), bloating (5.1% vs. 15.3%), and nausea (3.4% vs. 11.9%) were markedly less frequent with rifaximin. Functional improvement was observed in 94 patients (79.7%) receiving rifaximin compared with 68 patients (57.6%) receiving lactulose (P < 0.001). CONCLUSIONS: Rifaximin monotherapy demonstrated superior efficacy, safety, and tolerability compared to lactulose for preventing HE recurrence among patients with cirrhosis in a multi-center setting. These findings support rifaximin as a more effective long-term therapeutic option for secondary prophylaxis of HE.