Hepatic encephalopathy (HE) is a debilitating neuropsychiatric complication of cirrhosis, marked by cognitive deficits, motor impairments, and reduced quality of life. Elevated ammonia levels and systemic inflammation are central to its pathogenesis. Rifaximin, a minimally absorbed broad-spectrum antibiotic, has emerged as a cornerstone therapy for HE due to its ability to modulate gut microbiota, reduce ammonia production, and mitigate inflammation. While guidelines endorse rifaximin for HE management, the efficacy, safety, and optimal dosing of long-term use (≥6 months) remain contentious. This review synthesizes current evidence on rifaximin's long-term application, focusing on its mechanisms, clinical outcomes, safety profile, and cost-effectiveness.
Introduction
HE affects up to 40% of cirrhotic patients, significantly impairing survival and quality of life. It manifests as overt (OHE) or covert (CHE) forms, with CHE often progressing to OHE if untreated. Ammonia toxicity and gut dysbiosis drive HE pathogenesis, making therapies targeting these pathways critical. Rifaximin, with its gut-specific action, is recommended for HE treatment and prevention. However, uncertainties persist regarding its long-term use, including optimal dosing, resistance risks, and cost-benefit trade-offs. This review addresses these gaps by evaluating rifaximin's sustained efficacy and safety in HE management.
Pharmacology and Mechanisms of Rifaximin
Rifaximin, a rifamycin derivative, achieves high intestinal concentrations with minimal systemic absorption, making it ideal for gut-targeted therapy. Its mechanisms in HE include:
Microbiota Modulation: Reduces ammonia-producing bacteria (e.g., Streptococcus spp.) while preserving microbial diversity.
Barrier Enhancement: Strengthens tight junctions, reducing bacterial translocation and endotoxemia.
Anti-inflammatory Effects: Inhibits NF-κB signaling, lowering pro-inflammatory cytokines (e.g., TNF-α, IL-6).
Ammonia Detoxification: Downregulates glutaminase-2 and upregulates asparagine synthetase, aiding ammonia clearance.
These actions collectively improve the gut-liver axis dysfunction central to HE.
Long-term Efficacy in HE
Overt HE (OHE)
Combination Therapy: Rifaximin plus lactulose outperforms lactulose alone, reducing HE recurrence (HR 0.42) and hospitalizations (HR 0.50) over six months.
Dose Optimization: Low-dose rifaximin (400–800 mg/day) shows comparable efficacy to standard doses (1,200 mg/day), with improved cost-effectiveness and compliance.
Real-world Data: Sustained use (6–12 months) correlates with lower ammonia levels, fewer hospitalizations, and improved cognitive scores.
Covert HE (CHE)
Rifaximin normalizes ammonia levels and immune function in CHE responders, with continuous therapy yielding better cognitive outcomes than cyclic regimens.
Post-TIPS Prophylaxis
Rifaximin reduces OHE incidence post-TIPS (34% vs. 53% with placebo), particularly in patients with prior HE episodes.
Safety and Resistance
Rifaximin exhibits a favorable safety profile, with mild adverse effects (e.g., nausea, headache) in <1% of patients. Long-term studies (up to 24 months) report no increased risk of serious events, though rare cases of C. difficile infection and antibiotic resistance (e.g., cross-resistance to daptomycin) warrant vigilance.
Cost-effectiveness and Compliance
Economic Benefits: Adjunct rifaximin reduces annual hospitalizations by 59%, saving ~$7.5 million per 50% patient cohort.
Compliance Challenges: Only 35% of patients adhere to rifaximin beyond 12 months, driven by high out-of-pocket costs and complex regimens. Simplified dosing and patient education could improve retention.
Future Directions
Prospective studies are needed to:
Compare low-dose (800 mg/day) and standard-dose rifaximin head-to-head.
Assess long-term resistance patterns and oncological benefits (e.g., reduced gastrointestinal cancer risk).
Optimize prophylactic use in high-risk interventions like TIPS.
Conclusion
Long-term rifaximin use (≥6 months) is effective and safe for HE management, particularly when combined with lactulose. It reduces recurrence, hospitalizations, and cognitive decline while offering economic advantages. Low-dose regimens (400–800 mg/day) may balance efficacy and cost, though adherence barriers persist. Future research should refine dosing strategies and monitor resistance, ensuring personalized therapy for cirrhotic patients.
Full text
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The study was recently published in the Journal of Translational Gastroenterology .
Journal of Translational Gastroenterology (JTG) dedicates to improving clinical diagnosis and treatment, advancing understanding of the molecular mechanisms, and promoting translation from bench to bedside of gastrointestinal, hepatobiliary, and pancreatic diseases. The aim of JTG is to provide a forum for the exchange of ideas and concepts on basic, translational, and clinical aspects of gastroenterology, and promote cross-disciplinary research and collaboration.
