What is the role of Rifaximin (Rifamycin derivative) in the treatment of Hepatic Encephalopathy?

Role of Rifaximin in Treatment of Hepatic Encephalopathy

Rifaximin should be used as an add-on to lactulose for prevention of recurrent hepatic encephalopathy after a second episode, rather than as monotherapy for initial treatment. 1, 2

First-Line Treatment for Hepatic Encephalopathy

• Non-absorbable disaccharides (lactulose or lactitol) remain the first-line treatment for both initial episodes and prevention of recurrent hepatic encephalopathy in patients with cirrhosis 1, 3
• Lactulose significantly reduces the risk of recurrent hepatic encephalopathy with a risk ratio of 0.44 (95% CI: 0.31-0.64) compared to placebo 1, 2
• Lactulose should be titrated to achieve 2-3 soft bowel movements per day for optimal effectiveness 3, 2

Role of Rifaximin in Acute Hepatic Encephalopathy

• Rifaximin shows beneficial effects on complete resolution of acute hepatic encephalopathy and mortality compared to placebo 1
• However, current guidelines do not recommend rifaximin alone as initial treatment for overt hepatic encephalopathy due to potential biases in available studies 1
• Rifaximin should be initiated during an acute episode of hepatic encephalopathy if there is no clinical improvement after 24-48 hours of non-absorbable disaccharide therapy 4

Rifaximin for Prevention of Recurrent Hepatic Encephalopathy

• Rifaximin is strongly recommended as an add-on to lactulose for prevention of recurrent hepatic encephalopathy after a second episode (Grade 2+, Strong Agreement) 1
• A landmark randomized controlled trial showed that rifaximin (550 mg twice daily) added to lactulose decreased the risk of hepatic encephalopathy recurrence to 22.1% versus 45.9% with placebo plus lactulose (hazard ratio 0.42; 95% CI 0.28 to 0.64; p<0.001) 2, 5
• Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy (13.6% vs. 22.6%, hazard ratio 0.50; 95% CI, 0.29 to 0.87; p=0.01) 5
• Long-term treatment with rifaximin for more than 24 months has shown continued prevention of hepatic encephalopathy recurrence with a good safety profile 1

Rifaximin as Monotherapy

• Rifaximin monotherapy may be considered when lactulose is poorly tolerated in patients with cirrhosis (Expert Opinion, Strong Agreement) 1
• However, evidence supporting rifaximin monotherapy is limited, and guidelines state it is "difficult to recommend the use of rifaximin alone in the prevention" 1
• A meta-analysis of 7 trials with 999 patients showed that rifaximin was associated with a lower recurrence rate than control groups (risk ratio = 0.61 [0.50,0.73], P = .001) 6
• Some studies have shown conflicting results regarding rifaximin monotherapy, with one study showing no significant benefit over placebo in preventing recurrent hepatic encephalopathy 7

Dosing Recommendations

• For prevention of recurrent hepatic encephalopathy, rifaximin is dosed at 550 mg twice daily 2, 8, 5
• Some studies have investigated once-daily dosing (550 mg daily), which showed no significant difference compared to twice-daily dosing in preventing hepatic encephalopathy recurrence 9
• Rifaximin can be taken with or without food, though a high-fat meal may increase systemic exposure 8

Safety Considerations

• Rifaximin has not shown increased risk of bacterial resistance or Clostridium difficile-associated colitis in clinical trials 1
• The incidence of adverse events is similar between rifaximin and placebo groups 5, 6
• Caution should be exercised in patients with severe hepatic impairment (Child-Pugh Class C) as rifaximin exposure is significantly higher in these patients (21-fold higher compared to healthy subjects) 8

Clinical Approach to Hepatic Encephalopathy Management

1. Identify and treat precipitating factors of hepatic encephalopathy as the first priority 1
2. Start lactulose as first-line therapy for both acute episodes and prevention of recurrence 1, 3
3. Add rifaximin (550 mg twice daily) if a second episode occurs despite lactulose therapy 1
4. Consider rifaximin monotherapy only when lactulose is poorly tolerated 1
5. Implement therapeutic education programs for patients and caregivers to improve quality of life and limit hospitalizations 1