What is the preferred first‑line therapy for overt hepatic encephalopathy: lactulose or rifaximin?

Lactulose vs Rifaximin for Overt Hepatic Encephalopathy

Lactulose is the preferred first-line therapy for overt hepatic encephalopathy, with rifaximin reserved as add-on therapy when lactulose alone fails to prevent recurrence. 1

Initial Treatment of Acute Overt HE

Start with lactulose immediately after identifying and treating precipitating factors—rifaximin should not be used as monotherapy for acute episodes. 1, 2

Lactulose Dosing for Acute Episodes

• Initial dose: 25-45 mL (20-30 g) orally every 1-2 hours until the patient produces at least 2 soft or loose bowel movements per day 1, 2
• Maintenance dose: 25 mL every 12 hours, titrated to maintain 2-3 soft stools daily 1, 2
• Critical point: Lactulose reduces mortality and serious adverse events (GI bleeding, bacterial infections, hepatorenal syndrome) in patients with overt HE 1

Why Not Rifaximin Alone for Acute Episodes?

The 2023 French guidelines explicitly state that analysis of potential biases in randomized controlled trials indicates rifaximin cannot be recommended as monotherapy for overt HE, despite showing beneficial effects on HE resolution and mortality 1. This represents the most recent high-quality guideline evidence and should guide practice.

Prevention of Recurrent Episodes

After a patient experiences their first episode of overt HE, continue lactulose as monotherapy for secondary prophylaxis. 1

When to Add Rifaximin

Add rifaximin 550 mg twice daily only when lactulose alone fails to prevent recurrence (i.e., after a second breakthrough episode while on lactulose). 1, 2

• The landmark trial showed rifaximin added to lactulose (91% of patients were on lactulose) reduced recurrence risk by 58% (hazard ratio 0.42) compared to placebo 1, 2
• Combination therapy reduced HE-related hospitalizations by 50% (hazard ratio 0.50) 2, 3
• Rifaximin demonstrated good safety profile with continuation beyond 24 months, without increased risk of bacterial resistance or Clostridium difficile infection 1, 2

Evidence Quality and Strength

The 2023 French guidelines (most recent) provide Grade 1+ strong agreement recommendations prioritizing lactulose, while rifaximin receives Grade 2+ recommendations only as add-on therapy 1. The 2014 EASL/AASLD guidelines similarly recommend lactulose first-line (GRADE II-1, B, 1) with rifaximin as add-on (GRADE I, A, 1) 1.

Meta-Analysis Evidence

• Non-absorbable disaccharides (lactulose/lactitol) significantly improved resolution of acute/chronic overt HE and reduced mortality compared to placebo 1
• While rifaximin showed beneficial effects, the quality of supporting trials had methodological concerns that prevent recommending it as monotherapy 1

Special Circumstances

Rifaximin monotherapy may be considered only when lactulose is poorly tolerated, though this is based on expert opinion rather than robust clinical trial evidence 1, 3. This should be a rare exception, not routine practice.

Common Pitfalls to Avoid

• Do not use excessive lactulose doses: Overuse can cause aspiration, dehydration, hypernatremia, severe perianal irritation, and paradoxically precipitate HE 1
• Do not start rifaximin as monotherapy for acute episodes: Despite its efficacy, the evidence does not support this approach 1, 3
• Do not discontinue lactulose when adding rifaximin: The combination is more effective than rifaximin alone 1, 2
• Do not forget to identify and treat precipitating factors: This is the essential first step before any pharmacologic therapy 1

Cost Considerations

Lactulose is significantly less expensive than rifaximin, which further supports its use as first-line therapy 1. Rifaximin should be reserved for patients who truly need add-on therapy after failing lactulose monotherapy.