When is lactulose (lactose) preferred over Rifaximin (rifamycin derivative) for treating hepatic encephalopathy?

Lactulose vs. Rifaximin for Hepatic Encephalopathy

Lactulose should be used as first-line treatment for initial episodes of overt hepatic encephalopathy, while rifaximin should be added to lactulose after a second episode or when lactulose alone fails to prevent recurrence. 1, 2

Initial Treatment of Overt Hepatic Encephalopathy

First-Line Therapy

• Lactulose monotherapy is recommended as the first-line treatment for an initial episode of overt hepatic encephalopathy 1, 2
• Lactulose works by acidifying the gastrointestinal tract, inhibiting ammonia production by coliform bacteria 3
• Dosage should be titrated to achieve 2-3 bowel movements per day 2
• FDA-approved for prevention and treatment of portal-systemic encephalopathy 4

When to Consider Rifaximin

• Rifaximin is not recommended as monotherapy for initial episodes of overt hepatic encephalopathy 1
• Side effects of lactulose (diarrhea, bloating, nausea) may limit tolerability in some patients 1
• In cases where lactulose is poorly tolerated, rifaximin monotherapy may be considered as an alternative (Expert Opinion) 1

Prevention of Recurrent Hepatic Encephalopathy

After First Episode

• Continue lactulose as maintenance therapy to prevent recurrence 1, 2
• Lactulose reduces the risk of recurrent HE (RR = 0.44,95% CI: 0.31–0.64) 1

After Second Episode Within 6 Months

• Add rifaximin 550 mg twice daily to lactulose therapy 1, 2
• The combination of rifaximin and lactulose is superior to lactulose alone:
  • Reduces risk of HE recurrence by 58% compared to placebo (hazard ratio 0.42; 95% CI 0.28-0.64) 5, 2
  • Recurrence rate: 22.1% with combination vs. 45.9% with lactulose alone 2, 5
  • Significantly reduces hospitalization risk (13.6% vs. 22.6%) 5

Special Considerations

Efficacy Comparison

• For treatment of overt HE, combination therapy (rifaximin + lactulose) shows better outcomes than lactulose alone:
  • Higher complete reversal rates (76% vs. 50.8%) 6
  • Lower mortality (23.8% vs. 49.1%) 6
  • Shorter hospital stays (5.8 vs. 8.2 days) 6

Safety Considerations

• Rifaximin has minimal systemic side effects due to negligible absorption (<0.4%) 2
• Long-term rifaximin use has not shown increased risk of bacterial resistance or C. difficile-associated colitis 2
• Rifaximin should be used with caution in patients with severe hepatic impairment (Child-Pugh Class C) 7

Cost and Adherence

• The high cost of rifaximin may impact long-term adherence 2
• This is an important consideration when deciding between monotherapy and combination therapy

Algorithm for Treatment Decision

1. Initial episode of overt HE:

   • Start with lactulose (titrate to 2-3 bowel movements daily)
   • If lactulose is poorly tolerated → consider rifaximin monotherapy

2. After first episode resolution:

   • Continue lactulose maintenance therapy

3. After second episode within 6 months:

   • Add rifaximin 550 mg twice daily to lactulose therapy

4. For prevention of recurrence when lactulose alone fails:

   • Add rifaximin 550 mg twice daily

Patient Education

• Therapeutic education programs should be offered to patients and caregivers to improve medication adherence, help recognize early HE symptoms, and limit hospitalizations 1, 2
• Proper lactulose titration is essential to achieve optimal outcomes while minimizing side effects