What is the preferred treatment between rifaximin and lactulose for hepatic encephalopathy?

Treatment of Hepatic Encephalopathy: Rifaximin vs. Lactulose

Lactulose is the first-line treatment for episodic overt hepatic encephalopathy (OHE), while rifaximin is recommended as an add-on therapy to lactulose for prevention of OHE recurrence after a second episode. 1

Initial Treatment of Overt Hepatic Encephalopathy

• Identify and treat precipitating factors for hepatic encephalopathy as the first priority in management 1
• Lactulose is the first-choice treatment for episodic OHE with Grade II-1, B, 1 recommendation 1
• Non-absorbable disaccharides (lactulose/lactitol) are associated with significantly more frequent resolution of acute or chronic overt HE and reduction in mortality compared to placebo 1
• The FDA has approved lactulose for both prevention and treatment of portal-systemic encephalopathy, noting that it reduces blood ammonia levels by 25-50% 2

Prevention of Recurrent Episodes

• Lactulose is recommended for prevention of recurrent episodes of HE after the initial episode (Grade II-1, A, 1) 1
• Rifaximin as an add-on to lactulose is recommended for prevention of recurrent episodes of HE after the second episode (Grade I, A, 1) 1
• Rifaximin is FDA-approved specifically for "reduction in risk of overt hepatic encephalopathy recurrence in adults" 3
• In clinical trials for rifaximin's approval, 91% of patients were using lactulose concomitantly, highlighting its role as an add-on therapy 3

Mechanism of Action

• Lactulose works by acidifying the gastrointestinal tract, which inhibits production of ammonia by coliform bacteria 4
• Rifaximin decreases intestinal production and absorption of ammonia by altering gastrointestinal flora and is almost completely excreted unchanged in the feces 4

Clinical Evidence for Combination Therapy

• Rifaximin added to lactulose is the best-documented agent to maintain remission in patients who have already experienced one or more bouts of OHE while on lactulose treatment 1
• Long-term studies show that adding rifaximin to lactulose significantly reduces the risk of overt HE recurrence and HE-related hospitalization compared with lactulose therapy alone 5
• The recommended dose of rifaximin for hepatic encephalopathy is one 550 mg tablet taken orally twice daily 3

Special Considerations

• For patients who cannot tolerate lactulose, rifaximin alone may be considered, though this is based on expert opinion rather than strong evidence 1
• Neither rifaximin nor lactulose has been shown to prevent post-TIPS HE better than placebo, so routine prophylactic therapy is not recommended in this specific situation 1
• Alternative agents for patients nonresponsive to conventional therapy include oral branched-chain amino acids (BCAAs) and IV L-ornithine L-aspartate (LOLA) 1

Common Pitfalls and Caveats

• Rifaximin should not be used as monotherapy for initial treatment of overt HE, as evidence supports lactulose as first-line therapy 1
• Long-term antibiotics like neomycin and metronidazole, while effective, have significant side effects including ototoxicity, nephrotoxicity, and neurotoxicity that make them unsuitable for continuous long-term use 1
• Rifaximin has not been extensively studied in patients with more severe hepatic dysfunction (MELD scores >25), and there is increased systemic exposure in these patients 3
• Simple laxatives alone do not have the prebiotic properties of disaccharides like lactulose and are not recommended 1