Rifaximin treatment for reduction of risk of overt hepatic encephalopathy recurrence

Abstract

Hepatic encephalopathy (HE) is a common problem in patients with chronic liver disease and is characterized by diminished mentation and neuromuscular abnormalities. Symptoms range from subtle cognitive changes to coma and death. Gut-derived toxins such as ammonia are thought to play a central role in the pathogenesis of HE. Treatment strategies are directed at increased elimination or reduction of gut-derived ammonia in addition to correction of dynamic conditions that provoke bouts of HE. The standard of care for treatment of acute HE is lactulose, a nonabsorbable disaccharide that is thought to increase elimination and reduce absorption of ammonia. Although lactulose seems to work in the acute setting, the rate of recurrent HE on maintenance lactulose is high. Medications have been sought that reduce the rate of recurrent HE in patients at high risk for HE but none have been identified. Rifaximin is a poorly absorbed antibiotic that is thought to reduce ammonia production by eliminating ammonia-producing colonic bacteria. Many small studies have suggested that rifaximin is effective in treating acute HE and is extremely well tolerated. This led to a randomized, placebo-controlled, multicenter, multinational trial investigating the efficacy of rifaximin over a 6-month period in reducing the risk of recurrent HE in patients at baseline, but with a history of at least two bouts of acute HE in the previous 6 months prior to enrollment. Lactulose could be administered at the discretion of the investigator. A total of 299 patients were randomized to receive rifaximin or placebo; 91% of patients in each group received lactulose. Compared with placebo, patients at high risk for recurrent HE in the rifaximin group had highly statistically significant reductions in bouts of acute HE (58%) and reductions in hospitalizations related to HE (50%) over a 6-month period. The medication was well tolerated with a side-effect profile comparable to placebo. This led to the approval of rifaximin for reduction of risk of recurrent HE by the US Food and Drug Administration in March 2010. It is recommended that patients with a history of recurrent acute HE should be maintained on rifaximin with or without lactulose to reduce the risk of recurrent HE and related hospitalization.