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Antibiotic Rifaximin Maintains Remission of Hepatic Encephalopathy in People with Advanced Liver Disease

Treatment with the antibiotic rifaximin maintained remission from hepatic encephalopathy, or brain impairment, better than placebo in people with advanced liver disease, according to a report in the March 25, 2010 New England Journal of Medicine. The drug was well tolerated overall, and patients taking rifaximin were less likely to be hospitalized than placebo recipients.

Hepatic encephalopathy is a form of neurocognitive impairment caused by build-up of toxins such as ammonia -- thought to be produced by bacteria in the gut -- in people whose livers are so damaged that they cannot perform their normal filtering function (known as decompensated cirrhosis). Over years or decades, chronic hepatitis B and C can progress to decompensated liver disease.

Nathan Bass from the University of California at San Francisco and colleagues looked at the efficacy of rifaximin in preventing recurrent episodes of hepatic encephalopathy in patients with chronic liver disease. Rifaximin is a minimally absorbed oral broad-spectrum antibiotic that concentrates in the gastrointestinal tract. It has been used to treat acute hepatic encephalopathy, but its effectiveness in preventing recurrence has not been established.

This double-blind Phase 3 trial included 299 patients in the U.S., Canada, and Russia who had experienced at least 2 episodes of recurrent hepatic encephalopathy during the past 6 months but were currently in remission. Participants were randomly assigned to receive either 550 mg twice-daily rifaximin or placebo for 6 months. More than 90% also received lactulose, a laxative commonly used to reduce ammonia in the gut (though its efficacy is controversial).

Results

• The mean duration of treatment was 130 days in the rifaximin group and 106 days in the placebo group; both groups achieved better than 80% adherence.
• In an intent-to-treat analysis at 6 months, rifaximin significantly reduced the risk of recurrent episodes of hepatic encephalopathy as compared with placebo (hazard ratio 0.42, or a 58% reduction in risk).
• 22.1% of patients in the rifaximin group experienced a breakthrough episode of encephalopathy, compared with 45.9% in the placebo group.
• 13.6% of patients in the rifaximin group were hospitalized due to hepatic encephalopathy, compared with 22.6% in the placebo group, also a significant difference (hazard ratio 0.50.
• Adverse events were common given the participants' advanced stage of disease, but frequency was similar in the rifaximin and placebo groups (both 80%).

"Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo," the study authors concluded. "Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy."

"Our study shows the superiority of rifaximin therapy over treatment with lactulose alone," they elaborated in their discussion. More than 90% of patients received concomitant lactulose and a significant treatment effect was noted within 28 days after randomization. A previous study showed that lactulose alone was more effective than no treatment in preventing recurrent encephalopathy, but the effect was only apparent after about 4 months.

With regard to adverse events, the researchers noted that rifaximin appeared to be safer than various systemic antibiotics, which can cause kidney toxicity, hearing loss, and peripheral neuropathy with prolonged use. The risk of bacterial resistance also appears to be lower with rifaximin, since blood drug levels are minimal and bacteria outside the gastrointestinal tract are therefore not exposed to much selective pressure.

In an accompanying editorial, Stephen Riordan from the University of New South Wales andRoger Williams from University College London said that the Bass study "add[s] weight to the concept that treatments directed toward modulating gut flora are of value for the management of overt hepatic encephalopathy in patients with cirrhosis, at least for the prevention of recurrent episodes."

University of California, San Francisco, CA; California Pacific Medical Center, San Francisco, CA; Cedars-Sinai Medical Center, Los Angeles, CA; University of California, Fresno, CA; Scripps Clinical Research Center, La Jolla, CA; Metrohealth Medical Center, Case Western Reserve University, Cleveland, OH; University of Cincinnati Medical Center, Cincinnati, OH; Virginia Commonwealth University, Richmond, VA; University of Medicine and Dentistry of New Jersey, Newark, NJ; Weill Medical College of Cornell University, New York, NY; New York University School of Medicine, New York, NY; Asheville Gastroenterology Associates, Asheville, NC; Salix Pharmaceuticals, Morrisville, NC.

3/26/10

References

NM Bass, KD Mullen, A Sanyal, and others. Rifaximin Treatment in Hepatic Encephalopathy. New England Journal of Medicine362(12): 1071-1081. March 25, 2010.

S Riordan and R Williams. Gut Flora and Hepatic Encephalopathy in Patients with Cirrhosis. New England Journal of Medicine362(12): 1140-1142. March 25, 2010.