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Rifaximin Reduces Encephalopathy Recurrence, Improves Quality of Life in People with Liver Cirrhosis

The broad-spectrum antibiotic rifaximin (Xifaxan) improves quality of life for people with liver cirrhosis who experience recurrent episodes of hepatic encephalopathy, or brain disease, according to research presented at the 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010) last month in Vienna. Another analysis from the same study indicated that rifaximin works by lowering the level of ammonia in the blood.

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 with livers 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.

Rifaximin is a minimally absorbed broad-spectrum oral antibiotic that concentrates in the gastrointestinal tract. It has been used successfully to treat acute hepatic encephalopathy, and researchers recently reported that it maintained hepatic encephalopathy remission better than placebo. In March, the U.S. Food and Drug Administration (FDA) announced the approval of rifaximin for prevention of hepatic encephalopathy recurrence.

Quality of Life

In the first analysis presented at EASL, Arun Sanyal and colleagues, who conducted the aforementioned remission study, asked participants to complete the Chronic Liver Disease Questionnaire (CLDQ), a validated survey designed to assess health-related quality of life in people with chronic liver disease.

The Phase 3 RFHE3001 trial included 299 patients in the U.S., Canada, and Russia with liver cirrhosis (MELD score < 25) who had experienced at least 2 episodes of recurrent hepatic encephalopathy (Conn score > 2) 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.

The present analysis included a subset of 219 patients (the Americans and Canadians). About 70% were men, 80% were white, and the average age was about 57 years. The mean MELD score (a measure of liver disease severity) was 13.8 and 40% had experienced more than 2 hepatic encephalopathy episodes during the past 6 months.

The CLDQ was administered at baseline, every 2 weeks until week 8, then every 4 weeks through the end of treatment. The survey included 29 items in 6 domains: abdominal symptoms, fatigue, systemic symptoms, activity, emotional function, and worry. The overall score and the separate domain scores were ranked on a scale of 1-7, with higher scores indicating better quality of life.

Results

• Mean time-weighted average scores for the overall CLDQ were significantly higher in the rifaximin group compared with the placebo group (3.7 vs 2.9; P = 0.009).
• Participants in the rifaximin arm also had significantly better average scores on the separate domains:
• Fatigue (higher = less fatigue): 3.2 with rifaximin vs 2.5 with placebo (P = 0.008);
• Abdominal symptoms: 4.1 vs 3.3, respectively (P = 0.009);Systemic symptoms: 3.9 vs 3.2, respectively (P = 0.016);
• Activity: 3.7 vs 2.8, respectively (P = 0.002);
• Emotional function: 3.9 vs 3.0, respectively (P = 0.0065);
• Worry: 3.5 vs 2.8, respectively (P = 0.0436).
• Participants who experienced breakthough hepatic encephalopathy (recurrence despite treatment) had significantly worse quality of life scores than those who stayed in remission.
• Rifaximin was generally well-tolerated, with a safety profile comparable to that of placebo.

Based on these findings, the researchers concluded, "Rifaximin 550 mg twice-daily significantly improved quality of life overall and across individual domains over a 6 month treatment period in subjects with hepatic cirrhosis and recurrent, overt hepatic encephalopathy."

Ammonia Levels

In the second reported analysis, Sanyal's team evaluated the effect of rifaximin on venous (blood in veins) ammonia concentration in the same study, and looked at the association between ammonia concentration and breakthrough hepatic encephalopathy. Breakthrough was defined as a Conn score rising to > 2 or Conn score and asterixis (wrist tremor) grade each increasing by 1 point. Venous ammonia was measured at baseline and at days 24, 84, and 168 during treatment.

Results

• Out of the 299 enrolled participants, 104 (34.8%) experienced hepatic encephalopathy breakthrough and 194 (64.8%) maintained remission.
• Patients receiving rifaximin experienced a significantly larger decrease in venous ammonia concentration compared with placebo recipients (mean change of -5.7 vs -1.2 mcg/dL, respectively; P = 0.039).
• Participants with higher time-weighted average ammonia concentrations were significantly more likely to develop recurrent hepatic encephalopathy (P = 0.007).

"Rifaximin therapy protected against breakthrough overt hepatic encephalopathy and significantly decreased ammonia concentrations versus placebo," the investigators concluded. "The time-weighted average of venous ammonia concentrations independently predicted breakthrough hepatic encephalopathy in this 6 month study, underscoring the reliability and clinical relevance of Conn score-measured breakthrough hepatic encephalopathy episodes."

Investigator affiliations: Virginia Commonwealth University, Richmond, VA; University of California, San Francisco, CA; University of California at San Francisco, Fresno MEP, CA; Case Western Reserve University, Cleveland, OH; Cedars-Sinai Medical Center, Los Angeles, CA; Weill Medical College of Cornell University, New York, NY; California Pacific Medical Center, San Francisco, CA; Columbia University Medical Center, New York, NY; Delta Research Partners, LLC, Monroe, LA; Gastroenterology Associates of Central Georgia, Macon, GA; Salix Pharmaceuticals, Inc., Morrisville, NC.

5/28/10

References

Sanyal, N Bass, K Mullen, and others. Rifaximin treatment improved quality of life in patients with hepatic encephalopathy: results of a large, randomized, placebo-controlled trial. 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010). Vienna, Austria. April 14-18, 2010. (Abstract 15).

A Sanyal, N Bass, F Poordad, and others. Rifaximin decreases venous ammonia concentrations and time-weighted average ammonia concentrations correlate with overt hepatic encephalopathy (HE) as assessed by Conn score in a 6 month study. 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010). Vienna, Austria. April 14-18, 2010. (Abstract 195).