Reuters Health Information (2010-12-29): Rifaximin improves cognition in minimal hepatic encephalopathy
Drug & Device Development
Rifaximin improves cognition in minimal hepatic encephalopathy
Last Updated: 2010-12-29 15:25:07 -0400 (Reuters Health)
NEW YORK (Reuters Health) - By restoring cognitive function in patients with minimal hepatic encephalopathy (MHE), rifaximin treatment also improves their quality of life, investigators in India report.
The broad-spectrum antibiotic rifaximin (Xifaxan) is a nonabsorbable gut-specific antibiotic. It is thought to improve hepatic encephalopathy by depleting the supply of gut-derived bacterial ammonia associated with cirrhosis.
In March of this year, the U.S. Food and Drug Administration approved rifaximin for preventing recurrent hepatic encephalopathy. At the same time, the New England Journal of Medicine reported that rifaximin cut recurrence of overt hepatic encephalopathy by more than half. (See Reuters Health story of March 24, 2010).
"MHE is not widely tested for in clinical practice, but it's apparent to the patients and their families," Dr. Nathan M. Bass told Reuters Health. "They're 'off their game' in terms of work, particularly jobs with significant intellectual demand, and it impacts day-to-day skills, such as the ability to drive."
Dr. Bass, from the University of California, San Francisco, was the lead author of the NEJM article, but he was not involved in the present research.
Researchers at Dayanand Medical College and Hospital in Ludhiana, Punjab, led by Dr. Sandeep Singh Sidhu, studied the use of rifaximin in adults with MHE. A diagnosis of MHE required impairment on at least two of five neuropsychometric tests.
The investigators screened 281 patients with liver cirrhosis without overt hepatic encephalopathy and diagnosed 115 (41%) with MHE. Of the 94 who agreed to participate, 49 were randomized to oral rifaximin 400 mg three times daily for 8 weeks, and 45 were randomized to placebo. (Study drugs were provided by LUPIN Ltd.)
In the intent-to-treat analysis, patients taking rifaximin showed significantly greater rates of MHE reversal at two weeks (57% vs 18%) and at eight weeks (76% vs 20%), p < 0.0001 for both times, the researchers reported online December 14th in the American Journal of Gastroenterology.
The mean number of abnormal tests fell from 2.35 to 0.81 between baseline and eight weeks in the rifaximin group, and from 2.31 to 1.97 in the placebo group.
Rifaximin, but not placebo, was also associated with significant improvement in health-related quality of life, assessed with the Sickness Impact Profile (SIP) Questionnaire. Higher scores denote greater dysfunction. At baseline, mean total SIP scores were 2.12 in patients without MHE and 10.71 in those with MHE.
After 8 weeks, total SIP score had fallen by 4.61 points in the rifaximin group and by 0.88 in the placebo group. Rifaximin also led to significant improvements in six of 12 SIP scales, and in total psychosocial and physical sub-scores.
When the authors looked at potential confounders -- age, education, sex, residence, duration of cirrhosis and its etiology, esophageal varices and ascites - only the presence of MHE significantly affected total SIP score.
"Thus," Dr. Sidhu and colleagues conclude, "MHE has a significant impact on (a) patient's overall quality of life, and it deserves screening and treatment."
In e-mail to Reuters Health, Dr. Sidhu added, "Lactulose remains the standard of care in MHE. But if rifaximin proves to be as effective as and better tolerated than lactulose in future trials, it will become the standard of care."
His team is now planning to study the combination of rifaximin and lactulose for MHE patients nonresponsive to either drug alone. He said it will also be important to study the natural history of MHE at six months or one year after patients stop taking it.
"This study is well designed and quite impressive," Dr. Bass said. "Now we need to consider how best to test patients for MHE. Possibilities would be computer-based assessment tests or short psychometric protocols."
He noted that rifaximin is better tolerated than lactulose, and it does not appear to promote antibiotic resistance or propensity to infection with Clostridium difficile.
The one problem is cost: If used at the dose in this study, one month's supply of rifaximin could cost nearly $1600.
Neomycin and metronidazole - favored by insurance carriers, Dr. Bass said - are available as generics and cost much less. "But they're also much more toxic, and can cause hearing loss, nephrotoxicity, and peripheral neuropathy."
"If you're going to use an antibiotic for hepatic encephalopathy, I'd choose rifaximin, both for safety and proven efficacy," he said.
Am J Gastroenterol 2010.