Rifaximin Effectively Prevents Recurrence of Hepatic Encephalopathy

Emma Hitt, PhD

March 24, 2010

March 24, 2010 — Rifaximin treatment for 6 months more effectively maintains remission from hepatic encephalopathy (HE) than placebo, according to a report published March 25 in the New England Journal of Medicine.

"Rifaximin is currently under consideration by the US Food and Drug Administration (FDA) for the indication of preventing episodic HE,” said Nathan M. Bass, MB ChB, PhD, with the University of California, San Francisco.

"If approved, this will be the first new treatment to be approved in the USA for HE in 30 years and helps to fill an unmet need in the treatment of HE, a difficult problem for patients with advanced liver disease," he told Medscape Neurology.

Rifaximin Safe, Well Tolerated

Currently, rifaximin is indicated for the treatment but not the prevention of HE. To evaluate its potential for prevention, Dr. Bass and colleagues randomized 299 patients in remission from recurrent HE due to chronic liver disease to receive either 500 mg twice daily of rifaximin or placebo. Lactulose therapy was given concurrently to more than 90% of the patients.

Compared with placebo, rifaximin significantly reduced the risk for HE (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.28 – 0.64; P < .001). Of the patients, 22.1% experienced a breakthrough episode of HE compared with 45.9% in the control group. Hospitalizations occurred in 13.6% of the treatment group compared with 22.6% of the placebo group (HR, 0.50; 95% CI, 0.29 – 0.87; P = .01).

According to the study authors, the "reduced risk was seen across subgroups, further showing the consistency of the results, which expand previously reported findings of the efficacy of rifaximin in the treatment of overt hepatic encephalopathy."

The incidence of adverse events was comparable between the treatment and placebo groups, and rates of infection were similar.

Dr. Bass noted that rifaximin appears to be safe and well tolerated, although he anticipates that the manufacturer will conduct additional safety surveillance studies once rifaximin is approved for this indication. He added that less rigorous small trials have suggested that other antibiotics might have a similar benefit, "but these studies were very brief in duration, and the drugs studied have had significant issues with safety and tolerability," he said.

According to the study authors, the use of certain other antibiotics in HE is restricted because of toxic effects; aminoglycosides, for example, including neomycin and paromomycin, are associated with nephrotoxicity and ototoxicity, whereas prolonged use of metronidazole is associated with nausea and peripheral neuropathy.

Comparison With Lactulose

According to Dr. Bass, gut bacteria are important in generating ammonia, considered to be a key neurotoxin causing HE. "A poorly absorbed antibiotic such as rifaximin can reduce ammonia production by its effect upon gut bacteria," he said.

Dr. Bass noted that the current standard of care treatment for HE is lactulose, which often causes unpleasant gastrointestinal side effects.

"Although the results of the trial were obtained mostly in patients who were taking lactulose, to which rifaximin (or placebo) was added, an obvious question we need to address in future clinical studies is how effective rifaximin is in the absence of lactulose," he said.

More Studies Needed

In a related editorial, Stephen M. Riordan, MD, and Roger Williams, MD, pointed out that neither the current study nor a study evaluating lactulose alone by Sharma and colleagues has addressed the effect of lactulose or combined lactulose-rifaximin therapy on gut flora and ammonia production, "in particular how changes in the flora and production correlate with the clinical efficacy of the therapy," they write.

Dr. Riordan is with the University of New South Wales in Sydney, Australia, and Dr. Williams is with the University College London Medical School in the United Kingdom.

"Nonetheless," they write, "the trials add weight to the concept that treatment directed towards 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."

The editorialists suggest that the substantial rates of treatment failure highlight the need for additional research.

The study was sponsored by Salix Pharmaceuticals Inc. Dr. Bass reports that he has served as a consultant to Salix Pharmaceuticals. Dr. Riordan and Dr. Williams have disclosed no relevant financial relationships.

N Engl J Med. 2010;362:1071-1081, 1140-1142.