Rifaximin Treatment in Hepatic Encephalopathy

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Bass NM, Mullen KD, Sanyal A, et al
N Engl J Med. 2010;362:1071-1081
Background

Hepatic encephalopathy (HE) is a common and complex neuropsychiatric syndrome seen in patients with liver failure. It is characterized by neuropsychiatric disturbances in consciousness and behavior, personality changes, fluctuating neurologic signs, asterixis, and electroencephalographic changes. Although the etiology of HE is unknown, the accumulation of several gut-derived toxins, such as mercaptans, ammonia, and benzodiazepine, has been implicated. Current treatment options for HE include agents that reduce the concentration of these toxins, such as nonabsorbable disaccharides (eg, lactulose) and antibiotics. Because antibiotics can reduce or eliminate ammonia-producing bacteria as well as blood and brain ammonia levels, these agents can play a key role in the management of HE.

Both aerobic and anaerobic bacteria produce ammonia. Therefore, the spectrum of antibiotics used for short-term treatment or long-term maintenance or prophylaxis against HE may be too narrow for optimum reduction of ammonia levels. Traditionally, antibiotics used for HE include neomycin, paromomycin, vancomycin, and metronidazole. Complications of long-term use of these agents are considerable and include renal, auditory, and neurologic toxicities, as well as antibiotic-insduced microfloral resistances. Of note, no well-controlled prospective randomized studies of these antibiotic agents in treatment or prophylaxis of HE have been conducted.

Progressive interest in the efficacy of rifaximin, a minimally absorbed oral antibiotic with broad-spectrum coverage for gram-positive and gram-negative aerobes and anaerobes, for treatment of HE is evident in the literature. The efficacy of rifaximin has been assessed in more than15 studies, most of which are randomized clinical trials. Comparative studies of lactulose versus rifaximin have shown rifaximin to be more effective than nonabsorbable disaccharides. Rifaximin has greater or at least equivalent efficacy, and far fewer complications, compared with the antibiotics traditionally used for HE. Furthermore, rifaximin appears to be associated with a very low risk of inducing bacterial resistance. The long-term use of rifaximin for prevention of relapse of HE has not been well studied.
Study Summary

This prospective phase 3 multicenter/multinational randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of rifaximin, used concomitantly with lactulose, for the maintenance of remission of HE. Patients were randomly assigned to receive rifaximin, 550 mg twice daily, or placebo. Concomitant administration of lactulose was allowed (provided the entry dose was stable) and was balanced at 91% between the 2 groups. The efficacy data were analyzed by an intention-to-treat analysis for the 299 total patients (205 from the United States, 14 from Canada, and 80 from Russia). Baseline characteristics were similar for both study groups. Breakthrough episodes of HE were reported in 22.1% of patients receiving rifaximin and 45.9% of those receiving placebo. The hazard ratio for a breakthrough HE episode was 0.42 (95% confidence interval, 0.28-0.64; P < .001), which equates to a 58% risk reduction for patients who received rifaximin. The number needed to treat with rifaximin to prevent 1 episode of recurrent HE was 4. The number of adverse events was similar for both the rifaximin and placebo groups.
Viewpoint

Currently, more than 600,000 cases of cirrhosis have been diagnosed in the United States, accounting for an estimated 25,000 deaths from cirrhosis each year. As many as 200,000 patients in the United States have episodic overt HE, so the scope of the treatment problem is considerable.

This study shows the superiority of rifaximin plus lactulose over rifaximin alone. It corroborates previous retrospective studies that found that rifaximin reduces the risk for HE-related hospitalization. By focusing on the long-term outcomes, this study differs from previous studies that focused on the use of rifaximin in acute or overt HE. Clearly the data for both indications show robust efficacy and safety. The data are strong and most likely had a major influence on the US Food and Drug Administration, which recently approved rifaximin as a treatment to reduce risk for recurrence of overt HE in patients with advanced liver disease.[1]

Abstract

References

战战兢兢

"Rifaximin" 治疗肝性脑病

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Salix公司表示美国FDA专家顾问委员会表示支持利福昔明（rifaximin，Xifaxan）550 mg片剂用于治疗慢性肝衰竭引起的神经系统损害，顾问委员会投过投票表示支持该药用于肝性脑病。肝衰竭患者的肝性脑病引起神经损害，导致患者出现昏迷与无意识症状。

本品已获得了用于此症的罕用药地位，将在美国获得7年的市场独占权。在Ⅲ期临床研究中，本品显著降低肝性脑病复发风险。肝性脑病常发生在肝硬化患者中，在美国有60万肝硬化患者。本品现在以商品名Xifaxan在美国销售用于由埃希氏菌属引起的旅行者腹泻。

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