Long-Term Treatment with Rifaximin

San Diego—Patients with cirrhosis who took rifaximin had a reduced risk of hepatic encephalopathy (HE) and a reduced rate of hospitalization compared with patients in a placebo group, according to a 24-month, open-label maintenance trial. The drug also did not adversely effect survival.

Kevin D. Mullen, the study’s lead author and professor and director of hepatology at Case Western Reserve University School of Medicine, presented the results at DDW in an abstract session. Salix Pharmaceuticals, the drug’s manufacturer, sponsored the study.

In March 2010, the FDA approved rifaximin, which had previously been approved to treat traveler’s disease, to reduce the risk of the recurrence of overt HE in patients with advanced liver disease.

During a 6-month, randomized, double-blind, placebo-controlled trial, 299 patients with a history of ≥2 overt HE episodes with Conn score ≥2 within 12 months were randomized in a 1:1 ratio to receive 550 mg of rifaximin twice daily or placebo. They enrolled at 70 centers in the United States, Canada, and Russia and had 12 visits during the 6 months. In the trial, rifaximin reduced the risk of breakthrough HE by 58% and HE-related hospitalization by 50% compared with placebo (P<.0001 and P=.01, respectively).

The open-label maintenance trial included 152 patients from the randomized study (70 in the rifaximin group and 82 in the placebo group) plus 170 new patients who met the inclusion criteria and took rifaximin. The 82 patients who received placebo in the randomized trial switched to rifaximin in the maintenance trial, so every person in the maintenance trial took rifaximin. They had study visits every 3 months. Patients were allowed to have concomitant lactulose use, but it was not required.

The primary efficacy end point was the time to first breakthrough HE episode, which was defined as an increase in Conn score to ≥2 or an increase of 1 for both the Conn score and asterixis grade for patients with a baseline Conn score of 0.

In the randomized trial, after 168 days of treatment, 78% of patients in the rifaximin group and 54% of patients in the placebo group had maintained remission (hazard ratio [HR], 0.421; 95% confidence interval [CI], 0.276-0.641; P<.0001). During that same time period, 85% of patients who took rifaximin had not been hospitalized for an HE-related reason compared with 73% of placebo patients (HR, 0.500; 95% CI, 0.287-0.873; P=.0129).

In the open-label maintenance study, the long-term event rates for breakthrough HE episodes were 0.3 for the placebo patients from the randomized trial who crossed over to rifaximin, 0.4 for the patients new to rifaximin, and 0.24 for patients who were in the randomized study and continued to take rifaximin. The event rate was calculated as the number of events divided by the person-exposure years. The authors noted that during the randomized trial, the event rate was 0.6 in the rifaximin group and 1.59 in the placebo group.