Over years or decades, chronic hepatitis B or C, prolonged heavy alcohol use, and other factors that damage the liver can lead to advanced disease including cirrhosis and hepatocellular carcinoma. The liver can function for a while despite damage, but eventually decompensation may occur, with symptoms of liver failure such as ascites (abdominal fluid accumulation), bleeding varices (swollen veins) in the esophagus or stomach, and hepatic encephalopathy (brain impairment).

Hepatic Encephalopathy

At a late-breaker session at the Liver Congress, Omesh Goyal from Dayanand Medical College and Hospital in Ludhiana, India, reported findings from a study of rifaximin versus lactulose in the treatment of minimal hepatic encephalopathy (MHE) in patients with cirrhosis.

Hepatic encephalopathy is caused by the build-up of toxins such as ammonia in the blood when they can no longer be filtered out by a damaged liver. Symptoms may include confusion, reduced attention, cognitive impairment, memory problems, lethargy, and mood changes.

Rifaximin is a non-absorbable, gut-specific antibiotic; though lacking extensive study data, it has orphan drug status in the U.S. as a treatment for hepatic encephalopathy. Lactulose is a non-digestible sugar that improves transit of waste through the intestines and traps ammonia by altering gut acidity.

This prospective non-inferiority trial, conducted in Northern India, included 112 individuals with minimal hepatic encephalopathy, out of more than 500 cirrhotic patients screened. About 75% were men and the mean age was approximately 53 years. The most common cause of cirrhosis was alcohol use, followed by hepatitis C. Minimal hepatic encephalopathy was defined as abnormal results on at least 2 neuro-psychometric tests including number and figure connection tests, picture completion, digit symbol test, and block design test. They had no prior history of overt hepatic encephalopathy and no infections or gastrointestinal bleeding within the past 6 months.

Participants were randomly assigned to receive lactulose syrup (30-120 ml/day) or rifaximin tablets (400 mg 3 times daily) for 3 months. The researchers looked at improvement in neuro-psychometric test results and changes in health-related quality of life using the Sickness Impact Profile (SIP) questionnaire.

After 3 months or treatment, a similar proportion ofpatients experienced reversal of minimal hepatic encephalopathy in the rifaximin and lactulose groups (65% vs 67%, respectively). However, the difference did not reach the 5% threshold for non-inferiority. Both groups showed significant improvement in health-related quality of life -- including eating, recreation, work, communication, and alertness -- with rifaximin being non-inferior to lactulose. Adverse events occurred with similar frequency in both treatment arms.

"Although rifaximin and lactulose had similar rates of MHE reversal, the non-inferiority of rifaximin over lactulose for MHE reversal could not be established," the researchers concluded. However, they added, "rifaximin was non-inferior to lactulose in improvement of health-related quality of life, and also more cost-effective than lactulose."

During the question period, speakers noted that while rifaximin may cost less than lactulose in India, the opposite is true in many other countries.

A related study by Sudhir Maharshi and colleagues from GB Pant Hospital in New Delhi compared rifaximin versus lactulose for prevention of hepatic encephalopathy among cirrhotic patients with acute variceal bleeding. Gastrointestinal bleeding can trigger hepatic encephalopathy. Lactulose has been used for prophylaxis of encephalopathy after acute variceal bleeding, but rifaximin has not been well studied for this purpose.

This study included 53 Indian patients with cirrhosis and acute variceal bleeding who did not have hepatic encephalopathyat the time of presentation. Most were men and the mean age was approximately 43 years. They were randomized to receive either rifaximin or lactulose in addition to standard treatment for variceal bleeding. The primary endpoint was development of overt hepatic encephalopathywithin 5 days after randomization.

The likelihood of developing hepatic encephalopathy was similar in the 2 groups: 4 out of 26 (15%) patients taking rifaximin versus 5 out of 27 (19%) taking lactulose. Mortality was also similar in the 2 groups (3 patients in each).

Based on these findings, the researchers concluded, "Lactulose and rifaximin are equally effective for prophylaxis of hepatic encephalopathy in patients [with] cirrhosis with acute variceal bleed."

Esophageal Bleeding

A third study, presented by Bradley Confer from the Cleveland Clinic Foundation and colleagues at Digestive Disease Week, looked at rifaximin as a direct therapy for esophageal bleeding.

A proportion of patients with large esophageal varices experience bleeding despite standard management with non-selective beta blockers or esophageal band ligation, the researchers noted as background. Rifaximin has been associated with decreased hepatic vein pressure in some studies, so they hypothesized that it might help prevent or delay esophageal bleeding.

This retrospective cohort study included 238 cirrhotic patients with medium to large esophageal varices but no prior history of variceal bleeding. All were treated with beta blockers, band ligation, or both. In addition, 41% of participants received rifaximin at the discretion of their treating hepatologist to manage hepatic encephalopathy. Patients were followed until the first episode of esophageal bleeding, liver transplant, or death.

The cumulative incidence of esophageal variceal bleeding over 5 years was 4% among rifaximin recipients compared with 16% among those not taking rifaximin.

In a multivariate analysis, patients taking rifaximin had an 81% lower risk of bleeding within 5 years (hazard ratio 0.19). However, there was no significant difference in survival between patients taking or not taking rifaximin.

"The use of rifaximin in addition to standard medical therapy for the primary prophylaxis of esophageal variceal bleeding was associated with significantly reduced time to first esophageal variceal bleed," the researchers concluded. "This study potentially describes another use for rifaximin in decompensated cirrhosis, however, further prospective randomized control trial are necessary to validate the results."

5/21/14

References

O Goyal, SS Sidhu, RA Parker, et al. Rifaximin versus Lactulose in the Treatment of Minimal Hepatic Encephalopathy in Patients with Cirrhosis: A Prospective, Randomized, Active-Comparator, Non-Inferiority Trial. 49thEuropean Association for the Study of the Liver International Liver Congress (EASL 2014). London, April 9-13, 2014. Abstract O169.

S Maharshi, BC Sharma, S Srivastava, and A Jindal. Prophylaxis of Hepatic Encephalopathy in Acute Variceal Bleed in Patients With Cirrhosis: An Open Label Randomized Controlled Trial of Lactulose Versus Rifaximin. 49thEuropean Association for the Study of the Liver International Liver Congress (EASL 2014). London, April 9-13, 2014. Abstract O19.

B Confer, TG Theethira, M Dugum, et al. Rifaximin in Addition to Standard Medical Therapy Significantly Reduces the Time to First Esophageal Variceal Bleed. Digestive Disease Week (DDW 2014). Chicago, May 3-6, 2014. Abstract 488.