Chronic liver disease and cirrhosis affect hundreds of millions of patients all over the world, especially in China. One of these recurrent and difficult to treat complications is hepatic encephalopathy [33
]. Overt hepatic encephalopathy affects from 30 to 45% of patients with cirrhosis, and a higher percentage may be affected by minimal hepatic encephalopathy (MHE). It is a spectrum ranging from minimal hepatic encephalopathy (MHE) without recognizable clinical symptoms to overt HE with risk of cerebral edema and death. HE that results in diminished quality of life and survival is serious challenges on the healthcare system [7
]. Our treatment strategy is to reduce the production and absorption of ammonia and other gut-derived toxins. Many overt HE can be improved when precipitating factors are corrected, such as infection, gastrointestinal bleeding, dehydration, and electrolyte disturbances [5
]. Nonabsorbable disaccharides (lactulose and lactitol) were considered as standard treatment for hepatic encephalopathy, that have been proved effectively for the treatment of HE. Some severe adverse events, including diarrhea, abdominal pain, vomiting, and flatulence, may lead to the cessation of therapy with disaccharides. Some minimally absorbed antibiotics, such as neomycin, vancomycin, metronidazole, and oral quinolones, were previously shown in some studies to be effective in the treatment of both acute and chronic encephalopathy [16
]. The significant risk of severe toxicity is the reason why most agents are seldom used in practice. Rifaximin is a minimally absorbed antimicrobial agent with a broad spectrum against gram-positive and gram-negative aerobic and anaerobic enteric bacteria [34
]. Rifaximin seems the ideal drug that appears to be effective in the treatment of HE without carrying the risk of severe side effects. In 2010, FDA approved rifaximin as a drug of HE treatment. Is it reasonable to consider rifaximin as a first-line drug for HE? There is no consensus on it. Expense of rifaximin is great, and effectiveness of rifaximin is uncertain compared to nonabsorbable disaccharides. Results of some underpowered randomized controlled trials were inconsistent.
Here, we performed a meta-analysis containing eight randomized controlled trials assessing the efficacy and safety of rifaximin versus nonabsorbable disaccharides. Furthermore, we assessed the reduction of blood ammonia levels, and psychometric outcomes (mental status, grade of asterixis, electroencephalogram, portosystemic encephalopathy sum). Our study showed that rifaximin was as effective as nonabsorbable disaccharides but with fewer adverse events. A randomized, double-blind, placebo-controlled trial showed that rifaximin was effective in preventing hepatic encephalopathy. Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy [35
]. So, rifaximin is effective in the treatment and prevention of hepatic encephalopathy, but more studies are needed to assess its safety, including tolerance, toxicity, bacterial resistance, and mycotic infection.
For the secondary outcomes, patients in rifaximin group had lower serum ammonia levels, superior mental status, and asterixis profiles versus the control group with no statistical significance. On the other hand, the grade of EEG and PSE sums showed better results for patients in rifaximin group, when compared to their controls. So, maybe we can build an accurate scoring criteria to assess and quantify subtle clinical changes in the treatment of HE. Of course, there were some limitations in our meta-analysis. The RCTs included in our study did not have enough number of cases. We need more RCTs in recent years to make the conclusion more convincing. Five of the eight RCTs were carried out in Italy, and there were little information about other countries. These reasons will lead to bias. So, further studies on larger populations of patients are necessary to obtain more sufficient evidence for the evaluation of rifaximin versus nonabsorbable disaccharides for HE.
In summary, this study shows that rifaximin is as effective as nonabsorbable disaccharides, maybe better in some psychometric outcomes, with fewer adverse events. Sensitivity analysis showed significant difference in the treatment of acute HE, favoring the use of rifaximin, but the result may be not credible because of small samples. We suggest that rifaxinmin should be used as second-line, because of its expensive price and safety in long-term use. Patients who have severe adverse events in disaccharides therapy could use rifaximin instead.