Rifaximin Alfa and Liver Diseases: More Than a Treatment for Encephalopathy, a Disease Modifier

Abstract

RFX, a rifamycin-based antibacterial agent obtained by the culture of the actinomycete Streptomyces mediterranei, has a broad antibacterial spectrum covering gram- positive, gram-negative, aerobic, and anaerobic bacteria. RFX is an antibiotic that elicits its effect by inhibiting bacterial RNA synthesis. When administered orally, its intestinal absorption is extremely low (<0.4%), restricting antibacterial activity mainly in the intestinal tract, with few systemic side effects. RFX has been recommended by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver guidelines for the treatment of HE. RFX may contribute to restore hepatic function and to decrease the development of liver fibrosis. Its efficacy has been shown in patients with previous hepatic encephalopathy and several complications, such as infections, including spontaneous bacterial peritonitis, ascites and oesophageal variceal bleeding. Thus, RFX has an outstanding role in the therapeutic arsenal in hepatic cirrhosis, under the concept of disease modifier.

Keywords: hepatic cirrhosis therapy; liver disease; modifier; rifaximin.

Figure 1

Natural history of cirrhosis compensated and decompensated. After of the initial insult (alcohol, virus, metabolic syndrome, autoimmunity) the progression to compensated cirrhosis can last from 20 to 35 years. Likewise, compensated cirrhosis remains stable between 10 to 15 years before the decompensation phase. The current prevalence is mostly alcohol cirrhosis and hepatic steatosis.

Figure 2

Complications of cirrhosis and progression of compensated cirrhosis to ACLF. A compensated cirrhosis has alteration in intestinal biota, permeability, chronic inflammation, and portal hypertension. During the phase of compensated damage, the liver is subjected to numerous acute insults (alcohol, infections, bleeding, medications, etc) which at some point progress to Acute on Chronic Liver Failure (ACLF), organic failure, and high mortality.

Figure 3

Actions sites of Rifaximin in patients with cirrhosis. The rifaximin in the cirrhotic patients improve dysbiosis, and reduces oxidative stress, inflammation, activation of stellate cells, intestinal permeability, portal passage of PAMPS and lipopolysaccharides, and reduce of ammonia producing bacteria.

Figure 4

In patients with alcoholic liver disease proven by liver biopsy, treated for 18 months with RFX or placebo, changes observed in the biopsy at the end of treatment compared to the initial biopsy. With data from Israelsen M et al.

Figure 5

In patients with non-alcoholic steatohepatitis, treated with RFX or with placebo, with RFX at 6 months, improvement in inflammation markers was observed. With data from Abdel-Razik A et al *p<0.01 **p<0.05 Value compared to the initial 100%.

Figure 6

In patients with non-alcoholic steatohepatitis, treated with RFX or with placebo, with RFX at 6 months, improvement was observed in the metabolic markers of glucose metabolism. HOMA-R= hemostatic model to assess insulin resistance. With data from Abdel-Razik A et al Value compared to the initial 100%.

Figure 7

Proportion (%) of patients who developed spontaneous bacterial peritonitis (SBP) during antibiotic prophylaxis for 6 months. Primary prophylaxis = patients without previous episodes of SBP. Secondary prophylaxis = patients with previous episodes of SBP. All had risk factors for the development of SBP. Using data from Praharaj et al.

Figure 8

Patients with cirrhosis and HE, with prophylactic treatment with RFX or without RFX (control) for 6 months. Proportion of patients without complications (p<0.001 between groups). With data from Zeng et al.