Randomised Controlled Trial of Mechanistic Effects of Rifaximin in Cirrhosis and Chronic Hepatic Encephalopathy
Status:
Completed
Trial end date:
2016-10-01
Target enrollment:
Participant gender:
Summary
Patients with cirrhosis are particularly prone to infection which is frequently a precipitant
of hepatic encephalopathy, renal failure and circulatory collapse. Bacterial infections are
of particular concern in patients with cirrhosis because they are poorly tolerated. Sepsis
and associated endotoxaemia whereby bacteria produce inflammatory particles occur in
approximately 40% of hospitalized patients with cirrhosis and is a major cause of death.
Gut-derived and blood-borne pathogens can induce an inflammatory response within the liver
and spleen, which are the major organs that remove bacteria and their endotoxin (such as
lipopolysaccharide - LPS and bacterial DNA itself) from the bloodstream. Several mechanisms
have been identified and proposed in this process which depends upon a balance between the
barrier functions of the gut and the 'detoxifying' capacity of the liver. People with
established liver cirrhosis have been shown to have escape of endotoxin into the bloodstream
produced by bacteria that reside in their intestines, which becomes more permeable or
'leaky'.
Gut dysfunction is defined by changes in the types of bacteria within the gut and in overall
permeability allowing bacterial products which would otherwise be contained within the gut to
travel into the bloodstream and lymphatic system with detrimental effects elsewhere in the
body. This passage of bacterial products is termed bacterial translocation, and it's effects
on the liver and general immune system can be then be measured.
It has now become recognised that certain types of white blood cells such as neutrophils and
monocytes become dysfunctional and this predisposes to infection and may also have a more
direct pathogenic role in hepatic encephalopathy. Thus neutrophil and monocytes may be a
novel pharmacotherapeutic target in a condition where current therapies such as bowel
aperients (e.g. lactulose) are inadequate. A therapeutic strategy utilising Rifaximin, a
non-absorbable antibiotic, to modulate gut bacterial which produce ammonia, a chemical known
to be important in the cause of hepatic encephalopathy, could potentially lower gut-derived
systemic inflammation, endotoxaemia, infection and organ dysfunction in this population
improving outcomes and prolonging transplant-free survival.
We therefore plan to test if Rifaximin positively affects markers of immune dysfunction in
patients with liver cirrhosis experiencing chronic hepatic encephalopathy after 30 days of
treatment, as our primary research question.
Positive results from this study would support further trials into the potential benefit of
using Rifaximin to improve immune function, as well as reduce the recurrence of hepatic
encephalopathy, in patients with liver cirrhosis.