Rifaximin in Hepatic Encephalopathy

Hepatic Encephalopathy

According to the Australian Bureau of Statistics, liver diseases ranked in the top 20 leading causes of death from 2002–2011. During this period, deaths related to liver diseases have increased by 17%, from 1,354 deaths in 2002 to 1,589 deaths in 2011. Hepatic encephalopathy (HE) is a complication from hepatic cirrhosis and it has imposed a significant burden on patients, their carers, and Australia’s healthcare systems; as patients tend to lose the ability to care for themselves due to deteriorated cognitive function. They often require hospitalisation which puts a further strain on current shortages in healthcare professionals and hospital beds.

Hepatic encephalopathy is a neuropsychiatric syndrome which is caused by the inability of the liver to prevent ammonia from entering the blood circulation, leading to cerebral toxicity. In patients with chronic liver disease, precipitating factors such as metabolic stress, increase in gut protein, and central nervous system (CNS) depression by drugs or alcohol can lead to acute episodes of encephalopathy.

In the early stages of encephalopathy, patients can lose their cognitive abilities without any apparent signs. However, signs and symptoms of encephalopathy become increasingly apparent and debilitating as the disease progresses and the patient gradually loses both their cognitive and neuromuscular functions. Patients will develop mild signs and symptoms such as sleep disturbances, loss of concentration, drowsiness, tremor and ataxia in the early stages. As the disease progresses, patients can sometimes develop confusion, amnesia, and coma.

Treatment of Hepatic Encephalopathy

The current recommendation from Therapeutic Guidelines Australia (TGA) for treatment of acute hepatic encephalopathy is lactulose 30mL hourly. This is to induce rapid diarrhoea which subsequently reduces the absorption of ammonia by decreasing the number of colonic bacteria and lowering colonic pH. Once diarrhoea is achieved, administration frequency can be reduced to three or four times a day. In acute hepatic encephalopathy, precipitating factors such as electrolyte imbalances, infections, and removal of CNS depressing drugs need to be addressed.

To prevent recurrent episodes or chronic hepatic encephalopathy, lactulose 30mL three times a day is administered with the aim to produce two to three soft stools per day.

Rifaximin

In May 2012, rifaximin (Xifaxan^®) became available in Australia following its registration with the TGA. It is now used as a second-line treatment for the prevention of recurrence of hepatic encephalopathy.

Rifaximin, a semisynthetic broad spectrum antibiotic, works against gram-positive and gram-negative bacteria in the gastrointestinal tract (GIT). It has very low oral absorption with a negligible plasma level after administration; therefore rifaximin acts locally in the gastrointestinal tract, targeting GI flora. It is administered orally twice a day. No dosing adjustment is required in patients with hepatic insufficiency due to its low oral absorption.

A randomised study has been conducted which enrolled 299 patients who were in remission from recurrent hepatic encephalopathy due to cirrhosis. Study subjects were randomly assigned to either receive rifaximin 550mg or placebo twice daily for six months or until recurrence of hepatic encephalopathy. During this trial 22.1% of subjects who received rifaximin developed breakthrough hepatic encephalopathy compared to 45.9% in the placebo group. 13.6% of hospitalisations due to an hepatic encephalopathy episode were from the rifaximin group and 22.6% from the placebo group recorded from this trial. The trial demonstrated that rifaximin reduces the risk of recurrence of hepatic encephalopathy by 23.8% and the risk of hospitalisation by 9%.

Reduced hepatic encephalopathy recurrence and hospitalisation would improve patients’ quality of life and subsequently reduce financial cost of the disease to the healthcare system. However, more than 90% of patients in both groups received lactulose concomitantly. Thus, the benefit from rifaximin alone was not able to be determined from this trial.

Side effects reported in this trial which had higher occurrence in the rifaximin group were anaemia, ascites, vomiting, dizziness and peripheral oedema. Two cases of clostridium difficile infection were also reported in the rifaximin group where there were none reported in the placebo group. Patients should be warned of this side effect to ensure that they seek medical attention without delay if clostridium difficile associated diarrhoea is suspected.

Another concern with long term use of rifaximin is the development of drug resistant bacteria, including Staphylococcus aureus. Therefore, rifaximin should only be used as a second-line treatment where other treatments have failed or are contraindicated.

Although rifaximin is the only treatment that has demonstrated a reduction of recurrence of hepatic encephalopathy, and hospitalisation due to hepatic encephalopathy, it is not currently listed on the Pharmaceutical Benefit Scheme (PBS). Therefore, patients would currently have to pay several hundred dollars per month which limits the accessibility for pensioners or low income households. The Pharmaceutical Benefits Advisory Committee made a positive recommendation for the listing of rifaximin on the PBS at the April 2013 meeting. They recommended listing based on current high clinical demand and that this treatment is superior to the existing treatment.

In conclusion, based on currently available data, rifaximin and lactulose used concomitantly can reduce the recurrence of hepatic encephalopathy and reduce the risk of hospitalisation due to hepatic encephalopathy. Listing of rifaximin on the PBS will allow patients access to this treatment at an affordable price, improving their quality of life and reducing the burden on their community.