Key messages
The prevention and treatment of hepatic encephalopathy, in people with cirrhosis, largely depends on use of the compound lactulose. Rifaximin is not used to treat hepatic encephalopathy, at present, but it is used as an add-on to lactulose to help prevent hepatic encephalopathy in people whose response to lactulose is inadequate.
We found that combining rifaximin with lactulose improved hepatic encephalopathy, reduced the risk of dying, and reduced the risk of developing side effects in addition to preventing future relapses.
Its wider use in the management of people with hepatic encephalopathy needs to be considered.
What are cirrhosis and hepatic encephalopathy?
Cirrhosis is a long-term condition in which scar tissue (fibrosis) replaces normal liver tissue, often as a result of excess alcohol, being overweight, or having chronic hepatitis B/C infection. People with cirrhosis commonly develop a condition called hepatic encephalopathy which affects their mental function and their neurological function. This condition can have a negative effect on their survival. The exact reason why people with cirrhosis develop hepatic encephalopathy is unknown, but the toxin ammonia, which is produced mainly in the gut, is thought to play an important role. The severity of the symptoms of hepatic encephalopathy ranges from minor difficulties in mental function to obvious changes in movement, mental status, and consciousness. The minor changes in concentration, behaviour, and everyday function are classed as minimal hepatic encephalopathy. The more obvious abnormalities and changes in consciousness are classed as overt hepatic encephalopathy. The overt symptoms may occur in episodes or may be present at all times.
How is hepatic encephalopathy treated?
The non-absorbable disaccharides (sugars), lactulose and lactitol, are the most commonly used treatment for hepatic encephalopathy. They reduce ammonia levels in the blood through multiple actions, mainly in the gut. Rifaximin is an antibiotic that is not absorbed into the blood stream but works solely in the gut, where it reduces the production of ammonia by the gut bacteria and ammonia absorption into the blood system. This effect may benefit people with hepatic encephalopathy.
What did we want to find out?
We wanted to find out if rifaximin could be used to prevent and treat hepatic encephalopathy in people with cirrhosis; whether it does this better than no drug treatment, a dummy pill (placebo), or non-absorbable disaccharides; whether there may be additional benefit if rifaximin is used together with a non-absorbable disaccharide; and whether there were any unwanted side effects.
What did we do?
We searched for studies that looked at rifaximin compared with no treatment, placebo, or non-absorbable disaccharides in people with cirrhosis with, or at risk for developing, hepatic encephalopathy. We also searched for studies that used rifaximin plus non-absorbable disaccharides compared with non-absorbable disaccharides alone.
We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We identified 41 clinical studies involving 4545 people, who were randomly allocated to treatment groups. All participants had cirrhosis mainly due to excessive alcohol intake or chronic viral hepatitis. Participants were classed as having acute (13 studies), chronic (7 studies), or minimal (8 studies) hepatic encephalopathy, or were considered to be at risk for its development (13 studies). The studies compared rifaximin with a placebo (12 studies), no intervention (1 study), or lactulose/lactitol (14 studies). In 18 studies, rifaximin was given together with lactulose/lactitol and the results compared to the effect of giving lactulose/lactitol alone.
The analyses found that giving rifaximin alone may help improve health-related quality of life and the performance of tests used to assess mental function in people with minimal hepatic encephalopathy. However, lactulose is probably as effective and is considerably cheaper. There were no differences in the benefits and side effects of rifaximin when directly compared with lactulose/lactitol. However, when rifaximin was given together with lactulose/lactitol, it reduced the risk of death (from 14.8% to 10.1%), reduced the risk of unwanted side effects (from 34.4% to 17.6%), and resulted in improvement in hepatic encephalopathy (from 86.9% to 33.8%) when compared to use of lactulose alone.
What are the limitations of the evidence?
We are uncertain about or have only moderate confidence in our findings, meaning we cannot make more certain conclusions about the effects of rifaximin. This was mainly because people in the studies might have been aware of which treatment they were getting and not all the studies provided data about the outcomes we were interested in. Also, many studies were too small for us to be certain about their results. More high-quality studies are needed.
How up to date is this evidence?
The evidence is up to date to January 2023.
Compared to placebo/no intervention, rifaximin likely improves health-related quality of life in people with minimal hepatic encephalopathy, and may improve hepatic encephalopathy, particularly in populations with minimal hepatic encephalopathy and when it is used for prevention. Rifaximin likely has no overall effect on mortality, serious adverse events, health-related quality of life, or hepatic encephalopathy compared to non-absorbable disaccharides. However, when used in combination with a non-absorbable disaccharide, it likely reduces overall mortality risk, the risk of serious adverse events, improves hepatic encephalopathy, reduces the length of hospital stay, and prevents the occurrence/recurrence of hepatic encephalopathy. The certainty of evidence for these outcomes is very low to moderate; further high-quality trials are needed.
Hepatic encephalopathy describes the spectrum of neuropsychiatric changes that may complicate the course of cirrhosis and detrimentally affect outcomes. Ammonia plays a key role in its development. Rifaximin is a non-absorbable antibiotic that inhibits urease-producing bacteria and reduces absorption of dietary and bacterial ammonia.
To evaluate the beneficial and harmful effects of rifaximin versus placebo, no intervention, or non-absorbable disaccharides for: (i) the prevention of hepatic encephalopathy, and (ii) the treatment of minimal and overt hepatic encephalopathy, in people with cirrhosis, both when used alone and when combined with a non-absorbable disaccharide.
We searched the Cochrane Hepato-Biliary Group Clinical Trials Register, CENTRAL, MEDLINE, Embase, three other databases, the reference lists of identified papers, and relevant conference proceedings. We wrote to authors and pharmaceutical companies for information on other published, unpublished, or ongoing trials. Searches were performed to January 2023.
We included randomised clinical trials assessing prevention or treatment of hepatic encephalopathy with rifaximin alone, or with a non-absorbable disaccharide, versus placebo/no intervention, or a non-absorbable disaccharide alone.
Six authors independently searched for studies, extracted data, and validated findings. We assessed the design, bias risk, and participant/intervention characteristics of the included studies. We assessed mortality, serious adverse events, health-related quality of life, hepatic encephalopathy, non-serious adverse events, blood ammonia, Number Connection Test-A, and length of hospital stay.
We included 41 trials involving 4545 people with, or at risk for, developing hepatic encephalopathy. We excluded 89 trials and identified 13 ongoing studies. Some trials involved participants with more than one type of hepatic encephalopathy or more than one treatment comparison. Hepatic encephalopathy was classed as acute (13 trials), chronic (7 trials), or minimal (8 trials), or else participants were considered at risk for its development (13 trials). The control groups received placebo (12 trials), no/standard treatment (1 trial), or a non-absorbable disaccharide (14 trials). Eighteen trials assessed rifaximin plus a non-absorbable disaccharide versus a non-absorbable disaccharide alone. We classified 11 trials as at high risk of overall bias for mortality and 28 for non-mortality outcomes, mainly due to lack of blinding, incomplete outcome data, and selective reporting.
Compared to placebo/no intervention, rifaximin likely has no overall effect on mortality (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.50 to 1.38; P = 48, I2 = 0%; 13 trials, 1007 participants; moderate-certainty evidence), and there may be no overall effect when compared to non-absorbable disaccharides (RR 0.99, 95% CI 0.49 to 1.97; P = 0.97, I2 = 0%; 10 trials, 786 participants; low-certainty evidence). However, there is likely a reduction in the overall risk of mortality when comparing rifaximin plus a non-absorbable disaccharide to a non-absorbable disaccharide alone (RR 0.69, 95% CI 0.55 to 0.86; number needed to treat for an additional beneficial outcome (NNTB) = 22; P = 0.001, I2 = 0%; 14 trials, 1946 participants; moderate-certainty evidence).
There is likely no effect on the overall risk of serious adverse events when comparing rifaximin to placebo/no intervention (RR 1.05, 95% CI 0.83 to 1.32; P = 68, I2 = 0%; 9 trials, 801 participants; moderate-certainty evidence) and there may be no overall effect when compared to non-absorbable disaccharides (RR 0.97, 95% CI 0.66 to 1.40; P = 85, I2 = 0%; 8 trials, 681 participants; low-certainty evidence). However, there was very low-certainty evidence that use of rifaximin plus a non-absorbable disaccharide may be associated with a lower risk of serious adverse events than use of a non-absorbable disaccharide alone (RR 0.66, 95% CI 0.45 to 0.98; P = 0.04, I2 = 60%; 7 trials, 1076 participants).
Rifaximin likely results in an overall effect on health-related quality of life when compared to placebo/no intervention (mean difference (MD) -1.43, 95% CI -2.87 to 0.02; P = 0.05, I2 = 81%; 4 trials, 214 participants; moderate-certainty evidence), and may benefit health-related quality of life in people with minimal hepatic encephalopathy (MD -2.07, 95% CI -2.79 to -1.35; P < 0.001, I2 = 0%; 3 trials, 176 participants). The overall effect on health-related quality of life when comparing rifaximin to non-absorbable disaccharides is very uncertain (MD -0.33, 95% CI -1.65 to 0.98; P = 0.62, I2 = 0%; 2 trials, 249 participants; very low-certainty evidence). None of the combined rifaximin/non-absorbable disaccharide trials reported on this outcome.
There is likely an overall beneficial effect on hepatic encephalopathy when comparing rifaximin to placebo/no intervention (RR 0.56, 95% CI 0.42 to 0.77; NNTB = 5; P < 0.001, I2 = 68%; 13 trials, 1009 participants; moderate-certainty evidence). This effect may be more marked in people with minimal hepatic encephalopathy (RR 0.40, 95% CI 0.31 to 0.52; NNTB = 3; P < 0.001, I2 = 10%; 6 trials, 364 participants) and in prevention trials (RR 0.71, 95% CI 0.56 to 0.91; NNTB = 10; P = 0.007, I2 = 36%; 4 trials, 474 participants). There may be little overall effect on hepatic encephalopathy when comparing rifaximin to non-absorbable disaccharides (RR 0.85, 95% CI 0.69 to 1.05; P = 0.13, I2 = 0%; 13 trials, 921 participants; low-certainty evidence). However, there may be an overall beneficial effect on hepatic encephalopathy when comparing rifaximin plus a non-absorbable disaccharide to a non-absorbable disaccharide alone (RR 0.58, 95% CI 0.48 to 0.71; NNTB = 5; P < 0.001, I2 = 62%; 17 trials, 2332 participants; low-certainty evidence).