Background
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.

Objectives
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.

Search methods
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 We wrote to authors and pharmaceutical companies for information on other published, unpublished, or ongoing trials.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.

Selection criteria
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.

Data collection and analysis
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.

Main results
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).

Authors' conclusions
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.