Rifaximin Plus Lactulose Linked to Greater Effectiveness, Decreased Mortality in HE


Compared with the use of lactulose alone, rifaximin plus lactulose can provide additional benefits in terms of increased effectiveness rate and decreased mortality in patients with hepatic encephalopathy (HE).

In patients with hepatic encephalopathy (HE), use of rifaximin plus lactulose can provide benefits in terms of an increased effective rate and decreased mortality compared with lactulose alone, according to a review published in PLoS One.

Rifaximin and lactulose are nonabsorbable disaccharides, and they are considered a first-line treatment option for patients with HE and widely used in this patient population. Rifaximin, an oral antimicrobial agent, was granted FDA approval in 2010 for HE prevention and treatment and is recommended for use in combination with lactulose as a treatment strategy for patients with HE.

Due to limited and unclear data regarding whether the combination yields more benefits compared with lactulose alone, the review authors conducted a systematic review and meta-analysis of randomized controlled trials (RCTs).

The random-effects model was nused to calculate pooled effect estimates for the efficacy of the combination vs lactulose alone. The authors also conducted sensitivity, subgroup, and publication bias analyses.

Data from 7 RCTs enrolling 843 patients with HE were analyzed. Of these RCTs, 3 were conducted in Pakistan, 2 in India, and 2 in China. Four of the RCTs included patients with HE and 3 included patients with overt HE.

In patients with HE, use of rifaximin plus lactulose was associated with an increased effectiveness compared with lactulose alone (relative risk [RR], 1.30; 95% CI, 1.10-1.53; P = .002). The combination was also associated with a reduced mortality risk vs lactulose alone (RR, 0.57; 95% CI, 0.41-0.80; P = .001).

Pooled data for the effective rate were robust; this did not change by sequential exclusion of individual trials, according to the authors.

Sensitivity and subgroup analyses revealed that although there were significant differences in the incidence of effective rate between rifaximin plus lactulose and lactulose alone, the combination treatment was not associated with the incidence of effective rate when:

  • Pooled studies were conducted in India
  • Proportion of male patients was at least 70%
  • Patients had overt HE
  • Satients had other etiologies
  • Studies were of high quality

Pooled data for mortality were variable because of the smaller number of included RCTs.

Mortality risk was significantly reduced in patients treated with rifaximin plus lactulose when:

  • Pooled studies were conducted in Pakistan
  • Mean age was younger than 50 years
  • Proportion of male patients was less than 70.0%
  • Patients had HE
  • Patients had cirrhosis
  • Studies were of low quality

Using the Begg and Egger tests, no significant publication bias was found for the effective rate and the Begg test did not find a significant bias for mortality. However, the Egger test indicated potentially significant publication bias for mortality.

One of the RCTs also found the use of lactulose alone could improve neurological status in patients with overt HE.

“The potential reason for this could be that intestinal bacteria overmultiply and intestinal dynamics are disturbed in patients with cirrhosis, which could induce an increase in the levels of inflammatory markers and aggravating liver damage,” the authors said. “The use of rifaximin could inhibit the bacterial polymerase and block the transcription process of bacterial RNA, which could hinder the synthesis of bacterial protein and reduce the production of ammonia.”

Regarding the link between use of rifaximin plus lactulose and reduced risk of mortality in patients with HE, the authors said a possible explanation is that the combination may reduce sepsis-related death because of a decrease in the blood levels of a gut-related endotoxin.

“Moreover, the use of rifaximin plus lactulose might reduce the progression of HE and its severity,” they said. “However, in this study, there was only 1 study reporting adverse events between rifaximin plus lactulose and lactulose alone, which requires further verification in a large-scale RCT.”


Fu J, Gao Y, Shi L. Combination therapy with rifaximin and lactulose in hepatic encephalopathy: a systematic review and meta-analysis. PLoS One. 2022;17(4):e0267647. doi:10.1371/journal.pone.0267647

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