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Prolonged remission from hepatic encephalopathy with rifaximin: results of a placebo crossover analysis.

ABSTRACT: Rifaximin therapy reduced risk of hepatic encephalopathy (HE) recurrence and HE-related hospitalisations during a 6-month, randomised, placebo-controlled trial (RCT) and a 24-month open-label maintenance (OLM) study. However, the impact of crossover from placebo to rifaximin therapy is unclear.To study the impact of crossing over from placebo to rifaximin treatment on breakthrough HE and hospitalisation rates using a within-subjects design.Adults with cirrhosis and history of overt HE episodes, currently in HE remission, received placebo during the RCT and crossed over to rifaximin 550 mg twice daily during the OLM study. Rate of breakthrough overt HE episodes, hospitalisations and incidence and rate of adverse events (AEs) were analysed during RCT and first 6 months of OLM.Of 82 patients randomised to placebo in the RCT who crossed over to the OLM study, 39 experienced an HE episode during the RCT compared with 14 during the OLM study (P < 0.0001). Significantly lower rates of HE events were observed with rifaximin treatment compared with placebo treatment (P < 0.0001). Rates of HE-related hospitalisation were numerically lower during rifaximin treatment compared with placebo treatment, although not significant. Rates of most common AEs, serious AEs and infection-related AEs were similar between the two treatments.This analysis confirms the repeatability of results from the RCT on safety and efficacy of rifaximin 550 mg twice daily in reducing the risk of hepatic encephalopathy recurrence, and suggests these findings are translatable outside of a rigorous, controlled trial setting.

SUBMITTER: Bajaj JS

PROVIDER: S-EPMC4284039 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Prolonged remission from hepatic encephalopathy with rifaximin: results of a placebo crossover analysis.

Bajaj J S JS Barrett A C AC Bortey E E Paterson C C Forbes W P WP

Alimentary pharmacology & therapeutics 20141022 1

<h4>Background</h4>Rifaximin therapy reduced risk of hepatic encephalopathy (HE) recurrence and HE-related hospitalisations during a 6-month, randomised, placebo-controlled trial (RCT) and a 24-month open-label maintenance (OLM) study. However, the impact of crossover from placebo to rifaximin therapy is unclear.<h4>Aim</h4>To study the impact of crossing over from placebo to rifaximin treatment on breakthrough HE and hospitalisation rates using a within-subjects design.<h4>Methods</h4>Adults wi ...[more]

PMID: 25339518

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Project description:UnlabelledHepatic encephalopathy (HE) represents a dysfunctional gut-liver-brain axis in cirrhosis which can negatively impact outcomes. This altered gut-brain relationship has been treated using gut-selective antibiotics such as rifaximin, that improve cognitive function in HE, especially its subclinical form, minimal HE (MHE). However, the precise mechanism of the action of rifaximin in MHE is unclear. We hypothesized that modulation of gut microbiota and their end-products by rifaximin would affect the gut-brain axis and improve cognitive performance in cirrhosis. Aim To perform a systems biology analysis of the microbiome, metabolome and cognitive change after rifaximin in MHE.MethodsTwenty cirrhotics with MHE underwent cognitive testing, endotoxin analysis, urine/serum metabolomics (GC and LC-MS) and fecal microbiome assessment (multi-tagged pyrosequencing) at baseline and 8 weeks post-rifaximin 550 mg BID. Changes in cognition, endotoxin, serum/urine metabolites (and microbiome were analyzed using recommended systems biology techniques. Specifically, correlation networks between microbiota and metabolome were analyzed before and after rifaximin.ResultsThere was a significant improvement in cognition(six of seven tests improved, p<0.01) and endotoxemia (0.55 to 0.48 Eu/ml, p = 0.02) after rifaximin. There was a significant increase in serum saturated (myristic, caprylic, palmitic, palmitoleic, oleic and eicosanoic) and unsaturated (linoleic, linolenic, gamma-linolenic and arachnidonic) fatty acids post-rifaximin. No significant microbial change apart from a modest decrease in Veillonellaceae and increase in Eubacteriaceae was observed. Rifaximin resulted in a significant reduction in network connectivity and clustering on the correlation networks. The networks centered on Enterobacteriaceae, Porphyromonadaceae and Bacteroidaceae indicated a shift from pathogenic to beneficial metabolite linkages and better cognition while those centered on autochthonous taxa remained similar.ConclusionsRifaximin is associated with improved cognitive function and endotoxemia in MHE, which is accompanied by alteration of gut bacterial linkages with metabolites without significant change in microbial abundance.Trial registrationClinicalTrials.gov NCT01069133.

Dataset Information

Prolonged remission from hepatic encephalopathy with rifaximin: results of a placebo crossover analysis.

Publications

Prolonged remission from hepatic encephalopathy with rifaximin: results of a placebo crossover analysis.

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