title: Natural History of Patients Taking Rifaximin-α for Recurrent Hepatic Encephalopathy and Risk of Future Overt Episodes and Mortality: A Post-hoc Analysis of Clinical Trials Data.
abstract: Hepatic encephalopathy (HE) is a complication of cirrhosis signaling decompensation and is associated with mortality. There has been little characterization of HE once an incident episode has occurred and of what effect the transition to overt HE might have on outcomes. We characterized the relationships between the number of previous HE episodes and risk of subsequent episodes and mortality to better understand the natural history of HE.
  
  
  
  Data on 321 patients from a 24-month, open-label, nonrandomized trial evaluating the long-term safety profile and tolerability of twice-daily rifaximin-α 550 mg were analyzed. Patients were followed for a mean of 1.5 years (total follow-up of 467 years).
  
  
  
  There were a total of 334 HE episodes and 75 deaths, corresponding to unadjusted event rates of 715 HE episodes and 161 deaths per 1000 years. There was a direct association between rate of subsequent HE episodes and number of prior HE episodes; the risk of subsequent HE episodes was elevated for each additional HE episode (hazard ratio = 1.23; 95% CI, 1.19-1.29). There was a nonlinear, nonmonotonic relationship between risk of death and number of prior HE episodes; risk initially increased, then decreased, and finally plateaued as the number of prior HE episodes increased.
  
  
  
  Patients with a larger number of previous, overt HE episodes had a greater risk for subsequent episodes. However, mortality risk decreased after the third episode of HE. A plausible hypothesis to explain this finding is that risk of mortality may be reduced in patients receiving long-term rifaximin-α therapy.
authors.affiliation: Institute of Population Medicine, Cardiff University, Cardiff, UK; Cardiff School of Computer Science and Informatics, Cardiff University, Cardiff, UK.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Bannister
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK; Liver Unit, Freeman Hospital, Newcastle upon Tyne, UK.
authors.forename: James G
authors.initials: JG
authors.lastname: Orr
authors.affiliation: Reynolds Clinical Sciences Ltd, Winchester, UK.
authors.forename: Alan V
authors.initials: AV
authors.lastname: Reynolds
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK; Liver Unit, Freeman Hospital, Newcastle upon Tyne, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Hudson
authors.affiliation: Norgine Limited, Uxbridge, Middlesex, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Conway
authors.affiliation: Norgine Limited, Uxbridge, Middlesex, UK.
authors.forename: Amr
authors.initials: A
authors.lastname: Radwan
authors.affiliation: Global Epidemiology, Pharmatelligence, Cardiff, UK.
authors.forename: Christopher Ll
authors.initials: CL
authors.lastname: Morgan
authors.affiliation: Institute of Population Medicine, Cardiff University, Cardiff, UK; Global Epidemiology, Pharmatelligence, Cardiff, UK. Electronic address: Currie@cardiff.ac.uk.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Currie
mesh_terms: D005260:Female; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D006501:Hepatic Encephalopathy / Q000188:drug therapy / Q000209:etiology / Q000401:mortality; D006801:Humans; D008103:Liver Cirrhosis / Q000150:complications*; D008297:Male; D008875:Middle Aged; D012294:Rifamycins / Q000494:pharmacology*; D000078262:Rifaximin; D012306:Risk
chemical_list: D005765:Gastrointestinal Agents; D012294:Rifamycins; D000078262:Rifaximin
keywords: Targaxan; Xifaxan; chronic liver disease; cirrhosis; hepatic encephalopathy