Systematic Review of the Economic Burden of Overt Hepatic Encephalopathy and Pharmacoeconomic Impact of Rifaximin

Systematic Review



Hepatic encephalopathy (HE), a common neurologic complication in cirrhosis, is associated with substantial disease and economic burden. Rifaximin is a non-systemic antibiotic that reduces the risk of overt HE recurrence and overt HE-related hospitalizations.


Our objective was to provide an overview of the direct HE-related costs and cost benefits of rifaximin, lactulose, and rifaximin plus lactulose.


A systematic review of PubMed and relevant meeting abstracts was conducted to identify publications since 1 January 2007 reporting economic data related to HE and rifaximin and/or lactulose. Further, a public database and published literature were used to estimate current costs of hospitalization for overt HE, and potential cost savings of HE-related hospitalizations with rifaximin. The methodological quality of included studies was evaluated using the Drummond checklist.


A total of 16 reports were identified for inclusion in the systematic review. Globally, HE-related direct costs ranged from $US5370 to $US50,120 annually per patient. Rifaximin was associated with shorter hospital stays and reduced healthcare costs. Rifaximin also has the potential to reduce overt HE-related hospitalization risk by 50% compared with lactulose. Rifaximin was shown to have a favourable pharmacoeconomic profile compared with lactulose (based on the incremental cost-effectiveness ratio).


In addition to its clinical benefits (e.g. reduction in the risk of recurrence of overt HE, overt HE-related hospitalizations, favourable adverse event profile), economic data are favourable for the use of rifaximin in patients with a history of overt HE.


Data availability statement

Data sharing information is not applicable to this article as no datasets were generated or analysed during the current study.

Author contributions

GN and WZ contributed to the concept and objective of the article, established the parameters around the systematic review, and interpreted and critiqued the data. GN and WZ were involved in drafting and commenting on the article and approved the final version for submission. Guarantor: GN acts as the guarantor for this work.

Compliance with Ethical Standards


Technical editorial assistance was provided, under the direction of the authors, by Mary Beth Moncrief, PhD, and Sophie Bolick, PhD, Synchrony Medical Communications, LLC, West Chester, PA, USA. Funding for this support was provided by Salix Pharmaceuticals, Bridgewater, NJ, USA.

Conflict of interest

GN and WZ have no potential conflicts of interest that are relevant to the content of this article and neither they nor their respective institutions received funding for the manuscript. Salix Pharmaceuticals did not actively participate in content development but reviewed the manuscript for scientific accuracy. As disclosed in the funding statement, Salix Pharmaceuticals provided support for technical editorial assistance.


  1. 1.
    Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, et al. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014;60(2):715–35.CrossRefPubMedGoogle Scholar
  2. 2.
    Romero-Gómez M, Boza F, García-Valdecasas MS, García E, Aguilar-Reina J. Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy. Am J Gastroenterol. 2001;96(9):2718–23.CrossRefPubMedGoogle Scholar
  3. 3.
    Patidar KR, Bajaj JS. Covert and overt hepatic encephalopathy: diagnosis and management. Clin Gastroenterol Hepatol. 2015;13(12):2048–61.CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Bajaj JS, Wade JB, Sanyal AJ. Spectrum of neurocognitive impairment in cirrhosis: implications for the assessment of hepatic encephalopathy. Hepatology. 2009;50(6):2014–21.CrossRefPubMedGoogle Scholar
  5. 5.
    Bajaj JS, Riggio O, Allampati S, Prakash R, Gioia S, Onori E, et al. Cognitive dysfunction is associated with poor socioeconomic status in patients with cirrhosis: an international multicenter study. Clin Gastroenterol Hepatol. 2013;11(11):1511–6.CrossRefPubMedGoogle Scholar
  6. 6.
    Bajaj JS, Wade JB, Gibson DP, Heuman DM, Thacker LR, Sterling RK, et al. The multi-dimensional burden of cirrhosis and hepatic encephalopathy on patients and caregivers. Am J Gastroenterol. 2011;106(9):1646–53.CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Bruyneel M, Serste T, Libert W, van den Broecke S, Ameye L, Dachy B, et al. Improvement of sleep architecture parameters in cirrhotic patients with recurrent hepatic encephalopathy with the use of rifaximin. Eur J Gastroenterol Hepatol. 2017;29(3):302–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Nardelli S, Allampati S, Riggio O, Mullen KD, Prakash R, Gioia S, et al. Hepatic encephalopathy is associated with persistent learning impairments despite adequate medical treatment: a multicenter, international study. Dig Dis Sci. 2017;62(3):794–800.CrossRefPubMedGoogle Scholar
  9. 9.
    Umapathy S, Dhiman RK, Grover S, Duseja A, Chawla YK. Persistence of cognitive impairment after resolution of overt hepatic encephalopathy. Am J Gastroenterol. 2014;109(7):1011–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Barboza KC, Salinas LM, Sahebjam F, Jesudian AB, Wesiberg IL, Sigal SH. Impact of depressive symptoms and hepatic encephalopathy on health-related quality of life in cirrhotic hepatitis C patients. Metab Brain Dis. 2016;31(4):869–80.CrossRefPubMedGoogle Scholar
  11. 11.
    Arguedas MR, DeLawrence TG, McGuire BM. Influence of hepatic encephalopathy on health-related quality of life in patients with cirrhosis. Dig Dis Sci. 2003;48(8):1622–6.CrossRefPubMedGoogle Scholar
  12. 12.
    Bannister CA, Orr JG, Reynolds AV, Hudson M, Conway P, Radwan A, et al. 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. Clin Ther. 2016;38(5):1081–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Di Pascoli M, Ceranto E, Nardi PD, Donato D, Gatta A, Angeli P, et al. Hospitalizations due to cirrhosis: clinical aspects in a large cohort of Italian patients and cost analysis report. Dig Dis. 2017;35:433–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Jinjuvadia R, Liangpunsakul S, Consortium TREAHT. Trends in alcoholic hepatitis-related hospitalizations, financial burden, and mortality in the United States. J Clin Gastroenterol. 2015;49(6):506–11.PubMedCentralPubMedGoogle Scholar
  15. 15.
    Patidar KR, Thacker LR, Wade JB, White MB, Gavis EA, Fagan A, et al. Symptom domain groups of the patient-reported outcomes measurement information system tools independently predict hospitalizations and re-hospitalizations in cirrhosis. Dig Dis Sci. 2017;62(5):1173–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Atla PR, Sheikh MY, Gill F, Kundu R, Choudhury J. Predictors of hospital re-admissions among Hispanics with hepatitis C-related cirrhosis. Ann Gastroenterol. 2016;29(4):515–20.PubMedCentralPubMedGoogle Scholar
  17. 17.
    Chirapongsathorn S, Krittanwong C, Enders F, Pendergast R, Mara K, Borah B, et al. Incidence and cost analysis of hospital admission and 30-day readmission among patients with cirrhosis. Hepatol Commun. 2018;2(2):188–98.CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Tapper EB, Halbert B, Mellinger J. Rates of and reasons for hospital readmissions in patients with cirrhosis: a multistate population-based cohort study. Clin Gastroenterol Hepatol. 2016;14(8):1181–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Bajaj JS, Reddy KR, Tandon P, Wong F, Kamath PS, Garcia-Tsao G, et al. The 3-month readmission rate remains unacceptably high in a large North American cohort of patients with cirrhosis. Hepatology. 2016;64(1):200–8.CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Martel-Laferrière V, Homberger C, Bichoupan K, Dieterich DT. MELD score and antibiotics use are predictors of length of stay in patients hospitalized with hepatic encephalopathy. BMC Gastroenterol. 2014;14:185.CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    Roggeri DP, Roggeri A, Rossi E, Cinconze E, Gasbarrini A, Monici Preti P, et al. Overt hepatic encephalopathy in Italy: clinical outcomes and healthcare costs. Hepat Med. 2015;7:37–42.CrossRefPubMedCentralPubMedGoogle Scholar
  22. 22.
    ISPOR Scientific Presentations Database. Accessed 21 June 2017.
  23. 23.
    US Department of Health and Human Services. Agency for Healthcare Research and Quality. Healthcare Cost and Utilization Project (HCUPnet) database. Accessed 10 July 2017.
  24. 24.
    Drummond MF, Jefferson TO, The BMJ Economic Evaluation Working Party. Guidelines for authors and peer reviewers of economic submissions to the BMJ. BMJ. 1996;313(7052):275–83.CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    El Khoury AC, Klimack WK, Wallace C, Razavi H. Economic burden of hepatitis C-associated diseases in the United States. J Viral Hepat. 2012;19(3):153–60.CrossRefPubMedGoogle Scholar
  26. 26.
    El Khoury AC, Wallace C, Klimack WK, Razavi H. Economic burden of hepatitis C-associated diseases: Europe, Asia Pacific, and the Americas. J Med Econ. 2012;15(5):887–96.CrossRefPubMedGoogle Scholar
  27. 27.
    Poovorawan K, Treeprasertsuk S, Thepsuthammarat K, Wilairatana P, Kitsahawong B, Phaosawasdi K. The burden of cirrhosis and impact of universal coverage public health care system in Thailand: nationwide study. Ann Hepatol. 2015;14(6):862–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Benković V, Kolčić I, Ivičević Uhernik A, Vranešić Bender D, Oreb I, Stevanović R, et al. The economic burden of disease-related undernutrition in selected chronic diseases. Clin Nutr. 2014;33(4):689–93.CrossRefPubMedGoogle Scholar
  29. 29.
    Lee PC, Yang YY, Lin MW, Hou MC, Huang CS, Lee KC, et al. Benzodiazepine-associated hepatic encephalopathy significantly increased healthcare utilization and medical costs of Chinese cirrhotic patients: 7-year experience. Dig Dis Sci. 2014;59(7):1603–16.CrossRefPubMedGoogle Scholar
  30. 30.
    Andersen MM, Aunt S, Jensen NM, Homann C, Manniche J, Svendsen S, et al. Rehabilitation for cirrhotic patients discharged after hepatic encephalopathy improves survival. Dan Med J. 2013;60(8):A4683.PubMedGoogle Scholar
  31. 31.
    Stepanova M, Mishra A, Venkatesan C, Younossi ZM. In-hospital mortality and economic burden associated with hepatic encephalopathy in the United States from 2005 to 2009. Clin Gastroenterol Hepatol. 2012;10(9):1034–41.CrossRefPubMedGoogle Scholar
  32. 32.
    Irish W, Saynisch P, Mallow PJ, Fallon L, Gunnarsson C. Using the Medicare claims database to understand the economic burden of liver disease: a case study in hepatic encephalopathy. In: ISPOR Scientific Presentations Database; 2015. Accessed 11 July 2017.
  33. 33.
    Gluud LL, Vilstrup H, Morgan MY. Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev. 2016;5:CD003044.Google Scholar
  34. 34.
    Agarwalla A, Weber A, Davey S, Hamilton K, Goldberg D, Rhim AD, et al. Lactulose is associated with decreased risk of Clostridium difficile infection in decompensated cirrhosis. Clin Gastroenterol Hepatol. 2017;15(6):953–4.CrossRefPubMedGoogle Scholar
  35. 35.
    Bajaj JS, Ananthakrishnan AN, Hafeezullah M, Zadvornova Y, Dye A, McGinley EL, et al. Clostridium difficile is associated with poor outcomes in patients with cirrhosis: a national and tertiary center perspective. Am J Gastroenterol. 2010;105(1):106–13.CrossRefPubMedGoogle Scholar
  36. 36.
    Sharma BC, Sharma P, Lunia MK, Srivastava S, Goyal R, Sarin SK. A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am J Gastroenterol. 2013;108(9):1458–63.CrossRefPubMedGoogle Scholar
  37. 37.
    Vlachogiannakos J, Viazis N, Vasianopoulou P, Vafiadis I, Karamanolis DG, Ladas SD. Long-term administration of rifaximin improves the prognosis of patients with decompensated alcoholic cirrhosis. J Gastroenterol Hepatol. 2013;28(3):450–5.CrossRefPubMedGoogle Scholar
  38. 38.
    Courson A, Jones GM, Twilla JD. Treatment of acute hepatic encephalopathy: comparing the effects of adding rifaximin to lactulose on patient outcomes. J Pharm Pract. 2016;29(3):212–7.CrossRefPubMedGoogle Scholar
  39. 39.
    Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362(12):1071–81.CrossRefPubMedGoogle Scholar
  40. 40.
    Kimer N, Krag A, Møller S, Bendtsen F, Gluud LL. Systematic review with meta-analysis: the effects of rifaximin in hepatic encephalopathy. Aliment Pharmacol Ther. 2014;40(2):123–32.CrossRefPubMedGoogle Scholar
  41. 41.
    Neff GW, Jones M, Broda T, Jonas M, Ravi R, Novick D, et al. Durability of rifaximin response in hepatic encephalopathy. J Clin Gastroenterol. 2012;46(2):168–71.CrossRefPubMedGoogle Scholar
  42. 42.
    Tapper EB, Finkelstein D, Mittleman MA, Piatkowski G, Chang M, Lai M. A quality improvement initiative reduces 30-day rate of readmission for patients with cirrhosis. Clin Gastroenterol Hepatol. 2016;14(5):753–9.CrossRefPubMedGoogle Scholar
  43. 43.
    Bajaj JS, Barrett AC, Bortey E, Paterson C, Forbes WP. Prolonged remission from hepatic encephalopathy with rifaximin: results of a placebo crossover analysis. Aliment Pharmacol Ther. 2015;41(1):39–45.CrossRefPubMedGoogle Scholar
  44. 44.
    Lyon KC, Likar E, Martello JL, Regier M. Retrospective cross-sectional pilot study of rifaximin dosing for the prevention of recurrent hepatic encephalopathy. J Gastroenterol Hepatol. 2017;32(9):1548–52.CrossRefPubMedGoogle Scholar
  45. 45.
    Mullen KD, Sanyal AJ, Bass NM, Poordad FF, Sheikh MY, Frederick RT, et al. Rifaximin is safe and well tolerated for long-term maintenance of remission from overt hepatic encephalopathy. Clin Gastroenterol Hepatol. 2014;12(8):1390–7.CrossRefPubMedGoogle Scholar
  46. 46.
    Mantry PS, Mehta A, Graydon R. Efficacy and tolerability of rifaximin in combination with lactulose in end-stage liver disease patients with MELD greater than 20: a single center experience. Transpl Proc. 2014;46(10):3481–6.CrossRefGoogle Scholar
  47. 47.
    Hammond DA, Dayama N, Martin BC, editors. Impact of rifaximin and lactulose versus lactulose alone on hospitalization for acute recurrent hepatic encephalopathy. Boston: International Society for Pharmacoeconomics and Outcomes Research; 2017.Google Scholar
  48. 48.
    Congly SE, Leise MD. Rifaximin for episodic, overt hepatic encephalopathy: the data are catching up to clinical practice, but questions remain. Am J Gastroenterol. 2014;109(4):598.CrossRefPubMedGoogle Scholar
  49. 49.
    Bajaj JS, Riggio O. Drug therapy: rifaximin. Hepatology. 2010;52(4):1484–8.CrossRefPubMedGoogle Scholar
  50. 50.
    Leevy CB, Phillips JA. Hospitalizations during the use of rifaximin versus lactulose for the treatment of hepatic encephalopathy. Dig Dis Sci. 2007;52(3):737–41.CrossRefPubMedGoogle Scholar
  51. 51.
    Bajaj JS, Sanyal AJ, Bell D, Gilles H, Heuman DM. Predictors of the recurrence of hepatic encephalopathy in lactulose-treated patients. Aliment Pharmacol Ther. 2010;31(9):1012–7.PubMedGoogle Scholar
  52. 52.
    Rassameehiran S, Mankongpaisarnrung C, Sutamtewagul G, Klomjit S, Rakvit A. Predictor of 90-day readmission rate for hepatic encephalopathy. South Med J. 2016;109(6):365–9.CrossRefPubMedGoogle Scholar
  53. 53.
    Volk ML, Tocco RS, Bazick J, Rakoski MO, Lok AS. Hospital readmissions among patients with decompensated cirrhosis. Am J Gastroenterol. 2012;107(2):247–52.CrossRefPubMedGoogle Scholar
  54. 54.
    Wu D, Wu SM, Lu J, Zhou YQ, Xu L, Guo CY. Rifaximin versus nonabsorbable disaccharides for the treatment of hepatic encephalopathy: a meta-analysis. Gastroenterol Res Pract. 2013;2013:236963.PubMedCentralPubMedGoogle Scholar
  55. 55.
    Orr JG, Currie CJ, Berni E, Goel A, Moriarty KJ, Sinha A, et al. The impact on hospital resource utilisation of treatment of hepatic encephalopathy with rifaximin-α. Liver Int. 2016;36(9):1295–303.CrossRefPubMedGoogle Scholar
  56. 56.
    Aspinall R, Radwan A, Shaya G, Sodatonou H, Cipelli R. The impact of rifaximin-α on NHS hospital resource use in UK patients with hepatic encephalopathy: a retrospective observational study (Impress). J Hepatol. 2016;64:S283.CrossRefGoogle Scholar
  57. 57.
    Kabeshova A, Ben Hariz S, Tsakeu E, Benamouzig R, Launois R. Cost-effectiveness analysis of rifaximin-α administration for the reduction of episodes of overt hepatic encephalopathy in recurrence compared with standard treatment in France. Ther Adv Gastroenterol. 2016;9(4):473–82.CrossRefGoogle Scholar
  58. 58.
    Berni E, Poole CD, Conway P, Radwan A, Currie CJ. Cost effectiveness of rifaximin-α 550 mg in the reduction of recurrence of overt hepatic encephalopathy in United Kingdom. Value Health. 2015;18(7):A626.CrossRefGoogle Scholar
  59. 59.
    Whitehouse JT, Berni E, Conway P, Radwan A, Henrar R, Currie CJ. Evaluation of the cost effectiveness and societal impact of rifaximin-α 550 mg in the reduction of recurrence of overt hepatic encephalopathy in The Netherlands. Value Health. 2015;18(7):A629.CrossRefPubMedGoogle Scholar
  60. 60.
    Poole CD, Berni E, Conway P, Radwan A, Currie CJ. Evaluation of the cost effectiveness of rifaximin-α 550 mg in the reduction of recurrence of overt hepatic encephalopathy in Sweden. Value Health. 2015;18(7):A626.CrossRefGoogle Scholar
  61. 61.
    Berni E, Connolly M, Conway P, Radwan A, Currie CJ. Evaluation of the cost effectiveness of rifaximin-α in the reduction of recurrence of overt hepatic encephalopathy in Belgium. Value Health. 2015;18(7):A628.CrossRefPubMedGoogle Scholar
  62. 62.
    Bozkaya D, Barrett AC, Migliaccio-Walle K. Cost-effectiveness of rifaximin treatment in patients with hepatic encephalopathy. Hepatology. 2014;60(4 Suppl):389A–90A.Google Scholar
  63. 63.
    Sandler RS, Everhart JE, Donowitz M, Adams E, Cronin K, Goodman C, et al. The burden of selected digestive diseases in the United States. Gastroenterology. 2002;122(5):1500–11.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Florida Research Institute, Florida Digestive Health SpecialistsLakewood RanchUSA
  2. 2.Quantym Therapeutic DataSarasotaUSA

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