Top

BMC Gastroenterology

Published in:

Open Access 01-12-2024 | Rifaximin | Research

Preventive and therapeutic effects of rifaximin on hepatic encephalopathy with differential application dosages and strategies: a network meta-analysis

Authors: Guihua Fang, Shuna Liu, Bin Liu

Published in: BMC Gastroenterology | Issue 1/2024

Abstract

Background

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that affects the prognosis of patients with liver disease and is considered an independent risk factor for hospitalization and death. Rifaximin has been approved for HE treatment. This review will analyze the effect of rifaximin on different stages of HE with differential application dosages and strategies by traditional and network meta-analyses.

Methods

We performed a systematic search of PubMed, EmBase, and Cochrane Library databases up to February 26, 2023, to identify randomized controlled trials (RCTs) about rifaximin for the prevention and treatment of HE. The outcomes included incidence of HE and HE progression, HE reversal, mortality, and adverse effects.

Results

A total of 21 studies were included. In the primary prevention of HE, rifaximin significantly reduced the incidence of HE (OR: 0.66; 95% CI: 0.45, 0.96; p = 0.032). In secondary prevention, rifaximin significantly reduced the risk of recurrence in patients who were in remission (OR: 0.38; 95% CI: 0.28, 0.52; p < 0.001). In the treatment of minimal HE, rifaximin significantly reduced the breakthrough of MHE to OHE (OR: 0.17; 95% CI: 0.04,0.63; p = 0.008). Rifaximin also significantly improved the clinical symptoms of MHE and OHE patients (OR: 3.76; 95% CI: 2.69, 5.25; p < 0.001). However, rifaximin did not reduce mortality at any stage in HE patients (OR: 0.79; 95% CI: 0.58, 1.08; p = 0.133). Additionally, rifaximin did not increase the risk of adverse effects (OR: 0.96; 95% CI: 0.74, 1.24; p = 0.749). In the network meta-analysis, the 400 mg T.I.D. intervention had a relative advantage for HE risks in primary and secondary prevention. In the treatment of MHE, 600 mg b.i.d. was superior in preventing the breakthrough from MHE to OHE.

Conclusion

Rifaximin prevented HE risks and progression and improved clinical symptoms in patients with MHE but did not reduce mortality. For primary and secondary prevention, 400 mg t.i.d. could be considered. 600 mg b.i.d. could be considered in patients with MHE.

Available only for authorised users

Bloom PP, Tapper EB, Young VB. Lok. Microbiome therapeutics for hepatic encephalopathy. J Hepatol. 2021;75:1452–64. https://doi.org/10.1016/j.jhep.2021.08.004.CrossRefPubMedPubMedCentral

Haussinger D, Dhiman RK, Felipo V, Gorg B, Jalan R, Kircheis G, et al. Hepatic encephalopathy. Nat Rev Dis Primers. 2022;8:43. https://doi.org/10.1038/s41572-022-00366-6.CrossRefPubMed

Tranah TH, Ballester MP, Carbonell-Asins JA, Ampuero J, Alexandrino G, Caracostea A, et al. Plasma ammonia levels predict hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis. J Hepatol. 2022;77:1554–63. https://doi.org/10.1016/j.jhep.2022.07.014.CrossRefPubMed

Kaji K, Takaya H, Saikawa S, Furukawa M, Sato S, Kawaratani H, et al. Rifaximin ameliorates hepatic encephalopathy and endotoxemia without affecting the gut microbiome diversity. World J Gastroenterol. 2017;23:8355–66. https://doi.org/10.3748/wjg.v23.i47.8355.CrossRefPubMedPubMedCentral

Maeda Y, Murakami T. Diagnosis by Microbial Culture, Breath tests and urinary excretion tests, and treatments of small intestinal bacterial overgrowth. Antibiot (Basel). 2023;12. https://doi.org/10.3390/antibiotics12020263.

Tan W, Wang J, Shi PM, Feng LM, Shi J, Ning BF, et al. Effects of low-dose and high-dose Rifaximin in the treatment of Covert hepatic encephalopathy. J Clin Transl Hepatol. 2022;10:1099–106. https://doi.org/10.14218/JCTH.2021.00457.CrossRefPubMedPubMedCentral

Adachi JA, DuPont HL. Rifaximin: a novel nonabsorbed rifamycin for gastrointestinal disorders. Clin Infect Dis. 2006;42:541–7. https://doi.org/10.1086/499950.CrossRefPubMed

Gu Z, Duan M, Sun Y, Leng T, Xu T, Gu Y, et al. Effects of vitamin D3 on intestinal Flora in a mouse model of inflammatory bowel Disease treated with Rifaximin. Med Sci Monit. 2020;26:e925068. https://doi.org/10.12659/MSM.925068.CrossRefPubMedPubMedCentral

Luo M, Guo JY, Cao WK. Inflammation: a novel target of current therapies for hepatic encephalopathy in liver cirrhosis. World J Gastroenterol. 2015;21:11815–24. https://doi.org/10.3748/wjg.v21.i41.11815.CrossRefPubMedPubMedCentral

10.

Anand SK, Ahmad MH, Sahu MR, Subba R, Mondal AC. Detrimental effects of Alcohol-Induced inflammation on Brain Health: from neurogenesis to Neurodegeneration. Cell Mol Neurobiol. 2022. https://doi.org/10.1007/s10571-022-01308-2.CrossRefPubMed

11.

Yu X, Jin Y, Zhou W, Xiao T, Wu Z, Su J, et al. Rifaximin modulates the gut microbiota to prevent hepatic encephalopathy in liver cirrhosis without impacting the Resistome. Front Cell Infect Microbiol. 2021;11:761192. https://doi.org/10.3389/fcimb.2021.761192.CrossRefPubMed

12.

Ito T, Nakamura K, Kageyama S, Korayem IM, Hirao H, Kadono K, et al. Impact of Rifaximin Therapy on Ischemia/Reperfusion Injury in Liver Transplantation: a propensity score-matched analysis. Liver Transpl. 2019;25:1778–89. https://doi.org/10.1002/lt.25633.CrossRefPubMedPubMedCentral

13.

Jiang Q, Jiang XH, Zheng MH, Jiang LM, Chen YP, Wang L. Rifaximin versus nonabsorbable disaccharides in the management of hepatic encephalopathy: a meta-analysis. Eur J Gastroenterol Hepatol. 2008;20:1064–70. https://doi.org/10.1097/MEG.0b013e328302f470.CrossRefPubMed

14.

Eltawil KM, Laryea M, Peltekian K, Molinari M. Rifaximin vs. conventional oral therapy for hepatic encephalopathy: a meta-analysis. World J Gastroenterol. 2012;18:767–77. https://doi.org/10.3748/wjg.v18.i8.767.CrossRefPubMedPubMedCentral

15.

Wu D, Wu SM, Lu J, Zhou YQ, Xu L. Guo. Rifaximin versus Nonabsorbable disaccharides for the treatment of hepatic encephalopathy: a Meta-analysis. Gastroenterol Res Pract. 2013;2013:236963. https://doi.org/10.1155/2013/236963.CrossRefPubMedPubMedCentral

16.

Cheng J, Chen Y, Cao W, Zuo G. Is rifaximin better than nonabsorbable disaccharides in hepatic encephalopathy? A meta-analysis. Med (Baltim). 2021;100:e28232. https://doi.org/10.1097/MD.0000000000028232.CrossRef

17.

Kimer N, Krag A, Moller S, Bendtsen F, Gluud LL. Systematic review with meta-analysis: the effects of rifaximin in hepatic encephalopathy. Aliment Pharmacol Ther. 2014;40:123–32. https://doi.org/10.1111/apt.12803.CrossRefPubMed

18.

Wang Z, Chu P, Wang W. Combination of rifaximin and lactulose improves clinical efficacy and mortality in patients with hepatic encephalopathy. Drug Des Devel Ther. 2019;13:1–11. https://doi.org/10.2147/DDDT.S172324.CrossRefPubMed

19.

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:e0267647. https://doi.org/10.1371/journal.pone.0267647.CrossRefPubMedPubMedCentral

20.

Moon AM, Kim HP, Jiang Y, Lupu G, Bissram JS, Barritt AS, et al. Systematic review and Meta-analysis on the effects of Lactulose and Rifaximin on patient-reported outcomes in hepatic Encephalopathy. Am J Gastroenterol. 2023;118:284–93. https://doi.org/10.14309/ajg.0000000000002008.CrossRefPubMed

21.

Zacharias HD, Kamel F, Tan J, Kimer N, Gluud LL, Morgan MY. Rifaximin for prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev. 2023;7:CD011585. https://doi.org/10.1002/14651858.CD011585.pub2.CrossRefPubMed

22.

Han X, Luo Z, Wang W, Zheng P, Li T, Mei Z, et al. Efficacy and safety of Rifaximin Versus Placebo or other active drugs in critical ill patients with hepatic Encephalopathy. Front Pharmacol. 2021;12:696065. https://doi.org/10.3389/fphar.2021.696065.CrossRefPubMedPubMedCentral

23.

Dhiman RK, Thumburu KK, Verma N, Chopra M, Rathi S, Dutta U, et al. Comparative efficacy of Treatment options for minimal hepatic encephalopathy: a systematic review and network Meta-analysis. Clin Gastroenterol Hepatol. 2020;18:800–812e825. https://doi.org/10.1016/j.cgh.2019.08.047.CrossRefPubMed

24.

Cai XJ, Wang L, Hu CM. Efficacy of different drugs in the treatment of minimal hepatic encephalopathy: a network meta-analysis involving 826 patients based on 10 randomized controlled trials. J Cell Biochem. 2018;119:8336–45. https://doi.org/10.1002/jcb.26886.CrossRefPubMed

25.

Zhu GQ, Shi KQ, Huang S, Wang LR, Lin YQ, Huang GQ, et al. Systematic review with network meta-analysis: the comparative effectiveness and safety of interventions in patients with overt hepatic encephalopathy. Aliment Pharmacol Ther. 2015;41:624–35. https://doi.org/10.1111/apt.13122.CrossRefPubMed

26.

Marchese A, Salerno A, Pesce A, Debbia EA. Schito. In vitro activity of rifaximin, metronidazole and Vancomycin against Clostridium difficile and the rate of selection of spontaneously resistant mutants against representative anaerobic and aerobic bacteria, including ammonia-producing species. Chemotherapy. 2000;46:253–66. https://doi.org/10.1159/000007297.CrossRefPubMed

27.

Wang J, Zhang L, Hou X. Efficacy of rifaximin in treating with small intestine bacterial overgrowth: a systematic review and meta-analysis. Expert Rev Gastroenterol Hepatol. 2021;15:1385–99. https://doi.org/10.1080/17474124.2021.2005579.CrossRefPubMed

28.

Rahimi RS, Brown KA, Flamm SL, Brown RS. Jr. Overt hepatic encephalopathy: current pharmacologic treatments and improving clinical outcomes. Am J Med. 2021;134:1330–8. https://doi.org/10.1016/j.amjmed.2021.06.007.CrossRefPubMed

29.

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;32:1548–52. https://doi.org/10.1111/jgh.13759.CrossRefPubMed

30.

Zeng X, Tang XJ, Sheng X, Ni W, Xin HG, Chen WZ, et al. Does low-dose rifaximin ameliorate endotoxemia in patients with liver cirrhosis: a prospective study. J Dig Dis. 2015;16:665–74. https://doi.org/10.1111/1751-2980.12294.CrossRefPubMed

31.

Huang E, Esrailian E. Spiegel. The cost-effectiveness and budget impact of competing therapies in hepatic encephalopathy - a decision analysis. Aliment Pharmacol Ther. 2007;26:1147–61. https://doi.org/10.1111/j.1365-2036.2007.03464.x.CrossRefPubMed

32.

Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. The Cochrane collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. https://doi.org/10.1136/bmj.d5928.CrossRefPubMedPubMedCentral

33.

Bajaj JS, Hassanein TI, Pyrsopoulos NT, Sanyal AJ, Rahimi RS, Heimanson Z, et al. Dosing of Rifaximin Soluble Solid Dispersion Tablets in adults with cirrhosis: 2 Randomized, Placebo-controlled trials. Clin Gastroenterol Hepatol. 2023;21:723–731e729. https://doi.org/10.1016/j.cgh.2022.05.042.CrossRefPubMed

34.

Patel VC, Lee S, McPhail MJW, Da Silva K, Guilly S, Zamalloa A, et al. Rifaximin-alpha reduces gut-derived inflammation and mucin degradation in cirrhosis and encephalopathy: RIFSYS randomised controlled trial. J Hepatol. 2022;76:332–42. https://doi.org/10.1016/j.jhep.2021.09.010.CrossRefPubMed

35.

Abdel Moneim M, Abdelaziz DH, Ibrahim Nagy Y, Abdel Baki A, Attia AS, Sabry N. Rifaximin microbial resistance and its efficacy and safety as a secondary prophylaxis of hepatic encephalopathy in patients with hepatitis C virus-related cirrhosis. Int J Clin Pract. 2021;75:e14807. https://doi.org/10.1111/ijcp.14807.CrossRefPubMed

36.

Bureau C, Thabut D, Jezequel C, Archambeaud I, D’Alteroche L, Dharancy S, et al. The Use of Rifaximin in the Prevention of overt hepatic Encephalopathy after Transjugular Intrahepatic Portosystemic Shunt: a Randomized Controlled Trial. Ann Intern Med. 2021;174:633–40. https://doi.org/10.7326/M20-0202.CrossRefPubMed

37.

Zeng X, Sheng X, Wang PQ, Xin HG, Guo YB, Lin Y, et al. Low-dose rifaximin prevents complications and improves survival in patients with decompensated liver cirrhosis. Hepatol Int. 2021;15:155–65. https://doi.org/10.1007/s12072-020-10117-y.CrossRefPubMed

38.

Pawar VB, Surude RG, Sonthalia N, Zanwar V, Jain S, Contractor Q, et al. Minimal hepatic encephalopathy in indians: psychometric hepatic Encephalopathy score and Inhibitory Control Test for diagnosis and Rifaximin or lactulose for its reversal. J Clin Transl Hepatol. 2019;7:304–12. https://doi.org/10.14218/JCTH.2017.00037.CrossRefPubMedPubMedCentral

39.

Sarwar S, Muhyuddin B, Aleem A, Nadeem MA. Primary prophylaxis of hepatic encephalopathy in decompensated cirrhosis: low dose vs. full dose rifaximin. Pak J Med Sci. 2019;35:1446–50. https://doi.org/10.12669/pjms.35.5.549.CrossRefPubMedPubMedCentral

40.

Hasan S, Datta S, Bhattacherjee S, Banik S, Saha S, Bandyopadhyay D. A randomized controlled trial comparing the efficacy of a combination of Rifaximin and Lactulose with Lactulose only in the treatment of overt hepatic encephalopathy. J Assoc Physicians India. 2018;66:32–6.PubMed

41.

Higuera-de-la-Tijera F, Servin-Caamano AI, Salas-Gordillo F, Perez-Hernandez JL, Abdo-Francis JM, Camacho-Aguilera J, et al. Primary prophylaxis to prevent the development of hepatic encephalopathy in cirrhotic patients with Acute Variceal bleeding. Can J Gastroenterol Hepatol. 2018;2018:3015891. https://doi.org/10.1155/2018/3015891.CrossRefPubMedPubMedCentral

42.

Butt NI, Butt UI, Kakar A, Malik T. Siddiqui. Is Lactulose Plus Rifaximin Better than Lactulose alone in the management of hepatic Encephalopathy? J Coll Physicians Surg Pak. 2018;28:115–7. https://doi.org/10.29271/jcpsp.2018.02.115.CrossRefPubMed

43.

Khokhar N, Qureshi MO, Ahmad S, Ahmad A, Khan HH, Shafqat F, et al. Comparison of once a day rifaximin to twice a day dosage in the prevention of recurrence of hepatic encephalopathy in patients with chronic liver disease. J Gastroenterol Hepatol. 2015;30:1420–2. https://doi.org/10.1111/jgh.12970.CrossRefPubMed

44.

Sharma K, Pant S, Misra S, Dwivedi M, Misra A, Narang S, et al. Effect of rifaximin, probiotics, and l-ornithine l-aspartate on minimal hepatic encephalopathy: a randomized controlled trial. Saudi J Gastroenterol. 2014;20:225–32. https://doi.org/10.4103/1319-3767.136975.CrossRefPubMedPubMedCentral

45.

Ali B, Zaidi YA, Alam A. Anjum. Efficacy of Rifaximin in prevention of recurrence of hepatic encephalopathy in patients with cirrhosis of liver. J Coll Physicians Surg Pak. 2014;24:269–73.PubMed

46.

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;108:1458–63. https://doi.org/10.1038/ajg.2013.219.CrossRefPubMed

47.

Sanyal A, Younossi ZM, Bass NM, Mullen KD, Poordad F, Brown RS, et al. Randomised clinical trial: rifaximin improves health-related quality of life in cirrhotic patients with hepatic encephalopathy - a double-blind placebo-controlled study. Aliment Pharmacol Ther. 2011;34:853–61. https://doi.org/10.1111/j.1365-2036.2011.04808.x.CrossRefPubMed

48.

Sidhu SS, Goyal O, Mishra BP, Sood A, Chhina RS. Soni. Rifaximin improves psychometric performance and health-related quality of life in patients with minimal hepatic encephalopathy (the RIME trial). Am J Gastroenterol. 2011;106:307–16. https://doi.org/10.1038/ajg.2010.455.CrossRefPubMed

49.

Bajaj JS, Heuman DM, Wade JB, Gibson DP, Saeian K, Wegelin JA, et al. Rifaximin improves driving simulator performance in a randomized trial of patients with minimal hepatic encephalopathy. Gastroenterology. 2011;140:478–487e471. https://doi.org/10.1053/j.gastro.2010.08.061.CrossRefPubMed

50.

Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362:1071–81. https://doi.org/10.1056/NEJMoa0907893.CrossRefPubMed

51.

Riggio O, Masini A, Efrati C, Nicolao F, Angeloni S, Salvatori FM, et al. Pharmacological prophylaxis of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt: a randomized controlled study. J Hepatol. 2005;42:674–9. https://doi.org/10.1016/j.jhep.2004.12.028.CrossRefPubMed

52.

Williams R, James OF, Warnes TW, Morgan MY. Evaluation of the efficacy and safety of rifaximin in the treatment of hepatic encephalopathy: a double-blind, randomized, dose-finding multi-centre study. Eur J Gastroenterol Hepatol. 2000;12:203–8. https://doi.org/10.1097/00042737-200012020-00012.CrossRefPubMed

53.

!!!. INVALID CITATION!!!.

54.

Schiano T. D. Treatment options for hepatic encephalopathy. Pharmacotherapy. 2010;30:16S–21S. https://doi.org/10.1592/phco.30.pt2.16S.

55.

Pandico F, Citarella A, Cammarota S, Bernardi FF, Claar E, Coppola C, et al. Rifaximin Use, adherence and persistence in patients with hepatic encephalopathy: a real-world study in the South of Italy. J Clin Med. 2023;12. https://doi.org/10.3390/jcm12134515.

56.

Israelsen M, Madsen BS, Torp N, Johansen S, Hansen CD, Detlefsen S, et al. Rifaximin-alpha for liver fibrosis in patients with alcohol-related liver disease (GALA-RIF): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Gastroenterol Hepatol. 2023. https://doi.org/10.1016/S2468-1253(23)00010-9.CrossRefPubMedPubMedCentral

57.

Arab JP, Arrese M, Shah VH. Gut microbiota in non-alcoholic fatty liver disease and alcohol-related liver disease: current concepts and perspectives. Hepatol Res. 2020;50:407–18. https://doi.org/10.1111/hepr.13473.CrossRefPubMedPubMedCentral

Title: Preventive and therapeutic effects of rifaximin on hepatic encephalopathy with differential application dosages and strategies: a network meta-analysis
Authors: Guihua Fang
Shuna Liu
Bin Liu
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Rifaximin
Hepatic Encephalopathy
Hepatic Encephalopathy
Published in: BMC Gastroenterology / Issue 1/2024
Electronic ISSN: 1471-230X
DOI: https://doi.org/10.1186/s12876-024-03184-0

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2024

Transcriptional landscape of intestinal environment in DSS-induced ulcerative colitis mouse model

Dietary intervention reverses molecular markers of hepatocellular senescence in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH

Effect of cognitive-behavior therapy for children with functional abdominal pain: a meta-analysis

Association between colorectal cancer, the frequency of Bacteroides fragilis, and the level of mismatch repair genes expression in the biopsy samples of Iranian patients

Noninvasive models for the prediction of liver fibrosis in patients with chronic hepatitis B

The effect of an acute aspirin challenge on intestinal permeability in healthy adults with and without prophylactic probiotic consumption: a double-blind, placebo-controlled, randomized trial

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials