REVIEW | Hepatology, VOL. 74, NO. 3, 2021  The Use of Rifaximin in Patients With Cirrhosis Paolo Caraceni ,1 Victor Vargas,2 Elsa Solà,3 Carlo Alessandria,4 Koos de Wit ,5 Jonel Trebicka ,6,7 Paolo Angeli,8 Rajeshwar P. Mookerjee,9 François Durand,10 Elisa Pose,3 Aleksander Krag,11,12 Jasmohan S. Bajaj ,13 Ulrich Beuers,5 Pere Ginès ,3 and for the Liverhope Consortium Rifaximin is an oral nonsystemic antibiotic with minimal gastrointestinal absorption and broad-­spectrum antibacterial activity covering both gram-­positive and gram-­negative organisms. Rifaximin is currently used worldwide in patients with cirrhosis for preventing recurrent HE because its efficacy and safety have been proven by large randomized clini- cal trials. In the last decade, experimental and clinical evidence suggest that rifaximin could have other beneficial ef- fects on the course of cirrhosis by modulating the gut microbiome and affecting the gut-­ liver axis, which in turn can interfere with major events of the pathophysiological cascade underlying decompensated cirrhosis, such as systemic inflammatory syndrome, portal hypertension, and bacterial infections. However, the use of rifaximin for prevention or treatment of other complications, including spontaneous bacterial peritonitis or other bacterial infections, is not ac- cepted because evidence by clinical trials is still very weak. The present review deals in the first part with the potential impact of rifaximin on pathogenic mechanisms in liver diseases, whereas in the second part, its clinical effects are critically discussed. It clearly emerges that, because of its potential activity on multiple pathogenic events, the efficacy of rifaximin in the prevention or management of complications other than HE deserves to be investigated extensively. The results of double-­blinded, adequately powered randomized clinical trials assessing the effect of rifaximin, alone or in combination with other drugs, on hard clinical endpoints, such as decompensation of cirrhosis, acute-­ on-­ chronic liver failure, and mortality, are therefore eagerly awaited. (Hepatology 2021;74:1660-1673). M ore than four decades ago, an association with lactulose.(3) However, because neomycin is slightly between HE and abnormalities in ammo- absorbed, there were concerns about nephrotoxicity nia metabolism was observed.(1) The asso- and ototoxicity during long-­term treatment. Ten years ciation between circulating unmetabolized ammonia ago, a seminal controlled trial showed that rifaximin, level and HE was weak. However, because production another minimally absorbed antibiotic, was superior to of ammonia is closely related to the composition of gut placebo to prevent recurrent HE.(4) It rapidly became microbiota, the idea emerged that oral administration apparent that beyond HE, rifaximin could have bene- of minimally absorbed antibiotics that were effective ficial effects on the course of cirrhosis through interac- against ammonia-­producing bacteria could help treat tions with the gut-­liver axis.(5-­7) This review focuses on or prevent HE.(2) Neomycin, which is active against rifaximin in the management of HE in cirrhosis but urease-­producing bacteria, has been one of the first also on other documented or potential targets of rifax- minimally absorbed antibiotics to be used, and con- imin, including systemic inflammatory response syn- trolled trials showed it had similar efficacy compared drome, portal hypertension, and bacterial infections. Abbreviations: ACLF, acute-­on-­chronic liver failure; BDL, bile duct ligation; CHE, covert hepatic encephalopathy; hPXR, human pregnane X receptor; LPS, lipopolysaccharide; MELD, Model for End-­Stage Liver Disease; PXR, pregnane X receptor; RCT, randomized controlled trial; SBP, spontaneous bacterial peritonitis; TLR4, toll-­like receptor 4. Received August 4, 2020; accepted December 2, 2020. Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/10.1002/hep.31708/suppinfo. Supported by a H2020 Grant –­LIVERHOPE –­project number: 731875. The work described has been funded by a H2020 Grant –­LIVERHOPE –­ project number: 731875. P.G. has been funded by grant numbers PI16/00043 and PI20/00529, and E.S. is funded by PI18/00727, both of which are integrated in the Plan Nacional I+D+I and cofunded by ISCIII-­Subdirección General de Evaluación and European Regional Development Fund FEDER. E.P., E.S., P.G., and other members of the LIVERHOPE Consortium have been funded by a grant from AGAUR 2017SGR-­01281. © 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution-­NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. 1660 Hepatology, Vol. 74, No. 3, 2021 CARACENI ET AL. Pharmacological dosage adjustment in patients with advanced cirrho- sis is recommended. Characteristics of Rifaximin Both experimental and clinical data show that rifaxi- min has a broad-­spectrum antibacterial action covering Rifaximin is a semisynthetic, water-­ insoluble, gram-­positive and gram-­negative aerobic and anaero- rifamycin-­ based nonsystemic antibiotic with very bic bacteria.(8,12,13) Rifaximin elicits its antimicrobial low gastrointestinal absorption and good antibacte- properties by binding the beta-­subunit of the bacterial rial activity.(8) Compared with rifampicin, it contains DNA-­ dependent RNA polymerase and thus inhib- an extra pyrido-­ imidazole ring to reduce systemic iting bacterial RNA synthesis. It has the advantage absorption that is less than 1% after oral adminis- of low microbial resistance and few systemic adverse tration(8,9) (Fig. 1). Nevertheless, it is important to events and is safe in all patient populations.(8,12,13) note that rifaximin plasma concentrations are not Being virtually nonabsorbed, bioavailability of negligible in patients with cirrhosis, particularly in rifaximin within the gastrointestinal tract is high those with moderate-­to-­severe liver function impair- with intraluminal and fecal drug concentrations ment (Child B or C patients).(10) There are some largely exceeding the minimal inhibitory concentra- published reports on potential muscle toxicity in cir- tion values observed in vitro against a wide range of rhosis in patients receiving rifaximin in combination pathogenic organisms. The gastrointestinal tract rep- with simvastatin 40 mg/day.(11) However, the possi- resents, therefore, the primary therapeutic target of bility of these systemic muscle effects of rifaximin rifaximin.(8,9,12,13) seems remote because in studies with large numbers Rifaximin has been shown to modify the gut of patients with cirrhosis, no muscle or other sys- microbiome. However, changes in overall gut micro- temic adverse events have been reported (see later). biome composition have shown to be relatively sparse, The slight increase in systemic exposure to rifaximin and the effects on microbiome have been described in subjects with cirrhosis should be interpreted in to be mediated also by rifaximin-­induced changes in the context of its low systemic availability as well as bile acid composition and modulation of microbiome the rifaximin safety data in cirrhosis. Therefore, no function (see later).(14,15) View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.31708 Potential conflict of interest: Dr. Angeli is on the speakers’ bureau and received grants from Behring. He advises Ferring and Biovie. Dr. Caraceni advises and is on the speakers’ bureau for Grifols. He is on the speakers’ bureau for and received grants from Octapharma. He advises Mallinckrodt. He is on the speakers’ bureau for Kedrion. Dr. Vargas advises Promethere and is on the speakers’ bureau for Intercept. Dr. Alessandria consults for Alfa Sigma. Dr. Krag advises and is on the speakers’ bureau for Norgie. Dr. Bajaj advises Norgine and received grants from Bausch Health. Dr. Gines advises and received grants from Grifols, Gilead, and Mallinckrodt. He advises Novartis. ARTICLE INFORMATION: From the 1 University of Bologna, University Hospital S. Orsola-­ Malpighi di Bologna, Bologna, Italy; 2 Hospital Vall d’Hebron, Universitat Autònoma de Barcelona, CIEREHD, Barcelona, Catalonia, Spain; 3 Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBEReHD, Barcelona, Catalonia, Spain; 4 Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Torino, Turin, Italy; 5 Amsterdam University Medical Centers, Amsterdam, the Netherlands; 6 Goethe-­ University -­Frankfurt am Main, Frankfurt am Main, Germany; 7 EF-­ CLIF, Barcelona, Catalonia, Spain; 8 University Hospital of Padova, Padova, Italy; 9 Royal Free Hospital, University College London, London, United Kingdom; 10 Hospital Beaujon, APHP, Paris, France; 11 Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark; 12 Institute of Clinical Research, University of Southern Denmark, Odense, Denmark; 13 Virginia Commonwealth University Medical Center, Richmond, VA. ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO: Pere Ginès, M.D., Ph.D. 08036 Barcelona, Spain Liver Unit, Hospital Clínic Barcelona E-­mail: pgines@clinic.cat Villarroel 170 Tel.: +34 93 227 5400 1661 CARACENI ET AL. Hepatology, September 2021 Rifamycin Rifaximin FIG. 1. Molecular structure of rifaximin and rifampicin. Effects of Rifaximin on randomized study in stable cirrhosis with ascites (mean Model for End-­Stage Liver Disease [MELD] 11.7), Pathogenic Mechanisms of showed no reduction in portal pressure after 4 weeks of rifaximin and no improvement in renal function or Chronic Liver Diseases and major effects on inflammatory markers and gut micro- biota composition.(15,24) The reason(s) for the different Cirrhosis results of these studies is not known, but it is possible that unnoticed active alcohol use, differences in liver dis- IMPACT ON LIVER FIBROSIS AND ease severity, and/or duration of treatment may explain PORTAL HYPERTENSION differences across studies. Although the dynamic com- Antibiotics have been reported to protect against ponent of portal hypertension and markers of bacterial alcohol-­ associated liver disease in rat models,(16) translocation can change relatively quickly, structural whereas others report aggravation of fibrosis in a effects, such as reduction of fibrosis, are slow, and treat- carbon tetrachloride/alcohol rat model.(17) In a bile-­ ment duration of at least 12-­24 months is probably duct-­ ligated (BDL) model, rifaximin attenuated necessary to allow histological changes. fibrosis and portal hypertension,(18) and more recently, Of interest, a controlled study assessing the combi- rifaximin was shown to prevent alcohol-­induced liver nation of rifaximin with propranolol showed a greater injury in a murine obesity model, whereby pathologi- impact on portal pressure reduction and necessitated cal changes in the intestinal microbiota signature that a lower mean propranolol (25) dose compared with pro- were induced by chronic ethanol feeding were partly pranolol alone. A mechanistic explanation for- reversed by rifaximin.(19) warded for the observed beneficial effects on portal Given rifaximin’s ability to selectively target the gut pressure and fibrosis is provided by a study in BDL microbiota,(20) decreased liver fibrosis in preclinical mod- toll-­ like receptor 4 (TLR4) mutant mice, showing els,(18) and a favorable long-­term safety profile, it follows that rifaximin modulates TLR4 activation by lipo- that rifaximin may be a useful intervention in reducing polysaccharides (LPS), thus resulting downstream in fibrogenesis driven by gut microbiota components.(21) less fibronectin generation from activated stellate cells (18) From the established relationship between por- and endothelial cells. tal pressure and systemic inflammation,(22) it follows that rifaximin, through modulation of fibrosis and gut GUT-­LIVER AXIS AND SYSTEMIC microbiota, could be expected to lower portal pressure. INFLAMMATION Indeed, in an observational study, Vlachogiannakos et al.(23) showed that rifaximin significantly low- Patients with cirrhosis experience alterations ered portal pressure at 4 weeks, associated with in their gut-­liver axis: an altered gut microbiome, decreased plasma endotoxin levels. In contrast, another increased intestinal permeability, and lower gut 1662 Hepatology, Vol. 74, No. 3, 2021 CARACENI ET AL. luminal primary bile acid levels may contribute to affected by rifaximin. In addition, rifaximin increases increased bacterial translocation.(26) As mentioned transepithelial electrical resistance and viability before, rifaximin is minimally absorbed and is of human colonic tumor-­ derived Caco-­ 2 cells.(30) thought to act locally in the gut; therefore, rifaximin Rifaximin also decreases toxicity PXR dependently might exert modulating effects on elements of the caused by Clostridium diff icile toxin A via the TLR4 gut-­liver axis. pathway in Caco-­2 cells(30) (Fig. 2). In vitro, rifaximin enhances intestinal epithe- Rodent models expressing human PXR (hPXR) lial layer homeostasis through activation of human were established to investigate PXR-­dependent effects pregnane X receptor (PXR), leading to inhibi- of rifaximin in vivo, because rifaximin is a human, tion of NF-­κB–­dependent inflammatory pathways but not rodent, PXR agonist. Induction of biotrans- including TNF-­α, IL-­6, IL-­8, and IL-­10 secretion formation enzymes by rifaximin was confirmed in and by induction of biotransformation enzymes these hPXR mice.(28,29) Notably, favorable effects of phase 1 (e.g., cytochrome P450 3A4) or phase 2 rifaximin were also observed in mice without hPXR. (e.g., glutathione-­S-­transferase A1).(27-­29) Bacterial Serum LPS binding protein levels were markedly attachment and internalization in enterocytes is also enhanced after BDL in wild-­type mice and tended FIG. 2. Putative effects of rifaximin on the gut-­liver axis. Rifaximin was shown to increase intestinal epithelial homeostasis by PXR-­ dependent mechanisms. Among them, inhibition of NF-­κB; decrease of TNF-­α, IL-­6, IL-­8, and IL-­10 secretion; and induction of biotransformation phase 1 and 2 enzyme activities (e.g., cytochrome P450 3A4 [CYP3A4], glutathione S-­transferase alpha 1 [GSTA-­1]) are notable. Subtle changes in intestinal microbiome composition and lowering of virulence factors have also been observed. Effects of rifaximin on bacterial bile acid biotransformation are yet unclear. Rifaximin led to normalization of serum LPS binding protein levels and thereby lowering of the proinflammatory state in the liver. Figure created with Biorender.com. Abbreviation: RXR, retinoid X receptor. 1663 CARACENI ET AL. Hepatology, September 2021 to be normalized after rifaximin treatment, which is, GUT MICROBIOME again, an effect mediated by TLR4.(18) Effects of rifaximin on synthesis and metabolism The human gut microbiome is assumed to play a of bile acids and their enterohepatic circulation are role in many diseases.(35,36) Because the microbiome yet unclear. A reduction in the secondary/primary comprises trillions of microbial cells with high meta- fecal bile acids ratio after 8 weeks of rifaximin treat- bolic activity, it is likely that induced changes by spe- ment was observed in 6 patients with cirrhosis.(14) cific treatments may be complex and prone to bias of The relevance of this finding, however, is yet unclear interpretation.(35,36) Indeed, the liver is the first organ because plasma bile acid composition was not affected encountering microbial products that cross the gut in another study in 38 patients with cirrhosis after epithelial barrier; therefore, it is likely to be affected 90 days of rifaximin treatment.(31) by the gut microbiome and its changes in many The effects of rifaximin on systemic inflamma- ways.(37) Especially in end-­ stage cirrhosis, bacterial tory markers are not extensively studied in patients translocation seems to play a decisive role in different with cirrhosis. IL-­6, IL-­10, and/or TNF-­α levels in complications, including acute-­on-­chronic liver failure plasma were decreased in patients with NAFLD, (ACLF).(26,38) alcohol-­ associated cirrhosis, and cirrhosis with HE, Different studies have demonstrated that the effect respectively, with treatment periods ranging from 4 of rifaximin on the gut microbiome is limited on phy- to 12 weeks.(31-­33) In contrast, no effects of rifaximin lum, class, order, and family level(7,39) regardless of the on systemic cytokine levels were observed in patients part of the gastrointestinal tract that the sample was with cirrhosis and ascites after 4 weeks.(15) In patients taken from, which is quite unexpected for a minimally with NAFLD, rifaximin also improved insulin resis- absorbed antibiotic.(40) Interestingly, other antibiotics, tance, serum glucose, aspartate aminotransferase, such as norfloxacin, that are recommended as prophy- alanine aminotransferase, and gamma-­glutamyl tran- lactic therapy in decompensated cirrhosis(41) may have speptidase after 6 months.(32) a stronger effect on the microbiome composition than In contrast to patients with cirrhosis or NAFLD, rifaximin, at least in experimental cirrhosis.(42) rifaximin showed no effects on IL-­ 6 and IL-­ 10 The question that arises is how rifaximin interacts mRNA levels in peripheral blood mononuclear cells, with microbiome to improve HE and, potentially, serum CD14 levels, or LPS in 40 patients with com- other complications of cirrhosis. Maybe the very subtle mon variable immunodeficiency after 2 weeks.(34) changes of the microbiome composition (Lactobacillus, This suggests that the systemic inflammatory status Streptococcus, Veillonella) are sufficient to reduce hyper- may be regarded as a prerequisite for the beneficial ammonemia and endotoxemia in cirrhosis.(39,43,44) anti-­inflammatory effects of rifaximin on patients Those changes were consistent for Veillonella spe- with cirrhosis or NAFLD. cies only in the cohorts cited. The underlying mech- Given the barely detectable quantities of rifax- anisms are still under investigation, but older studies imin in the systemic circulation, local effects in the have demonstrated that rifaximin strongly changes gut have to be assumed as the basis for the beneficial the metabolism of the host with increased circulating effects of rifaximin in patients with liver diseases. The saturated and unsaturated fatty acids, which are asso- human intestinal epithelium may be regarded as the ciated with altered microbiome linkages with those key player mediating effects of rifaximin in patients metabolites.(39) This observation in humans is paral- with cirrhosis. Experimental studies are underway leled by another study in mice, which demonstrates exploring effects of rifaximin on human enterocyte that rifaximin decreased small-­ intestinal glutaminase transport, metabolism, and detoxification function. and increased cecal glutamine content and proba- It is yet unclear whether rifaximin exerts its effects bly thereby decreased ammonia production.(45) Along exclusively via PXR-­dependent mechanisms or also these lines, a recent study showed that rifaximin can PXR-­ independently. Further in-­ depth molecular impact phage-­ Streptococcus linkages, especially those characterization of rifaximin’s effects on systemic that produce ammonia.(46) However, the evidence so inflammatory activity via its effects on the enterocyte far is based either on cross-­sectional studies or longi- and, thereby, the gut-­liver axis in patients with cirrho- tudinal smaller studies, with diverging results not only sis is clearly needed. for the host effects but also for the microbiome effects. 1664 Hepatology, Vol. 74, No. 3, 2021 CARACENI ET AL. We therefore hope the ongoing larger, longitudinal, Inpatient Therapy for HE and multicenter studies within the H2020 projects GALAXY, LIVERHOPE, and MICROB-­PREDICT The four prongs for the therapy of HE in patients may lead to better understanding of the mechanisms of who are hospitalized include (a) caring for the patient action and possible stratification of patients who may who is unconscious, (b) evaluating other causes of or may not benefit from rifaximin treatment. altered mental status, (c) identifying and treating pre- cipitating factors, and (d) starting empiric therapy.(47) All these processes need to occur simultaneously. The Effects of Rifaximin on first-­line empiric therapy in most countries remains lactulose. The role of rifaximin in this setting is Prevention and Management unclear.(47) Prior smaller-­scale trials have shown that rifaxi- of Complications of min may be useful in reducing blood ammonia and asterixis compared with selected therapies, such as Cirrhosis neomycin and nonabsorbable disaccharides. One large open-­label study evaluated rifaximin compared RIFAXIMIN IN HE with lactulose with clinical outcomes centered on Given the alterations in gut-­liver-­brain axis in HE, survival and mental status recovery.(51) In that study, gut-­focused interventions have been the mainstay of rifaximin therapy was better than lactulose in inpa- therapy.(47) Lactulose and lactitol are first-­line treat- tient outcomes. These results need to be replicated ments, but they can be associated with adverse events in other centers. Rifaximin also has not been directly that can limit their acceptance.(48) Rifaximin, being an compared with L-­ ornithine L-­ aspartate therapy, orally available, minimally absorbed, and safe medica- which in some studies has shown improvement in tion, has been studied in all aspects of HE. mental status.(52) Although rifaximin was used off-­label for HE ther- Until now, there is a trend toward off-­label use of apy across several European countries, the widespread rifaximin in inpatients, but it is most likely a contin- use and labeling for HE specifically increased after the uation of rifaximin that they were already on prior to U.S. Food and Drug Administration approval based hospitalization. The use of rifaximin on discharge of on the pivotal randomized controlled trial (RCT) by patients with HE is a major quality indicator of ther- Bass et al. in 2010.(4) Table 1 shows a summary of apy because it is associated with a lower risk of HE the experience with rifaximin in HE, and details of recurrence (see the following). prominent trials are provided in Supporting Table S1. Prevention of Recurrence Covert HE Therapy The pivotal trial by Bass et al. randomized 299 Covert HE (CHE) is very common and can be patients with multiple HE episodes into receiving associated with poor survival, overt HE develop- daily rifaximin 550 mg bis in die (twice a day) ver- ment, and psychosocial impact. Double-­blind RCTs sus placebo over 6 months.(4) The primary endpoint have shown that rifaximin is better than placebo with was breakthrough hospitalizations because of HE, and respect to improvement in cognition, quality of life, secondary endpoints included prevention of hospital- and driving capability.(48,49) Although the mecha- izations with HE. More than 90% of patients were on nism is unclear, changes in microbial function and lactulose at baseline, which was continued through- immune features and enhanced brain activation have out the trial. In those randomized to rifaximin, there been found. The European Association for the Study was a significant reduction in breakthrough events of the Liver/American Association for the Study of and hospitalizations over the 6 months. The number Liver Diseases guidelines recommend therapy for needed to treat was 4 and 9 for the above two out- CHE on a case-­by-­case basis.(44) However, rifaximin comes, respectively. However, most participants had therapy for CHE is not currently cost-­effective, even MELD score <19, and the initial usage was focused to prevent major outcomes, such as traffic crashes.(50) on these patients with >2 episodes. This trial followed 1665 CARACENI ET AL. Hepatology, September 2021 TABLE 1. Summary of Studies Reporting the Use of Rifaximin for Treatment or Prevention of HE in Cirrhosis Number of Trials Type of Study (Sample Size) Results Short-­term therapy studies (5-­30 days) Rifaximin vs. placebo 1 (93) Asterixis improved only with rifaximin. PSE index, mental status, and intellectual func- tion improved similarly in both groups. Rifaximin 200 mg vs. 400 mg vs. 800 mg per 1 (54) PSE index improved only in 400-­mg and 800-­mg groups. day Rifaximin vs. other antibiotics 7 (227) Ammonia improved more with rifaximin than neomycin (1 RCT) or similarly in both (6 RCTs). PSE index improved similarly in both groups (1 RCT). Intellectual function or mental status improved similarly in both groups (5 RCTs). Asterixis improved faster with rifaximin than with neomycin (1 RCT). Rifaximin vs. nonabsorbable disaccharides 6 (448) Higher ammonia improvement with rifaximin (3 RCTs) or similarly in both groups (3 RCTs) Long-­term studies (3-­6 months cyclical) Rifaximin vs. nonabsorbable disaccharides 2 (80) Ammonia and mental status improved with both trials with all strategies compared with baseline. Higher improvement in PSE index, EEG, and mental status with rifaximin. In the second study, rifaximin ± lactitol did better than lactitol alone with mental status. Rifaximin vs. neomycin 1 (60) Improvement in psychometric/neurophysiologic tests, mental status, and ammonia were similar across both groups. Inpatient use Rifaximin + lactulose vs. lactulose alone 1 (120) Higher HE reversal and lower death in group given rifaximin and lactulose compared with lactulose alone Prevention of recurrence Rifaximin vs. placebo 1 (299) Reduction in recurrent HE episodes and hospitalization in the rifaximin group with significantly higher improvement in neurophysiological, quality of life, and ammo- nia in the rifaximin group. In both groups, 91% of patients were on lactulose. Real-­world and open-­label rifaxi- min experience Open-­label extension and precomparison/ 2 (474) Open-­label extension and addition of new patients on rifaximin was associated with postcomparison continued reduction in HE-­related and all-­cause hospitalization, and conversion of patients from placebo to rifaximin further reduced HE episodes. Evaluation of health care systems after rifaxi- 5 (760) Reduction in mean hospitalizations, readmissions, and length of stay min introduction Note: Adapted from Bajaj and Riggio 2010.(53) PSE index: a composite score for HE consisting of 100 × (mental status [Conn score] × 3 + asterixis grade × 1 + NCT grade × 1 + ammonia grade × 1 + EEG grade × 1 [if available]); it is not widely used at this time. EEG, ­electroencephalogram; PSE, portosystemic encephalopathy. smaller-­scale trials from Europe in which long-­term it can lead to reduction in HE episodes and hospital cyclical use was studied with good outcomes. However, admissions. the newer formulation’s ability to use it twice a day and drug agency approval meant that it could be pre- Barriers to Rifaximin Therapy scribed for patients to prevent HE.(53) Cost and lack of awareness remain major issues to rifaximin therapy. Even in tertiary care centers, 12.5% “Real-­World” Use of Rifaximin of patients who were admitted with HE were subse- Open-­label experiences and evaluation of a placebo-­ quently discharged without HE-­specific medications, assigned group that was subsequently given rifaximin which translated directly into readmissions.(55) Given showed continued reduction in HE-­related episodes, the expense of hospitalizations, studies have shown even outside the clinical trial setting.(54) Studies that rifaximin is cost-­effective for prevention of recur- focused on changes in resource utilization before rence, but greater education of providers, patients, and rifaximin compared with after rifaximin showed that caregivers is needed.(56) 1666 Hepatology, Vol. 74, No. 3, 2021 CARACENI ET AL. Given its track record of acceptance by patients and the moderate-­ to-­high risk of methodological and efficacy in prevention of HE, further trials that biases related to randomization, blinding, attrition, evaluate the role of rifaximin in CHE and inpatient and intention-­to-­treat analysis preclude the possibility therapy of HE are needed, especially in combination to reach solid conclusions.(6,62,63) or head-­to-­head against other established therapies. EFFECTS OF RIFAXIMIN ON EFFECTS OF RIFAXIMIN ON OTHER COMPLICATIONS OF BACTERIAL INFECTIONS CIRRHOSIS Based on its pharmacological characteristics and Several studies have assessed the impact of rifaximin the putative effects on pathogenetic mechanisms in prevention of complications of cirrhosis other than of cirrhosis, rifaximin is considered by many hepa- HE and bacterial infections(64-­71) (Table 2). Data are tologists to be the logical alternative to quinolones not univocal and are often burdened by serious meth- or other systemic antibiotics for the prophylaxis of odological issues. Taking this into consideration, it is spontaneous bacterial peritonitis (SBP) and poten- suggested that, by reducing serum levels of proinflam- tially of non-­ SBP bacterial infections, with the matory mediators linked to intestinal bacterial translo- belief that rifaximin is active on a broader range of cation, rifaximin may decrease portal hypertension and intestinal gram-­positive and gram-­negative bacteria, improve systemic hemodynamics (increasing systemic is safer, and carries a low risk of inducing resistance vascular resistances and mean arterial pressure) and to antibiotics. renal function (improving glomerular filtration rate and Unfortunately, after more than a decade of clinical urinary sodium excretion).(23-­25,66,70) Hence, valuable research, a conclusive indication on the use of rifaximin clinical benefits have been associated with rifaximin, in prevention of bacterial infections cannot currently including a reduction in the incidence of decompen- be given. Almost all the published data are related to sation of cirrhosis, all-­cause hospitalizations and read- primary or secondary prophylaxis for SBP. In general, missions, variceal bleeding, and acute kidney injury, retrospective studies have shown that the use of rifax- including hepatorenal syndrome, with a decreased risk imin is associated with lower incidence of SBP and of renal replacement therapy.(58,64,65,67-­69,72) A better other complications of the disease.(57,58) Conversely, control of difficult-­to-­treat/refractory ascites was also prospective observational studies have yielded less shown when rifaximin was added to treatment.(70,71) consistent results.(59) Only a few RCTs have been A reduction in mortality was suggested in some stud- performed so far, in Egypt and South Arabia, com- ies.(51,58,65,70,71) Although promising, these data must paring the efficacy of rifaximin versus norfloxacin; in be confirmed by well-­conducted, large RCTs. these studies, an advantage was seen in favor of rifax- imin given for primary or secondary SBP(60,61); in the SIDE EFFECTS former study, rifaximin was also given alternated to norfloxacin and compared with norfloxacin alone.(60) In the rifaximin data sheet, dizziness, headache, However, the strength of these positive results is constipation, abdominal pain, diarrhea, flatulence, undermined by some methodological drawbacks. nausea, rectal tenesmus, vomiting, and pyrexia are To overcome the limitations inherent to each sin- listed as frequent side effects (>1/100 to <1/10). gle study, several systematic reviews and meta-­analysis When used in HE, rifaximin side effects have assessing both the observational cohort studies and been mild and infrequent. In a review article includ- the RCTs have been performed. Again, results suggest ing the pivotal prophylaxis trial, rifaximin was well that only low-­quality evidence supports the superi- tolerated, and adverse events were similar to pla- ority of rifaximin over norfloxacin or other systemic cebo group.(4,73) In the pivotal study, there were two antibiotics for either primary or secondary SBP pro- cases of infection by C. diff icile versus none in the phylaxis.(6,62,63) In all these studies, the high hetero- control group. In the extension study, the frequency geneity in terms of patient inclusion criteria, type and of this infection did not increase and was reported modalities of administration of the comparative pro- in 6 patients.(74) All these patients presented pre- phylactic therapies, primary and secondary endpoints, disposing factors for this infection. Postmarketing 1667 CARACENI ET AL. Hepatology, September 2021 TABLE 2. Summary of Studies Evaluating the Effect of Rifaximin on Complications of Cirrhosis Other Than HE and Bacterial Infections Reference Study Design Patient Population Main Outcomes Assem et al. Prospective rand- 239 patients with cirrhosis Primary outcome: incidence of SBP 2016(60) omized, open-­ with ascites randomized to Overall, 10 patients developed HRS (6 patients [7.6%] in the norfloxacin label, comparative 3 groups: rifaximin (550 mg group, 2 [2.4%] in the rifaximin group and 2 [2.5%] in the combined multicenter study bid), norfloxacin, or alternat- group; P > 0.05). ing rifaximin/norfloxacin HRS was the main cause of mortality. Sharma et al. RCT 120 patients with overt HE ran- Primary outcome: reversal of HE 2013(51) domized into 2 groups: lactu- Addition of rifaximin was associated with the following: lose + rifaximin (1,200 mg/ -­Reduced mortality (24% vs. 49%, P < 0.05), with no differences in HRS-­ day) vs. lactulose + placebo related and gastrointestinal bleeding–­related deaths Dong et al. Retrospective study 88 patients on rifaximin Primary outcomes: incidence of AKI and HRS 2016(64) (550 mg bid) for ≥90 days vs. Rifaximin reduced the following: 88 matched controls -­The incidence rate ratio of AKI (IRR, 0.71; 95% CI, 0.54-­0.94) and HRS (IRR, 0.21; 95% CI, 0.06-­0.70) -­The requirement of RRT (5.7% vs. 15.9%; OR, 0.23; 95% CI, 0.07-­0.74) Vlachogiannakos Prospective, nonran- 23 patients with known Primary outcomes: survival, variceal bleeding, HE, SBP, HRS et al. 2013(65) domized case-­ hemodynamic response Rifaximin therapy was as follows: control study (HVPG) to short-­term rifaximin -­An independent negative predictor of variceal bleeding (RH, 0.246; 95% CI, treated with long-­term ri- 0.069-­0.870; P = 0.03) faximin (1,200 mg/day) vs. 46 matched controls -­The only factor associated with lower probability of HRS (RH, 0.110; 95% CI, 0.012-­0.973; P = 0.047) -­Predictor of 5-­year survival (RH for mortality, 0.258; 95% CI, 0.075-­0.891; P = 0.032) Kimer et al. Double-­blind RCT 54 stable outpatients with Primary outcomes: hepatic and systemic hemodynamics, renal function 2017(24) cirrhosis and ascites with No effect of rifaximin on the following: HVPG ≥ 10 mm Hg rand- -­HVPG (P = 0.94) omized to rifaximin 550 mg bid (n = 36) or placebo bid -­PRA (P = 0.12) or other vasoactive hormones (P = NS) (n = 18) for 4 weeks -­GFR (P = 0.14) Kalambokis et al. Open-­label, prospec- 13 patients with alcohol-­ Primary outcomes: systemic hemodynamics and renal function 2012(66) tive, single-­center associated cirrhosis and Rifaximin: pilot study ascites treated with rifaximin -­increased MAP (P = 0.05) in keeping with increased SVR (P = 0.01), (1,200 mg/day) for 4 weeks decreased PRA (P = 0.02), and decreased CO (P = 0.02) -­improved renal function, consistent with increase in GFR (P = 0.006) and urinary sodium excretion (P = 0.03) -­decreased plasma endotoxin (P = 0.005), IL-­6 (P = 0.01), and TNF-­α (P = 0.02) levels Vlachogiannakos Prospective study 30 patients with alcohol-­ Primary outcomes: hepatic hemodynamics et al. 2009(23) associated cirrhosis and Rifaximin: ascites treated with rifaximin -­decreased HVPG (P < 0.0001) (1,200 mg/day) for 28 days -­increased MAP (P < 0.05) -­reduced plasma endotoxin levels both in systemic (P < 0.0001) and splanchnic circulation (P < 0.0001) Lim et al. Open-­label RCT 73 patients with Primary outcome: HVPG response rate 2017(25) HVPG ≥ 12 mm Hg rand- The combination therapy achieved the following: omized to propranolol mono- -­a significant decline of HVPG (P = 0.016) therapy (n = 54) or rifaximin (1,200 mg/day) + propranolol -­higher HVPG response rate than propranolol alone (87% vs. 56%; (n = 19) for 3 months P = 0.034). -­higher rates of reduction of LPS (P = 0.009) and LPS binding protein (P = 0.002) compared with propranolol monotherapy 1668 Hepatology, Vol. 74, No. 3, 2021 CARACENI ET AL. TABLE 2. Continued Reference Study Design Patient Population Main Outcomes Salehi et al. Retrospective cohort 101 patients with HE: 66 treated Primary outcome: all-­cause emergency hospital admissions 2019(67) study with rifaximin vs. 35 naïve Rifaximin therapy achieved the following: -­reduced all-­cause admissions (P = 0.037) -­reduced admissions for complications of ascites, including HRS (P = 0.008) and variceal bleeding (P = 0.026) -­increased time to hospital readmission (P = 0.040) Kang et al. Retrospective cohort 1,042 patients with previous HE: Primary outcome: overall survival 2017(58) study 621 patients with HCC (173 Rifaximin was associated with lower risk of variceal bleeding in the following: receiving rifaximin 1,200 mg/ -­Entire cohort (HR, 0.520; 95% CI, 0.349-­0.773; P = 0.001) day + lactulose, 448 controls receiving lactulose alone) -­Non-­HCC cohort (aHR, 0.425; 95% CI, 0.220-­0.821; P = 0.011) and 421 without HCC (145 Rifaximin was associated with a nonsignificant trend toward lower risk of HRS rifaximin + lactulose, 276 in the following: lactulose alone) -­Non-­HCC cohort (HR, 0.595; 95% CI, 0.334-­1.060; P = 0.078) Rifaximin was associated with a lower risk of death in the following: -­Entire cohort (HR, 0.702; 95% CI, 0.504-­0.978; P = 0.036) -­Non-­HCC cohort (aHR, 0.697; 95% CI, 0.510-­0.954; P = 0.024) Flamm et al. Post hoc analysis 299 patients with cirrhosis and Primary outcome of RCT: time to a breakthrough episode of overt HE 2018(68) of a placebo-­ HE in remission, rand- In patients with MELD ≥ 12 and INR ≥ 1.2, rifaximin was associated with the controlled omized to rifaximin 550 mg following: multicenter RCT bid (n = 140) or placebo -­Reduced risk of any first complication (HR, 0.41; 95% CI, 0.25-­0.67; (n = 159) for 6 months P < 0.001) -­Nonsignificant trend for reduction in the overall risk of non-­HE complica- tions, including variceal bleeding and AKI/HRS (HR, 0.46; 95% CI, 0.18-­ 1.17; P = 0.10) In patients with MELD <12 and INR <1.2, rifaximin was associated with the following: -­Nonsignificant trend for reduction in the risk of any complication (HR, 0.26; 95% CI, 0.06-­1.20; P = 0.06) Ibrahim et al. RCT 80 patients with decompen- Primary outcome: incidence of HRS 2017(69) sated cirrhosis randomized -­Lower incidence of HRS in the rifaximin group (5% vs. 22.5%; P = 0.048) to rifaximin 550 mg bid for -­Being in the control group was a predictor of HRS at univariate analysis but 12 weeks (n = 40) or no treat- not at multivariate analysis (OR, 3.01; 95% CI, 0.46-­19.52; P = 0.249) ment (n = 40) Hanafy and RCT 600 patients with refractory Primary outcomes: control of ascites Hassaneen or rapidly recurrent ascites Rifaximin + midodrine was associated with the following: 2016(70) randomized to diuretic -­Improvement in hemodynamics, as expressed by increase in MAP and therapy + midodrine 5 mg reduction in PRA and aldosterone (P < 0.05 for all variables) tid + rifaximin 550 mg bid (n = 400) or diuretic therapy -­Improvement in renal function, as assessed by serum creatinine and BUN alone (n = 200) decrease, serum sodium increase, 24-­hour urine output and urinary sodium excretion increase (P < 0.05 for all variables) -­Better control of ascites, as expressed by a reduction in tapping of ascites (P < 0.0001), weight loss (P < 0.0001), higher rates of complete disap- pearance of ascites (80% vs. 15%; P < 0.0001) -­Improvement in overall survival (19.6 vs. 11.6 months; P < 0.0001) Lv et al. 2020(71) Prospective observa- 75 patients with ascites receiv- Primary outcomes: control of ascites and survival tional study ing SMT (n = 25) or SMT + Rifaximin was associated with the following: rifaximin 200 mg qid for 3 to -­Better control of ascites, as shown by enhanced response to diuretic 4 weeks (n = 50) therapy (P = 0.009) and more marked weight loss (P = 0.011) -­Increased survival (HR, 2.53; 95% CI, 1.01-­6.38; P = 0.048) Abbreviations: aHR, HR adjusted for Child-­Pugh class; AKI, acute kidney injury; bid, bis in die (twice a day); BUN, blood urea nitrogen; CO, cardiac output; GFR, glomerular filtration rate; HRS, hepatorenal syndrome; INR, international normalized ratio; IRR, incidence rate ratio; MAP, mean arterial pressure; PRA, plasma renin activity; qid, quater in die (four times a day); RH, relative hazard; RRT, renal replacement therapy; SMT, standard medical therapy; SVR, systemic vascular resistance; tid, ter in die (three times a day). 1669 CARACENI ET AL. Hepatology, September 2021 TABLE 3. Recommendations for Use of Rifaximin in the Management of Complications of Cirrhosis in Clinical Practice Recommended Recommended on a Case-­by-­Case Basis Needs Further Research and Therefore Not Recommended Currently Prevention of CHE (treatment not cost-­effective) Inpatient therapy of episodes of overt HE recurrence of HE Prevention of SBP recurrence Prevention of other complications of cirrhosis studies also described cases of C. diff icile infec- TABLE 4. Studies Reported in clinicaltrials.gov Investigating the Use of Rifaximin in Cirrhosis tion.(75) When rifaximin was used in prophylaxis of SBP, few side effects were observed. In a study, no Endpoints Number of Studies side effects were described,(57) and in others, they Prevention of complications of cirrhosis were uncommon, including abdominal pain, flatu- SBP 4 lence, nausea, dizziness, and headache.(60,61) CHE 3 It has been suggested that rifaximin may favor Decompensated cirrhosis 2 the muscular toxicity of statins in cirrhosis.(11) This HE in patients with transjugular intrahepatic portosys- 2 possibility seems unlikely because only three cases temic shunts of rifaximin rhabdomyolysis have been described ACLF* 1 Variceal bleeding 1 in a postmarketing database,(75) and it has not been Renal failure 1 observed in patients with cirrhosis treated with low Persistent HE 1 doses of simvastatin (20 mg/day) together with Other rifaximin.(76) Portal pressure 2 Systemic inflammation 1 B-­cell dysregulation 1 Future Directions Portal vein thrombosis Quality of life 1 1 Currently, the only accepted indication for rifaxi- min in cirrhosis is prevention of recurrent HE.(46) Use *Associated with simvastatin. of rifaximin for other indications, such as prevention of bacterial infections, including SBP, is not supported milieu resulting from the systemic spread of pathogen-­ by strong evidence; therefore, rifaximin should not be associated molecular patterns (PAMPs) and damage-­ used in clinical practice for indications other than HE associated molecular patterns from gut and diseased (Table 3). Nonetheless, because of its complex effects liver, respectively. The deep alterations in their gut-­ in gut-­liver axis and modulating gut microbiome, the liver axis favoring translocation of PAMPs as well as potential efficacy of rifaximin in prevention or man- viable bacteria have been the rationale for the use of agement of complications of cirrhosis other than HE rifaximin in prevention of several complications of cir- deserves to be investigated extensively. Ideally, studies rhosis. Rather than having a bactericidal effect, rifaxi- should be double-­blinded, with rifaximin alone or in min seems to have direct effects on bacterial function combination with other drugs, include large patient and virulence. Confirming this, its use results in very populations, and aimed at hard clinical endpoints, par- little change in stool microbiome in cirrhosis. In addi- ticularly prevention of decompensated cirrhosis, bac- tion, rifaximin does not appear to increase antibiotic terial infections, and ACLF. Some of these studies are resistance rates. Therefore, rifaximin represents an underway, and results are eagerly awaited (Table 4). antibiotic strategy that may prevent infections and other complications of cirrhosis without development of multidrug-­resistant bacteria. However, beyond the Conclusions prevention of recurrent HE, there are currently no other recommended indications for its use in cirrhosis. In recent years, the paradigm on pathophysiology Indeed, several studies have already shown a poten- of decompensation of cirrhosis has deeply changed. It tial favorable impact of rifaximin on several steps in is now clear that decompensated cirrhosis is charac- pathophysiology of decompensation. Accordingly, terized by sustained proinflammatory and pro-­oxidant beneficial effects of rifaximin have been described. 1670 Hepatology, Vol. 74, No. 3, 2021 CARACENI ET AL. Unfortunately, most of these data are not the result of 6) Goel A, Rahim U, Nguyen LH, Stave C, Nguyen MH. Systematic high-­quality RCTs but rather of not-­controlled “real-­ review with meta-­ analysis: rifaximin for the prophylaxis of world” studies, meta-­analysis, or systematic reviews. spontaneous bacterial peritonitis. Aliment Pharmacol Ther 2017;46:1029-­1036. This can explain why, up to now, the results are not 7) Bajaj JS. Review article: Potential mechanisms of action of rifaxi- so univocal and consistent as to be translated into min in the management of hepatic encephalopathy and other com- recommendations. plications of cirrhosis. Aliment Pharmacol Ther 2016;43(Suppl 1):11-­26. Acknowledgment: The Liverhope Consortium investi- 8) Scarpignato C, Pelosini I. 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