Received: 9 October 2021 | Revised: 31 January 2022 | Accepted: 15 February 2022 DOI: 10.1111/liv.15207 ORIGINAL ARTICLE Effect of rifaximin on infections, acute-­on-­chronic liver failure and mortality in alcoholic hepatitis: A pilot study (RIFA-­AH) César Jiménez1 | Meritxell Ventura-­Cots1,2,3 | Margarita Sala2,4 | 2,4 5 5 Margalida Calafat | Montserrat Garcia-­Retortillo | Isabel Cirera | 5 2,6 2,6 Nuria Cañete | Germán Soriano | María Poca | Macarena Simón-­Talero1,2 | José Altamirano7 | Michael Lucey8 | Guadalupe Garcia-­Tsao9 | Robert S. Brown Jr10 | Robert F. Schwabe11 | Elizabeth C. Verna12 | Bernd Schnabl13 | 14 15 Francisco Bosques-­Padilla | Philippe Mathurin | Juan Caballería2,16 | Alexandre Louvet15 | Debbie L. Shawcross17 | Juan G. Abraldes18 | Joan Genescà1,2 | Ramon Bataller3 | Víctor Vargas1,2 1 Vall d'Hebron Hospital Universitari, Liver Unit; Vall d'Hebron Institut de Recerca, Liver Unit, Universitat Autonoma de Barcelona, Department of Medicine, Barcelona, Spain 2 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain 3 Center for Liver Diseases, Pittsburgh Liver Research Center, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA 4 Gastroenterology Department, Hospital Universitari Germans Trias I Pujol, Badalona, Spain 5 Liver Section, Gastroenterology Department, Hospital del Mar, IMIM (Hospital del Mar Medical Research Institute), Universitat Autònoma de Barcelona, Barcelona, Spain 6 Department of Gastroenterology Hospital de la Santa Creu i Sant Pau Barcelona Spain, Institut d’Investigació Biomèdica Sant Pau IIB Sant Pau, Gastroenterology, Barcelona, Catalunya, ES, Universitat Autonoma de Barcelona, Medicine, Barcelona, Catalunya, Spain 7 Department of Internal Medicine, Hospital Quironsalud, Barcelona, Spain 8 Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA 9 Section of Digestive Diseases, Yale University, New Haven, Connecticut Section of Digestive Diseases, Department of Veterans Affairs Connecticut Healthcare, West Haven, Connecticut, USA 10 Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York City, New York, USA 11 Department of Medicine, Columbia University, New York City, New York, USA 12 Center for Liver Disease and Transplantation, Columbia University Irving Medical Center, New York City, New York, USA 13 Department of Medicine, University of California San Diego, La Jolla, California, USA 14 Hospital San José Tecnológico de Monterrey, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico 15 Service des Maladies de L’appareil Digestif et Unité INSERM U995, Lille, France 16 Liver Unit, Hospital Clinic, Barcelona, Spain 17 Department of Inflammation Biology, School of Immunology and Microbial Sciences, Institute of Liver Sciences, King’s College London, London, UK 18 Division of Gastroenterology, Liver Unit, University of Alberta, Edmonton, Canada Abbreviations: ACLF, acute-­on-­chronic liver failure; AH, alcoholic hepatitis; AKI, acute kidney injury; ALD, alcohol-­related liver disease; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRBSI, catheter-­related bloodstream infection; EH, hepatic encephalopathy; GIB, gastrointestinal bleeding; HBV, hepatitis B virus; HCV, hepatitis C virus; INTEAM, Integrated Approaches for Identifying Molecular Targets in Alcoholic Hepatitis; MELD, model for end-­s tage liver disease; PAMPs, pathogen-­associated molecular patterns; SAEs, serious adverse events; SB, spontaneous bacteraemia; SBP, spontaneous bacterial peritonitis; SID, selective intestinal decontamination; SIRS, systemic inflammatory response; UTI, urinary tract infection. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2022 The Authors. Liver International published by John Wiley & Sons Ltd. Liver International. 2022;42:1109–1120.  wileyonlinelibrary.com/journal/liv | 1109 1110 | JIMÉNEZ et al. Correspondence Victor Vargas, Liver Unit, Hospital Abstract Universitari Vall d’Hebron, Vall d’Hebron Background & Aims: Alcoholic hepatitis (AH) is associated with a high incidence of in- Research Institute (VHIR), Universitat Autònoma de Barcelona, CIBERehd, fection and mortality. Rifaximin reduces bacterial overgrowth and translocation. We Barcelona, Spain. aimed to study whether the administration of rifaximin as an adjuvant treatment to Email: vvargas@vhebron.net corticosteroids decreases the number of bacterial infections at 90 days in patients Funding information with severe AH compared to a control cohort. Grant of “Instituto de Salud Carlos III” EC11-­0 489. MV and MS are recipients Methods: This was a multicentre, open, comparative pilot study of the addition of of the Juan Rodés grant. BS is supported rifaximin (1200 mg/day/90 days) to the standard treatment for severe AH. The results by the NIH center P30 DK120515. INTEAM Funding Source: U01AA021908, were compared with a carefully matched historical cohort of patients treated with National Institute on Alcohol Abuse and standard therapy and matching by age and model of end-­stage liver disease (MELD). Alcoholism, National Institutes of Health, Bethesda, MD, USA. We evaluated bacterial infections, liver-­related complications, mortality and liver function tests after 90 days. Handling editor: Luca Valenti Results: Twenty-­one and 42 patients were included in the rifaximin and control groups respectively. No significant baseline differences were found between groups. The mean number of infections per patient was 0.29 and 0.62 in the rifaximin and control groups, respectively (p = .049), with a lower incidence of acute-­on-­chronic liver failure (ACLF) linked to infections within the treatment group. Liver-­related com- plications were lower within the rifaximin group (0.43 vs. 1.26 complications/patient respectively) (p = .01). Mortality was lower in the treated versus the control groups (14.2% vs. 30.9, p = .15) without significant differences. No serious adverse events were associated with rifaximin treatment. Conclusions: Rifaximin is safe in severe AH with a significant reduction in clinical com- plications. A lower number of infections and a trend towards a lower ACLF and mor- tality favours its use in these patients. KEYWORDS acute-­on-­chronic liver failure, alcohol-­related liver disease, bacterial infection, cirrhosis, rifaximin, severe alcoholic hepatitis 1 | I NTRO D U C TI O N Lay Summary Alcoholic hepatitis (AH) is characterized by an abrupt increase Rifaximin, a non-­absorbable antibiotic, may be useful in pa- in serum bilirubin levels, jaundice and liver-­related decompensa- tients with severe alcoholic hepatitis, reducing the number tions.1 Furthermore, it is the most severe form of alcohol-­related of infections and complications. This study is relevant be- liver disease (ALD), with mortality rates reaching 30% at 3 months. 2 cause there are currently few treatment options for severe Infection is one of the most frequent complications among patients alcoholic hepatitis. with AH. According to a recent meta-­analysis, the incidence of in- fection at 28 days was 20%, regardless of whether the patients re- ceived corticosteroid treatment.3 AH patients who presented with infections and/or systemic inflammatory response (SIRS) at baseline and virulence factors,5 which are part of exogenous inflammatory were more likely to present with multiorgan failure, and their 28-­day components and are the most well-­known and well-­studied fac- mortality rate increased up to 40%.4 This detrimental inflammatory tors. In AH, excessive alcohol consumption induces gut dysbiosis response is the result of a complex interaction between inflamma- and increases the permeability of the intestinal barrier, resulting in tory microbial and non-­microbial inducers. Microbial inducers of in- different PAMPs and inducing bacterial translocation.6 Endogenous flammation include pathogen-­associated molecular factors (PAMPs) inducers of inflammation are produced as a result of tissue injury JIMÉNEZ et al. | 1111 or damage and play a major role during AH episodes. Furthermore, The Institutional Review Board at the study sites and ‘Agencia there is a non-­microbial component of inflammation linked to the Española de Medicamento’ approved the study. Written informed adaptive response of the tissue to stress or malfunction.7 All these consent was obtained from all participants before enrolment. The components are key to the development of SIRS and infections. study was conducted in accordance with the Declaration of Helsinki Selective intestinal decontamination (SID) has proven useful in and the current laws and regulations (‘Real Decreto’ 223/2004). reducing the incidence of infections in patients with cirrhosis when Both studies were registered on the Clini​calTr​ials.gov website used either for primary or secondary prophylaxis.8–­10 Rifaximin is a (NCT02116556 and NCT02075918). non-­absorbable antibiotic that has been broadly used in cirrhotic pa- tients and has emerged as an alternative to standard therapy with quinolones, avoiding the adverse effects of conventional therapy 2.2 | Patient selection and the study protocol and the development of bacterial resistance to quinolones.11,12 The main aim of the current study was to explore the safety and Subjects from the study group were eligible for inclusion if they met the overall effects of rifaximin as an add-­on therapy to conventional following criteria: age between 18 and 70 years, a history of active alco- treatment in reducing the incidence of infection in patients with se- hol intake (>60 g OH/day for men and >40 g OH/day for women) during vere AH as compared with a historical control cohort. the previous 3 months to admission, level of aspartate aminotransferase (AST) > alanine aminotransferase (ALT), bilirubin level ≥ 3 mg/dl and a Maddrey discriminant function ≥32 or MELD ≥21. Subjects were ex- 2 | PATI E NT S A N D M E TH O DS cluded from enrolment if they met one of the following criteria: hyper- sensitivity or allergic reaction to the drug components, terminal illness 2.1 | General characteristics (defined as any concomitant disease with a vital prognosis shorter than 3 months), autoimmune hepatitis, concomitant hepatitis B virus (HBV), The study was designed as a pilot study. We choose the case–­control hepatitis C virus (HCV) or infection by human immunodeficiency virus, design over a randomized clinical trial since there was no evidence chronic jaundice (more than 3 months), presence of total vein thrombo- to support the efficacy and safety of rifaximin treatment in alcoholic sis, previous use of rifaximin (during the last 2 months), hepatocellular hepatitis before the recruitment period started. carcinoma beyond the Milan criteria and concomitant treatment with This is a multicentre, pilot, study and an open-­label evaluation pentoxifylline. In premenopausal women, a negative pregnancy test of rifaximin effects as an add-­on therapy to conventional treatment result was required, and breastfeeding was ruled out. The diagnosis of in reducing the incidence of infection in patients with severe AH AH was made based on clinical, analytical and radiological data,13 and a compared with a matched control cohort. Severity was defined by a biopsy-­proven diagnosis was required during the first 7 days after study model for end-­stage liver disease (MELD) score of ≥21 or a Maddrey inclusion. If the histology was incompatible with AH, the subject was discriminant function ≥32. The study included 21 consecutive pa- withdrawn. Another withdrawal criterion was the diagnosis of bile duct tients recruited from June 2013 to June 2015 who were admitted to obstruction revealed by ultrasound. Notably, all patients with baseline four tertiary academic medical centres in Barcelona (Figure 1). active bacterial infections or using systemic or prophylactic antibiotics An additional prospective cohort of patients with severe AH who were excluded. The inclusion and exclusion criteria for the control group received the current standard treatment, including corticosteroids, were the same as those for the study group (Figure 1). The study pro- was recruited between May 2014 and April 2019. These patients tocol patients received rifaximin 1200 mg/day (400 mg/8 h) for 90 days belonged to the INTEAM consortium (Integrated Approaches for as an add-­on to conventional therapy (support nutrition, preventive Identifying Molecular Targets in Alcoholic Hepatitis). From this co- therapy for withdrawal syndrome and corticosteroids if they did not hort, we selected 42 patients who fulfilled the same inclusion and exhibit any contraindications at the time of admission). The follow-­up exclusion criteria of the study cohort, including a liver biopsy con- visits were scheduled at 7 days, on discharge, and at 30, 60 and 90 days. sistent with AH, who did not receive rifaximin or prophylactic an- At all time points, the following data were collected: clinical his- tibiotics and were matched by age and MELD to the study cohort. tory (demographic data, previous disease and previous episodes of A total of 268 patients were recruited for the INTEAM consortium acute decompensation), physical examination, laboratory measure- observation at the time of selection. A total of 94 patients with se- ments, presence of bacterial infections and any liver-­related compli- vere alcoholic hepatitis, with no history of antibiotics for prophy- cations at admission and during follow-­up visits, including presence laxis or treatment, were assessed for eligibility. Of these patients, or worsening of ascites, gastrointestinal bleeding (GIB) and acute-­ only 49 had a definite diagnosis of AH as assessed by liver biopsy. on-­chronic liver failure (ACLF). Hepatic encephalopathy (HE) and Patients were then matched by MELD allowing a maximum deviance acute kidney injury (AKI) were included under ACLF or assessed as of 2.5 points and ± 3 years of age for each study patient. Forty-­t wo unique decompensations when they did not reach the ACLF defi- patients fulfilled all requirements and were included allowing a 2:1 nition.14 Finally, Maddrey, MELD, Child–­Pugh and ABIC prognostic matching. No differences in any analytical parameters or risk scores scores were used to evaluate disease severity, and the Lille score were observed between both groups (Table 1). was used to evaluate the response to standard therapy. 1112 | JIMÉNEZ et al. F I G U R E 1 Flowchart for the inclusion and exclusion of subjects and their allocation to the rifaximin and control groups. ACLF, acute-­ on-­chronic liver failure; OLT, orthotopic liver transplantation; ALT, alanine aminotransferase; AST, aspartate aminotransferase; HCC, hepatocellular carcinoma; INTEAM consortium (Integrated Approaches for Identifying Molecular Targets in Alcoholic Hepatitis); MELD, model for end-­stage liver disease JIMÉNEZ et al. | 1113 TA B L E 1 Baseline characteristics by the group 2.4 | Sample size and statistical analyses Rifaximin group Control group (n = 21) (n = 42) p We hypothesized that the add-­on of rifaximin would decrease the Sex (male), n(%) 16 (76.2%) 28 (66.7%) .43 proportion of infections at 90 days by 50% based on the expected Age, median (IQR) P25–­P75 55 (46.5–­60.0) 53.5 (43–­62) .99 incidence of infections observed in previous studies with cirrhotic Maddrey score, median 49 (38–­62) 49 (41.0–­6 4.7) .92 patients.15,16 The final sample size (n = 66) was calculated according (IQR) P25–­P75 to the potential loss of 15% of the patients. After 2 years of recruit- MELD score, median (IQR) 22 (19–­24) 23 (20.7–­25.0) .24 ment, we included 27 patients (40% of the expected recruitment). P25–­P75 Recalculation of the total sample size according to the observed ABIC score, median (IQR) 8 (7.4–­8.7) 8.6 (7.3–­9.1) .09 losses (9% of the included patients) resulted in 62 patients. P25–­P75 Descriptive statistics were used to summarize the data. Child–­Pugh score, median 9 (9–­11) 9 (8–­10) .78 Quantitative variables were described as mean and standard devi- (IQR) P25–­P75 ation for normally distributed variables or median and interquartile Haemoglobin (g/dl), median 10.7 (9.6–­13) 11.1 (9.7–­12.5) .65 range if normality criteria were not met. Percentages were calcu- (IQR) P25–­P75 lated using categorical data. Qualitative variables are described as Leucocytes (10e9/L), 8.1 (5.5–­10.3) 10.2 (7–­11.8) .32 frequencies and percentages. For categorical variables, between-­ median (IQR) P25–­P75 group differences were calculated using the chi-­square test or Platelets (10e9/L), median 109 (76–­129) 114 (94–­161) .78 (IQR) P25–­P75 Fisher’s exact test when necessary. For quantitative variables, between-­group differences were analysed using student’s t-­test or INR, median (IQR) P25–­P75 1.69 (1.48–­1.98) 1.69 (1.50–­1.98) .92 the Mann–­Whitney U test, as appropriate. Infection-­free survival Creatinine (mg/dl), median 0.68 0.78 (0.6–­1.0) .92 (IQR) P25–­P75 (0.59–­0.84) and survival times were compared using the Kaplan–­Meier estimator and log-­rank test. All statistical analyses were performed using the Bilirubin (mg/dl), median 10.22 15.1 (9.4–­22.1) .32 (IQR) P25–­P75 (8.48–­22.5) IBM SPSS Statistics version 22 software package. Albumin (g/dl), median 2.6 (2.3–­3.0) 2.9 (2.4–­3.1) .13 (IQR) P25–­P75 Abbreviations: IQR, interquartile range, P25–­P75, percentile 25–­75. 3 | R E S U LT S 3.1 | Characteristics of patients Proven infection was defined in the following cases: sponta- neous bacteraemia (SB) with positive cultures in the absence of an- Twenty-­seven patients were assessed for eligibility, and six of them other septic focus, catheter-­related bloodstream infection (CRBSI) were excluded for different reasons, mainly owing to the presence with positive culture, spontaneous bacterial peritonitis (SBP) with of infection at admission and the lack of histological confirma- a polymorphonuclear count in ascitic fluid >250/mm3 regardless of tion (Figure 1). Finally, 21 patients were included in the study and the result of ascitic fluid culture, urinary tract infection (UTI), signs/ matched by age and MELD to the study cohort. Patients in the two symptoms of infections, >20 leucocytes per field or positive urine groups showed similar baseline characteristics; the proportion of culture, respiratory infection or pneumonia as defined by clinical cri- males in the treatment cohort was slightly higher than the control teria or compatible chest radiography, cellulitis or other infections cohort (76.2% vs. 66.7%, p = .43). At admission, 2 out of 21 (9.5%) based on clinical criteria. patients in the rifaximin group and 4 of 42 (9.5%) in the control group presented hepatic encephalopathy. Patients in the control cohort exhibited higher bilirubin and creatinine levels without clinical or 2.3 | Objectives of the study statistically significant differences (Table 1). The primary aim was to investigate whether the administration of rifaximin as an adjuvant treatment to corticosteroids decreases the 3.2 | Clinical outcomes number of bacterial infections from baseline to 90 days in patients with severe AH compared to a control cohort. The secondary ob- 3.2.1 | Effects of treatment on infections jective was to investigate whether the add-­on of rifaximin to the standard therapy could result in the following: (a) decrease in the Six infections were reported in the rifaximin group and 26 in the incidence of liver-­related complications (non-­infectious complica- control group. Therefore, the mean number of infections per pa- tions), (b) decrease in the 28-­and 90-­day mortality, c) improvement tient was 0.29 in the rifaximin group, while it was 0.62 in the con- of bilirubin levels and MELD scores at 7, 30, 60 and 90 days and d) trol group (p = .049). The number of de novo infections was lower improvement of the response to corticosteroids assessed by the Lille in the rifaximin group than in the control group. In the rifaximin score. group, 4 out of 21 patients (19%) developed at least one infection 1114 | JIMÉNEZ et al. throughout the 90-­day follow-­up period, whereas in the control ACLF grade (from grade II to III). All cases were successfully treated, group, up to 18 out of 42 developed an infection (42.9%) (p = .061). and none of these patients died owing to infection. Twenty-­six infec- Six infections were reported in four patients within the rifaximin tions were reported in 18 patients in the control cohort. The most cohort. The infections included two SBPs, one CRBSI, one urinary frequent infection type was UTI (n = 7), followed by spontaneous bac- tract infection, one pneumonia and one case of cellulitis. Regarding teraemia (n = 6) and five cases of SBP and pneumonia. Remarkably, severity, in the rifaximin group, only one infection (16.6%) progressed 8 out of 26 infections (30%) progressed to sepsis, 2 sepsis resolved to sepsis (CRBSI caused by Candida albicans) and caused worsening of without further complications, while 6 developed ACLF (Table 2). TA B L E 2 Infections in the rifaximin and control groups Number of Death by Patient number infections Description (microorganisms) Sepsis ACLF infection Rifaximin group 1 1 pneumonia (S. marcescens + K. oxytoca) No No N 11 1 cellulitis (unknown) No No N a 12 3 SBP (C. albicans) Yes Yes No UTIb (C. albicans) CRBSIc (K. oxytoca + E. faecium) 15 1 SBPa (S. viridans) No No No Control group 3 1 SBPa (E. faecium) Yes Yes No 5 1 pyelonephritis (K. pneumoniae) No Yes No 9 2 pneumonia (P. jirovecii) Yes Yes Yes SBPa (E. faecium) 14 1 SBd (gram [−] bacillus) No No No 16 2 SBd (S. epidermidis + C. perfringens) Yes Yes Yes pneumonia (C. albicans) 17 1 pneumonia (unknown) Yes Yes Yes 19 1 colitis (C. difficile + vancomycin-­resistant No No No Staphylococcus aureus) 20 1 SBd (E. coli) No No No 21 2 colitis (Enterococcus sp.) No Yes No b UTI (C. albicans) 26 1 prostatitis (E. coli) Yes No No b 30 2 UTI (E. coli) Yes No No SBd (S. aureus) 31 1 UTIb (E. cloacae) No No No 35 1 UTIb (K. oxytoca + E. coli) No No No 37 1 SBPa (unknown) No Yes No 38 2 pneumonia (P. jirovecii) Yes Yes Yes a SBP (E. faecium) 39 2 SBd (gram [−] bacillus) No No No b UTI (E. coli) 40 3 SBd (E. faecium) Yes Yes Yes pneumonia (P. jirovecii) SBPa (unknown) 41 1 cellulitis (unknown) No No No a Spontaneous bacterial peritonitis. b Urinary tract infections. c Catheter-­related bloodstream infections. d Spontaneous bacteraemia. JIMÉNEZ et al. | 1115 In the control group cohort, seven patients developed ‘de novo’ 3.2.3 | Impact of treatment on liver function tests ACLF in addition to infection, and two patients showed worsening in the grade of the previous ACLF owing to infection, while in the The mean bilirubin levels and MELD scores at baseline and 7, 30, rifaximin group, no patient developed “de novo” ACLF in addition 60 and 90 days were compared between groups, and statistically to infection (0 vs. 7 p = .047) and only one patient presented with significant differences were only observed in bilirubin levels at day a worsening grade of ACLF during infection. Therefore, the total 60 between the rifaximin and control groups (p = .023). The changes number of ACLF events related to infections was one versus nine in bilirubin levels and MELD scores during the follow-­up at 7, 30, 60 (p = .81) (Table 2). and 90 days are shown in Figure 3. Finally, we assessed the corticos- At 90 days, the mean infection-­free survival time was higher in teroid response using the Lille score in the rifaximin group and found the treatment group; it was 70.6 days (71%) in the rifaximin group that 76% were responders (16/21), while in the control group, we versus 57.1 days (50%) in the control group, but the difference was found 61% of responders (26/42); the differences between groups not statistically significant (p = .12) (Figure 2). were not significant. 3.2.2 | Effects of treatment in liver-­related 3.3 | Mortality complications Three out of 21 patients (14.2%) died during follow-­u p in the During follow-­up, nine non-­infectious complications were reported rifaximin group as follows: one patient died owing to a brain in five patients (23.8%) within the rifaximin group. In the control haematoma related to lymphoma, another patient died owing group, 53 non-­infectious complications were reported in 23 patients to ACLF related to severe AH and the last patient committed (54.7%). The total number of complications per patient in the treat- suicide. ment group was 0.43, while the number of complications per patient In the control group, 13 out of 42 patients (30.9%) died in the control group was 1.26. (p = .010). during follow-­u p, as follows: 11 patients from ACLF (nine de- The most frequent non-­infectious complication within the ri- veloped de novo ACLF), another patient died of massive diges- faximin group was ascites (n = 3), representing one-­t hird of the tive bleeding and the last one died of liver failure without ACLF complications. Only one patient in the rifaximin group developed criteria (Table 3). Remarkably, eight patients from the control a ‘de novo’ ACLF not linked to an infectious episode, and only one group who died had a previous infection (in five, infection-­ patient developed mild hepatic encephalopathy. In the control triggered ACLF resulted in death), while no one died in the group, hepatic encephalopathy was the most frequent complica- rifaximin group owing to a secondary infection. Liver-­r elated tion (n = 14), representing 26.4% of the complications, followed mortality (excluding suicide) was higher in the control group by the development of ACLF (n = 10), representing 18.8%. Only (13 vs. 2) (p = .060). one patient from the rifaximin group presented with gastrointesti- The mean actuarial survival at 90 days was 80.7 days in the nal bleeding, while six patients from the control cohort presented treatment group and 71.7 days in the control group, without sig- with gastrointestinal bleeding. (Table 3). Finally, no effects on al- nificant differences; survival rates were 85.7% in the treatment cohol abstinence during follow-­u p were observed between the group versus 60% in the control group (p = .15) (Figure 4). There groups. were also no significant differences in mean liver transplantation-­ free survival. 3.4 | Adverse effects of rifaximin A total of 25 adverse events were reported in 14 patients. Eleven were serious adverse events (SAEs). However, none of the SAEs were considered to be related to the use of rifaximin. Of the re- maining 14 non-­s erious adverse events, only five adverse events in four patients were related to rifaximin. Four adverse events were recorded as possibly related (mild mesogastric pain, mild pruritus, moderate diarrhoea and moderate hyponatraemia), and the other was unlikely to be related to rifaximin (moderate ab- dominal wall haematoma). There was ‘restitutio ad integrum’ in the five cases, and rifaximin was not discontinued in any case F I G U R E 2 Infection-­free survival in the rifaximin and control groups (p = .12) (Table 4). 1116 | JIMÉNEZ et al. TA B L E 3 Non-­infectious liver complications developed during follow-­up and deaths in the rifaximin and control groups ACLF Non-­infectious liver complications developed Number of Patient number ACLF at admission resolution during follow-­up complications Death Rifaximin group 1 No No 0 Yes 6 No Gastrointestinal bleeding. ACLF 2 (Liver and 3 Yes cerebral). 12 ACLF 2 (Liver and coagulation) no Progressed to ACLF 3a for renal failure. Mild HE 2 No 13 No Ascites 1 No 14 No No 0 Yes 15 ACLF 1 (Liver failure) Yes Ascites 1 No 18 No Ascites. Acute kidney injury 2 No Control group 1 ACLF 2 (Liver and renal) No Ascites. Mild HE 2 No (OLT) 2 No ACLF 2 (Liver and coagulation). Gastrointestinal 3 Yes bleeding 3 No Mild HE. ACLF 2 (Liver and kidney) 3 Yes 4 No Gastrointestinal bleeding (massive). Acute kidney 2 Yes injury 5 ACLF 2 (Liver and coagulation) No Progressed to ACLF 3b for cerebral and renal 2 Yes failure) 6 No Gastrointestinal bleeding. Mild HE. ACLF 1 (Liver 3 Yes failure) 8 ACLF 2 (Liver and renal) Yes No 0 Yes 9 No Ascites. ACLF 3 (Renal, respiratory and cerebral) 4 Yes 10 No Severe HE 1 No 16 No ACLF 2 (Liver and respiratory) 2 Yes 17 No ACLF 3a (Liver, respiratory and cerebral) 3 Yes 18 No Mild HE. Ascites 2 No 20 No ACLF 1 (renal) 1 No 21 ACLF 1 (liver) No Progressed to ACLF 2 for renal failure 1 No (OLT) 27 No Ascites 1 No 30 ACLF 1 (liver) Yes Severe HE 1 No 32 No Severe HE 1 No 33 No Mild HE. Gastrointestinal bleeding. Ascites 3 No 36 ACLF 2 (Liver and renal) No Ascites. Mild HE. Gastrointestinal bleeding 3 Yes 37 No ACLF 2 (Liver and renal failure) 2 Yes 38 No Ascites. ACLF 3a (Liver, Renal and cerebral) 4 Yes 39 No Ascites 1 No 40 No Ascites. Gastrointestinal bleeding. ACLF 3b 6 Yes (Liver, renal, respiratory and circulatory) 41 No Mild HE. Ascites 2 No Abbreviations: ACLF, acute-­on-­chronic liver failure; HE, hepatic encephalopathy; OLT, orthotopic liver transplantation. 4 | DISCUSSION infection at 28 days was found to be 20%, 2 and whether the ad- ministration of corticosteroids played a role in the development Intestinal bacterial overgrowth and dysbiosis are key factors in the of infection was unclear. No differences were documented in this pathogenesis of AH. These events are directly related to an increase meta-­analysis between patients who received corticosteroid ther- in bacterial translocation, leading to infections, systemic inflamma- apy and those who did not. In contrast, the STOPAH trial associ- tion and vasodilation.17 The development of infections in patients ated the administration of corticosteroids with a higher incidence with severe AH is common. In a meta-­analysis, the incidence of of infections.16 JIMÉNEZ et al. | 1117 systemic antibiotics (amoxicillin-­clavulanic acid) showed negative results. 21 In the present pilot study, the administration of rifaximin was associated with a lower number of infections, liver-­related compli- cations and mortality rates compared to a prospectively collected cohort. Even though the study was underpowered by the sample size, the expected decrease of infections within the rifaximin group was achieved. Remarkably, only one infection was linked with bacterial translocation (SBP caused by Enterococcus faecium) in the rifaximin group (21 patients). In contrast, 10 infections related to bacterial translocation were recorded in the control group (five SBP, four cases of SB and one case of colitis caused by Clostridium difficile). These results support the hypothesis that rifaximin prevents the translocation of bacteria from the gastrointestinal tract in patients with AH.11,20 Another relevant finding was the lower significant number of non-­infectious complications (including ACLF) per patient in the ri- faximin group. This evidence supports the hypothesis that rifaximin could exert other beneficial effects in addition to its antimicrobial effects, as previously described. 20,22–­24 In fact, alcohol exerts direct toxicity on the liver and promotes intestinal dysbiosis, which favours liver dysfunction. 25 Alcohol changes the composition and biodiver- sity of normal flora, which increases the levels of lipopolysaccha- ride and other toxic substances, leading to an increase in intestinal permeability. 26,27 These changes promote bacterial infections in the F I G U R E 3 Bilirubin levels and MELD scores during the follow-­ liver, thereby causing a PAMP-­mediated response that facilitates up (baseline, 7, 30, 60 and 90 days). (A) Differences in the levels SIRS associated with AH. 28 Rifaximin might act on the SIRS asso- of bilirubin in the rifaximin and control groups at 60 days were ciated with severe AH and cirrhosis via the modulation of metabi- observed. (B) No differences in MELD score during the follow-­up; ome, 29 prevention of bacterial translocation and endotoxaemia.30,31 MELD, model for end-­stage liver disease The high risk of infection during the time course of severe AH has been confirmed in several studies; moreover, the infection in severe AH predicts and acts as a trigger to develop ACLF.32 A limitation of the study was the low number of included pa- tients, i.e., the anticipated sample size was not reached because the rigorous inclusion and exclusion criteria complicated the recruitment process. Another limitation was the comparison with a historical co- hort of patients from other countries. The susceptibility to infections among groups may differ according to the geographical epidemiol- ogy and local policies on antibiotics. It is important to note that the control cohort was exclusively composed of patients from academic centres, and the source of admission was the emergency room, as for the study group.33,34 All these factors might have impacted the clinical relevance of the findings reported in this paper. In summary, in this pilot study, the use of rifaximin as an add-­on F I G U R E 4 Actuarial survival in the rifaximin and control groups (p = .15) therapy to standard therapy for severe AH was associated with a lower number of infections, liver-­related complications and a trend towards lower ACLF and mortality rates. The rifaximin add-­on ther- Based on current evidence, targeting the microbiota seems to be apy also led to an improvement in biochemical markers (bilirubin and a good strategy for the prevention of infections during AH episodes. MELD). Thus, to test our hypothesis, we selected rifaximin, a non-­absorbable The promising results obtained suggest that further larger stud- antibiotic,18,19 whose impact on the microbiota has proven use- ies are warranted to validate intestinal decontamination in severe ful in patients with chronic liver disease.8,10,20 Other studies using AH. 1118 | JIMÉNEZ et al. TA B L E 4 Adverse events in the Grade rifaximin group Adverse events Serious (1–­4) Causality Recovered Right upper extremity paresis Yes 2 No No Epileptic crisis Yes 3 No No Epileptic status Yes 3 No No Cerebral vasculitis versus brain lymphoma Yes 4 No No Suspected pancreatic cancer Yes 4 No No Bronchoaspiration Yes 3 No No Rectal ulcer Yes 4 No No Laryngeal neoplasia Yes 4 No No Breast cancer Yes 4 No No Suicide Yes 4 No No Acute pancreatitis grade A Yes 1 No Yes Pleural effusion No 2 No Yes Hypoglycaemia No 1 No Yes Epidermoid cyst No 1 No Yes Hand burn No 2 No Yes Constipation (two patients No 1 No Yes Hyperglycaemia (two patients) No 2 No Yes Vomiting No 1 No Yes Pruritus No 1 Possible Yes Hyponatraemia No 2 Possible Yes Abdominal wall haematoma No 2 Unlikely Yes Diarrhoea No 2 Possible Yes Mesogastrium pain No 1 Possible Yes 5 | CO N C LU S I O N S contributions to this study. Finally, we thank all the members of the INTEAM consortium for providing the clinical data of the control In this pilot study, the use of rifaximin in patients with severe AH group. was proven to be safe. There was an improvement in liver function tests and a significant decrease in liver-­related complications com- C O N FL I C T O F I N T E R E S T pared with the controls. There was also a lower number of infections BS has been consulting for the Ferring Research Institute, and ACLF in patients treated with rifaximin. The observed effects Gelesis, HOST Therabiomics, Intercept Pharmaceuticals, Mabwell may support the use of rifaximin in these patients and justify further Therapeutics, Patara Pharmaceuticals and Takeda. BS’s institution UC studies in this field. San Diego has received research support from Axial Biotherapeutics, BiomX, CymaBay Therapeutics, NGM Biopharmaceuticals, Prodigy Biotech and Synlogic Operating Company. BS is a founder of Nterica S T U D I E S ’ R EG I S TRY/C LI N I ​C A LTR I​ A L S .G OV Bio. UC San Diego has registered several patents with BS as an in- I D E NTI FI E R ventor related to this work. DS has performed consultancy, deliv- ered paid lectures and is taking part in two investigator-­initiated Effects of Rifaximin in Severe Alcoholic Hepatitis: A Pilot Study studies (REEFSYS and EMITTIC) funded by Alfasigma/Norgine, who (RIFA-­AH), NCT02116556. Integrated approaches for identifying manufacture rifaximin. molecular targets in alcoholic hepatitis, NCT02075918. EudraCT: 2010–­0 00515-­8 0. E T H I C S A P P R OVA L S TAT E M E N T This study was approved by the local Ethics Committee for Clinical AC K N OW L E D G E M E N T S Research (CEIC) of the Vall d’Hebron University Hospital as a refer- The authors wish to acknowledge the late Dr. Juan Cordoba, who ence centre. designed the study and also appreciate his outstanding professional The consent form was obtained from each patient, freely and work and research contribution in liver diseases. We would like to voluntarily to participate in a particular clinical trial, after having thank all the patients and study teams for their participation and been informed of all aspects of the clinical trial which are relevant to JIMÉNEZ et al. | 1119 8. Ginés P, Rimola A, Planas R, et al. Norfloxacin prevents spontaneous the subject’s decision to participate. 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