Introduction

Hepatic encephalopathy (HE) is a potentially reversible neurocognitive syndrome that occurs in patients with acute or chronic liver disease [1]. It is the third most serious complication of decompensated liver cirrhosis, affecting at least 30% of cirrhotic patients. HE manifests as a wide spectrum of neuropsychiatric abnormalities, from subclinical changes (mild cognitive impairment) to marked disorientation, confusion, coma and even death in the worst scenarios [2]. The impaired quality of life of patients together with the morbidity and mortality of this syndrome impose a significant economic burden on caregivers and the healthcare system [3].

According to the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL), HE should be classified taking into account four factors: (1) underlying disease: type A resulting from acute liver failure (ALF), type B resulting predominantly from portosystemic bypass or shunting or type C resulting from cirrhosis; (2) severity of manifestations: including minimal HE (mHE) and grade 1 (covert HE) and grade 2–4 (overt HE) according to West Haven Criteria; (3) time course: episodic (1 episode of HE in 6 months), recurrent (2 or more HE episodes in 6 months), or persistent (denotes a pattern of behavioral alterations that are always present); and (4) precipitating factors: nonprecipitated or precipitated [4].

The pathophysiology of HE remains incompletely understood; however, ammonia has historically been considered to be the major contributor to HE development. Ammonia is primarily produced in the gut as an end product of protein digestion, amino acid deamination and bacterial urease activity. Under physiological conditions, it is mainly regulated by an intact urea cycle, maintaining blood ammonia levels at a safe concentration below 50 μM [5]. Under pathological conditions, as in liver diseases, ammonia exerts its deleterious effects through multiple pathways, including inflammation, pH alteration, oxidative stress, mitochondrial dysfunction, disruption of cellular bioenergetics, and alterations in membrane potential, affecting normal brain function [2]. For these reasons, most of the therapies for HE aim to reduce ammonia production and prevent ammonia absorption from the gut.

Systemic inflammation is another important player in the pathogenesis of HE. In animal models, it has been demonstrated that hyperammonemia per se induces peripheral inflammation [6]. The synergistic action of ammonia and inflammation exacerbates many of their effects on brain function [7]. In addition, hyperammonemia also exacerbates the deleterious effects of inflammation of other origins (the inflamed liver, infections or bacterial translocation), for example, by increasing oxidative stress and sensitivity to LPS [7,8,9].

Similarly, gut dysbiosis also plays a pathogenic role in HE, particularly in advanced stages of liver disease. This dysbiosis is mainly characterized by an overgrowth of some potentially pathogenic bacteria, including Enterococcaceae, Staphylococcaceae, and Enterobacteriaceae, together with reduced amounts of some beneficial autochthonous bacteria, such as Lachnospiraceae, Ruminococcaceae, and Clostridiales XIV [10,11,12]. These changes could contribute to bacterial translocation and an increased risk of infections, which may result in faster disease progression and poor survival, especially in patients with advanced cirrhosis [13].

Currently, two agents are being mostly used as treatments for HE: lactulose and rifaximin. Lactulose is a non-absorbable synthetic disaccharide made up of galactose and fructose. Its conversion to short-chain organic acids by gut bacteria results in reduced colonic pH that inhibits the proliferation of colonic bacteria and ammonia production. An acidic environment, on the one hand, destroys urease-producing bacteria involved in the production of ammonia [14] and, on the other hand, may also facilitate ammonia absorption, promoting the conversion of ammonia (NH3) to ammonium (NH4+) [3]. A meta-analysis including descriptive information from 38 randomized clinical trials with 1828 participants and quantitative data from 34 randomized clinical trials with 1764 participants revealed that treatment with non-absorbable disaccharides (including lactulose and lactitol) reduced mortality in patients with overt HE and decreased the risk of developing HE in the longer term compared to placebo/no intervention groups [15, 16].

Rifaximin is a non-absorbable antibiotic that acts on gut bacteria and results in decreased ammonia production. Currently, it is the only agent from this family that is approved for HE treatment. A recent systematic review involving 28 randomized clinical trials and 2979 patients with HE compared rifaximin treatment vs. placebo or other active drugs (non-absorbable disaccharides, other antibiotics, l-ornithine-l-aspartate (LOLA) and probiotics) [17]. The authors observed that rifaximin had a significant beneficial effect on the improvement of overt HE, reversal of MHE and prevention of recurrent HE compared to placebo [17]. These results agree with a previous meta-analysis including 19 randomized controlled trials with 1370 patients on rifaximin for HE [18].

Many other drugs, including branched-chain amino acids (BCAAs), LOLA, probiotics, glutaminase inhibitors and other antibiotics, have been used for the treatment of HE, but data to support their use are limited, preliminary or lacking. [4]. Similar conclusions can be drawn for a small number of drugs, so‐called ‘ammonia scavengers’, historically developed for their use in urea cycle disorders. These agents have been observed to decrease ammonia concentrations by serving as alternatives to urea for the excretion of waste nitrogen [19, 20]. Drugs that specifically target ammonia include sodium benzoate, glycerol phenylbutyrate, ornithine phenylacetate, AST-120, and polyethylene glycol.

In 2019, a comprehensive systematic review published in the Cochrane Database of Systematic Reviews evaluated the efficacy and harmful effects of these ammonia-scavenging drugs versus placebo, no intervention, or other active interventions for the prevention and treatment of HE in people with cirrhosis. They included three trials evaluating sodium benzoate [21,22,23], one trial evaluating glycerol phenylbutyrate [24], two trials evaluating ornithine phenylacetate [25, 26], two trials evaluating oral AST‐120 [27, 28] and three trials evaluating polyethylene glycol [29,30,31]. The authors concluded that all these agents lowered blood ammonia levels when compared to placebo, but none of the drugs lowered the blood ammonia levels when compared to a non‐absorbable disaccharide. Additionally, none of the drugs appeared to affect the risk of death and did not have any notable adverse effects [19].

Current practice guidelines published by AASLD and EASL recommend the use of lactulose as the first choice for the treatment of episodic HE and for the prevention of recurrent episodes of HE after the initial episode [4]. Rifaximin is recommended as an effective add-on to lactulose for the prevention of overt HE recurrence after the second episode [4]. Rifaximin alone has been successfully tested in animal models [32, 33], but no solid data exist in patients. Intravenous LOLA and oral BCAAs can be used as alternative or additional agents to treat patients nonresponsive to conventional therapy [4].

However, in addition to the numerous clinical trials demonstrating the efficacy of these drugs, HE remains a multifactorial condition, and more efforts are needed to treat any aspect of this syndrome. For example, it is still unclear how the liver affects brain homeostasis, which alterations in intestinal and microbiome functions affect normal liver functioning and which brain functions are particularly vulnerable to these events. Therefore, the research fields into pathophysiology and clinical management should remain in close contact.

In the last five years (January 2017-August 2022), only seven clinical trials have been completed (Table 1). Five of them tested old treatments such as rifaximin, lactulose, BCAAs and ornithine phenylacetate. Unfortunately, only one of them has already published their results, which is in line with previous reports [34]. The remaining two trials assessed the efficacy of new treatments: oral fecal transplant and albumin. The first study (NCT03152188) is a phase I trial determining the safety of fecal microbial transplant (FMT) capsules in HE. It was a randomized, single-blind, placebo-controlled clinical trial including 20 participants, and the obtained results were positive [35]. The second study (NCT03585257) is a phase II, double-blind, placebo-controlled randomized clinical trial assessing the impact of albumin on MHE and quality of life in individuals with prior HE already on standard of care. This study enrolled 48 participants, and the authors observed improved cognitive function and psychosocial quality of life in treated patients [36].

Table 1 Overview of completed clinical trials in HE during the last five years
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Currently, many of the aforementioned agents are still under the magnifying glass of clinical trials as well as some derivatives of these therapies, together with some potential new drugs.

This review aims to provide an overview and discussion of the current development of treatments in HE based on active clinical trials registered on the ClinicalTrials.gov website and to obtain new evidence about the management of this condition and the development of potential new therapeutic options for the future.

Methods

Data Collection

Data from ongoing clinical trials in HE were obtained from ClinicalTrials.gov. ClinicalTrials.gov is a database of privately and publicly funded clinical studies conducted around the world. To date, it includes over 420,000 trials conducted in 221 countries. The website is maintained by the National Library of Medicine (NLM) at the National Institutes of Health (NIH). Information on ClinicalTrials.gov is provided and updated by the sponsor or principal investigator of the clinical study [37]. On August 19th, 2022, all active HE drug trials were downloaded from ClinicalTrials.gov using the following search parameters:

  • Condition: Hepatic encephalopathy

  • Study type: Interventional

  • Phase: Early phase I, phase I, phase II, phase III and phase IV

  • Status parameter: “Recruiting”, “Not yet recruiting”, “Active, not recruiting”, or “Enrolling by invitation”.

The search produced 18 trials. One of them was excluded because it was not considered a potential intervention to treat HE. The remaining 17 trials and 23 resulting agents were classified into two different categories: “class of drugs” and “clinical trial’s phase”.

Trial Categorization by Class of Drug

  • Antimicrobials: agents used to prevent and treat infections. They include antibiotics, antivirals, antifungals and antiparasitics.

  • Microbiome restoration therapies (MRT): strategies aimed at restoring the gut microbiome.

  • Osmotic laxatives: medications that draw water into the stool, resulting in softer stools and more frequent, easier to pass bowel movements.

  • Other: It was assigned to agents whose category did not match with any of the above class of drugs.

Trial Categorization by Clinical Trial Phase

Each clinical trial was also categorized as phase I, II, III and IV, according to the stage of the clinical trial. “Early Phase I” and “Phase II” trials were grouped together, and those listed as Phase I/II or Phase II/III were classified as Phase I and Phase II, respectively.

Results

World Distribution of Active Clinical Trials in Hepatic Encephalopathy

On August 19th, 2022, a dataset of 18 interventional clinical trials was downloaded from the ClinicalTrials.gov website. One trial (NCT05070351) was excluded because it aimed to collect evidence to de-prescribe proton pump inhibitors to reduce the risk of HE after transjugular intrahepatic portosystemic shunt (TIPS) creation; thus, it was not considered a potential intervention to treat HE. Of the remaining 17 trials, 11 were distributed in North America (all in the USA), 2 in Europe (1 in Belgium, 1 in the Netherlands), 2 in Africa (both in Egypt), 1 in South Asia (Pakistan) and 1 in East Asia (China) (Table 2). The full list is available in supplementary file 1.

Table 2 Overview of current active clinical trials in HE
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Results from Trial Categorization by Class of Drug

The remaining 17 trials are currently testing 23 agents that were classified into four different categories based on their characteristics: antimicrobial, MRT, osmotic laxatives and other (Fig. 1A).

Fig. 1
figure 1

Percentage of active interventional studies classified by class of drug (A) or phase of clinical trial (B)

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Antimicrobial drugs included all agents used to prevent and treat infections, such as antibiotics, antivirals, antifungals and antiparasitics. These agents were the most abundant (39.1% of the total agents), and they included rifaximin, a nonabsorbable antibiotic that was FDA approved in 2010 to treat patients with HE (tested in 6 trials); rifamycin, a gut-specific antibiotic that has been FDA approved for the treatment of traveller's diarrhea (1 trial); nitazoxanide, an antiprotozoal agent approved by the FDA for the treatment of some types of diarrhea (1 trial); and colistin, the last-line antibiotic against gram-negative pathogens (1 trial).

MRT was the second most abundant class of drugs (26.1% of total agents). It encompasses a group of agents aimed at restoring gut microbiome function and composition. This category includes but is not limited to probiotics, prebiotics, and FMT. FMT is the transfer of fecal material from a donor into the intestinal tract of a recipient to directly change the recipient’s gut microbial composition and confer a health benefit. It was the most commonly used strategy (enema or capsule), being tested in 3 different trials, followed by VE303, a bacterial consortium (1 trial) and RBX7455, a preparation of live intestinal microorganisms (1 trial), both developed for high-risk Clostridioides difficile infection.

Osmotic laxatives draw water into the stool, resulting in softer stools and more frequent, easier-to-pass bowel movements. This class of agents contains 21,7% of total agents and includes lactulose (used in 4 trials), a non-absorbable disaccharide widely used in HE, and polyethylene glycol (PEG), an emerging solution suggested to be a valid alternative to lactulose in HE (1 trial).

Finally, under the “other” category, there were 3 agents (13.1% of remaining drugs) that did not match with any of the above classes of drugs. It contains methylprednisolone (used in 1 trial), an FDA-approved corticosteroid hormone for the management and treatment of allergic conditions, arthritis, asthma and acute exacerbation of multiple sclerosis; equine anti-thymocyte globulin (eATG), an immunosuppressive drug indicated for management of allograft rejection in renal transplant patients and treatment of moderate to severe aplastic anemia; and traditional Chinese medicine (TCM), an alternative medical practice drawn from traditional medicine in China, including acupuncture, diet, herbal therapy, meditation, physical exercise and massage.

Results from Trial Categorization by Clinical Trial Phase

Phase I (including early phase I, phase I and phase I/II) was the smallest set of clinical trials at 11.8% (Fig. 1B), with 4 agents employed in only two trials (Fig. 2). At this stage, colistin, FMT (in two different formulations: capsule vs enema) and lactulose are tested.

Fig. 2
figure 2

Schematic view of all agents active in phase I, phase II, phase III or phase IV trials for HE

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In contrast, phase II comprised the largest number of clinical trials in this review (41.2% of the total number of trials, including 7 studies and 8 agents; Fig. 2B). Phase II trials represented a broad range of different therapeutic approaches, since every category was represented (Fig. 2). In fact, at this stage ryfamicin (antimicrobial), FMT, VE303 and RBX7455 (MRT), lactulose (osmotic laxative) and methylprednisolone and eATG (other) are tested.

Of the active trials registered on clinicaltrials.gov, 34.7% of trials (and 6 agents) were listed as Phase III. It includes 2 antimicrobial agents, such as nitazoxanide and rifaximin (with two different formulations: tablets and soluble solid dispersion (SSD) tablets), and one agent under the “other” category (TCM) (Fig. 2).

Finally, under the Phase IV category (17.6% of total trials), 6 agents were listed, including 2 studies involving rifaximin (antimicrobials), 2 studies involving lactulose and one study involving polyethylene glycol (osmotic laxative) (Fig. 2).

Discussion

Based on information obtained by the clinicaltrials.gov platform, on August 19th, 2022, there were 17 active clinical trials in HE aiming to obtain more evidence about the safety and efficacy of well-known and already used agents but also to explore new possibilities in the management of this syndrome. In relation to the obtained results and according to the current knowledge of the condition, this report allows us to add some interesting considerations to the actual state of art of the syndrome.

First, based on the geographical distribution of the clinical trials, at least one nation of each continent (with the exception of Oceania) is realizing an interventional study in patients with HE. In fact, there are currently 11 ongoing clinical trials in the USA, 1 in Belgium, 1 in the Netherlands, 2 in Egypt, 1 in Pakistan and 1 in China. These results are in agreement with the incidence and prevalence of liver diseases observed in such countries. For example, Egypt had the highest age-standardized death rate of cirrhosis in all years from 1990 to 2017, despite a 22.4% decrease from 1990 (133.1 per 100,000 population) to 2017 (103.3 per 100,000 population) [38]. In 2017, 41.5% of deaths due to cirrhosis in Egypt were caused by hepatitis B and 34.4% (the highest worldwide death rate) were caused by hepatitis C [38]. Similarly, cirrhosis is one of most common causes of mortality or hospitalization in Pakistan, and most of these patients have evidence of hepatitis B (22%) or hepatitis C (28%) viral infection [39]. China also has a high age-standardized prevalence of people with compensated cirrhosis, summing to nearly 2000 cases per 100,000 inhabitants. Among high-income regions, the USA showed an unusual age pattern with an increase in cirrhosis deaths driven by alcohol-related liver disease in the 50–69 year age group from 1990 to 2017 [38].

Second, in relation to the analysis of trial categorization by clinical trial phase, it is surprising that phase I was the smallest set of clinical trials (11.8% of total studies), with four agents employed in only two trials. These numbers are probably a consequence of the COVID-19 pandemic, in which most studies and funding have been purposely prioritized for COVID-19 activities above all else. In fact, a recent long-term analysis suggests that the COVID-19 pandemic affected the initiation of clinical trials both in Europe and in the USA [40].

Phase II and phase III clinical trials were the most abundant categories, summing together 75,9% of total active studies and 14 agents. The purpose of a phase II and phase III clinical trial is to determine the right dosage and effectiveness in a larger number and in a wide variety of people who have the disease. In case of poor efficacy of treatment or unexpected serious adverse events, the permission to proceed to the next phase can be denied. In addition to the encouraging numbers in comparison with those observed in phase I, Phase II development remains the largest hurdle in drug development, showing the lowest transition success rate of the four phases. In fact, the overall success rate in phase II reported by the Biotechnology Innovation Organization (BIO) was approximately 31%, with a 36% success rate considering only the gastroenterology field [41]. Better numbers are expected in phase III, where the overall success rate is estimated to be approximately 58% (61% in gastroenterology) [41]. According to these statistics, 6 potential new drugs could reach phase IV.

Phase IV trials consist of clinical research conducted after a drug has been approved [42]. During this phase, the product can be tested in special patient populations, or further information about the risks, benefits and long-term effects can be collected. At this stage, 3 clinical trials and 5 agents were present. The first clinical trial (NCT04436601) will involve 102 participants and will compare the effect of PEG with lactulose for the treatment of HE in patients with liver cirrhosis. The investigators want to compare the resolution of HE as the main outcome. In addition, they would compare the length of stay, nonserious (mainly gastrointestinal) adverse events and 3 month outcome. This interventional study is based on investigators’ hypothesis that rapid purgation of the gut using PEG may resolve HE more effectively than lactulose. Previous phases of this clinical trial showed that PEG significantly decreased the time needed for resolution of HE and significantly shortened the hospital stay [31]. If confirmed, these data would add new evidence to the currently limited evidence on the use of PEG in the treatment of HE worldwide. In line with this hypothesis, a recent review suggests that PEG is able to improve the clinical efficacy of HE within 24 h better than lactulose and does not increase side effects [43]. Hence, PEG might be a useful alternative in 30% of those who do not respond to lactulose if favorable outcomes are demonstrated. The second study (NCT01846663) is a multicenter trial that aims to assess the pharmacokinetics of rifaximin in subjects with severe hepatic impairment and overt HE [44,45,46]. The third study (NCT04073290) is a multicenter, randomized, placebo-controlled, double-blind study involving patients undergoing elective transjugular intrahepatic portosystemic shunt (TIPS) placement for refractory ascites or secondary prophylaxis in variceal bleeding. Post-TIPS HE is a common (20–54%) and often severe complication [47]. The primary objective will be to assess the incidence of post-TIPS over HE within the first three months after prophylactic administration of lactulose and rifaximin versus placebo group. This clinical trial, involving 238 subjects, is estimated to be completed by September 2023, and the authors commit themselves to submit results for publication in a peer-reviewed journal [47].

Last but not least, the analysis of clinical trial categorization by class of drugs unveiled the presence of many old, few new and some borrowed agents already approved for the treatment of other pathologies.

Starting from the old drugs, lactulose and rifaximin are being used in 10 studies. In most cases, they are used as comparative drugs to test the efficacy and safety of new drugs. Notably, two studies (NCT05297448 and NCT05071716) involving 466 subjects each are randomized, double-blind, placebo-controlled, dose-ranging, multicenter studies to assess the efficacy and safety of rifaximin soluble solid dispersion (SSD) immediate release (IR) for the delay of encephalopathy decompensation in cirrhosis. Rifaximin is currently marketed as a 550 mg tablet, and SSD tablets were formulated to maximize the efficacy of rifaximin. Previous phase II clinical trials have shown that rifaximin SSD IR 40 mg may reduce hospitalization in patients with cirrhosis and shorten the duration of overt HE during hospitalization [48]. Among old drugs, TCM can also be included (NCT04073290). It is an alternative medical practice with a history of thousands of years. TCM has the advantages of low cost and high safety and modulates various biological activities, and it has been suggested to be effective in many liver conditions [49]. Currently, it is in phase III, and results are expected at the end of the year.

Among the borrowed agents, rifamycin SV MMX and nitazoxanide are antimicrobial agents that have been approved by the FDA for the treatment of some types of diarrhea [50, 51], and they are considered potential alternative therapies to rifaximin. Unlike rifaximin, rifamycin SV MMX mostly affects the colon, where the bacterial load is much larger than in the other parts of the gastrointestinal tract. This is achieved using a multimatrix structure (MMX), which creates a partially hydrophobic environment that hinders the penetration of aqueous fluids into the tablet core, thus lowering the rate of drug dissolution [52]. A recent phase I trial assessing the pharmacokinetics and safety of rifamycin SV MMX after single and multiple doses in 18 healthy subjects showed its safety and poor absorption, making this antibiotic suitable for small and large intestinal pathologies, including HE [53]. It is currently in phase II (NCT04082780), and it will be tested in cirrhotic patients with MHE. The results are expected in 2023. Encouraging results also came from nitazoxanide (NCT04161053), an antimicrobial agent that exerts its activity by interfering with the pyruvate ferredoxin/flavodoxin oxidoreductase-dependent electron transfer reaction, which is essential to anaerobic energy metabolism [54]. In fact, preliminary phase III data have shown a statistically significant improvement in CHESS score and mental status in addition to a significant reduction in Child score; additionally, nitazoxanide also showed a statistically significant decrease in serum ammonia, TNF-α, and octopamine levels compared to rifaximin [55]. In this category also belong VE303 (NCT04899115), a bacterial consortium, and RBX7455 (NCT04155099), a preparation of live intestinal microorganisms, both borrowed from high-risk Clostridioides difficile infection treatments and efficiently restore microbiome composition after antibiotic-induced dysbiosis. These two agents aim to safely and effectively improve cognitive function in patients with a history of overt HE by restoring microbiome composition and function, as documented in other studies [56].

As an emerging therapy for HE, colistin is an old antibiotic (new for HE) that became available for clinical use in the 1950 s, but it was largely shelved because of concerns about the potential for adverse effects, particularly nephrotoxicity [57]. It was resurrected in the 1990 s for use in cystic fibrosis patients, and it is now considered the last-line antibiotic against gram-negative pathogens. Its mechanism of action consists of solubilizing the bacterial cell membrane, resulting in a bactericidal effect [58]. Over the last decade, pharmacological and clinical interest in colistin has increased, and several conditions are testing it as a potential new treatment. As a new potential agent, it is currently in phase I (NCT05279586), and the efficacy and safety of colistin versus lactulose for secondary prophylaxis of overt HE will be tested in HE patients with liver cirrhosis.

Among the emerging therapies for HE, FMT is probably the most promising strategy. It has been demonstrated to be safe in HE [35] by possibly improving neurocognitive function and decreasing serious adverse events in HE patients by reducing ammonia synthesis and its clearance, reestablishing the integrity of the intestinal barrier and improving liver function [59]. FMT will be tested in 3 different trials (NCT03420482, NCT03796598, and NCT04932577) by two routes of administration (enema or capsule). Preliminary results from the first trial (NCT03420482) show that FMT capsules are safe and improve cognition in patients with a history of overt HE [60]. Similarly, preliminary data from the PROFIT trial have demonstrated that FMT is safe and feasible in patients with advanced stable cirrhosis, showing a striking reduction in plasma ammonia [61] and inflammation [62].

Lastly, an interventional, multicenter, three-arm, randomized, controlled trial (NCT04862221) launched this year aims to test immunosuppressive therapy for children with acute liver failure. The efficacy and safety of high doses of methylprednisolone (a widely used anti-inflammatory drug) or equine anti-thymocyte globulin (an immunosuppressive drug targeting a variety of lymphocyte surface proteins, activated B cells, bone marrow cells, and other cell types [63]) will be tested, and the survival rate will be determined. It is currently recruiting subjects, and results are expected in January 2026. If the positive outcomes are confirmed, it could also open new possibilities to treat HE or mHE patients with liver cirrhosis given that inflammation and immune response have been suggested to play a central role in the pathogenesis of HE, as demonstrated in patients and animal models [6, 8, 64,65,66]. Unfortunately, although many nonsteroidal anti-inflammatory drugs, such as ibuprofen or celecoxib, or anti-TNF-α inhibitors, including infliximab or etanercept, which have revolutionized the treatment of multiple inflammatory conditions, including rheumatoid arthritis, psoriasis and inflammatory bowel disease, have shown promising results in animal models of liver disease [6, 67,68,69,70], they have also been associated with different degrees of hepatotoxicity when tested in patients, including the reactivation of viral hepatitis, drug-induced liver injury and de novo autoimmune hepatitis [71,72,73]. Therefore, the fact that only two drugs belonging to this category have reached testing in humans indicates that more efforts are needed to reduce the enormous gap between these and the other and more classical drugs, which still dominate the pharmacological field in HE.

Conclusions

This review has provided a broad overview of the clinical interventional studies currently active in HE. There are currently 17 agents in four continents under the magnifying glass of clinical trials. Many of these drugs are old acquaintances in the field, such as lactulose and rifaximin, but there are also some interesting new entries, such as FMT and equine anti-thymocyte globulin, an immunosuppressive agent. Finally, the results also highlighted the presence of some therapies borrowed from other conditions, such as rifamycin SV MMX and nitazoxanide, two antimicrobial agents FDA approved for the treatment of some types of diarrhea, or VE303 and RBX7455, two microbiome restoration therapies currently used for the treatment of high-risk Clostridioides difficile infections. If working these “borrowed” agents, they could be used as valid alternatives to current therapies when they are ineffective.