Rifaximin in hepatic encephalopathy: More than just a ... - CyberLeninka

International Hepatology

Rifaximin in hepatic encephalopathy: More than just a non-absorbable antibiotic? Rajiv Jalan* Institute of Hepatology, 69–75 Chenies Mews, University College London, London WC1E 6HX, UK

COMMENTARY ON: Rifaximin Treatment in hepatic encephalopathy. Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, Sigal S, Sheikh MY, Beavers K, Frederick T, Teperman L, Hillebrand D, Huang S, Merchant K, Shaw A, Bortey E, Forbes WP. New E J Med 2010;362:1071– 108. Copyright 2010. Abstract reprinted with permission from Massachusetts Medical Society. All rights reserved. www.ncbi.nlm.nih.gov/pubmed/20335583 Abstract: Background. Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis. The efficacy of Rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute hepatic encephalopathy, but its efficacy for prevention of the disease has not been established. Methods. In this randomized, double-blind, placebo-controlled trial, we randomly assigned 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease to receive either Rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy. The key secondary end point was the time to the first hospitalisation involving hepatic encephalopathy. Results. Rifaximin significantly reduced the risk of an episode of hepatic encephalopathy, as compared with placebo, over a 6-month period (hazard ratio with Rifaximin, 0.42; 95% confidence interval [CI], 0.28–0.64; P < 0.001). A breakthrough episode of hepatic encephalopathy occurred in 22.1% of patients in the Rifaximin group, as compared with 45.9% of patients in the placebo group. A total of 13.6% of the patients in the Rifaximin group had a hospitalization involving hepatic encephalopathy, as compared with 22.6% of patients in the placebo group, for a hazard ratio of 0.50 (95% CI, 0.29–0.87; P = 0.01). More than 90% of patients received concomitant Lactulose therapy. The incidence of adverse events reported during the study was similar in the two groups, as was the incidence of serious adverse events. Conclusions. Over a 6-month period, treatment with Rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy. (ClinicalTrials.gov number, NCT00298038). Ó 2010 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. Keywords: Hepatic Encephalopathy; Ammonia; Inflammation; Rifaximin; Norfloxacin. Received 2 May 2010; accepted 5 May 2010 * Corresponding author. Tel.: +44 2076796552; fax: +44 2073800405. E-mail address: [email protected] (R. Jalan).

Hepatic Encephalopathy (HE) is a complex neuropsychiatric syndrome that occurs in patients with liver disease [1]. Its manifestations can vary widely from mild neurocognitive disturbances to severe confusion and coma. In acute liver failure, the hallmark of HE is an increase in intracranial pressure which can result in death from cerebral herniation. In patients with cirrhosis, up to 70% of patients in some series have evidence of minimal hepatic encephalopathy. The admission of cirrhotic patients to the hospital with a complication of cirrhosis such as HE is associated with a change in the natural history of cirrhosis, with 5-year mortality rates of up to 40% [2]. In a well-conducted, adequately powered, multi-centre study performed predominantly in the United States and Russia, Bass et al. randomised 299 cirrhotic patients to receive Rifaximin or placebo for 6 months [3]. Rifaximin is a poorly absorbed antibiotic which has a very wide range of anti-bacterial activity extending from gram negative to gram positive and anaerobic organisms. At the time of randomisation, these patients had recovered from the episode of HE and the question they addressed in this study was whether treatment of these patients with Rifaximin would allow maintenance of remission compared with placebo. Their data clearly show that treatment with Rifaximin reduced time to first episode of HE and also time to first HE related hospitalisation in this population of patients. It is not clear from the paper whether Rifaximin prevented the occurrence of a precipitating event or de novo HE episodes as acute episodes of HE are usually due to a precipitating illness. It is worth emphasising that this study did not address treatment of an acute episode of HE or minimal HE patients and restricted the entry to patients with a MELD score of less than 25. The reason for this MELD criteria restriction is not clear but important as Rifaximin is bio-available and pharmacokinetics in the context of more severe disease needs further clarification. It is of note and perhaps surprising that despite a reduction in hospital admissions from HE, there was no effect on survival. It is also important to recognise that over 90% patients in both groups were on treatment with Lactulose in addition to Rifaximin and whether there is a synergistic action of the two remains unclear. The investigators reported extensive safety data and apart from 2 cases of Clostridium difficile infections in the Rifaximin treated group there were no major issues. Obviously, as the drug affects a wide range of bacteria in the gut, the risk of super-infection is a theoretical possibility which will need to be addressed in the post-marketing surveillance studies [4]. Therefore, the current indications are limited to this groups of patients perhaps using a combination of Lactulose with Rifaximin.

Journal of Hepatology 2010 vol. 53 j 580–582

JOURNAL OF HEPATOLOGY

Fig. 1. A hypothetical framework to explain the current thinking about the pathogenesis of hepatic encephalopathy and how the Rifaximin data fit into the hypothesis. Ammonia can directly result in brain swelling and HE but it can also activate neutrophils and reduction in its levels reduces brain inflammation. Increased gut permeability, bacterial overgrowth, and increased gut transit time leads to increased bacterial translocation which leads to activation of systemic and brain inflammation. The role of alterations in the pathogen recognition receptors have not been clarified but the beneficial effects of Rifaximin argue strongly for an important role for these in orchestrating brain inflammation in liver failure.

In order to put these data into context, it is worth looking at studies of Norfloxacin, which is a more selective, poorly absorbed antibiotic with anti-bacterial activity predominantly on the gram negative organisms [5]. In a recently published study, patients with advanced cirrhosis and ascites were randomised to receive Norfloxacin or placebo. Norfloxacin administration reduced the 1-year probability of developing spontaneous bacterial peritonitis and hepatorenal syndrome and, improved the 3-month and the 1-year survival compared with placebo. There are several parallels in the two studies where gut bacteria is the target using two different agents with different microbiological profiles but the essential premise is directed at prevention of a complication of cirrhosis; HE with Rifaximin and hepatorenal syndrome with Norfloxacin. Despite larger number of patients included in the Rifaximin study, the lack of effect on survival is difficult to understand but may indicate a population at much lower risk of death and lack of power of the study to address this end point. Alterna-

tively, it may indicate that the much broader anti-bacterial property of Rifaximin is an issue which should be resolved in a headto-head study. Nevertheless, these studies stress the role of the ‘gut bacteria’ as an important therapeutic target and an alternative strategy includes probiotics [6] which has been shown to be effective in patients with minimal HE. More recently, a very different approach is being used to target the ‘gut’ using nonabsorbable charcoal, which is being trialled in patients with minimal HE [7]. For over 100 years, ammonia has been thought to be central in the pathogenesis of HE but more recently an important role of inflammation has been hypothesised [8]. Studies in patients with acute liver failure and cirrhosis have shown incontrovertibly that peripheral and brain inflammatory responses are important in modulating the effect of hyperammonemia [9]. In fact, reduction in ammonia using Ornithine phenylacetate in animal models was recently shown to reduce brain inflammation [10]. No data are


581

International Hepatology presented in this paper about the effect of Rifaximin on ammonia levels leading one to suggest that the action of Rifaximin in this context is related to alteration in gut bacterial translocation. How gut bacterial translocation may make patients more susceptible to HE is unclear but may point to clues regarding the pathogenesis and treatments of HE (Fig. 1) [11]. In conclusion, the study by Bass et al. is a trailblazer for trials in HE and the recent approval for use of Rifaximin by the FDA for maintenance of remission of HE provides the impetus for development of other new compounds for HE which has remained a condition without any specific treatment. The data provide novel insights into the pathogenesis of HE which will lead to the identification of new targets of therapy. Conflict of interest University College London has licensed its invention, Ornithine phenylacetate to Ocera Therapeutics. References [1] Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy-definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 2002;35:716–721.

582

[2] Ginés P, Quintero E, Arroyo V, Terés J, Bruguera M, Rimola A, et al. Compensated cirrhosis: natural history and prognostic factors. Hepatology 1987;7:122–128. [3] Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010;362: 1071–1081. [4] Johnson S. Recurrent Clostridium difficile infection: a review of risk factors, treatments, and outcomes. J Infect 2009;58:403–410. [5] Fernández J, Navasa M, Planas R, Montoliu S, Monfort D, Soriano G, et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology 2007;133:818–824. [6] Liu Q, Duan ZP, Ha DK, Bengmark S, Kurtovic J, Riordan SM. Symbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology 2004;39:1441–1449. [7] Hiraishi M, Takahama T, Yamazaki Z, Kanai F, Ohnishi K, Idezuki Y, et al. Effect of oral adsorbent on blood metabolites in hepatic failure dogs. Int J Artif Organs 1989;12:114–120. [8] Shawcross D, Jalan R. The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation. Cell Mol Life Sci 2005;62:2295–2304. [9] Jalan R, Olde Damink SW, Hayes PC, Deutz NE, Lee A. Pathogenesis of intracranial hypertension in acute liver failure: inflammation, ammonia and cerebral blood flow. J Hepatol 2004;41:613–620. [10] Davies NA, Wright G, Ytrebø LM, Stadlbauer V, Fuskevåg OM, Zwingmann C, et al. L-ornithine and phenylacetate synergistically produce sustained reduction in ammonia and brain water in cirrhotic rats. Hepatology 2009;50:155–164. [11] Wright G, Jalan R. Ammonia and inflammation in the pathogenesis of hepatic encephalopathy: Pandora’s box? Hepatology 2007;46:291–294.
