A SPECIAL ARTICLE

The Antibiotic Rifaximin Improves Hepatic Encephalopathy Symptoms in Patients With Due to C

Melissa Palmer

Oral rifaximin is a nonabsorbed antibiotic with broad-spectrum antimicrobial activity. Rifaximin 400 mg 3 times daily for 14 days was prospectively investigated in an out- patient setting for the treatment of mild hepatic encephalopathy (HE) in patients with cirrhosis due to hepatitis C virus (HCV). Patients were assessed 24 hours before and 14 days posttreatment. Thirty-seven consecutive patients were treated. Twenty-three patients were receiving pegylated interferon (IFN) plus ribavirin, and 12 patients had type 2 diabetes mellitus (DM). Overall, rifaximin improved HE symptoms and lowered serum ammonia to normal levels. Rifaximin was well tolerated, and no hypo/hyper- glycemic episodes were reported. Because systemic antibiotics are associated with nephrotoxicity, and lactulose administration in DM patients is not ideal, rifaximin may be a more appropriate treatment for DM patients. Hepatic encephalopathy symptoms can be mistaken for pegylated IFN plus ribavirin adverse effects, and patients treated with these medications should be periodically evaluated for HE.

INTRODUCTION decreased attention span, and slow or slurred speech. ubclinical or mild hepatic encephalopathy (HE) is Oral lactulose is a nonabsorbable disaccharide admin- estimated to affect up to 70% of patients with cir- istered as first-line treatment for HE. However, nonab- Srhosis (1–3). Mild HE is generally characterized sorbable disaccharides are often poorly tolerated due by subtle personality changes, such as irritability, to sweet taste and gastrointestinal (GI) side effects (4). changes in sleep patterns, short-term memory loss, These agents may also cause prolonged episodes of diarrhea, leading to dehydration, renal insufficiency, Melissa Palmer, M.D., Hepatologist, Private Practice, and worsening of HE symptoms, thereby necessitating Plainview, NY. (continued on page 74)

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Table 1 Table 2 West Haven Criteria for Stage 1 HE* (4,7) Demographics and Baseline Characteristics

1. Trivial lack of awareness Parameter Patients (N = 37) 2. Shortened attention span Male: female, n 25:12 3. Altered sleep patterns Mean age, y (range) 50 (43–66) 4. Euphoria or depression Cirrhosis confirmation, n biopsy 32 5. Asterixis Laboratory testing 5 6. Impaired performance in addition or subtraction Concomitant pegylated IFN plus * HE: hepatic encephalopathy. ribavirin, n 23 Concomitant SSRI 17 Type 2 DM, n 12 hospital admission (4,5). Antibiotic therapy has also been administered in the treatment of HE to help con- Increased ammonia levels, n 17* Mean ammonia levels, trol levels of intestinal bacteria. For example, µg/dL (range) 172 (67–248) neomycin has been administered, but it has limited activity against anaerobic bacteria and is associated Prior HE treatment, n Lactulose† 8 with an increased risk for nephrotoxicity, ototoxicity, and GI distress (4). Therefore, alternative treatments DM: diabetes mellitus; HE: hepatic encephalopathy; IFN: interferon; SSRI: selective serotonin reuptake inhibitor; continue to be investigated in order to effectively con- y: year. trol symptoms of HE while minimizing potential *Patients with both baseline and follow-up data. adverse effects of treatment. †Administered >2 months prior to current study. Rifaximin (Xifaxan®; Salix Pharmaceuticals, Inc, Morrisville, NC) is a nonabsorbed (<0.4%) oral antibi- had a history of severe or uncontrolled psychiatric dis- otic that targets the GI tract and exhibits in vitro activ- orders, neurologic disorders, renal insufficiency (crea- ity against gram-positive and gram-negative aerobic tinine >2 mg/dL), anemia (hemoglobin level <10 and anaerobic bacteria. Rifaximin is currently indicated g/dL), uncontrolled thyroid disease, or diabetes melli- in the United States for the treatment of travelers’ diar- tus (DM); were currently abusing alcohol; or were cur- rhea caused by noninvasive strains of Escherichia coli. rently being treated with sedatives. Patients were However, several studies have shown rifaximin to be treated with rifaximin 400 mg 3 times daily for 14 effective in the treatment of HE (6). Given the need for days. Patients were evaluated 24 hours before the start a convenient therapy that can be administered in an out- of therapy and 14 days after completion of therapy for patient setting, a series of patients with cirrhosis due to multiple parameters, including ammonia levels, aster- hepatitis C virus (HCV) and stage 1 HE were treated ixis, personality changes (irritability, anxiety, or with rifaximin to evaluate its tolerability and potential depression), short-term memory loss, attention span, benefit in the management of mild HE. reaction time, sleep patterns, ability to perform mental tasks (addition and subtraction), slow/slurred speech, and quality of life (QoL) composite score (assessed by CASE REVIEW Short Form-36). Tolerability and side-effect profile of Patients were prospectively recruited from a single, treatment were also assessed. private center in an outpatient setting. They were eli- A total of 37 consecutive patients were treated gible for treatment if they had cirrhosis due to HCV with rifaximin 1200 mg/d (Table 2). Twenty-three and stage 1 HE (determined by West Haven criteria; patients were concurrently receiving pegylated inter- Table 1) (4,7) and were not currently receiving HE feron (IFN) plus ribavirin for chronic HCV infection, treatment. Patients were ineligible for treatment if they and 17 of these 23 patients were receiving a selective

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A SPECIAL ARTICLE

Table 3 Symptom Improvement With Rifaximin Treatment in Patients with Cirrhosis Due to HCV Infection and Stage 1 HE

Patients With Symptom Improvement, n/N (%) All patients Patients Patients receiving concomitant not receiving concomitant antiviral therapy* antiviral therapy* Symptom (N = 37) (n = 23) (n = 14) Elevated serum ammonia levels 17/17 (100) 10/10 (100) 7/7 (100) Asterixis 34/35 (97) 21/22 (95) 13/13 (100) Personality changes† 27/36 (75) 16/22 (73) 11/14 (79) Short-term memory loss 31/35 (89) 18/21 (86) 13/14 (93) Attention span 26/31 (84) 15/18 (83) 11/13 (85) Reaction time 25/31 (81) 16/20 (80) 9/11 (82) Altered sleep patterns 20/30 (67) 13/20 (65) 7/10 (70) Ability to perform mental tasks‡ 24/27 (89) 18/20 (90) 6/7 (86) Slow or slurred speech 11/16 (69) 8/12 (67) 3/4 (75) Improvement in QoL 37/37 (100) 23/23 (100) 14/14 (100)

HCV: hepatitis C virus; HE: hepatic encephalopathy; QoL: quality of life. *Pegylated interferon and ribavirin. †Irritability, anxiety, or depression. ‡Addition and subtraction.

serotonin reuptake inhibitor for mild IFN-induced experiencing adverse events was low: three patients depression. Type 2 DM was reported in 12 patients; all (8%) reported mild bloating, and there was one report were well controlled by either a restricted diet (n = 5), each (2.7% each) of mild abdominal pain, diarrhea, oral hypoglycemic medication (n = 5), or insulin (n = nausea, and headache. There were no noticeable dif- 2). Baseline and posttreatment serum ammonia levels ferences in the incidence of adverse events between were available for 17 patients. There were no clinically patients receiving antiviral therapy and patients not significant differences in baseline demographics receiving antiviral therapy. No clinically relevant between patients receiving antiviral therapy versus changes in hematologic and biochemical laboratory patients who were not receiving antiviral therapy. parameters were observed with rifaximin treatment. Overall, rifaximin 1200 mg daily for 14 days Furthermore, no hypo- or hyperglycemic episodes improved multiple clinical symptoms of HE (Figure 1; were reported during the study. All patients who were Table 3). Rifaximin also lowered serum ammonia to previously treated with lactulose preferred treatment normal levels (<45 g/dL) in all 17 patients with avail- with rifaximin (8/8). able baseline and posttreatment serum ammonia lev- This pilot study indicated that rifaximin is well tol- els. Rifaximin was well tolerated, with all patients erated and effective in improving the symptoms of completing treatment. However, one patient missed stage 1 HE in patients with cirrhosis due to HCV. Oral two doses of rifaximin on day nine due to complaints rifaximin is easy to administer, allowing patients with of flatulence and abdominal bloating, which resolved stage 1 HE to be effectively managed in an outpatient without medical intervention. The number of patients setting, thereby facilitating the treatment and manage-

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Figure 1. Improvement in symptoms after treatment with rifaximin 400 mg 3 times daily for 14 days. QoL: quality of life. ment of mild HE. In addition, safe and effective treat- References ment of patients with HE and DM has been problem- 1. Gitlin N, Lewis DC, Hinkley L. The diagnosis and prevalence of subclinical hepatic encephalopathy in apparently healthy, ambu- atic. Lactulose may cause hyperglycemia as well as lant, non-shunted patients with cirrhosis. J Hepatol, 1986; 3:75- dehydration (secondary to diarrhea), and therefore lac- 82. 2. Gilberstadt SJ, Gilberstadt H, Zieve L, Buegel B, Collier RO Jr, tulose administration in patients with DM is not ideal McClain CJ. Psychomotor performance defects in cirrhotic (8, 9). Also, patients with chronic HCV are at least two patients without overt encephalopathy. Arch Intern Med, 1980; 140:519-521. times more likely than patients with non-HCV liver 3. Das A, Dhiman RK, Saraswat VA, Verma M, Naik SR. Preva- disease to have DM (10). In addition, patients with lence and natural history of subclinical hepatic encephalopathy in HCV cirrhosis and DM tend to have more severe HE cirrhosis. J Gastroenterol Hepatol, 2001; 16:531-535. 4. Blei AT, Cordoba J. Hepatic encephalopathy. Am J Gastroen- (11). Therefore, administration of an effective antibi- terol, 2001; 96:1968-1976. otic might be more appropriate in HE patients with 5. Warren SE, Mitas JA II, Swerdlin AH. Hypernatremia in hepatic failure. JAMA, 1980; 243:1257-1260. DM and/or HCV infection. Given that there are safety 6. Williams R, Bass N. Rifaximin, a nonabsorbed oral antibiotic, in issues with some antibiotics (e.g., neomycin-related the treatment of hepatic encephalopathy: Antimicrobial activity, efficacy, and safety. Rev Gastroenterol Disord, 2005; 5 suppl ototoxicity and nephrotoxicity), rifaximin may be an 1:10-18. appropriate choice to effectively control symptoms of 7. Atterbury CE, Maddrey WC, Conn HO. Neomycin-sorbitol and lactulose in the treatment of acute portal-systemic encephalopa- HE while minimizing potential treatment-related thy. A controlled, double-blind clinical trial. Am J Dig Dis. 1978; adverse effects in these patients. 23:398-406. It is also important to note that symptoms of HE 8. Trubo R. Researchers investigate factors linked to development of secondary diabetes. JAMA, 2005; 294:668-670. can be mistaken for side effects of pegylated IFN 9. Kirkman MS, Zimmerman DR, Filippini SA. Marked deteriora- and/or ribavirin (12). Therefore, patients with HCV tion in glycemic control with change in brand of lactulose syrup. South Med J, 1995; 88:492-493. cirrhosis being treated with pegylated IFN and/or rib- 10. Zein CO, Levy C, Basu A, Zein NN. Chronic hepatitis C and type avirin should be periodically evaluated for HE. Given II diabetes mellitus: A prospective cross-sectional study. Am J Gastroenterol, 2005; 100:48-55. the beneficial effects of rifaximin observed in this 11. Sigal SH, Stanca CM, Kontorinis N, Bodian C, Ryan E. Diabetes group of patients, a randomized, double-blind clinical mellitus is associated with hepatic encephalopathy in patients with HCV cirrhosis. Am J Gastroenterol, 2006; 101:1490-1496. trial of rifaximin in the treatment of HE in patients 12. Ahn J, Flamm S. Peginterferon-alpha(2b) and ribavirin. Expert with cirrhosis due to HCV is warranted. ■ Rev Anti Infect Ther, 2004; 2:17-25.

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