1. Journal club April 2010 Dr Aucamp Dr Buchel Rifaximin treatment in hepatic encephalopathy

2. BACKGROUND HEPATIC ENCEPHALOPATHY  Neuropsychiatric syndrome Deterioration in mental status Psychomotor dysfunction Impaired memory Increased reaction time Sensory abnormalities Poor concentration Disorientation Severe cases: Coma  Complication of cirrhosis  Burden on family, patient, system  Overt episodes Debilitating Without warning Incapable of self care Frequently result in hospitalization  Occurrence unrelated to cause of cirrhosis  Increase in frequency, increase in death

3. WHY THIS STUDY? CURRENT  Most therapies focus on treating episodes  Directed at reducing the nitrogenous load  Hypothesis: Systemic accumulation Gut derived neurotoxins e.g. Ammonia In patients with impaired liver function and porto-systemic shunting  Nonabsorbable disaccharides Decreases ammonia absorption Sharma et al reported it to be effective in prevention Side effects: GIT, taste Frequent non compliance  Oral antibiotics Neomycin, Vancomycin, Metronidazole With or without lactulose Reduce ammonia producing enteric bacteria Side effects: ototoxicity, nephrotoxicity peripheral neuropathy  Rifaximin Minimally absorbed, concentrate in GIT Broad spectrum activity against Gr + & - Low risk of inducing resistance More conducive to long term use More effective than lactulose At least equal to other antibiotics

4. METHODS INCLUSIONEXCLUSION  At least 18y  At least 2 episodes of overt encephalopathy Conn >2 Associated with hepatic cirrhosis In previous 6 months  Remission at enrolment Conn 0 or 1  MELD scale 25 or less  Expectation of transplant within 1 month  Presence of known precipitants GIT haemorrhage Placement of portosystemic shunt Trans jugular intrahepatic portosystemic shunt Chronic renal insufficiency (Cr > 177) Respiratory insufficiency Anemia (Hb < 8 ) Electrolyte abnormality ( Na 2.5) Potassium <2.5 Infection Active spontaneous bacterial peritonitis

5. METHODS STUDY DESIGN AND PROCEDURES  Multicenter, randomized, double-blind, placebo-controlled study  Conducted over a 6 month period  Screening visit, observation period, enrolment and 6-month treatment phase  On day 0, eligible patients were randomly assigned, in a 1:1 ratio, to receive either 550mg Rifaximin or placebo, twice daily, for 6 months or until they discontinued the study drug because of a breakthrough episode of encephalopathy or another reason  Concomitant use of lactulose was permitted  Study designed by representatives of Salix pharmaceuticals and the academic authors

6. METHODS EFFICACY AND SAFETY ASSESSMENTS  Clinic visits every two weeks through day 168 (end of study period)  Optional visits days 42, 70, 98, 126, 154  Patients were monitored by telephone in between clinic visits  Assessments included Conn score and asterixis grade  Investigators and site personnel who performed assessments were trained in order to ensure consistency across sites

7. METHODS STATISTICAL ANALYSIS  Efficacy data were analyzed for the intention-to-treat population, which included patients who received at least 1 dose of the study medication  Primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy Defined as: Time to increase from baseline Conn 0 or 1 to a score of 2 or more Time to increase from Conn 0 to 1 plus 1 unit increase in asterixis grade  Secondary end point was the time to first hospitalization  Cox potential-hazards model was used, with a 2 sided test and a significance level of 0.05 to compare the time to breakthrough between the groups  Kaplan-Meier methods were used to estimate the proportions of patients having breakthrough episodes at successive time points during the study  Same methods to study secondary end point  At least 100 patients per group were needed to show superiority of Rifaximin vs placebo  Safety assessments included adverse events, serious adverse events and adverse events consisting of infection

8. RESULTS STUDY PATIENTS  299 patients at 70 sites, were randomly assigned  All patients included in safety population and intention-to-treat population  Baseline characteristics similar in the two groups  Similar percentages of patients received lactulose at baseline (91.2% vs 91.%) and doses remained stable  Mean duration of treatment was 130.3 days in Rifaximin group vs 105.7 days in placebo group  Compliance 84.3% in Rifaximin group vs 84.9% in placebo group

9. RESULTS BREAKTHROUGH EPISODES Rifaximin group: 31 of 140 (22.1%) Placebo group:73 of 159 (45.9%) Relative risk:0.48 ----> risk in exposed is less than in unexposed NNTT:4 patients need to be treated for 6 months, to prevent one episode of overt hepatic encephalopathy The degree to which Rifaximin reduced the risk was consistent across subgroups HOSPITALIZATIONS Rifaximin group:19 of 140 (13.6%) Placebo group:36 of 159 (22.6%) Relative risk:0.60 ----> risk in exposed is less than in unexposed NNTT:9 patients need to be treated for 6 months to prevent one hospitalization involving hepatic encephalopathy.

12. RESULTS SAFETY Incidence of adverse events reported during the study was similar Rifaximin group:80% Placebo group:79.9% Clostridium difficile was reported in two patients, both had other risk factors Advanced age Numerous recent hospitalizations Multiple courses of antibiotics Use of pantoprazole (Pantoloc®) In both patients, Rifaximin was continued concomitantly with treatment for the infection, from which they fully recovered. 20 patients died during the study, 9 in Rifaximin group, 11 in placebo group Most of the deaths attributed to disease progression

14. DISCUSSION The study showed that the use of Rifaximin: Reduced the risk of hepatic encephalopathy During a 6 month period Among patients in remission Recent history of recurrent overt hepatic encephalopathy The reduced risk was seen across all subgroups Which expands previously reported findings of efficacy of Rifaximin in the treatment of overt hepatic encephalopathy The current study differs from previous studies in that it: Examined the protective effect of Rifaximin rather than the treatment effect Larger study group Longer study period

15. DISCUSSION This study showed the superiority of Rifaximin over treatment with Lactulose alone >90% of patients received concomitant lactulose during the study period Significant treatment effect after 28 days Lactulose treatment effects only after approximately 4 months Rifaximin therapy reduced the hospitalizations involving hepatic encephalopathy Shows clinical significance of the findings Supports the findings of previous retrospective chart reviews The safety profile of Rifaximin appears to be superior to that of systemic antibiotics, particularly for patients with liver disease The risk of bacterial resistance appears to be lower with Rifaximin than with systemic antibiotics Plasma levels of Rifaximin negligible, thus bacteria outside GIT not exposed to selective pressure

16. STUDY REVIEW ARE THE RESULTS VALID Did the study address a clear question?Yes Was the assignment of pts randomised?Yes Were all patients who entered the trial properly accounted for? Yes Were pts analysed in the groups to which they were randomised? Yes Were pts, health workers and study personnel “blind” to treatment? Yes Were the groups similar at the start?Yes Aside from the experimental interventions, were the groups treated equally? Yes

17. STUDY REVIEW How large was the treatment effect?Encephalopathy - RR reduction 58% Hospitalization - RR reduction 50% How precise was the treatment effect?Encephalopathy - 95% CI p = <0.001 Hospitalization - 95% CI p = 0.01 Can the results be applied to my patients care?No, at present Rifaximin not available in RSA What are the likely benefits?Prevent overt hepatic encephalopathy Prevent hospitalization Save money