The RIVET RCT: Rifamycin SV MMX improves muscle mass, physical function, and ammonia in cirrhosis and minimal encephalopathy.

BACKGROUND: Minimal hepatic encephalopathy (MHE) negatively affects the prognosis of cirrhosis, but treatment is not standard. Rifamycin SV MMX (RiVM) is a nonabsorbable rifampin derivative with colonic action. METHODS: In a phase 2 placebo-controlled, double-blind randomized clinical trial patients with MHE were randomized to RiVM or placebo for 30 days with a 7-day follow-up. The primary endpoint was a change in stool cirrhosis dysbiosis ratio. Gut-brain (cognition, stool/salivary microbiome, ammonia, brain magnetic resonance spectroscopy), inflammation (stool calprotectin/serum cytokines), patient-reported outcomes (sickness impact profile: total/physical/psychosocial, high = worse), and sarcopenia (handgrip, bioelectric impedance) were secondary. Between/within groups and delta (post-pre) comparisons were performed. RESULTS: Thirty patients (15/group) were randomized and completed the study without safety concerns. While cirrhosis dysbiosis ratio was statistically similar on repeated measures ANOVA (95% CI: -0.70 to 3.5), ammonia significantly reduced (95% CI: 4.4-29.6) in RiVM with changes in stool microbial α/ß-diversity. MHE status was unchanged but only serial dotting (which tests motor strength) improved in RiVM-assigned patients. Delta physical sickness impact profile (95% CI: 0.33 = 8.5), lean mass (95% CI: -3.3 to -0.9), and handgrip strength (95% CI: -8.1 to -1.0) improved in RiVM versus placebo. Stool short-chain fatty acids (propionate, acetate, and butyrate) increased post-RiVM. Serum, urine, and stool bile acid profile changed to nontoxic bile acids (higher hyocholate/ursodeoxycholate and lower deoxycholate/lithocholate) post-RiVM. Serum IL-1ß and stool calprotectin decreased while brain magnetic resonance spectroscopy showed higher glutathione concentrations in RiVM. CONCLUSIONS: RiVM is well tolerated in patients with MHE with changes in stool microbial composition and function, ammonia, inflammation, brain oxidative stress, and sarcopenia-related parameters without improvement in cognition. RiVM modulates the gut-brain axis and gut-muscle axis in cirrhosis.

Bristol Stool Scale as a Determinant of Hepatic Encephalopathy Management in Patients With Cirrhosis.

INTRODUCTION: Bowel movement (BM) frequency is used to titrate lactulose for hepatic encephalopathy (HE). However, stool consistency using the Bristol stool scale (BSS, 0-7) is often ignored. METHODS: The study included pre-BSS and post-BSS cohorts. BSS was incorporated into decision-making after training in outpatients with cirrhosis. Two to 3 BMs/d and BSS 3-4 were considered normal, whereas the rest were considered high or low; concordance between the metrics was evaluated. Medication changes and 6-month admissions were compared between this group (post-BSS) and a comparable previous group (pre-BSS). Concordance and regression analyses for all-cause admissions and HE-related admissions were performed, and comparisons were made for HE-related medication stability. In the longitudinal analysis, an outpatient group seen twice was analyzed for BSS and BMs. RESULTS: In the post-BSS cohort, 112 patients were included with only 46% BSS and BMs concordance and modest BSS/BMs correlation (r = 0.27, P = 0.005). Compared with a pre-BSS cohort (N = 114), there was a lower 6-month total (4% vs 0.36%, P < 0.001) or HE-related admission (1% vs 0.12%, P = 0.002). Regression showed model for end-stage liver disease (odds ratio [OR]: 1.10, P = 0.003) and pre-BSS/post-BSS (OR: 0.04, P < 0.001) for all-cause admissions and HE (OR: 3.59, P = 0.04) and preera/postera (OR: 0.16, P = 0.02) for HE-related admissions as significant. HE medication regimens were more stable post-BSS vs pre-BSS (32% vs 20%, P = 0.04), which was due to patients with BSS > BMs (P = 0.02). In the longitudinal analysis, 33 patients without medication changes or underlying clinical status changes were tested 36 ± 24 days apart. No changes in BSS (P = 0.73) or BMs (P = 0.19) were found. DISCUSSION: BSS is complementary and additive to BM frequency, can modulate the risk of readmissions and stabilize HE-related therapy changes in outpatients with cirrhosis, and could help personalize HE management.