Assessment of Potential Impact of Demographic and Baseline Disease Characteristics on Rifaximin Monotherapy versus Lactulose Combination Therapy for the Prevention of Overt Hepatic Encephalopathy (OHE) Recurrence

Abstract

Introduction: Rifaximin 550 mg is indicated for prevention of OHE recurrence in adults. A phase 4, open-label noninferiority trial evaluated the impact of baseline parameters on the efficacy of rifaximin alone vs rifaximin + lactulose for OHE recurrence prevention. Methods: Adults with cirrhosis and a previous OHE episode now in remission (Conn score ≤1) were randomized to rifaximin 550 mg BID alone or rifaximin 550 mg BID + lactulose (self-titrated; 2-3 soft stools/d) for 6 months. Breakthrough HE (Conn score ≥2) was monitored monthly. Time to onset of an OHE episode (primary endpoint) was assessed overall and by baseline parameters: age (< 65 y; ≥65 y), sex, race, prior lactulose use, diabetes status, MELD score, Conn score (0; 1), Child-Pugh class, asterixis grade (0; ≥1), duration of HE remission before study entry (≤90 days; >90 days), time since first diagnosis of advanced liver disease (< 50 months; 50 months), time since first diagnosis of HE (< 15 months; ≥15 months), number of HE episodes during past 6 months (1; >1), and cirrhosis etiology. Noninferiority was demonstrated if the upper limit 2-sided, 95% CI of hazard ratio (HR) of rifaximin to rifaximin + lactulose was < 1.6. Results: 113 patients were treated in the rifaximin alone group; 108 in rifaximin + lactulose group. Overall population mean MELD score was 11.9, 39.8% and 55.7% were Child-Pugh A and B, respectively, and baseline parameters were similar between groups. Breakthrough HE was reported in fewer patients in rifaximin + lactulose (13.9%) vs rifaximin alone (24.8%) groups; rifaximin + lactulose reduced the risk of breakthrough HE over 6 months to a greater degree (rifaximin alone vs combination HR, 2.0; 95% CI, 1.0-3.7; P=0.04). Demographic and baseline characteristics evaluated did not substantially alter the risk profile with rifaximin alone vs rifaximin + lactulose. In some subgroups (ie, Child-Pugh A [HR, 0.7; 95% CI, 0.2-2.4; P=0.6], remission duration >90 days [HR, 0.9; 95% CI, 0.4-2.1; P=0.7], prior 6-month HE episodes >1 [HR, 0.9; 95% CI, 0.3-2.7; P=0.9]), rifaximin alone reduced the risk of breakthrough HE to a greater degree than rifaximin + lactulose (ie, HR < 1); however, differences were not significant. Conclusion: Rifaximin + lactulose therapy appears to be consistently efficacious in prevention of OHE recurrence vs rifaximin alone and was unaltered by baseline characteristics evaluated. These data support the generalizability of the primary endpoint results.