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Roughly half as many patients with cirrhosis in remission from overt hepatic encephalopathy (OHE) experienced a breakthrough episode with rifaximin monotherapy compared with lactulose monotherapy, a post-hoc analysis of two randomized trials showed.

Over 6 months, 23.2% of patients receiving rifaximin monotherapy experienced an OHE breakthrough episode compared with 49% of patients receiving lactulose monotherapy (P<0.0001), reported Jasmohan S. Bajaj, MD, of Virginia Commonwealth University School of Medicine in Richmond, at the American College of Gastroenterology annual meeting.

Patients receiving rifaximin also had a longer time to breakthrough OHE episode versus patients receiving lactulose (HR 0.40, 95% CI 0.26-0.62, P<0.0001).

In addition, mortality was significantly higher in lactulose patients than in rifaximin patients (4.8% vs 1.6%, P<0.001). The time to all-cause mortality was significantly longer in the rifaximin group versus the lactulose group (HR 0.048, 95% CI 0.01-0.29, P<0.001). The number needed to treat to prevent mortality was 19.

"This is an important and timely study given the significant morbidity associated with overt hepatic encephalopathy," Yee Hui Yeo, MD, MSc, a clinical fellow at Cedars-Sinai Medical Center in Los Angeles, told MedPage Today. "What stands out is the magnitude of benefit observed, with rifaximin not only reducing OHE recurrence but also lowering all-cause mortality."

"These findings align with emerging insights into the microbiome's role in hepatic encephalopathy pathophysiology," he added.

Currently, rifaximin is only recommended as add-on therapy if first-line lactulose monotherapy fails to prevent an additional OHE episode, but nonadherence to lactulose can result in recurrence.

"For those who have actually dealt with patients dealing with lactulose, it has a plethora of side effects," Bajaj told attendees. "Many of them lead to patients not taking this, which includes GI adverse events, dosing and volume requirements -- which have to be incredibly personalized -- and there's an unpleasant taste."

Yeo noted that "rifaximin monotherapy could become a preferred option for secondary prophylaxis of OHE, particularly in patients struggling with lactulose adherence," though he also acknowledged the substantially higher price of rifaximin, which costs , compared with. "While cost remains a concern, when feasible, rifaximin could reduce hospital readmissions and improve both patient outcomes and caregiver burden."

Bajaj also addressed the substantial cost difference between the two drugs.

"Rifaximin is very expensive, but so is an unnecessary hospitalization for hepatic encephalopathy that can sometimes result in an ICU stay," he noted. "Lactulose is a cheap medication, but it requires a lot of human resources. Think about all the time you spend on the phone, explaining to the patient, explaining to the caregiver, getting phone calls from them, and then almost always seeing them in the hospital," most often because they could not tolerate the lactulose.

Although this post-hoc analysis suggests rifaximin is potentially more effective, its use would depend on whether insurance can cover it, he added.

For this analysis, the researchers analyzed data from and a phase IV open-label trial. Participants in both trials were adults with cirrhosis in remission from OHE after at least one (phase IV trial) or two (phase III trial) episodes in the preceding 6 months.

The combined 270 participants were predominantly white (87-90%) and male (60-68%) with an average age of 56-58 and an average baseline Model for End-Stage Liver Disease (MELD) score of 12-13. Nearly half had a Child-Pugh class score of B (48.5%), while 38.1% had an A score and 7.4% had a C score. Two-thirds (68.1%) had a baseline Conn score of 0 and the remaining third had a score of 1.

Patients were excluded from both trials if they had current gastrointestinal bleeding requiring hospitalization and transfusion, renal insufficiency requiring dialysis, respiratory insufficiency, anemia, hypovolemia or electrolyte abnormality, a current infection, or active spontaneous bacterial peritonitis. Additionally, those with a positive Clostridioides difficile stool test were excluded from the phase IV trial, and participants were excluded from the phase III trial if they were anticipating liver transplantation within a month after screening or if they had had a portosystemic shunt placed within 3 months before screening.

Of the participants, 125 received 550 mg of rifaximin twice daily for up to 6 months and 145 participants received lactulose titrated to result in two to three soft stools per day plus placebo for up to 6 months. Rifaximin patients had been in remission an average 90 days compared with 74 days for lactulose patients.

After the first few days of the trials, those in the phase III trial were assessed every 2 weeks, while those in the phase IV trial were assessed every 4 weeks, both through 24 weeks.

The difference in time to a breakthrough episode between the rifaximin group and the lactulose group was very similar to the difference seen with rifaximin plus lactulose versus lactulose plus placebo in the phase III trial.

In the current analysis, the proportion of patients requiring hospitalization related to hepatic encephalopathy during the 6 months of treatment was not significantly different between the rifaximin and lactulose groups (19.2% vs 23.4%, P=0.18).

"Not shockingly, drug-induced adverse events were higher in the lactulose group," Bajaj said. "This resulted in more discontinuation of medication, which kind of reflects our clinical practice."

Drug-related adverse effects occurred in 24.1% of lactulose patients and 6.4% of rifaximin patients, and 39.3% and 20% discontinued treatment due to an adverse effect. The rate of serious adverse effects was similar between the groups.

There was a statistically significantly higher rate of diarrhea in the lactulose group compared with the rifaximin group (14.5% vs 4.8%), Bajaj noted.

The trial's biggest limitation was that it was a post-hoc analysis of two separate trials, rather than a head-to-head comparison, and it had a relatively small sample size that can inhibit generalizability, Yeo pointed out.

"Additionally, the design may not fully capture the heterogeneity in real-world patient populations with cirrhosis, including differences in adherence, access to medications, and comorbidities," he said. "Given these limitations, these findings should be validated in larger, prospective, and diverse patient cohorts before making broad changes to current treatment guidelines."

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