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Adding fecal microbiota therapy to standard care for steroid-ineligible severe alcoholic-associated hepatitis appeared safe and effective in a small randomized trial from India.

Survival at 90 days reached 73% with fecal transplant delivered via a nasoduodenal tube compared with 40% with standard care alone (P=0.02), with more than twice as many patients alive at 6 months as well (60% vs 27%, P=0.03), reported Shiv Kumar Sarin, MBBS, MD, of the Institute of Liver and Biliary Sciences in New Delhi.

"[Fecal microbiota therapy] is safe in selected steroid-ineligible patients and leads to improvement in liver function and severity scores along with better liver transplant-free survival than standard medical therapy," said Sarin, adding that the approach should be further evaluated in a larger trial.

According to the findings presented at the American Association for the Study of Liver Disease annual Liver Meeting, held this year in San Diego, the investigational treatment was also associated with a lower incidence of hepatic encephalopathy and fewer alcohol relapses.

Severe alcoholic-associated hepatitis is linked with very poor survival rates. While corticosteroids remain the first choice of treatment, they are only effective in a subset of patients. "In our experience, about 80% of patients with [severe alcoholic-associated hepatitis] are steroid-ineligible when they are hospitalized," Sarin explained. "So for them, there are very few options."

The researchers hypothesized that modulation of gut microbiota through healthy-donor fecal microbiota transplantation would improve gut dysbiosis and 3-month survival in this difficult-to-treat patient population. This was supported by a prior involving eight patients.

In the U.S., the FDA has approved the fecal microbiome therapies Rebyota and Vowst for recurrent Clostridioides difficile infections, and prior research has suggested some promise with the approach for everything from cirrhosis to irritable bowel syndrome. Healthy-donor stool for the products is screened for a host of potential pathogens due to concerns over the spread of other disease.

Sarin presented data from a clinical trial involving 45 patients with severe alcoholic-associated hepatitis who were randomized 2:1 to standard care (adequate nutrition, albumin, and antibiotics/antifungals) with or without fecal microbiota therapy, which was administered through a nasoduodenal tube for 7 consecutive days.

Patients were defined as steroid ineligible if they had required hospitalization for drinking within the last 30 days and had either a Model for End-Stage Liver Disease (MELD) score of 20 or higher, a modified Maddrey's discriminant function (mDF) score of 80 or above, renal dysfunction, an infection controlled by antibiotics, a gastrointestinal bleed within the last 28 days, or severe comorbidities that increased susceptibility to complications associated with prednisolone.

Enrolled participants had a mean age of 40 years, the vast majority were men, and about a third were steroid-ineligible because of their mDF score. Other reasons included pneumonia, urinary tract infection, cellulitis, and acute kidney injury.

Patients were followed for 6 months, and the study's primary outcome was 90-day transplant free survival, with secondary outcomes including survival at 28 and 180 days, changes in MELD and mDF scores, safety, and other outcomes.

In addition to the survival benefit, Sarin reported greater improvements in MELD scores, mDF scores, and Glasgow Alcoholic Hepatitis Score (GAHS) with fecal microbiota therapy versus standard care alone:

• MELD at 3 months: -4.00 vs -0.23, respectively (P=0.021)
• MELD at 6 months: -5.92 vs -0.76 (P=0.016)
• mDF at 6 months: 58 vs 81 (P=0.04)
• GAHS at 6 months: 6.87 vs 8.00 (P=0.03)

Incidence of hepatic encephalopathy at day 90 was lower in the investigational arm as well (6% vs 40% in the control arm, P=0.05), as were alcohol relapses (10% vs 40%, P=0.01), and there was a significant increase in healthy bacteria by day 30 in the fecal microbiota therapy group.

As for safety, the incidence of adverse events was significantly higher in the fecal microbiota therapy group when it came to nasal and swallowing discomfort (50% vs 0%), and flatulence and bloating (43% vs 13%), but not for other adverse events such as reflux symptoms (17% vs 20%), new onset pneumonia (27% vs 47%), cellulitis (3% vs 6%), or gastrointestinal bleeding (3% vs 13%).

Sarin acknowledged the study had several limitations, including its small size and the fact that the majority of patients were on antibiotics, which may have altered their gut microbiome.

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