Summary of the study
The GALA-RIF study,1 published by Israelsen et al., aimed to compare the efficacy and safety of rifaximin-α with a placebo in patients with alcohol-related liver disease. Conducted at Odense University Hospital in Denmark, the trial involved 136 eligible adult participants with biopsy-proven alcohol-related liver disease and no previous decompensation. They were randomized to receive 550 mg of oral rifaximin-α twice daily or a placebo for 18 months. The primary endpoint was a decrease in liver fibrosis stage from baseline to 18-month treatment, as per the Kleiner fibrosis score. Although the results showed no significant difference in the reduction of fibrosis stage between the rifaximin-α and placebo groups, the rifaximin-α group had significantly lower rates of fibrosis progression compared to the placebo group. In the per-protocol population, 24% of patients in the rifaximin-α group experienced an increase in fibrosis stage compared to 43% in the placebo group. There were no significant differences between the groups regarding the reduction of hepatic lobular inflammation, steatosis, or ballooning. However, non-invasive markers, the FIB-4 index and PRO-C4, showed significant changes between the rifaximin-α and placebo groups at 18-month follow-up. Liver enzyme concentrations also changed more beneficially in the rifaximin-α group compared to the placebo group. Adverse events were reported in 71% of the rifaximin-α group and 78% of the placebo group, with gastrointestinal disorders, infections, and trauma being the most common. Serious adverse events occurred in 21% of the rifaximin-α group and 18% of the placebo group, with no cases of infections with Clostridioides difficile or multidrug-resistant bacteria. Three deaths occurred in the rifaximin-α group, but none were deemed related to the study drug. The authors concluded that although rifaximin-α did not significantly reduce liver fibrosis stage compared to the placebo, it demonstrated a lower rate of fibrosis progression.
Comments
Alcohol-related liver disease contributes significantly to cirrhosis and liver-related deaths.2 Liver fibrosis is a crucial factor, and with its early identification, there is an increased need for therapies to prevent cirrhosis progression. Currently, alcohol abstinence is the primary treatment, but its success rate is inconsistent. The gut-liver axis plays a vital role in the progression of alcohol-related liver disease, and targeting the gut microbiome and gut-barrier function has become a promising treatment approach.
Rifaximin, also known as Rifaximin-α, is a non-systemic, gut-selective antibiotic that is minimally absorbed into the bloodstream, making it particularly suitable for treating gastrointestinal disorders.3 The "α" designation is used to distinguish it from other rifamycin antibiotics and to emphasize its specific chemical structure, which is an alpha-pyrone derivative of rifamycin. Rifaximin-α, may help modulate the gut microbiome and repair the gut barrier and is often used for hepatic encephalopathy.4 However, its effectiveness and safety in treating alcohol-related liver disease were unknown.
The GALA-RIF study, an 18-month randomized double-blind placebo-controlled trial, provides valuable insights into the potential of rifaximin-α as a treatment for patients with alcohol-related liver disease1. Although the study did not achieve its primary endpoint of reduced liver fibrosis, it did demonstrate a reduction in fibrosis progression, possibly due to decreased liver inflammation. This result is significant because alcohol-related liver disease is a leading cause of cirrhosis, and progressive fibrosis is a key factor in liver-related morbidity and mortality.
The gut-liver axis is regarded as a significant contributor to alcohol-related liver damage. In individuals with cirrhosis, rifaximin enhances gut barrier function and lowers systemic inflammation. The findings from the GALA-RIF study support the idea that targeting the gut-liver axis could help halt fibrosis progression in patients with asymptomatic alcohol-related liver disease.
Strengths of the GALA-RIF study include its long intervention period, histological assessment of liver fibrosis as the primary outcome, and high compliance among participants, who are considered a vulnerable population. These factors lend credibility to the study's findings. However, the GALA-RIF trial also exhibits some weaknesses. No significant difference between the rifaximin-α and placebo-treated groups was observed for the primary endpoint of reduced liver fibrosis. This limitation highlights the need for a multicenter, phase 3 confirmatory efficacy trial with hard clinical endpoints. Another potential limitation is the study population's homogeneity, as all participants were White. The efficacy of rifaximin-α may differ among other racial and ethnic groups, necessitating further research.
Despite these weaknesses, the results of the GALA-RIF study have important implications for the management of alcohol-related liver disease. Although rifaximin-α did not promote liver fibrosis regression, it appeared to reduce fibrosis progression. This finding suggests that rifaximin-α could be beneficial for patients unable to achieve alcohol abstinence, serving as a secondary prevention strategy during relapse periods. By targeting the gut-liver axis, rifaximin-α may offer a promising new approach to managing alcohol-related liver disease and preventing progression to more severe stages of fibrosis and hepatic decompensation.
India faces the challenge of a high burden of liver diseases, with a significant proportion attributed to alcohol consumption.5 The availability of rifaximin-α as a treatment could help address this growing concern by providing a secondary prevention strategy during relapse periods and potentially preventing progression to more severe stages of fibrosis and hepatic decompensation. However, it is essential to note that the GALA-RIF study's results may not be directly generalizable to the Indian population. Further research is needed to assess the efficacy and safety of rifaximin-α in diverse racial and ethnic populations, including those in India.
Nonalcoholic steatohepatitis (NASH) is another prevalent cause of liver disease, cirrhosis, and liver transplantation requirements. Considering the common pathways in alcohol-related liver disease and NASH, along with strong preclinical evidence supporting the benefits of rifaximin-α in altering immune responses and reducing hepatic inflammation through the gut-liver axis, it is worth exploring the use of rifaximin-α in patients with liver diseases of other origins, particularly NASH.6
In conclusion, the GALA-RIF trial sheds light on the potential role of rifaximin-α in managing alcohol-related liver disease. While the study has its limitations, the reduction in fibrosis progression observed with rifaximin-α treatment suggests that this approach may benefit individuals struggling with alcohol abstinence. Further research is needed to confirm these findings and explore the implications for different racial and ethnic populations.
Credit authorship contribution statement
Ashish Kumar: Conceptualization, Writing - Original Draft.
Anil Arora: Writing - Review & Editing.
Praveen Sharma: Writing - Review & Editing.
Conflicts of interest
None.
Funding
None.
Footnotes
Given his role as Associate Editor, Ashish Kumar was not involved in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to the Editor-in-Chief.
References
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