Alcohol-associated liver disease (ALD) is a leading cause of liver-related mortality/morbidity, and there is no FDA-approved therapy for any stage of ALD. Advanced ALD conditions, including severe alcohol-associated hepatitis (sAH) and decompensated alcohol-associated cirrhosis (deAC), have especially poor outcomes. Indeed, the 90-day mortality for sAH is ~30%. Return to drinking impacts quality of life and mortality in these patients. There are limited drug therapies or well-studied behavior therapies in this patient population. An optimal approach would be the integration of AUD and ASLD care givers and therapies, but there are no guidelines for this approach. Our proposed AUD/ALD team approach seeks to overcome the perceived stigma of alcohol misuse which can adversely affect treatment seeking, quality of care and patient outcomes. The AlcHepNet study was stopped at the interim analysis because of the unexpected 90% 90-day survival in sAH patients treated with prednisone using the Lille stopping rule. These dramatic results need to be confirmed, and novel therapies such as IL-22 need to be studied in sAH. Treatment with Lactobacillus rhamnosus GG (LGG) improved MELD score at 30 days and reduced drinking at 6 months in patients with moderate AH. Acamprosate appears to be the safest FDA-approved therapy for AUD in patients with ALD, but safety and efficacy in severe ALD need to be evaluated. Take Control is a novel computer-based behavioral platform derived from the NIAAA’s Rethinking Drinking which we propose to evaluate in severe ALD. Based on preliminary data and knowledge gaps, our overall hypothesis is that an integrated management of ALD and AUD will improve clinical outcomes in patients with sAH and decompensated ALD. We will utilize the following AIMS: Aim 1. Perform a double- blind randomized controlled trial of treatment for steroid-eligible patients with severe AH. A masked study comparing daily prednisone for 28 days (with the 7-day Lille score-based stop rule) vs. IL-22 fusion protein (F- 652). Early intervention for AUD will include behavioral therapy platform (Take Control) in all subjects and either acamprosate or placebo before discharge from the hospital. The primary endpoint of the trial will be a composite measure of mortality, liver, and alcohol use related outcomes. Aim 2. Evaluate Lactobacillus rhamnosus GG (LGG) in patients with decompensated ALD cirrhosis. In patients with decompensated cirrhosis due to ALD, in whom corticosteroids are not effective, a randomized, placebo-controlled trial of LGG in combination with Take Control and locally accepted SOC for 6 months will be performed. A composite measure (as in AIM 1) at 6 months will be the primary end point for this AIM also. AIM 3. Build a platform for biosamples, data repositories, and patient registries to support site-specific and network-wide ancillary studies. The VCU site ancillary study will involve the evaluation of collagen fragments-based biomarkers (PROC3-6, CTX) as predictors of outcomes in sAH and deAC These studies will leverage the AlchepNet infrastructure to generate novel data on the benefits of combined ALD/AUD therapy for these typically underserved populations.

Project Narrative: Alcohol-associated liver disease (ALD) is a leading cause of mortality/morbidity, and there is no FDA-approved therapy for any stage of ALD. Unfortunately, patients with ALD rarely have their underlying alcohol use disorder (AUD) concomitantly addressed. This consortium links health care providers with expertise in AUD and ALD in a unified treatment strategy to evaluate novel combined treatments for AUD/ALD in patients with advanced ALD. The existing resources of the NIAAA-funded AlcHepNet are used for patient studies, biospecimen collection and site-specific ancillary studies.