ALCOHOLIC HEPATITIS CLINICAL AND TRANSLATIONAL NETWORK: LATE PHASE CLINICAL TRIALS AND OBSERVATIONAL STUDIES 6/9

ABSTRACTDespite the high clinical significance, there is limited knowledge of the management and treatment of COVID-19. Patients with alcohol associated liver disease (ALD) and COVID-19 are at increased risk for severe disease,morbidity and mortality. There are also data that alcohol consumption increases during isolation, like that causedby social distancing measures enacted during the COVID-19 pandemic, therefore the incidence and severity ofALD is likely to increase. Current treatment approaches for patients with severe COVID-19 include antiviralagents and supportive care. In our preliminary and pilot studies we have observed sarcopenia or loss of skeletalmuscle mass and impaired muscle strength in patients with ALD. Sarcopenia and accompanying contractiledysfunction contribute to longer hospital and intensive care stay, greater need for ventilatory support and pooroutcomes in acute respiratory distress syndrome (ARDS), a hallmark of severe COVID-19. The "cytokine storm"that occurs in patients with COVID-19 is accompanied by elevated circulating IL-6, and emerging data suggeststhat IL-6 inhibitors improve survival in patients with severe COVID-19. Despite the significant interest in IL-6inhibitors with multiple ongoing clinical trials underway, these agents increase the risk for secondary infections(a common occurrence in COVID-19) and are contraindicated in those with significant elevated plasmatransaminases. β-hydroxy β-methyl butyrate (HMB), a non-nitrogenous leucine metabolite with anabolicproperties, also inhibits plasma IL-6 while improving muscle mass and contractile function. We thereforehypothesize that COVID-19 worsens clinical outcomes and muscle loss in ALD patients, and that reversal ofmuscle loss by HMB through an IL-6 dependent manner will improve clinical outcomes in ALD patients. Thishypothesis will be tested through two interrelated, but independent specific aims: (1) establish the naturalcourse of COVID-19 infection in patients with ALD by determining whether COVID-19 is more severe inALD and whether COVID-19 worsens liver injury in ALD; (2) determine whether treatment with HMBimproves the acute and long-term consequences of COVID-19 in terms of skeletal muscle mass, skeletalmuscle function, and clinical outcomes in ALD patients. We will use clinical and biosamples to determineoutcomes and responses to intervention targeting the skeletal muscle in these patients. We anticipate HMB willreduce inflammatory markers including circulating IL-6, improve clinical outcomes in-hospital, reversesarcopenia, and improve long-term clinical outcomes. These human studies have the potential for immediatetranslation into clinical practice to rapidly improve immediate and long-term outcomes in ALD patients withCOVID-19. These studies will supplement the applicant's ongoing alcoholic hepatitis network grant supportedby the NIAAA.