Infliximab monotherapy for severe alcoholic hepatitis and predictors of survival: an open label trial

Abstract

Background/Aims: Severe alcoholic hepatitis (AH) is associated with very high mortality. Tumor necrosis factor-alpha (TNF-α) contributes to the progression of AH and TNF-α antagonists like infliximab may help in ameliorating the severity and complications of AH. There is a scarcity of data regarding the safety and efficacy of infliximab monotherapy in the treatment of AH. We evaluated infliximab monotherapy in patients with severe AH. Methods: Patients with severe AH (Maddrey's score > 32) received a single dose of infliximab 5mg/kg IV. The primary endpoint was survival assessed at one and two months. The secondary endpoints were reduction of the Maddrey's DF and development of any bacterial infections. Predictors of survival were assessed at admission and at day 7. Results: Nineteen patients were enrolled in the study and received infliximab. By the end of one month two patients died resulting in 1-month survival of 17/19 (89%). By the end of two months four additional patients died resulting in 2-month survival of 68%. At the end of one and two months, compared to baseline, there was significant improvement in median values of Maddrey's DF (p < 0.05). Median serum TNF-α levels decreased from 45 (range 11-19,880) at baseline to 20 (range 4-8600)pg/mL at 4 weeks (p=0.001). CRP levels, MELD score, and absolute neutrophil count decreased significantly. Five patients (26%) developed infection: three of them had pneumonia, while two developed a flare of pulmonary tuberculosis. Three patients recovered with treatment but two patients (10%) died (one with pneumonia leading to sepsis and the other of disseminated tuberculosis). Absence of hepatic encephalopathy at admission significantly predicted survival. Among patients who survived only 1/13 (8%) had hepatic encephalopathy at admission while among patients who died 4/6 (67%) had hepatic encephalopathy (p=0.017). Lille score and delta bilirubin at day 7 (DBD7) (defined as [baseline serum bilirubin minus serum bilirubin at day 7]×100÷baseline serum bilirubin), also predicted 2-month mortality. The area under ROC curve of DBD7 values for predicting survival was 0.77 (95% CI 0.55-0.99). DBD7 of >7.5% best predicted survival in the patients (sensitivity 85%, specificity 67%, PPV 85%, NPV 67%, and overall accuracy 79%). Conclusions: In severe AH, single dose infliximab is associated with improvement in parameters of severity and survival. However, infection remains a concern. Hepatic encephalopathy at admission, Lille score and DBD7 predicted 2-month mortality. Large randomized controlled trials are needed before infliximab can be recommended for AH.