Li’s Artificial Liver System Improves Survival In Patients With Hepatitis B Virus-related Acute-on-chronic Liver Failure: A Case-control Matched Analysis

Background & Aims: Acute-on-chronic liver failure(ACLF)is ACLF is critically ill with high mortality rate(50-90%)even from comprehensive medical treatment.The liver transplantation(LT)is currently the only available and curative therapy,however,a critical shortage of donor organs for transplantation result in the deaths of many patients waiting for LT.The nonbioartificial liver support system is recognized as a bridge to LT in hepatitis B virusrelated acute-on-chronic liver failure(HBV-ACLF)patients;however,its impact on patient survival remains unknown.The Chinese group on the study of severe hepatitis B(COSSH)organized a large,prospective,multicenter study and established a new diagnostic criteria for HBV-ACLF(COSSH-ACLF).In this study,we aimed to determine the survival effect of plasma exchange(PE)based-Li’s artificial liver system(Li-ALS)treatment on survival in HBV-ACLF patients and explore the mechanisms of the effect of Li-ALS on HBV-ACLF from a large multicentre cohort,on the basis of the COSSHACLF criteria.Four different rigorous analyses(multivariable-risk adjustment,casecontrol matching,propensity score matching(PSM)and inverse probability treatment weighting(IPTW))were performed to reduce bias and confounding.Methods: The clinical data of patients with HBV-ACLF collected in the period from July 2013 to December 2017 were obtained from the patients in the COSSH study open cohort.All patients were separated into two groups: a standard medical treatment(SMT)group(patients received only SMT),and an Li-ALS group(patients received an Li-ALS plus SMT).The main endpoints were cumulative survival rates at days 21,28 and 90.The secondary endpoints were 21-/28-/90-day LT-free mortality.A case-control matched analysis was used to reduce bias between the Li-ALS and SMT groups.The PSM and IPTW analysis were performed to confirm the survival effect of Li-ALS.A combination of human cytokine antibody array and bioinformatics analysis was used to identify differentially expressed cytokines and related biological pathway.Results: A total of 1103 patients were initially screened,and 924 patients with HBV-ACLF were finally enrolled in this study;507 patients were in the Li-ALS group(309 ACLF-1,176 ACLF-2,22 ACLF-3),and 417 patients were in the SMT group(245 ACLF-1,125 ACLF-2,47 ACLF-3).After case-control matching,276 one-to-one pairs were obtained(149 pairs for ACLF-1,108 pairs for ACLF-2 and 19 pairs for ACLF-3)for the Li-ALS and SMT groups.In the entire cohort,the median survival time was significantly longer in the Li-ALS group than in the SMT group(54 days vs.27 days,P <0.01).The cumulative survival rates at day 21/28/90 were significantly higher in patients who underwent Li-ALS treatment(73.3-/69.2-/56.5% vs.59.6-/56.6-/49.1%,respectively,P <0.01)than in those who underwent SMT only,especially in ACLF-2(52.7-/48.9-/33.2% vs.37-/33.2-/26.5%,P <0.05).In the 276-pair case-control matched cohort,a significantly longer survival time was also observed in the Li-ALS group than in the SMT group(48 days vs.26 days,P <0.05).Patients in the Li-ALS group had significantly higher survival rates than those with SMT only at day 21/28/90(72.5-/68.3-/55.9% vs.60.3-/57.4-/48.5%,respectively,P <0.05),especially in patients with ACLF-2(53.7-/50-/36.1% vs.37.5-/34.2-/26.3%,P <0.05).No significant differences were observed in ACLF-1 and ACLF-3.By a multivariable-adjusted analysis,Li-ALS treatment was associated with a significantly lower risk of mortality at day 21/28 [HR(95% CI): 0.721(0.565-0.921)/0.754(0.598-0.951),P <0.01],especially for ACLF-2 [HR(95% CI): 0.634(0.453-0.888)/0.589(0.419-0.828),P <0.05].These findings were also confirmed through PSM and IPTW analysis.After data analysis of human cytokine antibody array,12 cytokines were significantly differentially expressed during Li-ALS treatment.The production of cytokines involved in pro-inflammatory and immune activation(GCSF、E-Selectin、GRO-alpha、MIP-3beta、MICB、RANK and ICAM-3)was significantly decreased,whereas the immunomodulatory cytokines(IL-1 R4/ST2 and IL-2 Ralpha)increased post-Li-ALS compared to pre-Li-ALS.The main biological processes using functional enrichment analysis(with an adjusted P value <0.05)included inflammatory response,immune regulation,T cell activation,cytokine secretion,myeloid leukocyte differentiation and virus defense response.Conclusions: PE-based Li-ALS treatment can improve the short-term survival and associated with a significantly lower risk of short-term mortality in patients with HBV-ACLF,especially in ACLF-2.The efficacy of Li-ALS treatment on HBV-ACLF might be attributable to inhibition of inflammatory response,attenuation of immune activation and regulation of immune process.Early treatment with Li-ALS may help to reduce the unacceptably high mortality of patients with HBV-ACLF.