The Clinical Study On The Effectiveness Of Plasma Perfusion Combined With Plasma Exchange In Hepatitis B Virus-related Acute-on-chronic Liver Failure

Background:Acute-on-chronic liver failure(ACLF)is a complex clinical syndrome characterized by acute and severe hepatic decompensation of chronic liver disease and frequently accompanied by high incidences of extra-hepatic organ failures,complications and death.Targeted treatment options are still lacking currently.Various toxic substances often accumulate in patients with liver failure,including conjugated or unconjugated bilirubin,protoporphyrin,bile acid,glycoside derivatives,phenol,short and medium chain fatty acids,heterocyclic organic compounds,blood ammonia,creatinine,urea nitrogen and smaller proteins(such as certain cytokines).These toxic substances are considered to be one of the causes of hepatic encephalopathy(cerebral failure),hepatorenal syndrome(kidney failure),hemodynamic disturbance(coagulation failure)or immune paralysis(infection).The treatment for toxic substances may be an effective mean of treating complications of liver failure.Along with the continuous improvement of comprehensive treatment,the in-hospital mortality rate of ACLF has declined by 10%-20% in the last decade,it still stands at 50%-80% in patients with multiple organ failures.Although liver transplantation is regarded as the most effective treatment in ACLF patients,the shortage of liver donors results in high risk of mortality for ACLF patients on waiting lists.Artificial liver support system(ALSS)is an in vitro life support system that replaces liver functions to removes some harmful substances,supplys essential coagulation factors,albumin and other substances,and improves the internal environment,which creates conditions for hepatocyte regeneration or liver transplantation.Generally,ALSS include plasma perfusion(PP),plasma exchange(PE),double plasma molecular adsorption system(DPMAS),single-pass albumin dialysis system(SPAD),molecular adsorbent recirculating system(MARS),fractionated plasma separation and adsorption system(FPSA)and so on.In this study,PP combined with PE was employed.PP was performed with the plasma separation technology to separate patients’ plasma,which then flowed through a perfusion device(adsorption column)filled with anionic resin adsorbent.The adsorption property of anionic resin was used to remove toxins related to liver failure,such as bilirubin and bile acid.PE was performed with a membrane plasma filter for patients’ plasma separation and replacement of equivalent amounts of substitute plasma from healthy individuals,thereby removing toxins related to liver failure and supplementing essential substances such as coagulation factors and albumin.PP combined with PE is a commonly used ALSS technique in the treatment of liver failure in China.At present,domestic scholars have carried out some clinical studies on the treatment of ACLF patients with PP combined with PE,but there is no research report abroad.The clinical research that meets the international ACLF inclusion criteria is still scarce,and this limits the international clinical application of this artificial liver technology.In addition,the effect of PP combined with PE on survival rate in the treatment of ACLF patients remains controversial.Although there have been reports on the treatment of ACLF with PP combined with PE,these studies have the following shortcomings,which are mainly reflected in the lack of the control group,the lack of matching of baseline characteristics of patients between the groups,and few studies using statistical methods(such as propensity score matching)to correct baseline characteristics bias,etc.These factors limit the clinical interpretation of the research conclusions of related studies.Lastly,the survival benefits of ALSS for treating ACLF patients at different stages are still unclear.At present,most domestic scholars advocate ALSS treatment in the early stage of ACLF,but its specific indicators are still vague.Some studies have used model for end-stage liver disease score(MELDs)to guide ALSS treatment.But existing studies have confirmed that MELDs is not effective in predicting the prognosis of hepatitis B virus(HBV)related ACLF(HBV-related ACLF,HBV-ACLF)patients.Our previous studies(Hepatology International.2012,Hepatology International.2019)suggested that the number of complications was an important indicator that affected the 28-day and 90-day survival rates of ACLF patients,and could be used as an effective stratification method for ACLF disease severity.The number of organ failures is also a good indicator for the disease severity stratification of ACLF.When this study was carried out,there was only one international study that used the stratification method of organ failure number to explore the survival benefit of MARS treatment in ACLF subgroup.There has not been a clinical study on the survival benefit of the ACLF subgroup with PP combined with PE treatment using the number of organ failures and complications as indicators of disease stratification in China and abroad.Based on the above research status,this study will include HBV-ACLF patients defined by the Asian Pacific Association for the Study of the Liver-ACLF Research Consortium(AARC)criteria for cohort analysis,and use the propensity score matching(PSM)method to correct the clinical feature bias,and use the number of organ failures and complications for subgroup analysis,thus providing evidence-based medical evidence for the clinical application of PP combined with PE in the treatment of HBV-ACLF patients in China and abroad.Part Ⅰ The overall effectiveness of plasma perfusion combined with plasma exchange in the treatment of hepatitis B virus-related acute-on-chronic liver failureObjective: To evaluate the overall effectiveness of PP combined with PE treatment in patients with HBV-ACLF.Methods: 2021 patients who were diagnosed with chronic hepatitis B-related severe liver injury or acute decompensation of cirrhosis at the Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology from January 2013 to December 2018 were collected.The AARC ACLF criteria were used as HBV-ACLF diagnostic criteria.Among them,patients who only received standard medical therapy(SMT)were included in the SMT group,and patients who received SMT and PP combined with PE treatment were included in the PP + PE group.PSM method was used to correct baseline characteristics bias.Laboratory indicators,disease severity scores,28-day and 90-day cumulative survival rates or mortality and complications were used as evaluation indicators for effectiveness.Kaplan-Meier method was used to draw survival curve and Log rank test was used to evaluate survival difference.The Cox proportional hazard regression model was used for multivariate analysis to further evaluate the effectiveness of PP combined with PE treatment and prognostic factors.Results: A total of 898 patients with HBV-ACLF were enrolled,including 418 in the SMT group and 480 in the PP + PE group.1:1 PSM was performed,and 293 pair patients from the two groups were matched after PSM.Total bilirubin,international normalized ratio,prothrombin activity,MELDs,the chronic liver failure consortium-organ failure score(CLIF-OFs),the Chinese group on the study of severe hepatitis B-ACLF score(COSSH-ACLFs)and hepatic encephalopathy were significantly improved(p<0.05).Compared with the SMT group,the 28-day and 90-day cumulative survival rates of patients in the PP + PE group were significantly improved(post-PSM: Log rank,p<0.05).Before and after PSM,compared with SMT,PP combined with PE significantly reduced 28-and 90-day mortality risk(p<0.0001);Multivariate analysis of the Cox proportional hazards regression model showed that PP combined with PE treatment is a protective factor for the short-term prognosis of HBV-ACLF patients;Age,total bilirubin,international normalized ratio and brain failure are independent risk factors for the short-term prognosis of HBV-ACLF patients(p<0.0001).Conclusion: PP combined with PE treatment can improve liver function,coagulation function,disease severity scores and hepatic encephalopathy in patients with HBV-ACLF.Compared with SMT,PP combined with PE treatment can significantly improve the 28-day and 90-day survival rates of the overall population.PP combined with PE treatment,age,total bilirubin,international normalized ratio and brain failure are related to the short-term prognosis of HBV-ACLF patients.Part Ⅱ The subgroup analysis of plasma perfusion combined with plasma exchange in the treatment of hepatitis B virus-related acute-on-chronic liver failureObjective: To explore the subgroup of HBV-ACLF patients with survival benefit in PP combined with PE treatment.Methods: The AARC criteria were used as HBV-ACLF diagnostic criteria.Among them,patients who only received SMT were included in the SMT group,and patients who received SMT and PP combined with PE treatment were included in the PP + PE group.Single liver or extrahepatic organ failures were defined by the chronic liver failure-sequential organ failure assessment score(CLIF-SOFAs)criteria.Complications include ascites,infection,hepatopulmonary syndrome,hepatorenal syndrome,hepatic encephalopathy and upper gastrointestinal bleeding.The number of organ failures or complications was used as stratification indicators for subgroup analysis.PSM was used to correct baseline characteristics bias.Laboratory indicators,disease severity scores,28-day and 90-day cumulative survival rates or mortality were used as evaluation indicators for effectiveness.Kaplan-Meier method was used to draw survival curve and Log rank test was used to evaluate survival difference.The Cox time-dependent covariate regression model and the Cox proportional hazard regression model were used for multivariate analysis to further evaluate the effectiveness of PP combined with PE treatment.Results: A total of 898 patients with HBV-ACLF were enrolled,including 418 in the SMT group and 480 in the PP + PE group.Before PSM,there were 149,181 and 88 patients in the SMT group combined with zero,one and two or more organ failures,and 58,303 and 119 patients in the PP + PE group,respectively.There were 130,145 and 143 patients in the SMT group combined with zero,one and two or more complications,and 175,199 and 106 patients in the PP + PE group,respectively.After PSM,there were 48,159 and 58 pairs of patients in the SMT and PP + PE groups combined with zero,one and two or more organ failures,and there were 97,89 and 84 pairs in the SMT and PP + PE groups combined with zero,one and two or more complications,respectively.PP combined with PE treatment can significantly improve the total bilirubin,international normalized ratio,prothrombin activity,MELDs,CLIF-OFs and COSSH-ACLFs in different subgroups of patients(p<0.05).Compared with SMT,PP combined with PE treatment can significantly improve the 28-day and 90-day cumulative survival rates of patients with two or more organ failures or complications(before and after PSM: Log rank,p<0.05).Before and after PSM,compared with SMT,PP combined with PE treatment can significantly reduce the 28-day and 90-day mortality risk in subgroups of patients with two or more organ failures or complications(p<0.0001).Conclusion: PP combined with PE treatment can significantly improve liver function,coagulation function and disease severity scores of patients in different subgroups.HBV-ACLF patients with two or more organ failures or complications is the survival benefit subgroup after PP combined with PE treatment.