Long-term Outcomes Of Antiviral Therapy And Relationship Between Changes Of HBsAg Kinetics And Host Adaptive Immunity In Chronic Hepatitis B Patients

PART 1.POOR PROGNOSIS CORRELATES CHRONIC HEPATITIS B PATIENTS WITH LOW-LEVEL VIREMIAObjectives: Currently,there are not enough clinical data to address whether low-level viremia(LLV)observed during antiviral treatment will adversely affect the clinical outcome or whether treatment strategies need to be changed if LLV occurs.This study compared the clinical outcomes of patients with a maintained virological response(MVR)and patients who experienced LLV and their treatment strategies.Methods: A retrospective cohort of 674 patients with chronic hepatitis B virus(HBV)infection who received antiviral treatment for more than 12 months was analyzed for the development of end-stage liver disease(includeing decompensated liver cirrhosis and hepatocellular carcinoma)and treatment strategies during the follow-up period.Results: During a median 42-month follow-up,end-stage liver disease developed more frequently in patients who experienced LLV than in those who experienced MVR(7.73% and 15.85% versus 0.77% and 5.52% at 5and 10 years,respectively;P=0.000).After propensity score matching(PS matching),the trend was consistent with the result before matching.Especially in the high-risk group of four HCC risk models,LLV patients had a higher risk of development of HCC(p<0.05).By Cox proportional hazard model analysis,LLV was an independent risk factor for end-stage liver disease and HCC(HR=6.280,CI=2.081-18.951,p=0.001;HR=5.108,CI=1.392-18.737,respectively;p=0.014).Patients achieved a lower rate of end-stage liver disease by adjusting treatment compared to continuing the original treatment once LLV occurred(p<0.05).Conclusions: LLV was an independent risk factor for end-stage liver disease and HCC,and the treatment strategies can be modified if necessary.PART 2.EFFECT OF HOST ADAPTIVE IMMUNE FUNCTION ON HBSAG KINETICS IN NUCLEOS(T)IDE ANALOGUE EXPERIENCED CHRONIC HEPATITIS B PATIENTSObjectives: Hepatitis B s antigen(HBs Ag)is an important reference for the amount of covalently closed circular DNA.HBs Ag levels < 3,000 IU/ml in patients were related to partial restoration of immune function and patients may benefit from low HBs Ag levels.The purpose of this study was to evaluate the changes of HBs Ag kinetics and immunological characteristics of host adaptive function in nucleos(t)ide analogue experienced chronic hepatitis B patients who continued to take oral antiviral drug at low levels of HBs Ag.And to search for biomarkers that can predict the decline of HBs Ag.Methods: A total of 197 HBV infected patients with HBs Ag < 3,000 IU/ml and HBV DNA ?1,000 IU/ml after more than a year of antiviral therapy were divided into a nucleotide analogs(NAs)group and an entecavir(ETV)group.HBs Ag quantification were determined every 6 months until 42 months.The serum chemokine and cytokine levels at baseline and 6,18,and 30 months among 54 hepatitis B e antigen(HBe Ag)-positive matched patients were measured.Twenty-nine patients were divided into Group1(n = 11)and Group2(n = 18)according to HBs Ag levels reduction more than 0.5 log10 or not during January 2016 toOctober 2019.The phenotypes of cellular immunity and humoral immunity were detected by flow cytometry(FCM).Results: The cumulative incidences of HBs Ag reduction and the HBs Ag change in the NAs group were better than those in the ETV group(P<0.05).Interleukin(IL)4,IL5,IL10,TGF ?,IL17 and PD-1 decreased gradually during NAs treatment(p < 0.05),but the changes were not obvious during ETV treatment.Compared with the host adaptive immune function,there were significant differences between Group1 and Group2 in B cell surface molecules CD40,ICOSL and Tfh cell surface receptor CD40 L,IL21R and suppressor PD-1(p < 0.05).In Group1,more TN cells were observed to differentiate into TCM and TEFF to exert their antiviral effects.With the decrease of HBs Ag,Th1 and Th1/Th2 levels were higher and the level of Treg was lower than baseline,therefore the imbalance of T cell subsets was corrected(P < 0.05).At the same time,with the decrease of HBs Ag,Tim3/CCR4 decreased significantly and IFN ?/IFN ?/CCL5 increased significantly(p < 0.05).Finally,we found that the combination of IL4,IL23 and MDC levels in baseline and alanine aminotransferase(ALT)changes during antiviral therapy could predict HBs Ag reduction(AUC = 0.961,p < 0.000).Conclusions: NAs therapy had some advantages in promoting a reduction in HBs Ag.Humoral immune response and maturation of T cells play an important role in the loss of HBs Ag.Comparison of CD4+T cell subsets and its surface molecules showed that the exhausted immunity was alleviated and the antiviral activity was enhanced during HBs Ag reduction.In clinical practice,IL4,IL23,MDC and ALT may be biomarkers for predicting HBs Ag reduction.