Table 8_Altered expression of ADAR1, N4BP1, and PSME1 in PBMCs correlated with therapeutic outcomes in HBeAg-negative chronic hepatitis B patients treated with Peg-IFN-α.docx

Background and aimsPegylated interferon alpha (Peg-IFN-α) has the potential for eradicating hepatitis B surface antigen (HBsAg). The aim of our study is to investigate whether the expression levels of adenosine deaminase acting on RNA 1 (ADAR1), NEDD4-binding protein 1 (N4BP1), proteasome activator complex subunit 1 (PSME1) mRNAs in peripheral blood mononuclear cells (PBMCs) of HBeAg-negative chronic hepatitis B virus (HBV) patients are associated with the response to Peg-IFN-α treatment and HBsAg clearance.
MethodsIn this prospective study, HBeAg-negative chronic HBV patients treated with Peg-IFN-α were followed for 48 weeks. Patients were categorized into the virological response (VR) group and non-virological response (NVR) group based on the observed changes in HBV DNA and HBsAg levels at week 48 of treatment. Additionally, patients were classified into a serological response (SR) group and a non-serological response (NSR) group according to whether serum HBsAg loss or seroconversion occurred. The expression levels of ADAR1, N4BP1, and PSME1 mRNAs in PBMCs were detected by real-time quantitative PCR. The diagnostic performance of ADAR1, N4BP1, and PSME1 was assessed by analyzing the receiver operating characteristic (ROC) curve and calculating the area under the curve (AUC).
ResultsAfter the treatment period, the VR and SR rates were 47.25% and 35.16%, respectively. Dynamic changes in ADAR1, N4BP1, and PSME1 mRNA levels differed significantly between the VR and NVR groups, as well as between the SR and NSR groups. Multivariate analysis revealed that ADAR1 was independently associated with VR and SR at weeks 12 and 24; N4BP1 was independently associated with VR at weeks 12 and 24; PSME1 was independently associated with VR and SR at weeks 12 and 24. At week 24, the AUCs for ADAR1 in predicting VR and SR were 0.9230 and 0.8554. N4BP1 had AUCs of 0.7393 for VR at week 12 and 0.7198 for SR at week 24, while PSME1 had AUCs of 0.7418 for VR and 0.7426 for SR at week 12.
ConclusionsADAR1, N4BP1, and PSME1 are novel biomarkers for early therapeutic response to Peg-IFN-α and HBsAg clearance.
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背景与研究目的
聚乙二醇化干扰素α（Pegylated interferon alpha, Peg-IFN-α）具备清除乙型肝炎表面抗原（hepatitis B surface antigen, HBsAg）的潜力。本研究旨在探讨乙型肝炎e抗原（hepatitis B e antigen, HBeAg）阴性慢性乙型肝炎（hepatitis B virus, HBV）患者外周血单个核细胞（peripheral blood mononuclear cells, PBMCs）中作用于RNA的腺苷脱氨酶1（adenosine deaminase acting on RNA 1, ADAR1）、NEDD4结合蛋白1（NEDD4-binding protein 1, N4BP1）以及蛋白酶体激活复合物亚基1（proteasome activator complex subunit 1, PSME1）的mRNA表达水平，是否与Peg-IFN-α治疗应答及HBsAg清除相关。
研究方法
本研究为前瞻性队列研究，纳入接受Peg-IFN-α治疗的HBeAg阴性慢性HBV患者，随访时长为48周。根据治疗48周时HBV DNA及HBsAg水平的变化情况，将患者分为病毒学应答（virological response, VR）组与非病毒学应答（non-virological response, NVR）组；同时依据患者是否出现血清HBsAg消失或血清学转换，将其划分为血清学应答（serological response, SR）组与非血清学应答（non-serological response, NSR）组。采用实时定量聚合酶链反应（real-time quantitative PCR）检测PBMCs中ADAR1、N4BP1及PSME1的mRNA表达水平。通过分析受试者工作特征（receiver operating characteristic, ROC）曲线并计算曲线下面积（area under the curve, AUC），评估上述三个基因的诊断效能。
研究结果
治疗周期结束后，VR组与SR组的占比分别为47.25%与35.16%。VR组与NVR组、SR组与NSR组之间，ADAR1、N4BP1及PSME1的mRNA表达水平动态变化均存在显著差异。多因素分析结果显示，在治疗第12周与第24周，ADAR1表达水平分别与VR及SR独立相关；N4BP1表达水平在第12周与第24周均与VR独立相关；PSME1表达水平在第12周与第24周分别与VR及SR独立相关。在治疗第24周，ADAR1预测VR与SR的AUC分别为0.9230与0.8554；N4BP1在第12周预测VR的AUC为0.7393，在第24周预测SR的AUC为0.7198；PSME1在第12周预测VR与SR的AUC分别为0.7418与0.7426。
研究结论
ADAR1、N4BP1及PSME1可作为预测Peg-IFN-α早期治疗应答及HBsAg清除的新型生物标志物。
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