慢性乙型肝炎患者的血清标志物基线水平对干扰素治疗效果的预测价值

Predictive Value of Baseline Serum Marker Levels for the Effect of Interferon Therapy in Patients With Chronic Hepatitis B

目的 研究长效干扰素治疗核苷经治及初治慢性乙型肝炎(简称慢乙肝)病例的血清标志物变化及对临床预后的评价价值。方法 收集2019年10月–2022年4月411例慢乙肝加用长效干扰素病例的临床资料,对经治组及初治组病例的血清标志物进行比较,其中经治病例为HBV感染半年以后经核苷(酸)类治疗半年以上,初治病例为HBV感染半年以后未治疗或停止核苷(酸)类治疗半年以上。采用受试者工作特征曲线(ROC曲线),评价基线HBsAg和HBV前基因组RNA(HBV pgRNA)对两组病例临床治愈的预测价值。结果 经治组与初治组治愈率无明显差异。两组中治愈病例的基线HBV DNA、HBsAg及HBeAg水平均低于未治愈病例(P<0.000 1)。在治疗48周时,经治及初治组治愈病例的血清HBsAb水平(mIU/mL)高于未治愈病例(经治:78.97±22.57 vs. 0.99±0.38, P<0.000 1;初治:235.50±175.00 vs. 1.32±0.88,P<0.000 1),初治治愈病例的血清HBsAb水平(mIU/mL)高于经治治愈病例(235.50±175.00 vs. 78.97±22.57, P<0.000 1)。治疗0~60周内两组治愈病例的HBV pgRNA水平比未治愈组低(P<0.000 1)。多因素logistic回归及ROC曲线分析显示:血清基线HBsAg是影响经治和初治病例干扰素疗效的影响因素和预测指标,其曲线下面积分别为0.80[95%置信区间(confidence interval, CI):0.742 3~0.861 5,P<0.000 1]和0.74(95%CI:0.628 3~0.860 4,P=0.007 9),其最佳截断值分别为244.60 IU/mL和934.40 IU/mL。而初治病例的血清基线HBV pgRNA水平<1 340.00 copies/mL时有较好的敏感性和特异性预判疗效,其基线HBV pgRNA的曲线下面积为0.964 9(95%CI:0.904 2~1.000,P<0.000 1)。结论 经治和初治病例中获得临床治愈的患者其基线HBV DNA、HBsAg、HBeAg以及治疗期间HBV pgRNA水平更低,第48周HBsAb水平更高。基线HBsAg水平能有效预测经治及初治患者的临床治愈结局,基线HBV pgRNA水平对初治患者的治疗结局也呈现较高的预测价值。

Objective To study the changes in the serum markers in chronic hepatitis B patients who have had previous treatment with long-acting interferon therapy of nucleoside and those who have not and to assess the value of the serum markers for clinical prognosis evaluation.Methods The clinical data of 411 cases of chronic hepatitis B were collected.All cases were given the additional treatment of long-acting interferon between October 2019 to April 2022.The cases were divided into two groups,a previously treated group consisting of patients who had been treated with nucleoside and nucleotide analogues(NAs)for more than 6 months after they became infected with hepatitis B virus(HBV)for over 6 months and an initial treatment group,or treatment naïve group,consisting of patients who had HBV infection for over 6 months and received no treatment or patients who have stopped NAs therapy for more than 6 months.The serum marker levels of the previously treated group and the initial treatment group,i.e.,the previously treatment-naïve patients,were compared,and the receiver operating characteristics(ROC)curve was used to evaluate the value of the baseline levels of hepatitis B surface antigen(HBsAg)and HBV pregenomic RNA(pgRNA)for predicting the rate of cured cases in the two groups.Results There was no significant difference in the rate of cured cases between the previously treated group and the initial treatment group.The baseline HBV DNA,HBsAg,and hepatitis B e antigen(HBeAg)levels of the cured cases in both groups were significantly lower than those in the uncured cases(P<0.0001).After 48 weeks of treatment,the serum HBsAb levels(mIU/mL)of the cured cases in both the previously treated and initial treatment groups were significantly higher than those of the uncured cases in the two groups(previously treated group:78.97±22.57 vs.0.99±0.38,P<0.0001;initial treatment group:235.50±175.00 vs.1.32±0.88,P<0.0001).The serum HBsAb levels(mIU/mL)of the cured cases in the initial treatment groups were significantly higher than that of cured cases in the previously treated group(235.50±175.00 vs.78.97±22.57,P<0.0001).Within 0 to 60 weeks of treatment,HBV pgRNA levels of cured cases in both groups were significantly lower than those of the the uncured cases in both groups(P<0.0001).Multivariate logistic regression and ROC curve analysis showed that baseline serum HBsAg was the influencing factor and predictor of interferon efficacy in both the previously treated cases and the initial treatment cases,with the area under the curve(AUC)being 0.80(95%confidence interval[CI]:0.7423-0.8615,P<0.0001)and 0.74(95%CI:0.6283-0.8604,P=0.0079),respectively,and the optimal cut-off values being 244.60 IU/mL and 934.40 IU/mL,respectively.However,the baseline serum HBV pgRNA level of under 1340.00 copies/mL in the initial treatment cases led to better sensitivity and better specificity in efficacy prediction,with the AUC of the baseline HBV pgRNA being 0.9649(95%CI:0.9042-1.0000,P<0.0001).Conclusion Among the previously treated cases and the initial treatment cases,patients who achieve clinical cure have lower levels of HBV DNA,HBsAg,and HBeAg at baseline,lower level of HBV pgRNA over the course of their treatment,and higher level of HBsAb at week 48.Baseline HBsAg levels can be used to effectively predict the clinical cure outcomes in previously treated cases and initial treatment cases.Baseline HBV pgRNA levels also exhibit a high predictive value for treatment outcomes in initial treatment cases.