摘要
目的研究初治慢性乙型肝炎(CHB)患者接受聚乙二醇干扰素α-2b(Peg-IFNα-2b)抗病毒治疗的疗效及免疫机制。方法纳入2021年3月至2023年3月于南昌大学第二附属医院感染性疾病科就诊的166例初治CHB患者,均接受Peg-IFNα-2b治疗48周,检测并比较抗病毒治疗前后患者的乙型肝炎病毒(HBV)DNA、HBV血清学标志物、血清生物化学指标变化,以及外周血淋巴细胞亚群和血清细胞因子水平。统计学比较采用χ^(2)检验、曼-惠特尼U检验和配对样本t检验。采用逐步回归法进行多因素logistic回归分析实现乙型肝炎表面抗原(HBsAg)血清学转换的影响因素,并采用受试者操作特征曲线(ROC曲线)评估各项免疫指标对实现HBsAg血清学转换的预测效能。结果166例初治CHB患者Peg-IFNα-2b治疗48周后,HBV DNA阴转率为71.08%(118/166),乙型肝炎e抗原(HBeAg)阴转率为32.05%(25/78),HBsAg阴转率为20.48%(34/166)。治疗前HBsAg<200 IU/mL者的HBsAg阴转率为52.17%(24/46),HBsAg为200~<1200 IU/mL组为10.26%(4/39),HBsAg≥1200 IU/mL组为7.41%(6/81),三组患者HBsAg阴转率差异有统计学意义(χ^(2)=39.37,P<0.001)。治疗48周后血清丙氨酸转氨酶、天冬氨酸转氨酶、总胆红素、甲胎蛋白均低于治疗前,差异均有统计学意义(Z=9.33、8.58、5.99、2.36,均P<0.05)。58例CHB患者检测免疫指标,与治疗前比较,治疗48周后外周血淋巴细胞占有核细胞比例、CD3^(+)CD8^(+)T/CD3^(+)T、CD3^(+)CD4^(+)DR+/CD3^(+)CD4^(+)、CD3^(+)CD8^(+)DR+/CD3^(+)CD8^(+)、CD3^(+)CD8^(+)CD38^(+)/CD3^(+)CD8^(+)、CD3^(+)CD8^(+)CD28^(+)/CD3^(+)CD8^(+)和CD19^(+)B占淋巴细胞比例均升高(t=-2.56、t=-8.65、Z=-3.58、t=-3.66、Z=-3.04、t=-3.62、t=-3.87,均P<0.05),CD3^(+)T占淋巴细胞比例、CD3^(+)CD4^(+)T/CD3^(+)T、CD3^(+)CD4^(+)CD45RO^(+)/CD3^(+)CD4^(+)、CD3^(+)CD8^(+)CD45RO^(+)/CD3^(+)CD8^(+)和CD4^(+)/CD8^(+)比值均降低(t=3.13、t=5.61、t=3.69、Z=3.95、Z=7.33,均P<0.05),差异均有统计学意义。CD16^(+)CD56^(+)NK(自然杀伤细胞)占淋巴细胞比例、CD3^(+)CD4^(+)CD28^(+)/CD3^(+)CD4^(+)、CD3^(+)CD4^(+)CD38^(+)/CD3^(+)CD4^(+)治疗前后差异均无统计学意义(均P>0.05)。与治疗前比较,治疗48周后血清白细胞介素(IL)-8、IL-12P70、IL-17水平均下降(Z=2.85、3.26、4.12,均P<0.05),IL-2、IL-1β、α干扰素水平均升高(Z=-4.92、-4.85、-9.01,均P<0.001),差异均有统计学意义。IL-4、IL-6、IL-10治疗前后差异均无统计学意义(均P>0.05)。多因素回归分析结果显示:治疗前的CD3^(+)CD8^(+)T/CD3^(+)T[比值比(OR)=1.198,95%可信区间(CI)1.003~1.432,P=0.046]、CD3^(+)CD4^(+)DR+/CD3^(+)CD4^(+)(OR=1.185,95%CI 1.035~1.357,P=0.014)、CD3^(+)CD8^(+)DR+/CD3^(+)CD8^(+)(OR=0.813,95%CI 0.690~0.958,P=0.013)、CD3^(+)CD4^(+)CD38^(+)/CD3^(+)CD4^(+)(OR=0.678,95%CI 0.488~0.940,P=0.020)、CD3^(+)CD8^(+)CD38^(+)/CD3^(+)CD8^(+)(OR=1.272,95%CI 1.069~1.512,P=0.007)、CD19^(+)B占淋巴细胞比例(OR=0.752,95%CI 0.582~0.971,P=0.029)、IL-2(OR=8.568,95%CI 1.927~38.087,P=0.005)、IL-17(OR=0.728,95%CI 0.535~0.989,P=0.042)是实现HBsAg血清学转换的独立影响因素。治疗前的dCD19^(+)B占淋巴细胞比例(即CD19^(+)B占淋巴细胞比例的倒数)预测HBsAg实现血清学转换的曲线下面积(AUC)为0.716,灵敏度为0.636,特异度为0.809;IL-2的AUC为0.657,灵敏度为0.818,特异度为0.404;dIL-17(即IL-17的倒数)的AUC为0.624,灵敏度为0.727,特异度为0.489;IL-2与dIL-17作为联合预测因子的AUC为0.830,灵敏度为0.909,特异度为0.787。结论Peg-IFNα-2b治疗初治CHB患者具有良好的病毒学、生化学和血清学应答,HBsAg<200 IU/mL的患者疗效更佳,HBsAg阴转率可达到52.17%;Peg-IFNα-2b可通过提升T淋巴细胞活化亚群及功能亚群比例调节CHB患者的免疫功能;CD19^(+)B占淋巴细胞比例、IL-2、IL-17对HBsAg实现血清学转换具有预测价值。
Objective:To evaluate the efficacy and immunological mechanisms of pegylated interferon α-2b(Peg-IFNα-2b)antiviral therapy in treatment-naive patients with chronic hepatitis B(CHB).Methods:A total of 166 treatment-naive CHB patients,who were treated at Department of Infectious Diseases,the Second Affiliated Hospital of Nanchang University from March 2021 to March 2023,were enrolled in this study.All the patients received Peg-IFNα-2b therapy for 48 weeks.Serum hepatitis B virus(HBV)DNA,HBV serological markers,biochemical parameters,peripheral blood lymphocyte subsets and serum cytokine levels were detected and compared before and after treatment.Chi-square test,Mann-Whitney U test and paired sample t test were used for statistical comparison.Multivariate logistic regression analysis was used to analyze the influencing factors of hepatitis B surface antigen(HBsAg)seroconversion by stepwise regression method,and the receiver operator characteristic curve(ROC curve)was used to evaluate the predictive efficacy of immune indicators on HBsAg seroconversion.Results:Among the 166 treatment-naive CHB patients,the rate of HBV DNA negativity following 48 weeks of Peg-IFNα-2b therapy was 71.08%(118/166),the rate of hepatitis B e antigen(HBeAg)negativity was 32.05%(25/78),and the rate of HBsAg negativity was 20.48%(34/166).HBsAg negativity rate was 52.17%(24/46)in patients with baseline HBsAg<200 IU/mL,10.26%(4/39)in patients with baseline HBsAg 200 to<1200 IU/mL,and 7.41%(6/81)in patients with baseline HBsAg≥1200 IU/mL,and the difference was statistically significant(χ^(2)=39.37,P<0.001).After 48 weeks of treatment,serum levels of alanine transaminase(ALT),aspartate transaminase(AST),total bilirubin(TBil),and alpha-fetoprotein(AFP)were significantly lower than those before treatment(Z=9.33,8.58,5.99,2.36,respectively,all P<0.05).lmmune indicators were detected in 58 patients,and the proportion of peripheral blood lymphocytes increased significantly post-treatment,with notable increases in CD3^(+)CD8^(+)T/CD3^(+)T,CD3^(+)CD4^(+)DR+/CD3^(+)CD4^(+),CD3^(+)CD8^(+)DR+/CD3^(+)CD8^(+),CD3^(+)CD8^(+)CD38^(+)/CD3^(+)CD8^(+),CD3^(+)CD8^(+)CD28^(+)/CD3^(+)CD8^(+),and CD19^(+)B cells,and the differences were all statistically significant(t=-2.56,t=-8.65,Z=-3.58,t=-3.66,Z=-3.04,t=-3.62,t=-3.87,respectively,all P<0.05).Conversely,the proportion of CD3^(+),CD3^(+)CD4^(+)T/CD3^(+)T,CD3^(+)CD4^(+)CD45RO^(+)/CD3^(+)CD4^(+),CD3^(+)CD8^(+)CD45RO^(+)/CD3^(+)CD8^(+)and the CD4^(+)/CD8^(+)ratio decreased significantly post-treatment(t=3.13,t=5.61,t=3.69,Z=3.95,Z=7.33,respectively,all P<0.05).No significant differences were observed in the proportion of CD16^(+)CD56^(+)natural killer(NK)cells,CD3^(+)CD4^(+)CD28^(+)/CD3^(+)CD4^(+),CD3^(+)CD4^(+)CD38^(+)/CD3^(+)CD4^(+)cells before and after treatment(all P>0.05).Serum levels of interleukin(IL)-8,IL-12P70,and IL-17 significantly decreased post-treatment(Z=2.85,3.26,4.12,respectively,all P<0.05),while IL-2,IL-1β,and interferon(IFN)-αlevels were significantly elevated compared to baseline(Z=-4.92,-4.85,-9.01,respectively,all P<0.001).There were no significant differences in IL-4,IL-6,and IL-10 levels before and after treatment(all P>0.05).Logistic regression analysis identified CD3^(+)CD8^(+)T/CD3^(+)T(odd ratios(OR)=1.198,95%confidence interval(CI)1.003 to 1.432,P=0.046),CD3^(+)CD4^(+)DR+/CD3^(+)CD4^(+)(OR=1.185,95%CI 1.035 to 1.357,P=0.014),CD3^(+)CD8^(+)DR+/CD3^(+)CD8^(+)(OR=0.813,95%CI 0.690 to 0.958,P=0.013),CD3^(+)CD4^(+)CD38^(+)/CD3^(+)CD4^(+)(OR=0.678,95%CI 0.488 to 0.940,P=0.020),CD3^(+)CD8^(+)CD38^(+)/CD3^(+)CD8^(+)(OR=1.272,95%CI 1.069 to 1.512,P=0.007),CD19^(+)B cells(OR=0.752,95%CI 0.582 to 0.971,P=0.029),IL-2(OR=8.568,95%CI 1.927 to 38.087,P=0.005),and IL-17(OR=0.728,95%CI 0.535 to 0.989,P=0.042)as independent factors influencing HBsAg seroconversion.The area under the curve(AUC)of the proportion of dCD19^(+)B cells(the reciprocal of CD19^(+)B cells)for predicting HBsAg seroconversion was 0.716,the sensitivity was 0.636,and the specificity was 0.809.The AUC of IL-2 was 0.657,the sensitivity was 0.818,and the specificity was 0.404.The AUC of dIL-17(the reciprocal of IL-17 levels)was 0.624,the sensitivity was 0.727,and the specificity was 0.489.The AUC of IL-2 and dIL-17 as a combined predictor was 0.830,the sensitivity was 0.909,and the specificity was 0.787.Conclusions:Peg-IFNα-2b demonstrates significant antiviral,biochemical,and serological responses in treatment-naive CHB patients,with enhanced efficacy in patients exhibiting HBsAg levels<200 IU/mL.In patients with HBsAg<200 IU/mL,the rate of HBsAg negativity reached 52.17%.Peg-IFNα-2b can regulate the immune function of patients with CHB by increasing the proportion of activated T lymphocyte subsets and functional subsets.The proportion of CD19^(+)B cells,IL-2 levels,and IL-17 levels hold predictive value for achieving HBsAg seroconversion.
作者
宋淑芬
金奉仙
蓝玉
张功长
吴志国
周瑶
谢琼
杨龙
孙水林
Song Shufen;Jin Fengxian;Lan Yu;Zhang Gongchang;Wu Zhiguo;Zhou Yao;Xie Qiong;Yang Long;Sun Shuilin(Department of Infectious Diseases,the Second Affiliated Hospital of Nanchang University,Nanchang 330006,China)
出处
《中华传染病杂志》
北大核心
2025年第1期14-23,共10页
Chinese Journal of Infectious Diseases
基金
中国降低乙肝患者肝癌发生率(绿洲)工程项目。
