慢性乙型肝炎患者前S1蛋白C末端IgG抗体与干扰素早期疗效的相关性
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摘要
背景干扰素是目前确定的具有长期改善慢性乙型肝炎患者肝脏组织学的药物,一些临床实验显示,忽略人种的不同,大约20–30%的慢性乙型肝炎患者对干扰素产生应答,即HBV DNA转阴、e抗原的转换、转氨酶的复常,这种应答能长程改善疾病的预后,减少慢性乙型肝炎患者进展至肝癌的风险,发生应答的患者疗效确切,但应答率较低,因此在治疗前分析影响应答的各个预测因素十分必要。
目的检测HBV B基因型患者血清中抗前S1蛋白C末端(94-117aa)IgG抗体,探讨其与干扰素治疗早期应答的关系。
方法对使用干扰素治疗的B基因型慢性乙型肝炎患者69例进行前瞻性研究,其中普通干扰素(α-1b,α-2b)42例,PEG干扰素(α-2a)27例,采用型特异性引物PCR方法进行基因型测定。按照HBV B基因型序列合成前S1蛋白C末端(94–117aa)多肽,用酶联免疫吸附法检测其相应抗体的存在情况。干扰素早期应答以随访12周时的病毒载量下降幅度及转氨酶和血清学标志物的变化为指标进行评价。根据抗前S1蛋白C末端(94–117aa)抗体的反应性将69例B基因型的慢性乙型肝炎患者分为两组,评判两组干扰素疗效的差别。
结果抗前S1蛋白C末端(aa94–117)IgG抗体(简称抗S1)阳性组和阴性组分别为21例和48例,两组间干扰素种类分布无显著性差异(x2=1.413,P=0.235)。治疗12周时,抗S1阳性组和阴性组HBV DNA下降值平均分别为3.37lg拷贝/ml和0.33lg拷贝/ml,Z=-3.658,P=0.000,差异有统计学意义;ALT下降值平均分别为92 U/L和30.5 U/L,Z =-2.132,P=0.033,差异有统计学意义。治疗12周时,抗S1阳性组有41.2%(7/17)发生HBeAg阴转,5.9%(1/17)发生血清学转换,抗S1阴性组仅有12.8%(5/39)发生HBeAg阴转,没有病例出现血清学转换(0/39),Z= -5.11, P=0.000,差异有统计学意义;抗S1阳性组与阴性组分别有71.4%(15/21)和16.7%(8/48)发生病毒学应答,x2=19.71,P=0.00,差异有统计学意义;两组分别有23.8%(5/21)和6.3%(3/48)发生完全应答,52.4%(11/21)和18.8%(9/48)发生部分应答,Z=-4.84, P =0.000,差异有统计学意义。抗前S1 C末端(94–117aa)IgG抗体在预测干扰素的早期应答中阳性预测值为71.4%,阴性预测值则为83.3%。
结论可以通过对治疗前血清中抗前S1 C末端抗体的检测,筛选出合适的慢乙型肝炎患者,进行个体化治疗,提高干扰素治疗的应答率。
Background Alpha-Interferon (IFN-alpha) is the only agent with an established long-term beneficial effect on the natural history of chronic hepatitis B (CHB). Several controlled clinical trials using IFN-alpha have shown that approximately 20–30% of treated patients with CHB, regardless of ethnic background, will lose HBV DNA and HBeAg and normalise transaminases. This response has been shown to have beneficial long-term effects on disease outcome, in addition the risk of developing hepatocellular carcinoma is reduced in IFN-alpha-treated patients with CHB. Because of the therapeutic benefit experienced by the group of patients with the capacity to respond to IFN-alpha therapy, identification of pretreatment factors predicting response is needed.
Objective To determine the relationship between IgG antibody against the C-terminal region of the preS1 protein of hepatitis B virus and the capacity of early response to interferon therapy in chronic hepatitis B.
Methods 69 patients with chronic hepatitis B virus (genotype B) infection were recruited in this study. 42 patients were treated with interferon-α-1b orα-2b, and 27 patients were treated with PEG interferon (α-2a). Peptide mimicking the C-terminal region of the preS1 protein(94-117aa) of genotype B HBV were synthesised, and the IgG antibody against this peptide was measured by enzymelinked immunosorbent assay (ELISA), and the early response to IFN-alpha therapy was judged by the effect on the viral kinetics, transaminase and the status of HBeAg at 12th week after the treatment.
Results 21 patients were positive for anti-preS1 antibody, and 48 patients were negative for anti-preS1 antibody. The average decrease in viral levels was 3.37lg copies/ml and 0.33lg copies/ml in anti-PreS1 positive patients and anti-preS1 negative patients, respectively 12 weeks after the treatment, the difference between the two groups was significant (Z = -3.658, P = 0.000 ); the average decrease in ALT levels was 92 U/L and 30.5 U/L in two groups, respectively (Z = -2.132, P = 0.033). The rate of hepatitis B e antigen (HBeAg) loss was 41.2% (7/17) and the rate of anti-HBe seroconversion was 5.9% (1/17) in anti-PreS1 positive group, however, the rate of hepatitis B e antigen loss were only 12.8% (5/39) and none of the patients in anti-PreS1 negative group showed anti-HBe seroconversion, difference between the two groups was significant (Z = -5.110, P = 0.000). The rates of response were 71.4% (15/21) and 16.7% (8/48) , respectively in anti-PreS1 positive group and anti-PreS1 negative group. The rates of complete response were 23.8% (5/21) and 6.25% (3/48) , respectively in these two groups. The positive predictive value (PPV) of anti-C-terminal region of preS1 (94-117aa) antibody in predicting early response was 71.6% and the negative predictive value (NPV) was 83.3%.
Conclusions Detection of anti-C-terminal region of preS1 (94-117aa) antibody may help to improve the efficacy of INF-alpha therapy for chronic hepatitis B (CHB).
目的检测HBV B基因型患者血清中抗前S1蛋白C末端(94-117aa)IgG抗体,探讨其与干扰素治疗早期应答的关系。
方法对使用干扰素治疗的B基因型慢性乙型肝炎患者69例进行前瞻性研究,其中普通干扰素(α-1b,α-2b)42例,PEG干扰素(α-2a)27例,采用型特异性引物PCR方法进行基因型测定。按照HBV B基因型序列合成前S1蛋白C末端(94–117aa)多肽,用酶联免疫吸附法检测其相应抗体的存在情况。干扰素早期应答以随访12周时的病毒载量下降幅度及转氨酶和血清学标志物的变化为指标进行评价。根据抗前S1蛋白C末端(94–117aa)抗体的反应性将69例B基因型的慢性乙型肝炎患者分为两组,评判两组干扰素疗效的差别。
结果抗前S1蛋白C末端(aa94–117)IgG抗体(简称抗S1)阳性组和阴性组分别为21例和48例,两组间干扰素种类分布无显著性差异(x2=1.413,P=0.235)。治疗12周时,抗S1阳性组和阴性组HBV DNA下降值平均分别为3.37lg拷贝/ml和0.33lg拷贝/ml,Z=-3.658,P=0.000,差异有统计学意义;ALT下降值平均分别为92 U/L和30.5 U/L,Z =-2.132,P=0.033,差异有统计学意义。治疗12周时,抗S1阳性组有41.2%(7/17)发生HBeAg阴转,5.9%(1/17)发生血清学转换,抗S1阴性组仅有12.8%(5/39)发生HBeAg阴转,没有病例出现血清学转换(0/39),Z= -5.11, P=0.000,差异有统计学意义;抗S1阳性组与阴性组分别有71.4%(15/21)和16.7%(8/48)发生病毒学应答,x2=19.71,P=0.00,差异有统计学意义;两组分别有23.8%(5/21)和6.3%(3/48)发生完全应答,52.4%(11/21)和18.8%(9/48)发生部分应答,Z=-4.84, P =0.000,差异有统计学意义。抗前S1 C末端(94–117aa)IgG抗体在预测干扰素的早期应答中阳性预测值为71.4%,阴性预测值则为83.3%。
结论可以通过对治疗前血清中抗前S1 C末端抗体的检测,筛选出合适的慢乙型肝炎患者,进行个体化治疗,提高干扰素治疗的应答率。
Background Alpha-Interferon (IFN-alpha) is the only agent with an established long-term beneficial effect on the natural history of chronic hepatitis B (CHB). Several controlled clinical trials using IFN-alpha have shown that approximately 20–30% of treated patients with CHB, regardless of ethnic background, will lose HBV DNA and HBeAg and normalise transaminases. This response has been shown to have beneficial long-term effects on disease outcome, in addition the risk of developing hepatocellular carcinoma is reduced in IFN-alpha-treated patients with CHB. Because of the therapeutic benefit experienced by the group of patients with the capacity to respond to IFN-alpha therapy, identification of pretreatment factors predicting response is needed.
Objective To determine the relationship between IgG antibody against the C-terminal region of the preS1 protein of hepatitis B virus and the capacity of early response to interferon therapy in chronic hepatitis B.
Methods 69 patients with chronic hepatitis B virus (genotype B) infection were recruited in this study. 42 patients were treated with interferon-α-1b orα-2b, and 27 patients were treated with PEG interferon (α-2a). Peptide mimicking the C-terminal region of the preS1 protein(94-117aa) of genotype B HBV were synthesised, and the IgG antibody against this peptide was measured by enzymelinked immunosorbent assay (ELISA), and the early response to IFN-alpha therapy was judged by the effect on the viral kinetics, transaminase and the status of HBeAg at 12th week after the treatment.
Results 21 patients were positive for anti-preS1 antibody, and 48 patients were negative for anti-preS1 antibody. The average decrease in viral levels was 3.37lg copies/ml and 0.33lg copies/ml in anti-PreS1 positive patients and anti-preS1 negative patients, respectively 12 weeks after the treatment, the difference between the two groups was significant (Z = -3.658, P = 0.000 ); the average decrease in ALT levels was 92 U/L and 30.5 U/L in two groups, respectively (Z = -2.132, P = 0.033). The rate of hepatitis B e antigen (HBeAg) loss was 41.2% (7/17) and the rate of anti-HBe seroconversion was 5.9% (1/17) in anti-PreS1 positive group, however, the rate of hepatitis B e antigen loss were only 12.8% (5/39) and none of the patients in anti-PreS1 negative group showed anti-HBe seroconversion, difference between the two groups was significant (Z = -5.110, P = 0.000). The rates of response were 71.4% (15/21) and 16.7% (8/48) , respectively in anti-PreS1 positive group and anti-PreS1 negative group. The rates of complete response were 23.8% (5/21) and 6.25% (3/48) , respectively in these two groups. The positive predictive value (PPV) of anti-C-terminal region of preS1 (94-117aa) antibody in predicting early response was 71.6% and the negative predictive value (NPV) was 83.3%.
Conclusions Detection of anti-C-terminal region of preS1 (94-117aa) antibody may help to improve the efficacy of INF-alpha therapy for chronic hepatitis B (CHB).
引文
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