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当今世界各国慢性乙型肝炎(慢乙肝)病人基数仍然众多,虽然乙肝疫苗研制完成,但全球仍约有2.9亿人感染,其中发展中国家更是重中之重[1-2]。在成人中,急性感染通常会自行消退,但在新生儿和幼儿中,慢性感染很常见,慢性肝炎、肝硬化甚至肝癌是慢乙肝恶化的最终结局[3]。为了治疗慢乙肝,现目前抗病毒药物主要是采取核苷类抗病毒药物(NUCs)或者干扰素(IFN)[4],其中NUCs以恩替卡韦和替诺福韦为一线药物。慢乙肝病人运用这些药物长期治疗可明显降低疾病临床进展的发生[5],但不能完全治愈HBV,因为HBV共价闭合环状DNA(cccDNA)不能被彻底清除[6]。IFN-λ3、IFN-λ4基因多态性和IFN-λ3水平是病毒性和非病毒性肝病中肝脏炎症和纤维化程度的决定因素[7]。替诺福韦可以提升病人的IFN-λ3水平,因此临床中迫切能够寻找到新的依据及治疗方案。
IFN-λ1,IFN-λ2,IFN-λ3和IFN-λ4[8-9],它们统属于Ⅲ型干扰素(IFN-λ)家族。所有IFN-λ家族成员都通过独特的异二聚体受体发出信号,该受体由CRF2-12(IL-28RA)和ICRF2-4组成。类似于Ⅰ型干扰素,Ⅲ型干扰素通过激活分别与CRF2-12和CRF2-4相关的JAK1和TYK2来诱导干扰素刺激因子(ISGS),从而导致STAT1/STAT2和ISGS的磷酸化[10]。核苷酸类似物如阿德福韦和替诺福韦,而非核苷类似物,如恩替卡韦,在诱导IFN-λ3的表达水平提供了额外的作用。IFN-λ3诱导HBV病人产生ISGS,降低乙肝表面抗原(HBsAg)[11]。但其在HBV感染中的作用现阶段尚无完全明确的定义。本文旨在探讨其与疾病进展的关系和核苷(酸)类抗病毒药物之间的关系。现作报道。
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慢乙肝组、肝硬化组、肝细胞癌组病人年龄、ALT、AST、GGT、ALP、ALB、TBIL、LogHBV-DNA、IFN-λ3和是否经抗病毒治疗差异均有统计学意义(P < 0.01)(见表 1)。未抗病毒治疗的各组IFN-λ3水平为对照组、慢乙肝组、肝硬化组、肝细胞癌组依次递减(P < 0.01)(见表 2)。
分组 n 年龄/岁 ALT/(U/L) AST/(U/L) GGT/(U/L) ALP/(U/L) 慢乙肝 85 45.86±12.34 28.21±19.51 28.15±18.35 34.31±37.57 71.79±22.19 肝硬化 24 57.71±8.96 54.13±37.00 57.25±39.00 63.96±36.57 78.50±31.82 肝细胞癌 62 62.86±8.19 61.34±58.64 62.53±56.06 86.00±32.79 96.37±28.45 F — 53.59 13.06 15.41 37.94 16.16 P — < 0.01 < 0.01 < 0.01 < 0.01 < 0.01 分组 n HBsAg/ (IU/mL) ALB/ (g/L) TBIL/ (μmmol/L) LogHBV-DNA IFN-λ3/ (pg/mL) 治疗 未治疗 慢乙肝 85 4 299.68±11 265.73 46.29±4.45 13.98±6.71 2.03±1.59 191.46±34.39 55 30 肝硬化 24 2 678.37±3 476.79 38.60±6.40 31.85±28.03 4.15±1.55 178.16±30.59 0 24 肝细胞癌 62 2 725.81±6 072.65 36.37±4.93 46.64±40.96 3.43±1.05 113.24±21.04 46 19 F — 0.69 77.70 26.10 29.73 129.15 39.07* P — >0.05 < 0.01 < 0.01 < 0.01 < 0.01 < 0.01 *示χ2值 表 1 病例组研究对象基线资料比较(x±s)
分组 n IFN-λ3/(pg/mL) 对照组 20 252.81±38.06 慢乙肝 30 186.48±30.75** 肝硬化 24 178.16±30.59** 肝细胞癌 19 95.20±14.00**## $\bigtriangledown \bigtriangledown $ F — 90.48 P — <0.01 MS组内 — 898.87 q检验:与对照组比较**P < 0.01;与慢乙肝组比较##P < 0.01;与肝炎肝硬化组比较$\bigtriangledown \bigtriangledown $P < 0.01 表 2 未抗病毒治疗的各组血清中IFN-λ3的水平
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已抗病毒治疗的病人中,恩替卡韦或替诺福韦治疗前ALT、AST、HBsAg、TBIL、logHBV-DNA与治疗后比较差异均有统计学意义(P < 0.01)。恩替卡韦治疗前后IFN-λ3差异无统计学意义(P>0.05),替诺福韦治疗前后IFN-λ3差异有统计学意义(P < 0.01)(见表 3)。
分组 n ALT/(U/L) AST/(U/L) HBsAg/(IU/mL) TBIL/(μmol/L) logHBV-DNA IFN-λ3/(pg/mL) 恩替卡韦治疗前 27 82.19±37.56 72.11±32.04 7 531.11±10 376.67 31.44±21.65 5.12±1.25 167.58±15.54 恩替卡韦治疗6月后 27 27.41±10.53 28.11±12.38 1 630.26±3 476.05 16.09±7.25 1.50±0.60 176.80±37.47 t — 7.30* 6.66* 2.80* 3.49* 13.55 1.18* P — < 0.01 < 0.01 < 0.01 < 0.01 < 0.01 >0.05 替诺福韦治疗前 28 120.14±72.21 95.04±49.23 8 622.54±7 904.94 37.07±26.34 5.52±0.79 155.77±15.15 替诺福韦治疗6个月后 28 24.57±17.65 26.25±9.59 3 184.09±10 116.29 14.29±5.15 1.44±0.45 210.94±26.00 t — 0.88* 7.26* 2.24* 4.49* 23.95 9.70* P — < 0.01 < 0.01 < 0.05 < 0.01 < 0.01 <0.01 *示t′值 表 3 恩替卡韦和替诺福韦治疗慢乙肝病人的数据资料比较(x±s)
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将慢乙肝相关性肝细胞癌依据用药分为恩替卡韦组和替诺福韦组。在恩替卡韦组中IFN-λ3(107.32±15.52)pg/mL,明显低于替诺福韦组中的(130.42±16.92)pg/mL,差异具有统计学意义(t=4.81,P < 0.01)。
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Pearson相关分析显示,未治疗慢性乙型肝炎病人血清IFN-λ3与HBsAg、logHBV-DNA呈正相关关系(r=0.302,r=0.314,P < 0.05);与ALT、AST、GGT、ALP、TBIL、ALB水平无明显相关性(r=0.018,r=0.020, r=0.049,r=0.074,r=0.123,r=0.078,P>0.05)(见表 4、图 1~2)。
指标 LogHBV-DNA HBsAg IFN-λ3 LogHBV-DNA 1 HBsAg 0.541* 1 IFN-λ3 0.314* 0.302* 1 *P < 0.05 表 4 未治疗慢性乙型肝炎病人IFN-λ3与HBV-DNA、HBsAg之间的关系
恩替卡韦或替诺福韦治疗慢性乙型肝炎病毒感染干扰素-λ3的水平研究
Study on the level of interferon-λ3 in chronic hepatitis B virus infection patients treated with entecavir or tenofovir
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摘要:
目的分析乙型肝炎病毒(HBV)感染各临床阶段中干扰素(IFN)-λ3水平变化的临床意义,及与替诺福韦和恩替卡韦治疗的关系。 方法选取HBV感染病人174例及20名乙型肝炎表面抗原(HBsAg)阴性的健康体检者,采用ELISA法检测IFN-λ3在血清中的表达水平,并收集肝功能、总胆红素(TBIL)、白蛋白(ALB)等相关的临床检查指标。观察IFN-λ3在慢性乙型肝炎病人不同临床阶段的分布水平趋势,及现一线抗病毒药物(替诺福韦与恩替卡韦)在规律服用后病人血清IFN-λ3的变化,分析IFN-λ3与疾病进展和不同抗病毒药物之间的关系。 结果未抗病毒治疗的各组IFN-λ3水平为对照组、慢乙肝组、肝硬化组、肝细胞癌组依次递减(P<0.01)。已抗病毒治疗的病人中,恩替卡韦或替诺福韦治疗前丙氨酸氨基转移酶、天冬氨酸氨基转移酶、HBsAg、TBIL、logHBV-DNA与治疗后比较差异均有统计学意义(P<0.01)。恩替卡韦治疗前后IFN-λ3差异无统计学意义(P>0.05),替诺福韦治疗前后IFN-λ3差异有统计学意义(P<0.01)。IFN-λ3水平与慢乙肝、肝硬化病人的HBsAg、HBV-DNA数值呈正相关,与病人的肝功能、TBIL、ALB等临床指标无关。 结论IFN-λ3与HBV活动进展有关系,与肝脏功能本身无关。替诺福韦具有诱导血清IFN-λ3水平上升的附加药理作用,高水平IFN-λ3有助于加强IFN-α清除HBV。 Abstract:ObjectiveTo analyze the clinical significance of the level changes of interferon(IFN)-λ3 in different clinical stages of hepatitis B virus(HBV) infection, and its relationship with tenofovir(TDF) and entecavir(ETV) treatment. MethodsThe serum levels of IFN-λ3 of 174 HBV-infected patients and 20 HBsAg negative healthy examiners were detected using ELISA, and the clinical indexes of liver function, total bilirubin(TBIL), albumin(ALB) and other related indexes were collected.The distribution trend of IFN-λ3 levels in hepatitis B patients at different clinical stages were observed.The changes of serum levels of IFN-λ3 after regular administration of current first-line antiviral drugs(TDF and ETV), and the relationship between IFN-λ3 and disease progression, different antiviral drugs were analyzed. ResultsThe levels of IFN-λ3 in the control group, chronic hepatitis B group, liver cirrhosis group and hepatocellular carcinoma group decreased successively(P<0.01).Among patients treated with antiviral drugs, the differences of the levels of alanine aminotransferase, aspartate aminotransferase, HBsAg, TBIL, and LogHBV-DNA between before and after ETV or TDF treatment were statistically significant(P<0.01), the difference of the level of IFN-λ3 in patients between before and after ETV treatment was not statistically significant(P>0.05), and the difference of the level of IFN-λ3 in patients between before and after TDF treatment was statistically significant(P<0.01).The serum level of IFN-λ3 was positively correlated with the levels of HBsAg and HBV-DNA in chronic hepatitis B and cirrhosis patients, but not related to the liver function, TBIL, ALB and other clinical indicators. ConclusionsIFN-λ3 is associated with the progression of hepatitis B virus activity, and not with liver function itself.TDF has the additional pharmacological effects of inducing the increase of serum IFN-λ3 level, and the high level of IFN-λ3 can enhance the clearance of HBV by IFN-α. -
Key words:
- hepatitis B /
- interferon-λ3 /
- entecavir /
- tenofovir
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表 1 病例组研究对象基线资料比较(x±s)
分组 n 年龄/岁 ALT/(U/L) AST/(U/L) GGT/(U/L) ALP/(U/L) 慢乙肝 85 45.86±12.34 28.21±19.51 28.15±18.35 34.31±37.57 71.79±22.19 肝硬化 24 57.71±8.96 54.13±37.00 57.25±39.00 63.96±36.57 78.50±31.82 肝细胞癌 62 62.86±8.19 61.34±58.64 62.53±56.06 86.00±32.79 96.37±28.45 F — 53.59 13.06 15.41 37.94 16.16 P — < 0.01 < 0.01 < 0.01 < 0.01 < 0.01 分组 n HBsAg/ (IU/mL) ALB/ (g/L) TBIL/ (μmmol/L) LogHBV-DNA IFN-λ3/ (pg/mL) 治疗 未治疗 慢乙肝 85 4 299.68±11 265.73 46.29±4.45 13.98±6.71 2.03±1.59 191.46±34.39 55 30 肝硬化 24 2 678.37±3 476.79 38.60±6.40 31.85±28.03 4.15±1.55 178.16±30.59 0 24 肝细胞癌 62 2 725.81±6 072.65 36.37±4.93 46.64±40.96 3.43±1.05 113.24±21.04 46 19 F — 0.69 77.70 26.10 29.73 129.15 39.07* P — >0.05 < 0.01 < 0.01 < 0.01 < 0.01 < 0.01 *示χ2值 表 2 未抗病毒治疗的各组血清中IFN-λ3的水平
分组 n IFN-λ3/(pg/mL) 对照组 20 252.81±38.06 慢乙肝 30 186.48±30.75** 肝硬化 24 178.16±30.59** 肝细胞癌 19 95.20±14.00**## $\bigtriangledown \bigtriangledown $ F — 90.48 P — <0.01 MS组内 — 898.87 q检验:与对照组比较**P < 0.01;与慢乙肝组比较##P < 0.01;与肝炎肝硬化组比较 P < 0.01$\bigtriangledown \bigtriangledown $ 表 3 恩替卡韦和替诺福韦治疗慢乙肝病人的数据资料比较(x±s)
分组 n ALT/(U/L) AST/(U/L) HBsAg/(IU/mL) TBIL/(μmol/L) logHBV-DNA IFN-λ3/(pg/mL) 恩替卡韦治疗前 27 82.19±37.56 72.11±32.04 7 531.11±10 376.67 31.44±21.65 5.12±1.25 167.58±15.54 恩替卡韦治疗6月后 27 27.41±10.53 28.11±12.38 1 630.26±3 476.05 16.09±7.25 1.50±0.60 176.80±37.47 t — 7.30* 6.66* 2.80* 3.49* 13.55 1.18* P — < 0.01 < 0.01 < 0.01 < 0.01 < 0.01 >0.05 替诺福韦治疗前 28 120.14±72.21 95.04±49.23 8 622.54±7 904.94 37.07±26.34 5.52±0.79 155.77±15.15 替诺福韦治疗6个月后 28 24.57±17.65 26.25±9.59 3 184.09±10 116.29 14.29±5.15 1.44±0.45 210.94±26.00 t — 0.88* 7.26* 2.24* 4.49* 23.95 9.70* P — < 0.01 < 0.01 < 0.05 < 0.01 < 0.01 <0.01 *示t′值 表 4 未治疗慢性乙型肝炎病人IFN-λ3与HBV-DNA、HBsAg之间的关系
指标 LogHBV-DNA HBsAg IFN-λ3 LogHBV-DNA 1 HBsAg 0.541* 1 IFN-λ3 0.314* 0.302* 1 *P < 0.05 -
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