核苷（酸）类药物应答不佳的慢性乙型肝炎患者优化治疗过程中血清IL-21的动态变化及意义

doi:10.3877/cma.j.issn.1674-1358.2016.02.003

中华实验和临床感染病杂志(电子版) ›› 2016, Vol. 10 ›› Issue (02) : 140 -145. doi: 10.3877/cma.j.issn.1674-1358.2016.02.003

临床论著

核苷（酸）类药物应答不佳的慢性乙型肝炎患者优化治疗过程中血清IL-21的动态变化及意义

闫改勤¹, 纪世博², 刘顺爱³, 欧蔚妮², 赵莹莹², 马艳华¹, 成军⁴, 邢卉春⁴^,^†(

)

^1. 100015　北京，北京大学地坛医院教学医院
^2. 100015　北京，首都医科大学附属北京地坛医院肝病中心
^3. 100015　北京，首都医科大学附属北京地坛医院传染病研究所
^4. 100015　北京，北京大学地坛医院教学医院；100015　北京，首都医科大学附属北京地坛医院肝病中心

收稿日期:2016-01-07 出版日期:2016-04-15
通信作者: 邢卉春
基金资助:
国家科技重大专项课题项目(No. 2014ZX10005001); 国家自然科学基金项目(No. 81201160); 北京市中医药科技项目(No. JJ2014-25); 国家"十二五"传染病重大专项(No. 2012ZX10002003)

The dynamic changes and signification of IL-21 in the optimally treated chronic hepatitis B patients with poor response to nucleos(t)ide analogue drugs

Gaiqin Yan¹, Shibo Ji², Shun'ai Liu³, Weini Ou², Yingying Zhao², Yanhua Ma¹, Jun Cheng⁴, Huichun Xing⁴^,^†()

^1. Peking University Ditan Teaching Hospital, Beijing 100015, China
^2. Center of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
^3. Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
^4. Peking University Ditan Teaching Hospital, Beijing 100015, China; Center of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China

Received:2016-01-07 Published:2016-04-15
Corresponding author: Huichun Xing

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引用本文：

闫改勤, 纪世博, 刘顺爱, 欧蔚妮, 赵莹莹, 马艳华, 成军, 邢卉春. 核苷（酸）类药物应答不佳的慢性乙型肝炎患者优化治疗过程中血清IL-21的动态变化及意义[J]. 中华实验和临床感染病杂志(电子版), 2016, 10(02): 140-145.

Gaiqin Yan, Shibo Ji, Shun'ai Liu, Weini Ou, Yingying Zhao, Yanhua Ma, Jun Cheng, Huichun Xing. The dynamic changes and signification of IL-21 in the optimally treated chronic hepatitis B patients with poor response to nucleos(t)ide analogue drugs[J]. Chinese Journal of Experimental and Clinical Infectious Diseases(Electronic Edition), 2016, 10(02): 140-145.

目的

通过检测核苷（酸）类似物治疗应答不佳慢性乙型肝炎患者在优化治疗过程中血清IL-21表达水平，探讨血清IL-21水平的动态变化与患者对抗病毒应答的相关性。

方法

检测25例核苷（酸）类似物治疗应答不佳的慢性乙型肝炎患者在接受优化的核苷（酸）类似物抗病毒治疗基线、12周、24周、36周、52周、64周、76周、88周和104周的血清并检测IL-21水平、HBV DNA定量、HBsAg、HBsAb、HBeAg、HBeAb和肝功能等相关指标，分析这些指标的动态变化及其之间的相关性；另选取15例HBV携带者、15例健康志愿者做对照。

结果

核苷（酸）类似物治疗应答不佳的慢性乙型肝炎患者优化治疗基线血清IL-21水平与无症状携带者血清IL-21水平差异无统计学意义，但均显著高于健康对照组（P = 0.000、0.003）；核苷（酸）类似物应答不佳的慢性乙型肝炎患者在优化治疗过程中血清HBV DNA、HBsAg、HBeAg、HBeAb均呈下降趋势，且HBV DNA水平及HBsAg浓度于治疗12周内下降速度最快，HBsAg浓度降低速度随治疗时间延长逐渐减慢。基线IL-21水平与优化治疗12～24周时的病毒量变化对数值存在中等强度的负相关性（r =-0.55、P = 0.015），36周时IL-21水平与36～52周病毒量变化存在中等强度的负相关性（r =-0.62、P = 0.001）。核苷（酸）类药物优化治疗过程中患者血清IL-21浓度呈现先升高后下降的趋势，峰值浓度在36周，为66.41 pg/ml，显著高于基线IL-21浓度（P = 0.001），治疗至88周及104周时患者血清IL-21水平恢复到基线状态。

结论

乙型肝炎病毒感染的患者血清IL-21浓度升高，优化核苷（酸）类抗病毒治疗后，慢性乙型肝炎患者血清IL-21水平呈现一过性升高，峰值与HBV DNA的抑制及HBsAg、HBeAg等变化有一定的相关性。

关键词: 肝炎病毒, 乙型, 肝炎, 乙型, 慢性, 白细胞介素21

Objective

To investigate of the levels of serum interleukin-21 (IL-21) in the optimally treated chronic hepatitis B (CHB) patients with poor response to nucleos(t)ide analogue drugs to investigate the relationship between the the serum IL-21 levels, the dynamic changes and patients’ viral response to antiviral therapy.

Methods

The serum of a total of 25 CHB patients with a poor response to nucleos(t)ide analogue antiviral therapy was detached before and after optimally treated for 12, 24, 36, 52, 64, 76, 88 and 104 weeks, and the levels of IL-21, HBsAg, HBsAb, HBeAg, HBeAb, HBV DNA load and the liver function were dedected, respectively. And then the dynamic changes of these indicators and the correlation were analyzed. Fifteen cases of hepatitis B virus carriers and 15 cases of healthy volunteers were selected as controls.

Results

There was no significant differences between the levels of the baseline IL-21 of the chronic hepatitis B patients poorly respond to nucleos(t)ide analogue antiviral therapy and the hepatitis B virus carriers, but they all significantly higher than the level of serum IL-21 concentration of the healthy people (P < 0.05). During the optimal therapy of the chronic hepatitis B patients poorly respond to nucleos(t)ide analogue antiviral therapy, the level of the serum HBV DNA, HBsAg, HBeAg and HBeAb all declined, and a rapid decline of HBV DNA during the first 12 weeks of treatment was observed, and the pace of the reduction of HBsAg slowed down with time. There was a moderate negative correlation between the IL-21 concentration of baseline and the logarithmic change of HBV load from 12 weeks to 24 weeks after treatment (r =-0.55, P < 0.05). A moderate negative correlation between the IL-21 concentration at week 36 and the decline of HBV load from week 36 to week 52 was also obversed (r =-0.62, P < 0.01). And the levels of IL-21 of the patients with CHB during treatment with nucleos(t)ide analogues increased at first and then declined and the peak concentration was 66.41 pg/ml, which came around at week 36 and was significantly higher than the baseline (P < 0.05), but at the 88th week and 104th week, the IL-21 declined to the levels that showed no significant differences compared with the baseline.

Conclusions

The levels of serum IL-21 increased in the patients with HBV infection, and after the optimal antiviral treatment with nucleos(t)ide analogue drugs, the levels of serum IL-21 of patients with CHB increased transiently, and some relevance were observed between the supression of HBV DNA, as well as the changes of the HBsAg, HBeAg and the peek concentration of the serum IL-21 of patients with CHB.

Key words: Hepatitis B virus, Chronic hepatitis B, Interleukin-21

表1 CHB患者基线、携带者和健康对照组临床资料和IL-21浓度^a

项目	CHB组（n = 25）	携带者（n = 15）	健康对照（n = 15）
性别（男/女）^b	16/9	9/6	6/9
年龄（岁）^c	33.56 ± 9.79	36.00 ± 11.68	27.8 ± 1.3
ALT（U/L）	59.5 ± 40.9	< 50.00	< 50.00
AST（U/L）	26.8（91.2，16.0）	< 35.00	< 35.00
TBil（μmol/L）	12.4（33.6，7.2）	< 18.80	< 18.80
DBil（μmol/L）	4.0（10.6，2.5）	< 6.80	< 6.80
TP（g/L）	80.09 ± 4.64	79.56 ± 1.88	74.39 ± 3.27
ALB（g/L）	47.1（52.3，32.0）	49.4（57.3，46.1）	47.25 ± 2.28
GLB（g/L）	32.60 ± 3.59	30.2（35.6，21.7）	27.15 ± 3.33
HBV DNA（拷贝/ml）	1.03 × 10⁶（5.94 × 10⁸，1.38 × 10⁴）	8.49 × 10²（1.35 × 10⁸，1.03 × 10²）^d	—
HBsAg（IU/ml）	19 781（108 682，79）	+	—
IL-21（pg/ml）	50.25 ± 11.99	24.0（294.8，4.1）	4.35（38.2，0）

表1 CHB患者基线、携带者和健康对照组临床资料和IL-21浓度^a

项目	CHB组（n = 25）	携带者（n = 15）	健康对照（n = 15）
性别（男/女）^b	16/9	9/6	6/9
年龄（岁）^c	33.56 ± 9.79	36.00 ± 11.68	27.8 ± 1.3
ALT（U/L）	59.5 ± 40.9	< 50.00	< 50.00
AST（U/L）	26.8（91.2，16.0）	< 35.00	< 35.00
TBil（μmol/L）	12.4（33.6，7.2）	< 18.80	< 18.80
DBil（μmol/L）	4.0（10.6，2.5）	< 6.80	< 6.80
TP（g/L）	80.09 ± 4.64	79.56 ± 1.88	74.39 ± 3.27
ALB（g/L）	47.1（52.3，32.0）	49.4（57.3，46.1）	47.25 ± 2.28
GLB（g/L）	32.60 ± 3.59	30.2（35.6，21.7）	27.15 ± 3.33
HBV DNA（拷贝/ml）	1.03 × 10⁶（5.94 × 10⁸，1.38 × 10⁴）	8.49 × 10²（1.35 × 10⁸，1.03 × 10²）^d	—
HBsAg（IU/ml）	19 781（108 682，79）	+	—
IL-21（pg/ml）	50.25 ± 11.99	24.0（294.8，4.1）	4.35（38.2，0）

表2 优化治疗过程中慢性乙型肝炎患者肝功能指标变化^a

随访时间	ALT（U/L）	AST（U/L）	TBil（µmol/L）
基线	59.5 ± 40.9	37.8 ± 19.8	11.9（33.6，5.3）
12周	48.2 ± 36.9	27.1（94.1，17.1）	12.7 ± 4.5
24周	33.5 ± 15.0	24.9 ± 6.1	15.6 ± 11.6
36周	21.7（238.4，14.9）	24.2（91.4，13.2）	12.8 ± 5.2
52周	25.5（120.8，12.4）	21.5 ± 11.0	13.6 ± 5.1
64周	27.5 ± 15.7	21.9 ± 7.2	11.7 ± 4.5
76周	24.4 ± 11.6	21.0 ± 6.1	11.5 ± 3.6
88周	27.8 ± 22.6	21.2 ± 7.3	12.0 ± 5.4
104周	21.2（240.8，8.8）	19.1（101.4，13.1）	12.3 ± 4.4

表2 优化治疗过程中慢性乙型肝炎患者肝功能指标变化^a

随访时间	ALT（U/L）	AST（U/L）	TBil（µmol/L）
基线	59.5 ± 40.9	37.8 ± 19.8	11.9（33.6，5.3）
12周	48.2 ± 36.9	27.1（94.1，17.1）	12.7 ± 4.5
24周	33.5 ± 15.0	24.9 ± 6.1	15.6 ± 11.6
36周	21.7（238.4，14.9）	24.2（91.4，13.2）	12.8 ± 5.2
52周	25.5（120.8，12.4）	21.5 ± 11.0	13.6 ± 5.1
64周	27.5 ± 15.7	21.9 ± 7.2	11.7 ± 4.5
76周	24.4 ± 11.6	21.0 ± 6.1	11.5 ± 3.6
88周	27.8 ± 22.6	21.2 ± 7.3	12.0 ± 5.4
104周	21.2（240.8，8.8）	19.1（101.4，13.1）	12.3 ± 4.4

图1 慢性乙型肝炎患者优化方案治疗过程中血清IL-21水平的动态变化

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