直接抗病毒药物治疗慢性丙型肝炎合并血小板减少患者的效果分析

王涛; 李凤惠; 梁静; 向慧玲; 刘芳; 吕洪敏; 钱宝鑫; 田佳骏

doi:10.3969/j.issn.1001-5256.2022.01.014

直接抗病毒药物治疗慢性丙型肝炎合并血小板减少患者的效果分析

DOI: 10.3969/j.issn.1001-5256.2022.01.014

天津市第三中心医院消化肝病科，天津市重症疾病体外生命支持重点实验室，天津市人工细胞工程技术研究中心，天津 300170

基金项目:

天津2019科技重大专项与工程重大疾病防治科技重大专项 (19ZXDBSY00030)

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。

作者贡献声明：王涛负责课题设计，资料分析，撰写论文；李凤惠、向慧玲、刘芳、吕洪敏参与收集数据，修改论文；钱宝鑫、田佳骏提供统计学支持；梁静负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
梁静，haolele77@sina.com

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出版历程
- 收稿日期: 2021-04-24
- 录用日期: 2021-06-29
- 出版日期: 2022-01-20

Clinical effect of direct-acting antiviral agents in treatment of chronic hepatitis C patients with thrombocytopenia

Department of Gastroenterology and Hepatology, Tianjin Third Central Hospital; Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases; Artificial Cell Engineering Technology Research Center, Tianjin 300170, China

Research funding:

Tianjin Science and Technology Major Project and Critical Disease Prevention and Control Project 2019 (19ZXDBSY00030)

摘要

摘要: 目的探讨慢性丙型肝炎(CHC)合并血小板(PLT)减少患者应用直接抗病毒药物(DAA)的临床疗效及对PLT的影响。方法回顾分析2018年4月—2019年3月在天津市第三中心医院接受DAA治疗合并PLT减少(PLT＜150×10⁹/L)的CHC患者83例，应用无干扰素方案的DAA治疗12~24周，评估治疗结束(EOT)及结束后第12周患者病毒学应答、肝功能指标、PLT、肝硬度(LSM)的变化。正态分布的计量资料组间比较采用重复测量资料的方差分析。非正态分布的计量资料组间比较前进行正态转换，后行重复测量资料的方差分析。logistic回归分析影响PLT升高的预测因素。绘制受试者工作特征曲线(ROC曲线)评价基线LSM对治疗后PLT升高的预测价值。结果 83例CHC合并PLT减少的患者中，肝硬化患者占61.4%，治疗结束后12周持续病毒学应答(SVR12)率为98.8%。与基线相比较，EOT及SVR12时，患者血清AST、ALT、GGT、TBil、Glo水平下降，Alb水平升高，LSM明显下降，差异均有统计学意义(P值均＜0.05)。患者PLT在EOT[(110.4±44.6)×10⁹/L]和SVR12[(109.0±47.7)×10⁹/L]时均较基线[(97.8±33.2)×10⁹/L]显著升高(P值均＜0.01)。获得SVR12时，PLT升高与无升高组患者肝硬化比例、基线LSM及基线WBC水平差异均有统计学意义(P值均＜0.05)；多因素logistic回归分析表明，基线LSM是DAA治疗后PLT明显升高的独立预测因子(OR=0.929, 95%CI: 0.864~0.999, P＜0.05)。基线LSM水平预测PLT升高的ROC曲线下面积为0.644，cut-off值为20.15 kPa，其灵敏度和特异度分别为81.0%和48.6%。基线PLT大于100×10⁹/L组PLT升高幅度更明显(P＜0.05)。结论 CHC合并PLT减少患者在DAA治疗及获得SVR12后，肝功能、LSM有明显改善，基线LSM是PLT升高的独立预测因素，与基线相比较，PLT在EOT及SVR12有明显提升。
- 丙型肝炎, 慢性 /
- 抗病毒药 /
- 血小板减少 /
- 治疗学
Abstract: Objective To investigate the clinical effect of direct-acting antiviral agent (DAA) in the treatment of chronic hepatitis C (CHC) patients with thrombocytopenia and its effect on platelet count (PLT). Methods A retrospective analysis was performed for 83 CHC patients with thrombocytopenia (PLT < 150×10⁹/L) who received the DAA treatment regimen without interferon for 12-24 weeks in Tianjin Third Central Hospital from April 2018 to March 2019, and the changes in virologic response, liver function parameters, PLT, and liver stiffness measurement (LSM) were evaluated at the end of treatment (EOT) and at week 12 after EOT. Quantitative data accord with normal distribution were compared by repeated measures ANOVA. Normal transformation was performed before the comparison between skewed data, then repeated measures ANOVA was carried out. A logistic regression analysis was used to investigate the predictive factors for PLT elevation, and the receiver operating characteristic (ROC) curve was plotted to analyze the value of LSM in predicting PLT elevation after treatment. Results Among the 83 CHC patients with thrombocytopenia, 61.4% had liver cirrhosis, and the rate of sustained virologic response at week 12 after the end of treatment (SVR12) was 98.8%. From baseline to EOT and SVR12, the patients had significant reductions in the serum levels of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, total bilirubin, and globin, a significant increase in the serum level of albumin, and a significant reduction in LSM (all P < 0.05). For all patients, PLT at EOT and SVR12 was significantly higher than that at baseline [EOT vs baseline: (110.4±44.6)×10⁹/L vs (97.8±33.2)×10⁹/L, P < 0.01; SVR12 vs baseline: (109.0±47.7)×10⁹/L vs (97.8±33.2)×10⁹/L, P < 0.01]. At SVR12, there were significant differences in the proportion of patients with liver cirrhosis, baseline LSM, and baseline white blood cell count between the PLT elevation group and the non-PLT elevation group (all P < 0.05). The multivariate logistic regression analysis showed that LSM was an independent predictive factor for significant PLT elevation after DAA treatment (odds ratio=0.929, 95% confidence interval: 0.864-0.999, P < 0.05). Baseline LSM had an area under the ROC curve of 0.644 in predicting PLT elevation, with a sensitivity of 81.0% and a specificity of 48.6% at a cut-off value of 20.15 kPa. The patients with PLT > 100×10⁹/L at baseline had a greater increase in PLT(P < 0.05). Conclusion CHC patients with thrombocytopenia have significant improvements in liver function and LSM after receiving DAA treatment and obtaining SVR12, and baseline LSM is an independent predictive factor for PLT elevation. There is a significant increase in PLT from baseline to EOT and SVR12.
- Hepatitis C, Chronic /
- Antiviral Agents /
- Thrombocytopenia /
- Therapeutics

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图 1 患者纳入流程

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图 2 LSM预测DAA治疗结束后12周时PLT升高的ROC曲线

下载: 全尺寸图片幻灯片

表 1 纳入83例患者的基线临床特征

项目	数值
BMI(kg/m²)	23.4±3.2
肝硬化基础[例(%)]	51(61.4)
HCV RNA(log₁₀IU/ml)	6.3(5.7~6.7)
PLT(×10⁹/L)	97.8±33.0
WBC(×10⁹/L)	4.4(3.9~5.4)
Cr(μmol/L)	64.0(53.0~73.0)
Alb(g/L)	44.4(40.5~46.8)
ALT(U/L)	41.0(26.0~82.3)
AST(U/L)	51.5(32.8~75.3)
TBil(μmol/L)	17.2(13.0~25.3)
GGT(U/L)	48.0(26.0~72.0)
Glo(g/L)	34.4(29.7~36.8)
LSM(kPa)	15.5(11.1~23.6)
APRI	1.4(0.8~2.5)
初治[例(%)]	68(81.9)
HCV基因型[例(%)]
1b	68(81.9)
2a	12(14.5)
3a	2(2.4)
6a	1(1.2)

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表 2 82例患者DAA治疗后肝功能、LSM、APPRI比较

项目	基线	EOT	SVR12
AST(U/L)	53.0(33.0~76.5)	24.0(19.0~30.0)¹⁾	24.0(20.0~31.0)¹⁾
ALT(U/L)	42.0(26.5~84.5)	18.0(14.0~26.3)¹⁾	20.0(15.0~28.3)¹⁾
GGT(U/L)	47.5(25.8~73.8)	21.5(15.8~34.0)¹⁾	21.0(15.5~30.0)¹⁾
Alb(g/L)	44.4(40.4~46.8)	46.8(43.8~49.3)¹⁾	48.0(43.8~49.8)¹⁾
Glo(g/L)	34.1(29.7~36.8)	32.3(28.0~34.7)¹⁾	31.4(28.3~33.5)¹⁾
TBil(μmol/L)	17.1(13.0~24.3)	16.8(11.6~22.4)¹⁾	14.1(10.6~17.5)¹⁾
LSM(kPa)	15.2(11.0~22.8)	15.0(11.9~20.5)¹⁾	13.1(9.9~17.4)¹⁾²⁾
APRI	1.40(0.85~2.53)	0.60(0.36~0.87)¹⁾	0.60(0.39~1.04)¹⁾
注：1)与基线比较，P＜0.05；2)与EOT比较，P＜0.01。

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表 3 PLT升高组与无升高组基线特征对比

项目	PLT升高组(n=43)	PLT无升高组(n=39)	统计值	P值
年龄(岁)	60.7±9.2	61.1±9.9	t=-0.479	0.632
男性[例(%)]	14(32.6)	15(38.5)	χ²=0.312	0.577
肝硬化[例(%)]	21(48.8)	29(74.4)	χ²=5.598	0.018
初治[例(%)]	6(14.0)	9(23.1)	χ²=1.139	0.286
Alb(g/L)	44.7(42.2~47.4)	43.3(39.8~46.8)	Z=-1.030	0.303
Glo(g/L)	33.4(29.5~36.3)	34.8(29.6~38.1)	Z=-0.730	0.465
AST(U/L)	46(26~100)	57(35~69)	Z=-0.383	0.702
ALT(U/L)	49.5(22.8~102.3)	39.0(29.0~72.0)	Z=-0.662	0.508
ALP(U/L)	92(65~108)	86(70~99)	Z=-0.430	0.667
GGT(U/L))	48(29~85)	42(22~72)	Z=-1.109	0.267
TBil(μmol/L)	16.9(13.1~27.0)	17.2(12.0~23.8)	Z=-0.076	0.940
AFP(ng/mL)	6.0(3.8~13.6)	6.7(3.2~14.6)	Z=-0.306	0.759
APRI	1.30(0.70~2.80)	1.41(1.04~1.91)	Z=-0.482	0.630
LSM(kPa)	13.6(10.4~19.7)	19.2(11.6~26.3)	Z=-2.191	0.028
HCV RNA(log₁₀IU/mL)	6.4(5.7~6.8)	6.1(5.7~6.5)	Z=-1.393	0.164
WBC(×10⁹/L)	4.8(4.1~5.8)	4.2(3.5~4.9)	Z=-1.996	0.046
PLT(×10⁹/L)	99(79~136)	93(67~115)	Z=-1.458	0.145
HGB(g/L)	138(128~152)	136(127~149)	Z=-0.683	0.495
Cr(μmol/L)	64(52~77)	64(53~71)	Z=-0.245	0.806

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表 4 logistic回归分析PLT升高的预测因素

参数	OR	95%CI	P值
基线肝硬化	0.440	0.126~1.533	0.197
基线WBC	1.225	0.809~1.853	0.337
基线PLT	0.989	0.970~1.009	0.275
基线LSM	0.929	0.864~0.999	0.046
基线ALT	1.004	0.995~1.013	0.378
基线GGT	1.012	0.997~1.028	0.122

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