三磷酸次黄嘌呤核苷基因多态性对利巴韦林联合直接抗病毒药物治疗丙型肝炎致溶血性贫血的预测价值

徐金凤; 仇丽霞; 于海滨; 刘义荣; 张晶; 柳雅立; 林伟

doi:10.3969/j.issn.1001-5256.2021.10.012

三磷酸次黄嘌呤核苷基因多态性对利巴韦林联合直接抗病毒药物治疗丙型肝炎致溶血性贫血的预测价值

DOI: 10.3969/j.issn.1001-5256.2021.10.012

徐金凤¹,
仇丽霞²,
于海滨²,
刘义荣²,
张晶²,
柳雅立^2, ,,
林伟^2, ,

1.
河北中石油中心医院感染科，河北廊坊 065000
2.
首都医科大学附属北京佑安医院丙肝与中毒性肝病科，北京 100071

基金项目:

北京市属医院科研培育计划项目 (PX2018058);

首都医学大学附属北京佑安医院院内中青年人才孵育项目 (YNKTTS20180114);

廊坊市科技支撑计划项目 (2019013010)

详细信息

通信作者:
柳雅立，xxbi@163.com

林伟，linwei1978@sina.com

徐金凤与仇丽霞对本文贡献相同，同为第一作者

中图分类号: R512.63
计量
- 文章访问数: 460
- HTML全文浏览量: 85
- PDF下载量: 32
- 被引次数: 0
出版历程
- 收稿日期: 2021-03-18
- 录用日期: 2021-04-12
- 出版日期: 2021-10-20

Association of inosine triphosphate pyrophosphatase gene polymorphisms with ribavirin combined with direct-acting antiviral agent in treatment of hepatitis C patients with hemolytic anemia

Jinfeng XU¹,
Lixia QIU²,
Haibin YU²,
Yirong LIU²,
Jing ZHANG²,
Yali LIU^{2
, ,},
Wei LIN^{2
, ,}

1.
Department of Infectious Diseases, Hebei Petrochina Central Hospital, Langfang, Hebei 065000, China
2.
Department of Hepatitis C & Toxic Liver Diseases, Beijing YouAn Hospital, Capital Medical University, Beijing 100071, China

Research funding:

The Research and Cultivation Program of the Municipal Hospital of Beijing (PX2018058);

Young and Middle-aged Talent Incubation Project in the Hospital of Beijing YouAn Hospital, Capital Medical University (YNKTTS20180114);

The Planned Project of Langfang Science and Technology (2019013010)

摘要

摘要: 目的探讨慢性丙型肝炎治疗过程中利巴韦林(RBV)引起溶血性贫血的影响因素，为临床早期预测利巴韦林相关溶血性贫血发生提供借鉴。方法选取2018年1月—2019年7月于河北中石油中心医院门诊及住院就诊的丙型肝炎且应用直接抗病毒药物(DAA)联合RBV方案抗病毒治疗患者。三磷酸次黄嘌呤肌苷(ITPA)基因rs1127354位点主要等位基因是C等位基因，次要等位基因为A等位基因，将AA与AC合并与CC基因型进行比较。在治疗过程中，当Hb水平＜100 g/L时，RBV减量至600 mg；当Hb＜85 g/L时停用RBV治疗。在抗病毒治疗前进行血常规、肝功能、肝脏硬度值、HCV RNA、HCV病毒基因型及ITPA基因型检测，在2、4、8、12周对患者进行血常规检测。不符合正态分布的计量资料组间比较采用Mann-Whitney U检验。结果本研究共纳入病例49例，慢性丙型肝炎患者22例，肝硬化27例，持续病毒学应答率为95.9%。因贫血RBV减量者3例(其中AA/AC组2例，CC组1例)，停药3例(其中AA/AC组1例，CC组2例)，均为肝硬化患者，6例患者最终均达到持续病毒学应答。DAA+RBV抗HCV治疗过程中，RBV相关溶血的发生较轻微，AA/AC型与CC型两组患者Hb较基线下降最大值比较差异无明显统计学意义(Z=-0.18，P=0.87)。结论本研究在RBV联合DAA治疗过程中，因为贫血RBV停药和减量的均为肝硬化患者，ITPA基因型与患者Hb较基线下降最大值无明显统计学关系，故在应用RBV前进行ITPA基线检测未能增加治疗过程中的安全性，因此不建议进行常规的ITPA基因多态性检测。
- 丙型肝炎, 慢性 /
- 贫血, 溶血性 /
- 利巴韦林 /
- 危险因素
Abstract: Objective To investigate the influencing factors for ribavirin (RBV)-induced hemolytic anemia in the treatment of chronic hepatitis C, and to provide a reference for the early prediction of ribavirin-related hemolytic anemia in clinical practice. Methods A total of 49 patients with chronic hepatitis C who attended or were hospitalized in Hebei Petrochina Central Hospital from January 2018 to July 2019 and received antiviral therapy with direct-acting antiviral agent (DAA) and RBV were enrolled, with a major allele of C allele and a minor allele of A allele at the rs1127354 locus of the inosine triphosphate pyrophosphatase (ITPA) gene, and the patients with AA and AC genotypes were compared with those with CC genotype. During treatment, RBV was reduced to 600 mg when hemoglobin (Hb) level was < 100 g/L and was withdrawn when Hb level was < 85 g/L. Routine blood test, liver function, liver stiffness measurement, HCV RNA, HCV genotype, and ITPA genotype were measured before antiviral therapy, and the routine blood test was performed at weeks 2, 4, 8, and 12 of treatment. The Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups. Results A total of 49 patients were enrolled in this study, among whom 22 had chronic hepatitis C and 27 had liver cirrhosis, with a sustained virologic response (SVR) rate of 95.9%. The dose of RBV was reduced in 3 patients (2 in the AA/AC group and 1 in the CC group) due to anemia, and RBV was withdrawn in 3 patients (1 in the AA/AC group and 2 in the CC group); all these 6 patients had liver cirrhosis and finally achieved SVR. During the anti-HCV therapy with DAA+RBV, there was relatively mild RBV-related hemolysis, and the maximum reduction in Hb from baseline was compared between the patients with AA/AC genotype at ITPA rs1127354 and those with CC genotype, which showed no significant difference between the two groups (Z=-0.18, P=0.87). Conclusion During the treatment with RBV+DAA, RBV is withdrawn or reduced for liver cirrhosis patients due to anemia, and no obvious statistical relation is observed between ITPA genotype and the maximum reduction in Hb from baseline. Therefore, detection of ITPA genotype before the application of RBV does not improve safety during treatment, and it is not recommended to perform conventional detection of ITPA gene polymorphisms.
- Hepatitis C, Chronic /
- Anemia, Hemolytic /
- Ribavirin /
- Risk Factors

HTML全文

图 1 DAA+RBV治疗过程中CC组与非CC组Hb下降情况比较

下载: 全尺寸图片幻灯片

表 1 DAA+RBV治疗的丙型肝炎患者基线临床资料

指标	数值
男性[例(%)]	22(44.9)
年龄(岁)	58.6±8.1
ITPA基因型[例(%)]
AA	1(2.0)
AC	9(18.4)
CC	39(79.6)
HCV RNA基因分型[例(%)]
1b	35(71.4)
2a	6(12.2)
分型失败	8(16.3)
WBC(×10⁹/L)	3.7(2.9~5.4)
NEU(×10⁹/L)	2.3(1.5~2.9)
RBC(×10¹²/L)	4.7±0.4
Hb(g/L)	126.9±19.8
PLT(×10⁹/L)	96.0(63.3~137.8)
ALT(U/L)	27.7(20.6~37.8)
AST(U/L)	40.7(29.4~61.2)
GGT(U/L)	44.9(28.1~71.7)
白蛋白(g/L)	38.4±4.6
PT(s)	14.1±1.4
INR	1.1±0.1
HCV RNA log值	5.7±1.5
MELD评分	3.8(1.9~5.2)
Child分级[例(%)]
A级(5~6)	17(34.7)
B级(7~10)	10(20.4)
SVR12[例(%)]	47(95.9)
CHC	22/22(100.0)
代偿期肝硬化	16/17(94.1)
失代偿期肝硬化	9/10(90.0)

下载: 导出CSV

表 2 3例RBV停药患者的ITPA基因型及Hb变化情况

ITPA基因型	基线	2周	4周	8周	12周
CC	110	80	81	93	109
CC	64	95	92	88	91
AC	116	125	84	100	98

下载: 导出CSV

表 3 3例RBV减量药患者的ITPA基因型及Hb变化情况

ITPA基因型	基线	2周	4周	8周	12周
CC	129	-	91	95	114
AC	120	-	91	95	114
AC	98	162	105	97	104

下载: 导出CSV

参考文献(15)

[1]	LAVANCHY D. The global burden of hepatitis C[J]. Liver Int, 2009, 29 Suppl 1: 74-81. DOI: 10.1111/j.1478-3231.2008.01934.x.
[2]	BUNCHORNTAVAKUL C, MANEERATTANAPORN M, CHAVALITDHAMRONG D. Management of patients with hepatitis C infection and renal disease[J]. World J Hepatol, 2015, 7(2): 213-225.
[3]	Chinese Society of Hepatology and Chinese Society of Infectious Diseases, Chinese Medical Association. The guideline of prevention and treatment for hepatitis C: A 2015 update[J]. J Clin Hepatol, 2015, 31(12): 1961-1979. DOI: 10.3969/j.issn.1001-5256.2015.12.003. 中华医学会肝病学分会, 中华医学会感染病学分会. 丙型肝炎防治指南(2015年更新版)[J]. 临床肝胆病杂志, 2015, 31(12): 1961-1979. DOI: 10.3969/j.issn.1001-5256.2015.12.003.
[4]	RAO HY, WEI L. EASL recommendations on treatment of Hepatitis C 2015[J]. J Clin Hepatol, 2015, 31(7): 1008-1017. DOI: 10.3969/j.issn.1001-5256.2015.07.004. 饶慧瑛, 魏来. 2015年欧洲肝病学会丙型肝炎治疗推荐意见[J]. 临床肝胆病杂志, 2015, 31(7): 1008-1017. DOI: 10.3969/j.issn.1001-5256.2015.07.004.
[5]	XU JF, ZHANG XH, LIU YL, et al. Influencing factors for hemolytic anemia in patients with chronic hepatitis C treated by ribavirin combined with pegylated interferon-α[J]. J Clin Hepatol, 2019, 35(2): 319-322. DOI: 10.3969/j.issn.1001-5256.2019.02.015. 徐金凤, 张晓慧, 柳雅立, 等. 利巴韦林联合聚乙二醇干扰素α治疗慢性丙型肝炎发生相关溶血性贫血的影响因素分析[J]. 临床肝胆病杂志, 2019, 35(2): 319-322. DOI: 10.3969/j.issn.1001-5256.2019.02.015.
[6]	CHENG YQ, ZHAO P, WANG XF. Research advances in the anti-HCV mechanism of ribavirin[J]. Foreign Med Sci(Epidemiol Loimol), 2003, 30(3): 156-160. https://www.cnki.com.cn/Article/CJFDTOTAL-GWLX200303010.htm 程勇前, 赵平, 王晓峰. 利巴韦林抗HCV作用机制研究进展[J]. 国外医学(流行病学传染病学分册), 2003, 30(3): 156-160. https://www.cnki.com.cn/Article/CJFDTOTAL-GWLX200303010.htm
[7]	FELLAY J, THOMPSON AJ, GE D, et al. ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C[J]. Nature, 2010, 464(7287): 405-408. DOI: 10.1038/nature08825.
[8]	OCHI H, MAEKAWA T, ABE H, et al. ITPA polymorphism affects ribavirin-induced anemia and outcomes of therapy-a genome-wide study of Japanese HCV virus patients[J]. Gastroenterology, 2010, 139(4): 1190-1197. DOI: 10.1053/j.gastro.2010.06.071.
[9]	MATSUURA K, TANAKA Y, WATANABE T, et al. ITPA genetic variants influence efficacy of PEG-IFN/RBV therapy in older patients infected with HCV genotype 1 and favourable IL28B type[J]. J Viral Hepat, 2014, 21(7): 466-474. DOI: 10.1111/jvh.12171.
[10]	RAU M, STICKEL F, RUSSMANN S, et al. Impact of genetic SLC28 transporter and ITPA variants on ribavirin serum level, hemoglobin drop and therapeutic response in patients with HCV infection[J]. J Hepatol, 2013, 58(4): 669-675. DOI: 10.1016/j.jhep.2012.11.027.
[11]	CLARK PJ, AGHEMO A, DEGASPERI E, et al. Inosine triphosphatase deficiency helps predict anaemia, anaemia management and response in chronic hepatitis C therapy[J]. J Viral Hepat, 2013, 20(12): 858-866. DOI: 10.1111/jvh.12113.
[12]	MURAKAWA M, ASAHINA Y, NAGATA H, et al. ITPA gene variation and ribavirin-induced anemia in patients with genotype 2 chronic hepatitis C treated with sofosbuvir plus ribavirin[J]. Hepatol Res, 2017, 47(11): 1212-1218. DOI: 10.1111/hepr.12867.URABEA.
[13]	SUZUKI F, SUZUKI Y, AKUTA N, et al. Influence of ITPA polymorphisms on decreases of hemoglobin during treatment with pegylated interferon, ribavirin, and telaprevir[J]. Hepatology, 2011, 53(2): 415-421. DOI: 10.1002/hep.24058.
[14]	MORIO K, IMAMURA M, KAWAKAMI Y, et al. ITPA polymorphism effects on decrease of hemoglobin during sofosbuvir and ribavirin combination treatment for chronic hepatitis C[J]. J Gastroenterol, 2017, 52(6): 746-753. DOI: 10.1007/s00535-016-1279-9.
[15]	URABE A, SAKAMORI R, TAHATA Y, et al. Predictive factors of anemia during sofosbuvir and ribavirin therapy for genotype 2 chronic hepatitis C patients[J]. Hepatol Res, 2019, 49(8): 853-859. DOI: 10.1111/hepr.13354.