直接抗病毒药物治疗HCV相关肝细胞癌肝移植受者的研究进展

朱倩; 张明媛; 牛俊奇

doi:10.3969/j.issn.1001-5256.2021.10.039

直接抗病毒药物治疗HCV相关肝细胞癌肝移植受者的研究进展

DOI: 10.3969/j.issn.1001-5256.2021.10.039

吉林大学第一医院肝胆胰内科, 长春 130021

基金项目:

国家自然科学基金 (81970519)

详细信息

通信作者:
牛俊奇，junqi_niu@163.com

中图分类号: R512.63;R735.7
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- 文章访问数: 455
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- PDF下载量: 49
- 被引次数: 0
出版历程
- 收稿日期: 2021-03-24
- 录用日期: 2021-04-29
- 出版日期: 2021-10-20

Advances in direct-acting antiviral therapy for liver transplant recipients with HCV-related hepatocellular carcinoma

Department of Hepatology, The First Hospital of Jilin University, Changchun 130021, China

Research funding:

National Natural Science Foundation of China (81970519)

摘要

摘要: 直接抗病毒药物的上市使丙型肝炎的治疗取得了里程碑式进展，但其在HCV相关肝细胞癌(HCC)肝移植中应用的具体时机和有效性尚待进一步探讨。归纳了目前国内外相关的指南、共识及推荐意见，分别总结了不同治疗时机的优势，并针对直接抗病毒药物对移植后HCV相关HCC复发率的影响这一具有争议性的问题，作出了现有相关研究的回顾性分析，认为直接抗病毒药物治疗可以减少HCV相关HCC肝移植受者的肝癌复发风险。治疗时机的选择需综合考虑肝功能、移植等待时间、HCV阳性器官的利用等多方面因素。
- 癌, 肝细胞 /
- 肝炎病毒属 /
- 肝移植 /
- 抗病毒药
Abstract: The launch of direct-acting antiviral agents is a milestone in the treatment of hepatitis C, but further studies are needed to explore its specific timing and effectiveness in liver transplantation for HCV-related hepatocellular carcinoma (HCC). This article summarizes related guidelines, consensus statements, and recommendations in China and globally and the advantages of different treatment timing strategies. Furthermore, a retrospective analysis of related studies is performed to investigate the controversial topic of the impact of direct-acting antiviral agents on the recurrence rate of HCV-related HCC after liver transplantation, and it is pointed that direct-acting antiviral agents can reduce the risk of HCC recurrence in liver transplant recipients with HCV-related HCC. The selection of treatment timing should consider various factors such as liver function, waiting time for donors, and utilization of HCV-positive organs.
- Carcinoma, Hepatocellular /
- Hepacivirus /
- Liver Transplantation /
- Antiviral Agents

HTML全文

表 1 HCV相关HCC的肝移植受者接受DAA治疗后HCC复发率

第一作者，年份	地区	研究类型	纳入人群(例)	治疗时间及分组	中位随访时间	DAA治疗时机	SVR率	肝癌复发率
Yang JD，2016 ^[18]	荷兰	回顾性	81	移植前DAA治疗18例移植前未治疗63例	NA	移植前	NA	27.8%(5/18)
				移植前DAA治疗18例移植前未治疗63例				9.5%(6/63)
ANRS，2016 ^[19]	法国	前瞻性	314(CO23 CUPILT队列)		70.3(70±64)个月	移植后	96.8%(12周)	2.2%(7/314)
Zanetto A，2017 ^[20]	美国	回顾性	23	移植前DAA治疗9例	10(6~19)个月	移植前	NA	12.5%(1/8)
				对照组14例	7(5~19)个月	移植后	NA	8.3%(1/12)
Zanaga LP，2019 ^[21]	巴西	回顾性	36	DAA治疗	20个月(自DAA治疗)	移植后	100%	0(0/36)
Bielen R，2017 ^[22]	比利时	回顾性	22	IFN+DAA治疗1例	NA	NA	NA	0(0/22)
				DAA治疗21例
Emamaullee JA，2019 ^[23]	加拿大	回顾性	25	移植前达到SVR 13例	＞2年	NA	100%(25/25)	23.1%(3/13)
				移植后达到SVR 12例				17.7%(2/12)
Jain A，2019 ^[24]	美国	NA	47	DAA治疗且获得SVR 20例	(50.5±25.4)个月	NA	100%(20/20)	0(0/20)
				DAA治疗未获得SVR 5例	(50.5±25.4)个月		0(0/5)	60%(3/5)
				未DAA治疗20例	(71.2±23.8)个月		NA	5%(1/20)
Gorgen A，2020 ^[25]	加拿大	回顾性	875	移植前DAA治疗121例	2.1年	移植前	93.4%(113/121)	6.6%(8/121)
				移植前IFN治疗112例	2.9年	移植前	33% (37/112)	15.2%(17/112)
				未抗病毒治疗142例	2.7年	NA	NA	28.2%(40/142)
				移植后DAA治疗395例	4.5年	移植后	96.5%(381/395)	6.3%(25/395)
				移植后IFN治疗105例	7.8年	移植后	67.6%(71/105)	11.4%(12/105)
Adhoute X，2018 ^[26]	法国	回顾性	8	DAA治疗组3例	68(24~75)个月	移植后	NA	16.7%(1/3)
				未DAA治疗组5例	32(25~69)个月			20.0%(1/5)
注: NA，原文中未描述。

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参考文献(27)

[1]	REIG M, MARIÑO Z, PERELLÓ C, et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy[J]. J Hepatol, 2016, 65(4): 719-726. DOI: 10.1016/j.jhep.2016.04.008.
[2]	de MARTEL C, GEORGES D, BRAY F, et al. Global burden of cancer attributable to infections in 2018: A worldwide incidence analysis[J]. Lancet Glob Health, 2020, 8(2): e180-e190. DOI: 10.1016/S2214-109X(19)30488-7.
[3]	HUESING-KABAR A, DOHNA CZ, HEINZOW H, et al. Risk factors for allograft failure in liver transplant recipients[J]. Z Gastroenterol, 2018, 56(7): 745-751. DOI: 10.1055/s-0043-125225.
[4]	FORMAN LM, LEWIS JD, BERLIN JA, et al. The association between hepatitis C infection and survival after orthotopic liver transplantation[J]. Gastroenterology, 2002, 122(4): 889-896. DOI: 10.1053/gast.2002.32418.
[5]	FERRARESE A, ZANETTO A, GAMBATO M, et al. Liver transplantation for viral hepatitis in 2015[J]. World J Gastroenterol, 2016, 22(4): 1570-1581. DOI: 10.3748/wjg.v22.i4.1570.
[6]	CURRY MP, FORNS X, CHUNG RT, et al. Sofosbuvir and ribavirin prevent recurrence of HCV infection after liver transplantation: An open-label study[J]. Gastroenterology, 2015, 148(1): 100-107. e1. DOI: 10.1053/j.gastro.2014.09.023.
[7]	MANNS M, SAMUEL D, GANE EJ, et al. Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: A multicentre, open-label, randomised, phase 2 trial[J]. Lancet Infect Dis, 2016, 16(6): 685-697. DOI: 10.1016/S1473-3099(16)00052-9.
[8]	CHARLTON M, EVERSON GT, FLAMM SL, et al. Ledipasvir and sofosbuvir plus ribavirin for treatment of HCV infection in patients with advanced liver disease[J]. Gastroenterology, 2015, 149(3): 649-659. DOI: 10.1053/j.gastro.2015.05.010.
[9]	BELLI LS, BERENGUER M, CORTESI PA, et al. Delisting of liver transplant candidates with chronic hepatitis C after viral eradication: A European study[J]. J Hepatol, 2016, 65(3): 524-531. DOI: 10.1016/j.jhep.2016.05.010.
[10]	PASCASIO JM, VINAIXA C, FERRER MT, et al. Clinical outcomes of patients undergoing antiviral therapy while awaiting liver transplantation[J]. J Hepatol, 2017, 67(6): 1168-1176. DOI: 10.1016/j.jhep.2017.08.008.
[11]	BESTE LA, GREEN PK, BERRY K, et al. Effectiveness of hepatitis C antiviral treatment in a USA cohort of veteran patients with hepatocellular carcinoma[J]. J Hepatol, 2017, 67(1): 32-39. DOI: 10.1016/j.jhep.2017.02.027.
[12]	PRENNER SB, VANWAGNER LB, FLAMM SL, et al. Hepatocellular carcinoma decreases the chance of successful hepatitis C virus therapy with direct-acting antivirals[J]. J Hepatol, 2017, 66(6): 1173-1181. DOI: 10.1016/j.jhep.2017.01.020.
[13]	SINGAL AG, LIM JK, KANWAL F. AGA clinical practice update on interaction between oral direct-acting antivirals for chronic hepatitis C infection and hepatocellular carcinoma: Expert review[J]. Gastroenterology, 2019, 156(8): 2149-2157. DOI: 10.1053/j.gastro.2019.02.046.
[14]	TERRAULT NA, MCCAUGHAN GW, CURRY MP, et al. International liver transplantation society consensus statement on hepatitis C management in liver transplant candidates[J]. Transplantation, 2017, 101(5): 945-955. DOI: 10.1097/TP.0000000000001708.
[15]	European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2018[J]. J Hepatol, 2018, 69(2): 461-511. DOI: 10.1016/j.jhep.2018.11.004.
[16]	Organ Transplantation Branch, Chinese Medical Doctor Association, Chinese Society of Organ Transplantation, Chinese Medical Association. The Chinese clinical practice guideline on liver transplantation for hepatocellular carcinoma (2018)[J]. J Clin Hepatol, 2019, 35(2): 275-280. DOI: 10.3969/j.issn.1001-5256.2019.02.008. 中国医师协会器官移植医师分会, 中华医学会器官移植学分会. 中国肝癌肝移植临床实践指南(2018版)[J]. 临床肝胆病杂志, 2019, 35(2): 275-280. DOI: 10.3969/j.issn.1001-5256.2019.02.008.
[17]	Chinese Society of Hepatology, Chinese Medical Association, Chinese Society of Infectious Diseases, Chinese Medical Association. Guidelines for the prevention and treatment of hepatitis C(2019 version)[J]. J Clin Hepatol, 2019, 35(12): 2670-2686. DOI: 10.3969/j.issn.1001-5256.2019.12.008. 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(2019年版)[J]. 临床肝胆病杂志, 2019, 35(12): 2670-2686. DOI: 10.3969/j.issn.1001-5256.2019.12.008.
[18]	YANG JD, AQEL BA, PUNGPAPONG S, et al. Direct acting antiviral therapy and tumor recurrence after liver transplantation for hepatitis C-associated hepatocellular carcinoma[J]. J Hepatol, 2016, 65(4): 859-860. DOI: 10.1016/j.jhep.2016.06.023.
[19]	ANRS collaborative study group on hepatocellular carcinoma (ANRS CO22 HEPATHER, CO12 CirVir and CO23 CUPILT cohorts). Lack of evidence of an effect of direct-acting antivirals on the recurrence of hepatocellular carcinoma: Data from three ANRS cohorts[J]. J Hepatol, 2016, 65(4): 734-740. DOI: 10.1016/j.jhep.2016.05.045.
[20]	ZANETTO A, SHALABY S, VITALE A. Dropout rate from the liver transplant waiting list because of hepatocellular carcinoma progression in hepatitis C virus-infected patients treated with direct-acting antivirals[J]. Liver Int, 2017, 23(9): 1103-1112. DOI: 10.1111/liv.13422
[21]	ZANAGA LP, SANTOS AG, ATAÍDE EC, et al. Recurrent hepatitis C treatment with direct acting antivirals - a real life study at a Brazilian liver transplant center[J]. Braz J Med Biol Res, 2019, 52(8): e8519. DOI: 10.1590/1414-431X20198519.
[22]	BIELEN R, MORENO C, van VLIERBERGHE H, et al. The risk of early occurrence and recurrence of hepatocellular carcinoma in hepatitis C-infected patients treated with direct-acting antivirals with and without pegylated interferon: A Belgian experience[J]. J Viral Hepat, 2017, 24(11): 976-981. DOI: 10.1111/jvh.12726.
[23]	EMAMAULLEE JA, BRAL M, MEEBERG G. HCV eradication with direct-acting antivirals does not impact HCC progression on the waiting list or HCC recurrence after liver transplantation[J]. Can J Gastroenterol Hepatol, 2019, 2019: 2509059. DOI: 10.1155/2019/2509059.
[24]	JAIN A, MILLER D, SCHREIBMAN I, et al. Is there increased risk of hepatocellular carcinoma recurrence in liver transplant patients with direct-acting antiviral therapy?[J]. Hepatol Int, 2019, 13(2): 190-198. DOI: 10.1007/s12072-019-09930-x.
[25]	GORGEN A, GALVIN Z, HUANG AC, et al. The impact of direct-acting antivirals on overall mortality and tumoral recurrence in patients with hepatocellular carcinoma listed for liver transplantation: An international multicenter study[J]. Transplantation, 2020, 104(10): 2087-2096. DOI: 10.1097/TP.0000000000003115.
[26]	ADHOUTE X, PENARANDA G, RAOUL JL, et al. Hepatocellular carcinoma recurrence in hepatitis C virus-related cirrhosis treated with direct-acting antivirals: A case-control study[J]. Eur J Gastroenterol Hepatol, 2018, 30(4): 368-375. DOI: 10.1097/MEG.0000000000001082.
[27]	DONATO MF, INVERNIZZI F, ROSSI G, et al. Interferon-free therapy of hepatitis C during wait list and post-transplant risk of hepatocellular carcinoma recurrence[J]. J Hepatol, 2017, 67(6): 1355-1356. DOI: 10.1016/j.jhep.2017.07.026.