直接抗病毒药物在丙型肝炎肝硬化患者中的应用进展

冉锡萍; 蔡大川

doi:10.12449/JCH240828

直接抗病毒药物在丙型肝炎肝硬化患者中的应用进展

DOI: 10.12449/JCH240828

冉锡萍¹,
蔡大川^2, , ,

1.
重庆医科大学附属第二医院感染病科，重庆 401336
2.
感染性疾病分子生物学教育部重点实验室，重庆医科大学病毒性肝炎研究所，重庆 400010

基金项目:

重庆市科卫联合医学科研重点项目 (2022ZDXM001);

重庆市首批公共卫生重点学科（专科）

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：冉锡萍负责查阅相关文献，分析/解释数据和起草文章；蔡大川负责对文章的知识性内容作批评性审阅与指导。

详细信息

通信作者:
蔡大川， cqmucdc@cqmu.edu.cn （ORCID： 0000-0003-3269-8549）

计量
- 文章访问数: 170
- HTML全文浏览量: 78
- PDF下载量: 22
- 被引次数: 0
出版历程
- 收稿日期: 2023-12-12
- 录用日期: 2024-01-12
- 出版日期: 2024-08-25

Advances in the application of direct-acting antivirals in patients with hepatitis C cirrhosis

Xiping RAN¹,
Dachuan CAI^{2
, ,
,}

1.
Department of Infectious Diseases，The Second Affiliated Hospital of Chongqing Medical University，Chongqing 401336，China
2.
Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education，Institute for Viral Hepatitis，Chongqing Medical University，Chongqing 400010，China

Research funding:

Chongqing Medical Scientific Research Key Project （Joint Project of Chongqing Health Commission and Science and Technology Bureau） (2022ZDXM001);

The First Batch of Key Disciplines on Public Health in Chongqing

More Information

Corresponding author: CAI Dachuan， cqmucdc@cqmu.edu.cn （ORCID： 0000-0003-3269-8549）

摘要

摘要: 慢性丙型肝炎病毒感染可导致肝硬化的发生，肝硬化后出现肝细胞癌等并发症是慢性肝病患者的主要死亡原因。抗病毒治疗可以实现持续病毒学应答，改善肝炎、肝纤维化，进而延缓病程进展。直接抗病毒药物（DAA）在丙型肝炎肝硬化患者中的安全性和有效性已被证实，其是否能改善肝硬化患者疾病并发症和预后逐渐成为讨论和研究的热点。相关数据主要由国外学者报告，我国DAA上市较晚，尚缺乏中远期数据。本文回顾了最新的相关研究，对DAA在丙型肝炎肝硬化患者中的应用现状及其对临床预后的影响进行综述。
- 肝炎病毒属 /
- 肝硬化 /
- 直接抗病毒药物 /
- 治疗结果
Abstract: Chronic hepatitis C virus （HCV） infection can lead to liver cirrhosis， and complications after liver cirrhosis， including hepatocellular carcinoma （HCC）， are the leading causes of death in patients with chronic liver diseases. Antiviral therapy can help to realize sustained virologic response， improve hepatitis and liver fibrosis， and delay disease progression. The safety and efficacy of direct-acting antivirals （DAAs） have been confirmed in patients with HCV-related liver cirrhosis， and whether DAAs can improve the complications and prognosis of patients with liver cirrhosis has gradually become a research hotspot. Related data are mainly reported by foreign scholars， and since DAAs have not been marketed in China for a long time， there is still a lack of mid- and long-term data. This article reviews the latest studies on the application of DAAs in patients with HCV-related liver cirrhosis and the impact of DAAs on clinical prognosis.
- Hepacivirus /
- Liver Cirrhosis /
- Direct-Acting Antivirals /
- Treatment Outcome

HTML全文

表 1 近3年报道丙型肝炎代偿期肝硬化患者使用DAA达SVR后HCC发病风险的研究

Table 1. Summary of studies related to the risk of HCC in patients with compensated liver cirrhosis using DAA to achieve SVR in the last three years

作者	年份	研究地点	研究类型	总人数（例）	随访时间	HCC（例）	发病（%）	发病率（%/人年）
Kondili等^［35］	2023	意大利	前瞻性	1 839	28.47个月	98	5.33
Ciancio等^［36］	2023	意大利	前瞻性	1 000	48个月	71	7.10	1.97
Choi等^［37］	2022	韩国	前瞻性	218	4.1年	17	7.80	2.89
Semmler等^［38］	2022	奥地利	前瞻性	475	41个月	22	4.60	1.45
Sanduzzi-zamparelli等^［39］	2022	西班牙	前瞻性	122	48个月	10	8.20	2.24
Younossi等^［40］	2022	美国	前瞻性	730	168周	37	5.07
D’ambrosio等^［41］	2022	意大利	前瞻性	480	51个月	32	6.67

下载: 导出CSV

表 2 近3年报道丙型肝炎失代偿期肝硬化患者使用DAA达SVR后HCC发病风险的研究

Table 2. Summary of studies related to the risk of HCC in patients with decompensated liver cirrhosis using DAA to achieve SVR in the last three years

作者	年份	研究地点	研究类型	总人数（例）	随访时间	HCC（例）	发病（%）	发病率（%/人年）
Kondili等^［35］	2023	意大利	前瞻性	225	28.47个月	21	9.33
Semmler等^［38］	2022	奥地利	前瞻性	52	41个月	12	23.10	7.00
Younossi等^［40］	2022	美国	前瞻性	124	168周	21	16.94
D’ambrosio等^［41］	2022	意大利	前瞻性	89	51个月	14	15.73

下载: 导出CSV

参考文献(45)

[1]	CUI FQ, BLACH S, MANZENGO MINGIEDI C, et al. Global reporting of progress towards elimination of hepatitis B and hepatitis C[J]. Lancet Gastroenterol Hepatol, 2023, 8( 4): 332- 342. DOI: 10.1016/S2468-1253(22)00386-7.
[2]	CARRAT F, FONTAINE H, DORIVAL C, et al. Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: A prospective cohort study[J]. Lancet, 2019, 393( 10179): 1453- 1464. DOI: 10.1016/S0140-6736(18)32111-1.
[3]	IOANNOU GN, FELD JJ. What are the benefits of a sustained virologic response to direct-acting antiviral therapy for hepatitis C virus infection?[J]. Gastroenterology, 2019, 156( 2): 446- 460. DOI: 10.1053/j.gastro.2018.10.033.
[4]	IOANNOU GN, GREEN PK, BERRY K. HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma[J]. J Hepatol, 2017: S0168-8278(17)32273- 0. DOI: 10.1016/j.jhep.2017.08.030.
[5]	MAURO E, CRESPO G, MONTIRONI C, et al. Portal pressure and liver stiffness measurements in the prediction of fibrosis regression after sustained virological response in recurrent hepatitis C[J]. Hepatology, 2018, 67( 5): 1683- 1694. DOI: 10.1002/hep.29557.
[6]	INNES H, MCDONALD SA, HAMILL V, et al. Declining incidence of hepatitis C related hepatocellular carcinoma in the era of interferon-free therapies: A population-based cohort study[J]. Liver Int, 2022, 42( 3): 561- 574. DOI: 10.1111/liv.15143.
[7]	AN J, PARK DA, KO MJ, et al. Direct-acting antivirals for HCV treatment in decompensated liver cirrhosis patients: A systematic review and meta-analysis[J]. J Pers Med, 2022, 12( 9): 1517. DOI: 10.3390/jpm12091517.
[8]	CURRY MP, O’LEARY JG, BZOWEJ N, et al. Sofosbuvir and Velpatasvir for HCV in patients with decompensated cirrhosis[J]. N Engl J Med, 2015, 373( 27): 2618- 2628. DOI: 10.1056/NEJMoa1512614.
[9]	BHATTACHARYA D, ARONSOHN A, PRICE J, et al. Hepatitis C guidance 2023 update: AASLD-IDSA recommendations for testing, managing, and treating hepatitis C virus infection[J]. Clin Infect Dis, 2023: ciad319. DOI: 10.1093/cid/ciad319.
[10]	European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C: Final update of the series[J]. J Hepatol, 2020, 73( 5): 1170- 1218. DOI: 10.1016/j.jhep.2020.08.018.
[11]	Chinese Society of Hepatology and Chinese Society of Infectious Diseases, Chinese Medical Association. Guidelines for the prevention and treatment of hepatitis C(2022 version)[J]. Chin J Infect Dis, 2023, 41( 1): 29- 46. DOI: 10.3760/cma.j.cn311365-20230217-00045. 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(2022年版)[J]. 中华传染病杂志, 2023, 41( 1): 29- 46. DOI: 10.3760/cma.j.cn311365-20230217-00045.
[12]	BROWN RS Jr, BUTI M, RODRIGUES L, et al. Glecaprevir/pibrentasvir for 8 weeks in treatment-naïve patients with chronic HCV genotypes 1-6 and compensated cirrhosis: The EXPEDITION-8 trial[J]. J Hepatol, 2020, 72( 3): 441- 449. DOI: 10.1016/j.jhep.2019.10.020.
[13]	RAO HY. Key points in hepatitis C guidance 2023 update: American Association for the Study of Liver Diseases-Infectious Diseases Society of America recommendations for testing, managing, and treating hepatitis C virus infection[J]. J Clin Hepatol, 2023, 39( 12): 2798- 2803. DOI: 10.3969/j.issn.1001-5256.2023.12.008. 饶慧瑛.《美国肝病学会/美国感染病学会丙型肝炎指导意见: HCV感染的检测、管理和治疗(2023年更新)》意见要点[J]. 临床肝胆病杂志, 2023, 39( 12): 2798- 2803. DOI: 10.3969/j.issn.1001-5256.2023.12.008.
[14]	WEI L, WANG GQ, ALAMI NN, et al. Glecaprevir-pibrentasvir to treat chronic hepatitis C virus infection in Asia: Two multicentre, phase 3 studies- a randomised, double-blind study(VOYAGE-1) and an open-label, single-arm study(VOYAGE-2)[J]. Lancet Gastroenterol Hepatol, 2020, 5( 9): 839- 849. DOI: 10.1016/S2468-1253(20)30086-8.
[15]	ZHANG WY, ZHANG J, TANG S, et al. Efficacy and safety of sofosbuvir-based regimens in hepatitis C patients with decompensated cirrhosis: A systematic review and meta-analysis[J]. J Clin Transl Hepatol, 2023, 11( 1): 144- 155. DOI: 10.14218/JCTH.2022.00006.
[16]	WONG YJ, TRAN S, HUANG CF, et al. Real-world treatment outcome with protease inhibitor direct-acting antiviral in advanced hepatitis C cirrhosis: A REAL-C study[J]. Hepatol Int, 2023, 17( 5): 1150- 1161. DOI: 10.1007/s12072-023-10547-4.
[17]	NAKAJIMA T, KARINO Y, HIGE S, et al. Factors affecting the recovery of hepatic reserve after sustained virologic response by direct-acting antiviral agents in chronic hepatitis C virus-infected patients[J]. J Gastroenterol Hepatol, 2021, 36( 2): 367- 375. DOI: 10.1111/jgh.15280.
[18]	OGAWA E, KAWANO A, OOHO A, et al. Long-term hepatic function of patients with compensated cirrhosis following successful direct-acting antiviral treatment for hepatitis C virus infection[J]. J Gastroenterol Hepatol, 2022, 37( 2): 371- 377. DOI: 10.1111/jgh.15703.
[19]	KOTANI K, ENOMOTO M, UCHIDA-KOBAYASHI S, et al. Short-term hepatocyte function and portal hypertension outcomes of sofosbuvir/velpatasvir for decompensated hepatitis C-related cirrhosis[J]. J Gastroenterol, 2023, 58( 4): 394- 404. DOI: 10.1007/s00535-023-01963-2.
[20]	VERNA EC, MORELLI G, TERRAULT NA, et al. DAA therapy and long-term hepatic function in advanced/decompensated cirrhosis: Real-world experience from HCV-TARGET cohort[J]. J Hepatol, 2020, 73( 3): 540- 548. DOI: 10.1016/j.jhep.2020.03.031.
[21]	KRASSENBURG LAP, MAAN R, RAMJI A, et al. Clinical outcomes following DAA therapy in patients with HCV-related cirrhosis depend on disease severity[J]. J Hepatol, 2021, 74( 5): 1053- 1063. DOI: 10.1016/j.jhep.2020.11.021.
[22]	MEUNIER L, BELKACEMI M, PAGEAUX GP, et al. Patients treated for HCV infection and listed for liver transplantation in a French multicenter study: What happens at five years?[J]. Viruses, 2022, 15( 1): 137. DOI: 10.3390/v15010137.
[23]	BADIA ARANDA E, FERNÁNDEZ MARCOS C, PUEBLA MAESTU A, et al. Evolution of patients with chronic hepatitis C infection with advanced fibrosis or cirrhosis cured with direct-acting antivirals. Long-term follow-up[J]. Gastroenterol Hepatol, 2022, 45( 10): 767- 779. DOI: 10.1016/j.gastrohep.2022.02.002.
[24]	LENS S, ALVARADO-TAPIAS E, MARIÑO Z, et al. Effects of all-oral anti-viral therapy on HVPG and systemic hemodynamics in patients with hepatitis C virus-associated cirrhosis[J]. Gastroenterology, 2017, 153( 5): 1273- 1283. DOI: 10.1053/j.gastro.2017.07.016.
[25]	ROCKEY DC, FRIEDMAN SL. Fibrosis regression after eradication of hepatitis C virus: From bench to bedside[J]. Gastroenterology, 2021, 160( 5): 1502- 1520. DOI: 10.1053/j.gastro.2020.09.065.
[26]	ROEHLEN N, CROUCHET E, BAUMERT TF. Liver fibrosis: Mechanistic concepts and therapeutic perspectives[J]. Cells, 2020, 9( 4): 875. DOI: 10.3390/cells9040875.
[27]	BARBOSA WF, ANDRADE VG, BRAZ AMM, et al. Cirrhosis regression after SVR with indirect methods of fibrosis analysis: How far is it real?[J]. Clin Exp Med, 2022, 22( 2): 269- 275. DOI: 10.1007/s10238-021-00749-1.
[28]	D’AMICO G, GARCIA-PAGAN JC, LUCA A, et al. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: A systematic review[J]. Gastroenterology, 2006, 131( 5): 1611- 1624. DOI: 10.1053/j.gastro.2006.09.013.
[29]	LENS S, BAIGES A, ALVARADO-TAPIAS E, et al. Clinical outcome and hemodynamic changes following HCV eradication with oral antiviral therapy in patients with clinically significant portal hypertension[J]. J Hepatol, 2020, 73( 6): 1415- 1424. DOI: 10.1016/j.jhep.2020.05.050.
[30]	TAHATA Y, SAKAMORI R, MAESAKA K, et al. Effect of sofosbuvir and velpatasvir therapy on clinical outcome in hepatitis C virus patients with decompensated cirrhosis[J]. Hepatol Res, 2023, 53( 4): 301- 311. DOI: 10.1111/hepr.13868.
[31]	de FRANCHIS R, BOSCH J, GARCIA-TSAO G, et al. Baveno VII-Renewing consensus in portal hypertension[J]. J Hepatol, 2022, 76( 4): 959- 974. DOI: 10.1016/j.jhep.2021.12.022.
[32]	SANGIOVANNI A, DEL NINNO E, FASANI P, et al. Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance[J]. Gastroenterology, 2004, 126( 4): 1005- 1014. DOI: 10.1053/j.gastro.2003.12.049.
[33]	MORGAN RL, BAACK B, SMITH BD, et al. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: A meta-analysis of observational studies[J]. Ann Intern Med, 2013, 158( 5 Pt 1): 329- 337. DOI: 10.7326/0003-4819-158-5-201303050-00005.
[34]	CONTI F, BUONFIGLIOLI F, SCUTERI A, et al. Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals[J]. J Hepatol, 2016, 65( 4): 727- 733. DOI: 10.1016/j.jhep.2016.06.015.
[35]	KONDILI LA, QUARANTA MG, CAVALLETTO L, et al. Profiling the risk of hepatocellular carcinoma after long-term HCV eradication in patients with liver cirrhosis in the PITER cohort[J]. Dig Liver Dis, 2023, 55( 7): 907- 917. DOI: 10.1016/j.dld.2023.01.153.
[36]	CIANCIO A, RIBALDONE DG, SPERTINO M, et al. Who should not be surveilled for HCC development after successful therapy with DAAS in advanced chronic hepatitis C? Results of a long-term prospective study[J]. Biomedicines, 2023, 11( 1): 166. DOI: 10.3390/biomedicines11010166.
[37]	CHOI GH, JANG ES, KIM YS, et al. Hepatocellular carcinoma, decompensation, and mortality based on hepatitis C treatment: A prospective cohort study[J]. World J Gastroenterol, 2022, 28( 30): 4182- 4200. DOI: 10.3748/wjg.v28.i30.4182.
[38]	SEMMLER G, MEYER EL, KOZBIAL K, et al. HCC risk stratification after cure of hepatitis C in patients with compensated advanced chronic liver disease[J]. J Hepatol, 2022, 76( 4): 812- 821. DOI: 10.1016/j.jhep.2021.11.025.
[39]	SANDUZZI-ZAMPARELLI M, MARIÑO Z, LENS S, et al. Liver cancer risk after HCV cure in patients with advanced liver disease without non-characterized nodules[J]. J Hepatol, 2022, 76( 4): 874- 882. DOI: 10.1016/j.jhep.2021.11.023.
[40]	YOUNOSSI ZM, RACILA A, MUIR A, et al. Long-term patient-centered outcomes in cirrhotic patients with chronic hepatitis C after achieving sustained virologic response[J]. Clin Gastroenterol Hepatol, 2022, 20( 2): 438- 446. DOI: 10.1016/j.cgh.2021.01.026.
[41]	D’AMBROSIO R, DEGASPERI E, ANOLLI MP, et al. Incidence of liver- and non-liver-related outcomes in patients with HCV-cirrhosis after SVR[J]. J Hepatol, 2022, 76( 2): 302- 310. DOI: 10.1016/j.jhep.2021.09.013.
[42]	CHEUNG MCM, WALKER AJ, HUDSON BE, et al. Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis[J]. J Hepatol, 2016, 65( 4): 741- 747. DOI: 10.1016/j.jhep.2016.06.019.
[43]	VILLA E, DONGHIA R, BALDACCINI V, et al. GALAD outperforms aMAP and ALBI for predicting HCC in patients with compensated advanced chronic liver disease: A 12-year prospective study[J]. Hepatol Commun, 2023, 7( 10): e0262. DOI: 10.1097/HC9.0000000000000262.
[44]	FAN R, PAPATHEODORIDIS G, SUN J, et al. aMAP risk score predicts hepatocellular carcinoma development in patients with chronic hepatitis[J]. J Hepatol, 2020, 73( 6): 1368- 1378. DOI: 10.1016/j.jhep.2020.07.025.
[45]	SHARMA SA, KOWGIER M, HANSEN BE, et al. Toronto HCC risk index: A validated scoring system to predict 10-year risk of HCC in patients with cirrhosis[J]. J Hepatol, 2017: S0168-8278(17)32248- 1. DOI: 10.1016/j.jhep.2017.07.033.