免疫检查点抑制剂抗肿瘤治疗与HBV再激活的关系

陈顺; 解有成; 王俊科; 赵宝银; 张久聪; 王盼; 于晓辉

doi:10.3969/j.issn.1001-5256.2023.06.027

免疫检查点抑制剂抗肿瘤治疗与HBV再激活的关系

DOI: 10.3969/j.issn.1001-5256.2023.06.027

陈顺^{1, 2},
解有成¹,
王俊科¹,
赵宝银¹,
张久聪¹,
王盼¹,
于晓辉^1, , ,

1.
中国人民解放军联勤保障部队第九四O医院消化内科，兰州 730050
2.
兰州大学第二医院消化内科，兰州 730000

基金项目:

甘肃省重点研发计划 (20YF8FA099);

甘肃省青年科技基金 (20JR10RA016);

甘肃省非感染性肝病临床医学研究中心 (21JR7RA017)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：陈顺负责查阅文献，撰写论文；解有成、赵宝银、王俊科参与收集数据；于晓辉、张久聪、王盼负责修改文章并最后定稿。

详细信息

通信作者:
于晓辉, yuxiaohui@126.com (ORCID: 0000-0002-8633-3281)

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- 文章访问数: 273
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- 被引次数: 0
出版历程
- 收稿日期: 2022-09-30
- 录用日期: 2022-10-28
- 出版日期: 2023-06-20

Association between immune checkpoint inhibitor antitumor therapy and hepatitis B virus reactivation

1.
Department of Gastroenterology, The 940 Hospital of Joint Logistic Support Force of PLA, Lanzhou 730050, China
2.
The Second Hospital of Lanzhou University, Lanzhou 730000, China

Research funding:

Gansu Provincial Key R&D Program (20YF8FA099);

Gansu Provincial Youth Science and Technology Fund (20JR10RA016);

Gansu Provincial Clinical Medical Research Centre for Non － infectious Liver Diseases (21JR7RA017)

More Information

Corresponding author: YU Xiaohui, yuxiaohui@126.com (ORCID: 0000-0002-8633-3281)

摘要

摘要: 近年来，免疫检查点抑制剂(ICI)单药和联合治疗在从实体瘤到淋巴瘤等多种恶性肿瘤中取得了广泛的疗效，并且成为了多种癌症的标准化和系统化治疗模式。然而，在HBV感染的恶性肿瘤患者中，ICI应用的安全性研究尚不多见。有早期研究陆续报道在临床中ICI抗肿瘤治疗所致的HBV再激活。本文通过回顾已有文献，对近年来ICI在慢性病毒感染的癌症患者中的临床试验及应用进展进行综述，阐明这类特殊群体应用ICI的有效性及安全性，以期为临床用药提供一定参考。
- 肝肿瘤 /
- 乙型肝炎, 慢性 /
- 再感染 /
- 免疫检查点抑制剂
Abstract: In recent years, monotherapy and combination therapy with immune checkpoint inhibitors (ICIs) have achieved good efficacy in a variety of malignancies from solid tumors to lymphomas and have become a standardized and systematic treatment modality for many cancers. However, there is still a lack of studies on the safety of ICIs in hepatitis B virus (HBV)-infected patients with malignancies, and early studies have reported HBV reactivation due to ICI antitumor therapy in clinical practice. With reference to related literature, this article reviews the recent clinical trials and application of ICIs in cancer patients with chronic viral infection and clarifies the efficacy and safety of ICIs in this special population, in order to provide a reference for clinical medication.
- Liver Neoplasms /
- Hepatitis B, Chronic /
- Reinfection /
- Immune Checkpoint Inhibitors

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图 1 NAs抑制ICI所致的HBVr示意图

Figure 1. Diagram of NAs inhibit HBVr caused by ICI

下载: 全尺寸图片幻灯片

表 1 不同指南对HBVr的定义

Table 1. Definitions of HBV reactivation in different guidelines

指南	CHB患者HBVr	既往HBV感染者HBVr
指南	满足以下任何一项可诊断	满足以下任何一项可诊断
美国胃肠病学会(AGA)2015年指南	·在无法获得的DNA基线水平的患者中：没有明确的定义 ·可获得的DNA基线，以前检测不到的患者中：新的可检测的DNA ·可获得的DNA基线水平，以前可以检测到患者中：≥10倍的增长	·反向血清转换，HBsAg阳性状态
亚太肝病学会(APASL)2016年指南	·不可获得DNA基线水平的患者中：≥20 000 IU/mL ·可获得DNA基线，以前检测不到的患者中：重新检测HBV DNA到100 IU/mL的水平 ·可获得DNA基线，以前可检测到的：比基线水平增加≥2 lg	·未明确的定义
欧洲肝病学会(EASL)2017年指南	·未明确的定义	·未明确的定义
美国肝病学会(AASLD)2018年指南	·在无法获得HBV DNA基线水平的患者中≥10 000 IU/mL ·可获得DNA基线水平，在以前未检测的患者中≥1 000 IU/mL ·可检测的DNA基线水平，以前可以检测患者中≥100倍的增加	·进展为可检测到的DNA ·HBsAg的重新出现(也称为反向血清转换)
韩国肝病学会(KASL)2019年指南	·血清HBV DNA增加超过基线水平的100倍	·HBsAg阴性血清转换为阳性·检测血清HBV DNA从无到阳性
中华医学会感染病学/肝病学分会2019年指南	·HBsAg阳性/抗-HBc阳性，或HBsAg阴性/抗-HBc阳性患者接受免疫抑制治疗或化学治疗时，HBV DNA较基线升高≥2 lgIU/mL或基线HBV DNA阴性者转为阳性，或HBsAg由阴性转为阳性	·未明确的定义
美国临床肿瘤学会(ASCO)2020年指南	·与AASLD指南相同	·与AASLD指南相同

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表 2 正在进行的ICI抗癌症患者中HBVr的临床试验

Table 2. Ongoing clinical trial of ICI against HBV reactivation in cancer patients

临床试验号	例数	疾病	ICI	临床试验分期	研究内容
NCT04680598	800	肝细胞癌合并HBsAg阳性患者	纳武单抗特瑞普利单抗派姆单抗信迪利单抗卡瑞利珠单抗阿替利珠单抗	-	低HBV DNA载量和高HBV DNA载量患者在接受抗病毒预防和ICI时的HBVr情况
NCT04180072	48	局部晚期或转移性和/或不能切除的肝细胞癌合并HBsAg阳性患者	阿替利珠单抗	-	ICI联合蛋白激酶B抑制剂治疗晚期肝癌和慢性HBV感染所致的肝癌的总有效率及HBVr情况
NCT04294498	43	肝细胞癌合并HBsAg且HBV DNA≥2 000 IU/mL	度伐利尤单抗	Ⅱ	评估在度伐利尤单抗治疗中HBVr情况
NCT01658878	1 100	未感染的肝细胞癌受试者，HCV感染的肝细胞癌受试者和HBV感染的受试者	纳武单抗伊匹木单抗	Ⅰ、Ⅱ	用于评估尼武单抗或尼武单抗与其他药物联合使用在HBV、HCV合并晚期肝细胞癌患者中的有效性、安全性和耐受性

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参考文献(41)

[1]	KONG X, LU P, LIU C, et al. A combination of PD-1/PD-L1 inhibitors: The prospect of overcoming the weakness of tumor immunotherapy (Review)[J]. Mol Med Rep, 2021, 23(5): 362. DOI: 10.3892/mmr.2021.12001.
[2]	HASLAM A, GILL J, PRASAD V. Estimation of the percentage of US patients with cancer who are eligible for immune checkpoint inhibitor drugs[J]. JAMA Netw Open, 2020, 3(3): e200423. DOI: 10.1001/jamanetworkopen.2020.0423.
[3]	SHI Y, ZHENG M. Hepatitis B virus persistence and reactivation[J]. BMJ, 2020, 370: m2200. DOI: 10.1136/bmj.m2200.
[4]	YUEN MF, CHEN DS, DUSHEIKO GM, et al. Hepatitis B virus infection[J]. Nat Rev Dis Primers, 2018, 4: 18036. DOI: 10.1038/nrdp.2018.36.
[5]	LOOMBA R, LIANG TJ. Hepatitis B reactivation associated with immune suppressive and biological modifier therapies: current concepts, management strategies, and future directions[J]. Gastroenterology, 2017, 152(6): 1297-1309. DOI: 10.1053/j.gastro.2017.02.009.
[6]	SMALLS DJ, KIGER RE, NORRIS LB, et al. Hepatitis B virus reactivation: risk factors and current management strategies[J]. Pharmacotherapy, 2019, 39(12): 1190-1203. DOI: 10.1002/phar.2340.
[7]	CHEN CY, TIEN FM, CHENG A, et al. Hepatitis B reactivation among 1962 patients with hematological malignancy in Taiwan[J]. BMC Gastroenterol, 2018, 18(1): 6. DOI: 10.1186/s12876-017-0735-1.
[8]	AKIYAMA S, COTTER TG, SAKURABA A. Risk of hepatitis B virus reactivation in patients with autoimmune diseases undergoing non-tumor necrosis factor-targeted biologics[J]. World J Gastroenterol, 2021, 27(19): 2312-2324. DOI: 10.3748/wjg.v27.i19.2312.
[9]	SAITTA C, POLLICINO T, RAIMONDO G. Occult hepatitis B virus infection: An update[J]. Viruses, 2022, 14(7): 1504. DOI: 10.3390/v14071504.
[10]	ASAI A, HIRAI S, YOKOHAMA K, et al. Effect of an electronic alert system on hepatitis B virus reactivation in patients receiving immunosuppressive drug therapy[J]. J Clin Med, 2022, 11(9): 2446. DOI: 10.3390/jcm11092446.
[11]	KUSUMOTO S, ARCAINI L, HONG X, et al. Risk of HBV reactivation in patients with B-cell lymphomas receiving obinutuzumab or rituximab immunochemotherapy[J]. Blood, 2019, 133(2): 137-146. DOI: 10.1182/blood-2018-04-848044.
[12]	VOICAN CS, MIR O, LOULERGUE P, et al. Hepatitis B virus reactivation in patients with solid tumors receiving systemic anticancer treatment[J]. Ann Oncol, 2016, 27(12): 2172-2184. DOI: 10.1093/annonc/mdw414.
[13]	LAU G, YU ML, WONG G, et al. APASL clinical practice guideline on hepatitis B reactivation related to the use of immunosuppressive therapy[J]. Hepatol Int, 2021, 15(5): 1031-1048. DOI: 10.1007/s12072-021-10239-x.
[14]	ANASTASOPOULOU A, ZIOGAS DC, SAMARKOS M, et al. Reactivation of tuberculosis in cancer patients following administration of immune checkpoint inhibitors: current evidence and clinical practice recommendations[J]. J Immunother Cancer, 2019, 7(1): 239. DOI: 10.1186/s40425-019-0717-7.
[15]	LIN G, ZHUANG W, CHEN XH, et al. Increase of programmed death ligand 1 in non-small-cell lung cancers with chronic hepatitis B[J]. Ann Oncol, 2018, 29(2): 516-517. DOI: 10.1093/annonc/mdx694.
[16]	ZHANG X, ZHOU Y, CHEN C, et al. Hepatitis B virus reactivation in cancer patients with positive hepatitis B surface antigen undergoing PD-1 inhibition[J]. J Immunother Cancer, 2019, 7(1): 322. DOI: 10.1186/s40425-019-0808-5.
[17]	SCHÖNRICH G, RAFTERY MJ. The PD-1/PD-L1 axis and virus infections: a delicate balance[J]. Front Cell Infect Microbiol, 2019, 9: 207. DOI: 10.3389/fcimb.2019.00207.
[18]	European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection[J]. J Hepatol, 2017, 67(2): 370-398. DOI: 10.1016/j.jhep.2017.03.021.
[19]	MORENO-CUBERO E, LARRUBIA JR. Specific CD8(+) T cell response immunotherapy for hepatocellular carcinoma and viral hepatitis[J]. World J Gastroenterol, 2016, 22(28): 6469-6483. DOI: 10.3748/wjg.v22.i28.6469.
[20]	LI B, YAN C, ZHU J, et al. Anti-PD-1/PD-L1 Blockade immunotherapy employed in treating hepatitis B virus infection-related advanced hepatocellular carcinoma: a literature review[J]. Front Immunol, 2020, 11: 1037. DOI: 10.3389/fimmu.2020.01037.
[21]	WANG X, HE Q, SHEN H, et al. Genetic and phenotypic difference in CD8(+) T cell exhaustion between chronic hepatitis B infection and hepatocellular carcinoma[J]. J Med Genet, 2019, 56(1): 18-21. DOI: 10.1136/jmedgenet-2018-105267.
[22]	KUMAGAI S, TOGASHI Y, KAMADA T, et al. The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies[J]. Nat Immunol, 2020, 21(11): 1346-1358. DOI: 10.1038/s41590-020-0769-3.
[23]	KNOLLE PA, THIMME R. Hepatic immune regulation and its involvement in viral hepatitis infection[J]. Gastroenterology, 2014, 146(5): 1193-1207. DOI: 10.1053/j.gastro.2013.12.036.
[24]	EL-KHOUEIRY AB, SANGRO B, YAU T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial[J]. Lancet, 2017, 389(10088): 2492-2502. DOI: 10.1016/S0140-6736(17)31046-2.
[25]	ZHU AX, FINN RS, EDELINE J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial[J]. Lancet Oncol, 2018, 19(7): 940-952. DOI: 10.1016/S1470-2045(18)30351-6.
[26]	PU D, YIN L, ZHOU Y, et al. Safety and efficacy of immune checkpoint inhibitors in patients with HBV/HCV infection and advanced-stage cancer: A systematic review[J]. Medicine (Baltimore), 2020, 99(5): e19013. DOI: 10.1097/MD.0000000000019013.
[27]	TERRAULT NA, LOK A, MCMAHON BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance[J]. Hepatology, 2018, 67(4): 1560-1599. DOI: 10.1002/hep.29800.
[28]	ZIOGAS DC, KOSTANTINOU F, CHOLONGITAS E, et al. Reconsidering the management of patients with cancer with viral hepatitis in the era of immunotherapy[J]. J Immunother Cancer, 2020, 8(2). DOI: 10.1136/jitc-2020-000943.
[29]	TIO M, RAI R, EZEOKE OM, et al. Anti-PD-1/PD-L1 immunotherapy in patients with solid organ transplant, HIV or hepatitis B/C infection[J]. Eur J Cancer, 2018, 104: 137-144. DOI: 10.1016/j.ejca.2018.09.017.
[30]	KOTHAPALLI A, KHATTAK MA. Safety and efficacy of anti-PD-1 therapy for metastatic melanoma and non-small-cell lung cancer in patients with viral hepatitis: a case series[J]. Melanoma Res, 2018, 28(2): 155-158. DOI: 10.1097/CMR.0000000000000434.
[31]	SHAH NJ, AL-SHBOOL G, BLACKBURN M, et al. Safety and efficacy of immune checkpoint inhibitors (ICIs) in cancer patients with HIV, hepatitis B, or hepatitis C viral infection[J]. J Immunother Cancer, 2019, 7(1): 353. DOI: 10.1186/s40425-019-0771-1.
[32]	SCHEINER B, KIRSTEIN MM, HUCKE F, et al. Programmed cell death protein-1 (PD-1)-targeted immunotherapy in advanced hepatocellular carcinoma: efficacy and safety data from an international multicentre real-world cohort[J]. Aliment Pharmacol Ther, 2019, 49(10): 1323-1333. DOI: 10.1111/apt.15245.
[33]	PERTEJO-FERNANDEZ A, RICCIUTI B, HAMMOND SP, et al. Safety and efficacy of immune checkpoint inhibitors in patients with non-small cell lung cancer and hepatitis B or hepatitis C infection[J]. Lung Cancer, 2020, 145: 181-185. DOI: 10.1016/j.lungcan.2020.02.013.
[34]	LEE PC, CHAO Y, CHEN MH, et al. Risk of HBV reactivation in patients with immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma[J]. J Immunother Cancer, 2020, 8(2): e001072. DOI: 10.1136/jitc-2020-001072.
[35]	ZHANG X, TIAN D, CHEN Y, et al. Association of hepatitis B virus infection status with outcomes of non-small cell lung cancer patients undergoing anti-PD-1/PD-L1 therapy[J]. Transl Lung Cancer Res, 2021, 10(7): 3191-3202. DOI: 10.21037/tlcr-21-455.
[36]	HE MK, PENG C, ZHAO Y, et al. Comparison of HBV reactivation between patients with high HBV-DNA and low HBV-DNA loads undergoing PD-1 inhibitor and concurrent antiviral prophylaxis[J]. Cancer Immunol Immunother, 2021, 70(11): 3207-3216. DOI: 10.1007/s00262-021-02911-w.
[37]	WONG GL, WONG VW, HUI VW, et al. Hepatitis flare during immunotherapy in patients with current or past hepatitis B virus infection[J]. Am J Gastroenterol, 2021, 116(6): 1274-1283. DOI: 10.14309/ajg.0000000000001142.
[38]	ZHONG L, ZHONG P, LIU H, et al. Hepatitis B virus infection does not affect the clinical outcome of anti-programmed death receptor-1 therapy in advanced solid malignancies: Real-world evidence from a retrospective study using propensity score matching[J]. Medicine (Baltimore), 2021, 100(49): e28113. DOI: 10.1097/MD.0000000000028113.
[39]	YOO S, LEE D, SHIM JH, et al. Risk of hepatitis b virus reactivation in patients treated with immunotherapy for anti-cancer treatment[J]. Clin Gastroenterol Hepatol, 2022, 20(4): 898-907. DOI: 10.1016/j.cgh.2021.06.019.
[40]	PAN S, YU Y, WANG S, et al. Correlation of HBV DNA and hepatitis B surface antigen levels with tumor response, liver function and immunological indicators in liver cancer patients with HBV infection undergoing PD-1 inhibition combinational therapy[J]. Front Immunol, 2022, 13: 892618. DOI: 10.3389/fimmu.2022.892618.
[41]	HAGIWARA S, NISHIDA N, IDA H, et al. Clinical implication of immune checkpoint inhibitor on the chronic hepatitis B virus infection[J]. Hepatol Res, 2022, 52(9): 754-761. DOI: 10.1111/hepr.13798.