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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- 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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