慢性乙型肝炎患者低病毒血症的研究现状及挑战

doi:10.16150/j.1671-2870.2024.01.004

摘要/Abstract

摘要：

虽然新生儿普遍接种慢性乙型肝炎病毒（hepatitis B virus，HBV）疫苗，HBV的感染率开始大幅下降，但2016年我国慢性HBV感染者仍有8 600万例。2019年，全球有2.96亿例慢性HBV感染者，且每年约有82万人死于HBV感染所致的肝衰竭、肝硬化或肝细胞癌（hepatocellular carcinoma，HCC）等相关疾病。多数慢性乙型肝炎患者经恩替卡韦、替诺福韦、丙酚替诺福韦等规范抗病毒治疗后，可以取得抑制病毒复制、延缓疾病进展的疗效。但随着人们对疾病更深层次的认识及检测技术的提升，临床发现部分患者经规范治疗48周后，血清HBV DNA低于2 000 IU/mL，但持续或间歇地高于检测下限，即为低病毒血症状态。低病毒血症的发生机制目前尚不明确。相关研究已经表明，HBV低病毒血症影响患者的临床预后，主要表现为促进肝脏炎症、肝纤维化的进展及发生肝硬化失代偿、肝细胞癌、耐药的风险升高。对于HBV低病毒血症患者的治疗方案也尚未有明确建议。本文将对HBV低病毒血症的定义、可能的发生机制、临床意义及临床管理策略等方面进行介绍，为临床医师提供参考。

关键词: 乙型肝炎病毒感染, 低病毒血症, 核苷（酸）类似物

Abstract:

Although newborns are generally vaccinated against chronic hepatitis B virus, incidence of HBV infection decreases. However, in 2016, there were still 86 million cases of chronic HBV infection in China. In 2019, there were 296 million cases of chronic HBV infection worldwide, and approximately 820 000 people die from related diseases caused by HBV infection annually, such as liver failure, cirrhosis or HCC. Mostly, the clinical treatment of patients with chronic hepatitis B can achieve therapeutic effects of inhibiting virus replication and delaying disease progression after standar-dized antiviral treatments (such as entecavir, tenofovir, and propofol tenofovir). But with a deeper understanding of the di-sease and the improvement of detection technology, it has been found in clinical practice that some patients, after 48 weeks of standardized treatment, had serum HBV DNA levels below 2 000 IU/mL and continuously or intermittently exceeding the lower limit of detection， which indicates a state of low-level viremia（LLV）. The mechanism of LLV is currently unclear. Related studies have shown that LLV of HBV affects the clinical prognosis of patients, mainly manifesting as promoting liver inflammation, development of liver fibrosis, and an increased risk of decompensated cirrhosis, hepatocellular carcinoma, and drug resistance. In addition, there are no clear recommendations for the treatment of patients with HBV LLV. This article will review the definition, possible mechanisms, clinical significance, and clinical management strategies of HBV LLV, providing reference for clinical physicians.

Key words: Hepatitis B virus infection, Low level viremia, Nucleos(t)ide analogues

中图分类号:

王娇娇, 蔡大川. 慢性乙型肝炎患者低病毒血症的研究现状及挑战[J]. 诊断学理论与实践, 2024, 23(01): 23-29.

WANG Jiaojiao, CAI Dachuan. Current research and challenges of low-level viremia in patients with chronic hepatitis B[J]. Journal of Diagnostics Concepts & Practice, 2024, 23(01): 23-29.

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作者	年份	总人数（n）	LLV患者HBV DNA水平（IU/mL）
Kim等^[9]	2017	875	12~2 000
Kim等^[10]	2019	565	9~2 000
Lee等^[11]	2020	894	12~2 000
Sun等^[12]	2021	212	100~2 000（抗病毒治疗过程中）
Li等^[13]	2021	211	20~2 000（ETV治疗≥48周）

临床试验	年份	研究药物	研究终点HBV DNA水平
AI463022^[20]	2008	ETV	<300拷贝/mL
NCT00116805、NCT00117676^[21]	2008	TDF、阿德福韦酯	<400拷贝/mL（69 IU/mL)
NCT01940471、NCT01940341^[22]	2018	TDF、TAF	<29 IU/mL

高灵敏度HBV DNA	HBV RNA	乙肝核心相关抗原
1.提高LLV检出率	1.不被NAs抑制	1.反映肝内cccDNA水平
2.反映病毒复制水平	2.反映肝内cccDNA的水平及转录活性	2.预测肝硬化与HCC发生的风险^[30]
3.评估抗病毒治疗疗效	3.联合HBV DNA预测HCC发生风险^[31]	3.联合HBV RNA预测病毒复发^[2]
	4.联合乙肝核心相关抗原预测病毒复发^[2]