慢性乙型肝炎患者低病毒血症的研究现状及挑战
收稿日期: 2023-11-10
网络出版日期: 2024-05-30
基金资助
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专科
Current research and challenges of low-level viremia in patients with chronic hepatitis B
Received date: 2023-11-10
Online published: 2024-05-30
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。
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 . DOI: 10.16150/j.1671-2870.2024.01.004
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.
| [1] | NGUYEN M H, WONG G, GANE E, et al. Hepatitis B virus advances in prevention, diagnosis, and therapy[J]. Clin Microbiol Rev, 2020, 33(2):e00046-19. |
| [2] | 中华医学会肝病学分会, 中华医学会感染病学分会. 慢性乙型肝炎防治指南(2022年版)[J]. 中华肝脏病杂志, 2022, 30(12):1309-1331. |
| Chinese Society of Hepatology, Chinese Medical Association; Chinese Society of Infectious Diseases, Chinese Medical Association. Guidelines for the prevention and treatment of chronic hepatitis B (version 2022)[J]. Zhonghua Gan Zang Bing Za Zhi, 2022, 30(12):1309-1331. | |
| [3] | TERRAULT N A, BZOWEJ N H, CHANG K M, et al. AASLD guidelines for treatment of chronic hepatitis B[J]. Hepatology, 2016, 63(1):261-283. |
| [4] | GARCíA-GASCó P, MAIDA I, BLANCO F, et al. Episodes of low-level viral rebound in HIV-infected patients on antiretroviral therapy frequency, predictors and outcome[J]. J Antimicrob Chemother, 2008, 61(3):699-704. |
| [5] | CRESPO-BERMEJO C, DE ARELLANO E R, LARA-AGUILAR V, et al. Persistent low-level viremia in persons living with HIV undertreatment An unresolved status[J]. Virulence, 2021, 12(1):2919-2931. |
| [6] | TERRAULT N A, LOK A S F, MCMAHON B J, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B AASLD 2018 Hepatitis B Guidance[J]. Clin Liver Dis (Hoboken), 2018, 12(1):33-34. |
| [7] | 鲁凤民, 封波, 郑素军, 等. 核苷(酸)类似物经治的慢性乙型肝炎患者低病毒血症的研究现状[J]. 临床肝胆病杂志, 2021, 37(6):1268-1274. |
| LU F M, FENG B, ZHENG S J, et al. Current status of the research on low-level viremia in chronic hepatitis B patients receiving nucleos(t)ide analogues[J]. J Clin Hepatol, 2021, 37(6):1268-1274. | |
| [8] | ZHANG Q, CAI D C, HU P, et al. Low-level viremia in nucleoside analog-treated chronic hepatitis B patients[J]. Chin Med J (Engl), 2021, 134(23):2810-2817. |
| [9] | KIM J H, SINN D H, KANG W, et al. Low-level viremia and the increased risk of hepatocellular carcinoma in patients receiving entecavir treatment[J]. Hepatology, 2017, 66(2):335-343. |
| [10] | KIM T S, SINN D H, KANG W, et al. Hepatitis B virus DNA levels and overall survival in hepatitis B-related hepatocellular carcinoma patients with low-level viremia[J]. J Gastroenterol Hepatol, 2019, 34(11):2028-2035. |
| [11] | LEE S B, JEONG J, PARK J H, et al. Low-level viremia and cirrhotic complications in patients with chronic hepatitis B according to adherence to entecavir[J]. Clin Mol Hepatol, 2020, 26(3):364-375. |
| [12] | SUN F, LIU Z, WANG B. Correlation between low-level viremia and hepatitis B-related hepatocellular carcinoma and recurrence a retrospective study[J]. BMC cancer, 2021, 21(1):1103. |
| [13] | LI Z B, LI L, NIU X X, et al. Switching from entecavir to tenofovir alafenamide for chronic hepatitis B patients with low-level viraemia[J]. Liver Int, 2021, 41(6):1254-1264. |
| [14] | ALLWEISS L, DANDRI M. The Role of cccDNA in HBV Maintenance[J]. Viruses, 2017, 9(6):156. |
| [15] | WEI L, PLOSS A. Mechanism of Hepatitis B Virus cccDNA Formation[J]. Viruses, 2021, 13(8):1463. |
| [16] | CHANG M L, LIAW Y F. Hepatitis B flares in chronic hepatitis B pathogenesis, natural course, and management[J]. J Hepatol, 2014, 61(6):1407-1417. |
| [17] | YAN Y, ALLWEISS L, YANG D, et al. Down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes prevents hepatitis B virus infection[J]. Emerg Microbes Infect, 2019, 8(1):879-894. |
| [18] | ALLWEISS L, VOLZ T, GIERSCH K, et al. Proliferation of primary human hepatocytes and prevention of hepatitis B virus reinfection efficiently deplete nuclear cccDNA in vivo[J]. Gut, 2018, 67(3):542-552. |
| [19] | HIGASHI-KUWATA N, HAYASHI S, KUMAMOTO H, et al. Identification of a novel long-acting 4’-modified nucleoside reverse transcriptase inhibitor against HBV[J]. J Hepatol, 2021, 74(5):1075-1086. |
| [20] | YUAN Y, ILOEJE U H, HAY J, et al. Evaluation of the cost-effectiveness of entecavir versus lamivudine in hepatitis BeAg-positive chronic hepatitis B patients[J]. J Manag Care Pharm, 2008, 14(1):21-33. |
| [21] | MARCELLIN P, HEATHCOTE E J, BUTI M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B[J]. N Engl J Med, 2008, 359(23):2442-2455. |
| [22] | AGARWAL K, BRUNETTO M, SETO W K, et al. 96?weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection[J]. J Hepatol, 2018, 68(4):672-681. |
| [23] | European Association For The Study Of The Liver. EASL clinical practice guidelines management of chronic hepatitis B virus infection[J]. J Hepatol, 2012, 57(1):167-185. |
| [24] | SUN Y, WU X, ZHOU J, et al. Persistent low level of hepatitis B virus promotes fibrosis progression during therapy[J]. Clin Gastroenterol Hepatol, 2020, 18(11):2582-2591.e6. |
| [25] | MAK L Y, HUANG Q, WONG D K H, et al. Residual HBV DNA and pgRNA viraemia is associated with hepatocellular carcinoma in chronic hepatitis B patients on antiviral therapy[J]. J Gastroenterol, 2021, 56(5):479-488. |
| [26] | ZHANG Q, PENG H, LIU X, et al. Chronic hepatitis B infection with low level viremia correlates with the progression of the liver disease[J]. J Clin Transl Hepatol, 2021, 9(6):850-859. |
| [27] | WONG G L H, WONG V W S, CHAN H Y, et al. Undetectable HBV DNA at month 12 of entecavir treatment predicts maintained viral suppression and HBeAg-seroconversion in chronic hepatitis B patients at 3 years[J]. Aliment Pharmacol Ther, 2012, 35(11):1326-1335. |
| [28] | LIU S, ZHOU B, VALDES J D, et al. Serum hepatitis B virus RNA a new potential biomarker for chronic hepatitis B virus infection[J]. Hepatology, 2019, 69(4):1816-1827. |
| [29] | TESTONI B, LEBOSSé F, SCHOLTES C, et al. Serum hepatitis B core-related antigen (HBcrAg) correlates with covalently closed circular DNA transcriptional activity in chronic hepatitis B patients[J]. J Hepatol, 2019, 70(4):615-625. |
| [30] | ANDO Y, ISHIGAMI M, ISHIZU Y, et al. Cumulative incidence and risk factors for the development of hepatocellular carcinoma in patients with chronic hepatitis B who achieved sustained disappearance of viremia by nucleos(t)ide analog treatment[J]. Hepatol Res, 2018, 48(3):E240-E251. |
| [31] | LIU S, DENG R, ZHOU B, et al. Association of serum hepatitis B virus RNA with hepatocellular carcinoma risk in chronic hepatitis b patients under nucleos(t)ide analogues therapy[J]. The J Infect Dis, 2022, 226(5):881-890. |
| [32] | 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. |
| [33] | OGAWA E, NOMURA H, NAKAMUTA M, et al. Tenofovir alafenamide after switching from entecavir or nucleos(t)ide combination therapy for patients with chronic hepatitis B[J]. Liver Int, 2020, 40(7):1578-1589. |
| [34] | NING Q, HAN M, SUN Y, et al. Switching from entecavir to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B a randomised open-label trial (OSST trial)[J]. J Hepatol, 2014, 61(4):777-784. |
| [35] | DUSHEIKO G, AGARWAL K, MAINI M K. New Approaches to Chronic Hepatitis B[J]. N Engl J Med, 2023, 388(1):55-69. |
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