关于“HBV DNA 定量检测结果评价”相关问题商榷:也谈证据、证据、还是证据

摘要/Abstract

摘要： 乙型肝炎病毒(HBV)检测下限(LLOD)与定量下限(LLOQ)是HBV DNA 检测两个重要的技术参数,但临床使用混乱的现象普遍。为了早日实现世界卫生组织提出的“2030 年消除病毒性肝炎作为公共卫生危害”目标,中华医学会肝病学分会肝炎学组针对《慢性乙型肝炎防治指南(2022 年版)》中尚未形成共识的问题,于《中华肝脏病杂志》第6期发布了《加速消除乙型肝炎病毒感染:扩大预防和治疗专家建议》,其中,有关“HBV DNA 定量检测结果评价”的建议为:“启动抗病毒治疗、自然史分期、功能性(临床)治愈和部分治愈、完全病毒学应答和维持病毒学应答的 HBV DNA 值,应以LLOQ而不是以 LLOD为标准”,“HBV DNA 阳性是指其水平＞ 10 IU/mL 或 20 IU/mL”。笔者学习后,觉得此建议可能存在与扩大治疗理念及高灵敏检测推荐相悖、不利于更好的疗效监测、成本效益欠佳、混淆概念等问题,以致影响HBV 感染管理的正确决策与相关信息的有效、准确传播;同时为此建议提供的证据并不真实,可能影响建议的可信度,故提出商榷。

关键词: 乙型肝炎病毒, HBV DNA, 检测下限, 定量下限

肖丽, 杨秀珍, 汪波, 王欣茹, 薛荣荣, 咸建春. 关于“HBV DNA 定量检测结果评价”相关问题商榷:也谈证据、证据、还是证据[J]. 肝脏, 2024, 29(10): 1176-1179.

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参考文献

[1] 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.
[2] 中华医学会肝病学分会肝炎学组,中华肝脏病杂志编辑委员会. 加速消除乙型肝炎病毒感染:扩大预防和治疗专家建议[J]. 中华肝脏病杂志, 2024, 32(6):497-503.
[3] 李彤,崔富强,周乙华,等.实事求是是科学工作者的美德——兼复赵英仁、陈耀龙教授的回复[J].肝脏,2020,25(02):115-116.
[4] 国家食品药品监督管理总局关于发布乙型肝炎病毒脱氧核糖核酸定量检测试剂注册技术审查等4项指导原则的通告(第3号)[EB/OL].(2013-05-17).[2024-07-03]. https://www.nmpa.gov.cn/xxgk/ggtg/ylqxggtg/ylqxqtggtg/20130517120001692.html.
[5] Clinical & Laboratory Standards Institute. EP17A2 | Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures, 2nd Edition[EB/OL].(2012-06-18).[2023-07-03]. https://clsi.org/standards/products/method-evaluation/documents/ep17/.
[6] 中华医学会肝病学分会. 扩大慢性乙型肝炎抗病毒治疗的专家意见[J]. 中华肝脏病杂志,2022,30(02):131-136.
[7] 庄辉. 慢性乙型肝炎:从“只治”到“全治”[J].中华肝脏病杂志,2024,32(5):389-393.
[8] Terrault NA, Lok ASF, 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.
[9] Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level[J]. JAMA. 2006, 295(1):65-73.
[10] Wong RJ, Kaufman HW, Niles JK, et al. Simplifying Treatment Criteria in Chronic Hepatitis B: Reducing Barriers to Elimination[J]. Clin Infect Dis. 2023, 76(3):e791-e800.
[11] 邱功钦,谢丹,陈姿任,等. 高敏PCR在HBV极低病毒载量的慢性乙型肝炎患者中检测的临床意义[J].临床肝胆病杂志,2024,40(03):483-488.
[12] Yang HC, Tsou HH, Pei SN,et al. Quantification of HBV core antibodies may help predict HBV reactivation in patients with lymphoma and resolved HBV infection[J]. J Hepatol. 2018,69(2):286-292.
[13] Damiani AS, Holzmayer V, Galli C, et al. Serological and Molecular Characterization of Occult HBV Infection in Blood Donors from South Italy[J]. Viruses. 2023 Dec 31;16(1):71.
[14] 郑钧正. 必须高度重视医学名词术语规范化[J].医学研究杂志,2022,51(02):5-7+4.
[15] 审定原则及方法——全国科学技术名词审定委员会[EB/OL].(2015-12-28). [2024-07-13]. http://www.cnterm.cn/sdgb/sdyzjff/
[16] 科技名词术语的统一和规范化的意义[J].中国现代医药杂志,2022,24(01):60.
[17] 王吉耀,夏君. 规范指南制定,提高指南质量[J]. 肝脏, 2021,26(12):1301-1302.
[18] 李静,毕燕华,黄月华,等. 高敏与普通荧光定量PCR技术在不同病毒载量慢乙肝患者HBV-DNA检测的一致性及应用价值[J]. 热带医学杂志, 2023, 23(2):198–202.
[19] Ciotti M, Marcuccilli F, Guenci T, et al. Evaluation of the Abbott RealTime HBV DNA assay and comparison to the Cobas AmpliPrep/Cobas TaqMan 48 assay in monitoring patients with chronic cases of hepatitis B[J]. J Clin Microbiol. 2008 , 46(4):1517-9.
[20] Lok AS, Zoulim F, Dusheiko G,et al. Hepatitis B cure: From discovery to regulatory approval[J]. J Hepatol. 2017 , 67(4):847-861.
[21] Cornberg M, Lok AS, Terrault NA, et al. Guidance for design and endpoints of clinical trials in chronic hepatitis B - Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference[J]. J Hepatol. 2020 , 72(3):539-557.
[22] Ghany MG, Buti M, Lampertico P, et al. Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D: Report from the 2022 AASLD-EASL HBV-HDV Treatment Endpoints Conference[J]. J Hepatol. 2023, 79(5):1254-1269.
[23] 卢建华,杨莉,赵召霞,等.高敏与普通荧光定量PCR技术在慢乙肝患者抗病毒疗效监测中的对比研究[J].分子诊断与治疗杂志,2019,11(05):361-364.
[24] 丁洋,窦晓光. 再谈2019中国乙型肝炎母婴传播防治指南:证据,证据,还是证据[J].中华肝脏病杂志, 2020, 28(2):2.
[25] 冯静,戴毅敏,胡娅莉. 参考文献理解和引用失误会导致指南推荐意见证据不足[J]. 肝脏,2020,25(03):230-232.
[26] 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.
[27] Drafting Committee for Hepatitis Management Guidelines, the Japan Society of Hepatology. Japan Society of Hepatology Guidelines for the Management of Hepatitis?B Virus Infection: 2019 update[J]. Hepatol Res,2020 , 50(8):892-923.
[28] Chang JI, Sinn DH, Cho H, et al. Clinical Outcomes of Hepatitis B Virus-Related Hepatocellular Carcinoma Patients with Undetectable Serum HBV DNA Levels[J]. Dig Dis Sci,2022, 67(9):4565-4573.
[29] Sarin SK, Kumar M, Lau GK, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update[J]. Hepatol Int,2016, 10(1):1-98.
[30] Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines for management of chronic hepatitis B[J]. Clin Mol Hepatol,2019, 25(2):93-159.
[31] Guidelines for the prevention, diagnosis, care and treatment for people with chronic hepatitis B infection[EB/OL].(2024-03).[2024-07-11]. https://www.who.int/publications/i/item/9789240090903
[32] Ortonne V, Wlassow M, Bouvier-Alias M, et al. Diagnosis and Monitoring of Hepatitis B Virus Infection Using the Cobas? HBV Test for Use on the Cobas? 4800 System[J]. Microorganisms, 2021, 9(3):573.
[33] Yan Y, Chang L, Ji H, et al. Evaluation of the Aptima HBV Quant Assay Compared to Abbott RealTime M2000 HBV Quant Assay and Procleix Ultrio Plus dHBV Assay in Plasma Samples[J]. Microbiol Spectr, 2022, 10(4):e0176122.
[34] Han JJ, Guo YF, Zhang XY, et al. Pevalence and associated factors of low-level viremia in chronic hepatitis B patients after long-term therapy with nucleos(t)ide analogs[J].Turk J Gastroenterol, 2023, 34(1):53-61.
[35] Kim JH, Sinn DH, 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.
[36] 石宇婧,丁银,敖玲,等. 极低病毒血症:抗乙型肝炎病毒治疗过程中需要关注的临床新问题[J]. 中华肝脏病杂志,2021,29(12):1147-1150.
[37] 王春妍,曹宇,冯永美,等. 经NAs长期治疗后HBV DNA低于检测下限乙型肝炎肝硬化患者的HBV RNA水平分析及其意义[J]. 中华肝脏病杂志,2022,30(07):758-762.
[38] 中华医学会肝病学分会基础医学与实验诊断协作组. 乙型肝炎病毒标志物临床应用专家共识[J]. 中华肝脏病杂志, 2023, 31(4):389-400.
[39] Tseng TC, Liu CJ, Yang HC, et al. High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load[J]. Gastroenterology,2012, 142(5):1140-1149.e3; quiz e13-4.
[40] Lee HW, Park SY, Lee YR, et al. Episodic Detectable Viremia Does Not Affect Prognosis in Untreated Compensated Cirrhosis With Serum Hepatitis B Virus DNA <2,000 IU/mL[J]. Am J Gastroenterol,2022, 117(2):288-294.
[41] 沈弢,龙璐,邓中平,等. 新型国产乙型肝炎病毒核酸定量检测试剂的质量评价[J]. 中华检验医学杂志,2013,36(03):280-285.
[42] 中华医学会肝病学分会,中华医学会感染病学分会. 关于临床实践指南制订的规范[J]. 中华肝脏病杂志,2015,23(12):881-887.
[43] 殷海光. 逻辑新引·怎样判别是非[M]. 成都: 四川人民出版社, 2018: 337-361.
[44] 肖丽,彭海林,王蔚,等.高灵敏HBV DNA试剂定量下限与检测下限误用可能影响慢性HBV感染的正确诊疗[J].肝脏,2023,28(11):1271-1274.
[45] 游苏宁.科技期刊应引导并开展学术争鸣[J]. 编辑学报, 2004, 16(5):3.
[46] 黄锦华,魏秀菊,王柳,等. 科技期刊开展学术争鸣推动学科发展——以转基因食品安全为例[J].中国科技期刊研究, 2018, 029(011):1165-1170.
[47] 中华医学会肝病学分会关于保持学术独立和学术公正的倡议[J].中华肝脏病杂志,2008,16(08):576-576.