慢性乙型肝炎患者血清HBV RNA检测的临床意义

鲁凤民; 窦晓光; 张文宏; 王福生

doi:10.3969/j.issn.1001-5256.2018.05.005

慢性乙型肝炎患者血清HBV RNA检测的临床意义

DOI: 10.3969/j.issn.1001-5256.2018.05.005

1. 北京大学医学部基础医学院病原生物学系
2. 中国医科大学附属盛京医院感染科
3. 复旦大学附属华山医院感染科
4. 解放军三〇二医院感染病诊疗与研究中心

详细信息

中图分类号: R512.62
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出版历程
- 收稿日期: 2018-03-30
- 出版日期: 2018-05-20

Clinical significance of serum HBV RNA measurement in chronic hepatitis B patients

Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center

摘要

摘要: 在强效核苷及核苷酸类药物(NAs)抗病毒治疗时代,绝大部分慢性乙型肝炎(CHB)患者血清HBV DNA水平低于检测下限,但血清HBV DNA消失仅提示病毒的逆转录过程被有效抑制,并不能真实反映肝细胞内共价闭合环状DNA(ccc DNA)的转录活性状态。另一方面,部分经过长期治疗的患者肝组织ccc DNA接近耗竭或残余静默,但因HBV DNA片段的整合,血清HBs Ag仍持续阳性。如何真实地评判肝细胞内ccc DNA的存在和转录活性,仍是一个亟待解决的问题。血清HBV RNA为来自肝组织内ccc DNA转录体,因未能有效地转换成rc DNA,转而以HBV RNA病毒样颗粒的方式释放进入血液循环。因此在NAs治疗下,血清HBV RNA能够定性反映肝组织内的ccc DNA是否有转录活性。目前多数专家认为,在现有治疗手段下很难达到CHB的"完全治愈"。对此,笔者提出了从"部分治愈"、"准临床治愈"、再到"临床治愈"(或"功能性治愈")的阶梯性提升模式,建议以ccc DNA消失或静默为基础、以HBV RNA持续阴性为依据的"部分治愈"预测NAs停药后复发或病毒学反弹风险,并在此基础上的以血清HB...
- 肝炎,乙型,慢性 /
- 肝炎病毒,乙型 /
- RNA /
- DNA,环状 /
- 核苷类 /
- 核苷酸类
Abstract: In the era of antiviral therapy with potent nucleos ( t) ide analogues ( NAs) , serum HBV DNA is reduced to a level below the lower limit of detection in most chronic hepatitis B ( CHB) patients, but the loss of serum HBV DNA only indicates that reverse transcription of virus is effectively inhibited and cannot truly reflect the transcriptional activity of covalently closed circular DNA ( ccc DNA) in hepatocytes.In addition, some patients, although with almost depleted or residual, silent ccc DNA in liver tissue, were still positive for serum HBs Ag after long-term treatment due to the integration of HBV DNA fragments. How to truly evaluate the presence and transcriptional activity of ccc DNA in hepatocytes is still a problem that needs to be solved urgently. Serum HBV RNA comes from ccc DNA transcript in liver tissue and is released into blood circulation as virus-like HBV RNA particles, since it is not effectively transformed to rc DNA. Therefore, in patients receiving the treatment with NAs, serum HBV RNA can qualitatively reflect the transcriptional activity of ccc DNA in liver tissue. At present, most scholars think it is hard to achieve " complete cure" of CHB with current therapies. Therefore, we put forward a ladder-like improvement pattern from " partial cure" to " para-functional cure" and " clinical cure" ( or " functional cure") . " Partial cure" based on the elimination or silence of ccc DNA and persistently negative HBV RNA should be used to predict the risk of recurrence or virological rebound after drug withdrawal, and a low serum level of HBs Ag combined with these two criteria should be used as the criteria for " quasi-clinical cure".The clinical significance of serum HBV RNA measurement needs to be addressed in multi-cohort clinical trails and/or improved in the real world studies.
- hepatitis B, chronic /
- hepatitis B virus /
- RNA /
- DNA, circular /
- nucleosides /
- nucleotides

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参考文献(33)

[1]SCHWEITZER A, HORN J, MIKOLAJCZYK RT, et al.Estimations of worldwide prevalence of chronic hepatitis B virus infection:a systematic review of data published between 1965 and 2013[J].Lancet, 2015, 386 (10003) :1546-1555.

[2]NASSAL M.HBV ccc DNA:viral persistence reservoir and key obstacle for a cure of chronic hepatitis B[J].Gut, 2015, 64 (12) :1972-1984.

[3]REGEV A, BERHO M, JEFFERS LJ, et al.Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection[J].Am J Gastroenterol, 2002, 97 (10) :2614-2618.

[4]BEDOSSA P, DARGRE D, PARADIS V.Sampling variability of liver fibrosis in chronic hepatitis C[J].Hepatology, 2003, 38 (6) :1449-1457.

[5]BRAVO AA, SHETH SG, CHOPRA S.Liver biopsy[J].N Engl J Med, 2001, 344 (7) :495-500.

[6]ROUSSELET MC, MICHALAK S, DUPRF, et al.Sources of variability in histological scoring of chronic viral hepatitis[J].Hepatology, 2005, 41 (2) :257-264.

[7]GRIMM D, THIMME R, BLUM HE.HBV life cycle and novel drug targets[J].Hepatol Int, 2011, 5 (2) :644-653.

[8]SEEGER C, MASON WS.Hepatitis B virus biology[J].Microbiol Mol Biol Rev, 2000, 64 (1) :51-68.

[9]KCK J, THEILMANN L, GALLE P, et al.Hepatitis B virus nucleic acids associated with human peripheral blood mononuclear cells do not originate from replicating virus[J].Hepatology, 1996, 23 (3) :405-413.

[10]WANG J, SHEN T, HUANG X, et al.Serum hepatitis B virus RNA is encapsidated pregenome RNA that may be associated with persistence of viral infection and rebound[J].J Hepatol, 2016, 65 (4) :700-710.

[11]JANSEN L, KOOTSTRA NA, van DORT KA, et al.Hepatitis B virus pregenomic RNA is present in virions in plasma and is associated with a response to pegylated interferon alfa-2a and nucleos (t) ide analogues[J].J Infect Dis, 2016, 213 (2) :224-232.

[12]LU FM, WANG J, CHEN XM, et al.The potential use of serum HBV RNA to guide the functional cure of chronic hepatitis B[J].Chin J Hepatol, 2017, 25 (2) :105-110. (in Chinese) 鲁凤民, 王杰, 陈香梅, et al.乙型肝炎病毒RNA病毒样颗粒的发现及其对抗病毒治疗临床实践的潜在影响[J].中华肝脏病杂志, 2017, 25 (2) :105-110.

[13]WANG J, DU M, HUANG H, et al.Reply to:"Serum HBV pgRNA as a clinical marker for ccc DNA activity":Consistent loss of serum HBV RNA might predict the"para-functional cure"of chronic hepatitis B[J].J Hepatol, 2017, 66 (2) :462-463.

[14]MAK LY, WONG DK, CHEUNG KS, et al.Hepatitis B core-related antigen (HBcr Ag) :an emerging marker for chronic hepatitis B virus infection[J].Aliment Pharmacol Ther, 2018, 47 (1) :43-54.

[15]LI W, ZHAO J, ZOU Z, et al.Analysis of hepatitis B virus intrahepatic covalently closed circular DNA and serum viral markers in treatment-naive patients with acute and chronic HBV infection[J].PLo S One, 2014, 9 (2) :e89046.

[16]Chinese Society of Hepato Iogy and Chinese Society of Infectious Diseases, Chinese Medical Association.The guideline of prevention and treatment for chronic hepatitis B:a 2015 update[J].J Clin Hepatol, 2015, 31 (12) :1941-1960. (in Chinese) 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 (2015年更新版) [J].临床肝胆病杂志, 2015, 31 (12) :1941-1960.

[17]LEVRERO M, TESTONI B, ZOULIM F.HBV cure:why, how, when?[J].Curr Opin Virol, 2016, 18:135-143.

[18]SAITTA C, TRIPODI G, BARBERA A, et al., Hepatitis B virus (HBV) DNA integration in patients with occult HBV infection and hepatocellular carcinoma[J].Liver Int, 2015, 35 (10) :2311-2317.

[19]Mac NAB GM, ALEXANDER JJ, LECATSAS G, et al.Hepatitis B surface antigen produced by a human hepatoma cell line[J].Br J Cancer, 1976, 34 (5) :509-515.

[20]EDMAN JC, GRAY P, VALENZUELA P, et al.Integration of hepatitis B virus sequences and their expression in a human hepatoma cell[J].Nature, 1980, 286 (5772) :535-538.

[21]SEEGER C, MASON WS.Molecular biology of hepatitis B virus infection[J].Virology, 2015, 479-480:672-686.

[22]JIANG S, YANG Z, LI W, et al.Re-evaluation of the carcinogenic significance of hepatitis B virus integration in hepatocarcinogenesis[J].PLo S One, 2012, 7 (9) :e40363.

[23]MANESIS EK, PAPATHEODORIDIS GV, TINIAKOS DG, et al.Hepatitis B surface antigen:relation to hepatitis B replication parameters in HBe Ag-negative chronic hepatitis B[J].J Hepatol, 2011, 55 (1) :61-68.

[24]THOMPSON AJ, NGUYEN T, ISER D, et al.Serum hepatitis B surface antigen and hepatitis B e antigen titers:disease phase influences correlation with viral load and intrahepatic hepatitis B virus markers[J].Hepatology, 2010, 51 (6) :1933-1944.

[25]GIERSCH K, ALLWEISS L, VOLZ T, et al.Serum HBV pgRNA as a clinical marker for ccc DNA activity[J].J Hepatol, 2017, 66 (2) :460-462.

[26]HUANG H, WANG J, LI W, et al.Serum HBV DNA plus RNA shows superiority in reflecting the activity of intrahepatic ccc DNA in treatment-naive HBV-infected individuals[J].J Clin Virol, 2018.[Epub ahead of print]

[27]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.

[28]WANG J, YU Y, LI G, et al.Relationship between serum HBVRNA levels and intrahepatic viral as well as histologic activity markers in entecavir-treated patients[J].J Hepatol, 2017.[Epub ahead of print]

[29]PAPATHEODORIDIS G, VLACHOGIANNAKOS I, CHOLONGITAS E, et al.Discontinuation of oral antivirals in chronic hepatitis B:a systematic review[J].Hepatology, 2016, 63 (5) :1481-1492.

[30]NING Q, HAN M, SUN Y, et al.Switching from entecavir to PegI FN alfa-2a in patients with HBeA g-positive chronic hepatitis B:a randomised open-label trial (OSST trial) [J].J Hepatol, 2014, 61 (4) :777-784.

[31]HU P, JIA S, ZHANG WH, et al.A multi-center randomized study on the efficacy and safety of switching to peginterferon alpha-2a (40KD) for 48 or 96 weeks in HBeA g positive CHB patients with a prior NUC history for 1 to 3 years:an interim analysis of NEW SWITCH study[J].Hepatology, 2014, 60 (6) :1273a-1274a.

[32]LU F, WANG J, CHEN X, et al.Potential use of serum HBV RNA in antiviral therapy for chronic hepatitis B in the era of nucleos (t) ide analogs[J].Front Med, 2017, 11 (4) :502-508.

[33]WANG FS, ZHANG Z.Host immunity influences disease progression and antiviral efficacy in humans infected with hepatitis B virus[J].Expert Rev Gastroenterol Hepatol, 2009, 3 (5) :499-512.

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