HDV RNA检测的临床意义与方法

林妍雪; 秦艳丽; 张继明

doi:10.3969/j.issn.1001-5256.2022.12.028

HDV RNA检测的临床意义与方法

DOI: 10.3969/j.issn.1001-5256.2022.12.028

复旦大学附属华山医院感染科，上海市传染病与生物安全应急响应重点实验室，国家传染病医学中心，上海 200040

基金项目:

国家自然科学基金 (81871640);

国家自然科学基金 (82172255)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：林妍雪负责查阅文献和撰写文章；秦艳丽负责修改文章；张继明负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
张继明，jmzhang@fudan.edu.cn

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出版历程
- 收稿日期: 2022-04-25
- 录用日期: 2022-05-26
- 出版日期: 2022-12-20

Clinical significance and methods of hepatitis D virus RNA detection

Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China

Research funding:

National Natural Science Foundation of China (81871640);

National Natural Science Foundation of China (82172255)

More Information

Corresponding author: ZHANG Jiming, jmzhang@fudan.edu.cn (ORCID: 0000-0001-5820-950X)

摘要

摘要: HDV感染的流行率和危害程度一直被低估，低筛查率和低诊断率或带来严重疾病负担。HDV RNA作为病毒复制的直接证据，对于丁型肝炎的诊断和管理具有重要意义。本文总结了HDV RNA检测的临床意义，并介绍了检测方法的进展，以期促进丁型肝炎的筛查和诊断。
- 丁型肝炎 /
- RNA, 病毒 /
- 诊断 /
- 逆转录聚合酶链反应
Abstract: The prevalence and severity of hepatitis D virus (HDV) infection have always been underestimated, and the low screening and diagnosis rates may bring severe disease burden. HDV RNA, as the direct evidence of viral replication, is of great importance for the diagnosis and management of hepatitis D. This article summarizes the clinical significance of HDV RNA detection and introduces the advances in detection methods, in order to facilitate the screening and diagnosing of hepatitis D.
- Hepatitis D /
- RNA, Viral /
- Diagnosis /
- Reverse Transcriptase Polymerase Chain Reaction

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参考文献(59)

[1]	RIZZETTO M, CANESE MG, ARICÒ S, et al. Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers[J]. Gut, 1977, 18(12): 997-1003. DOI: 10.1136/gut.18.12.997.
[2]	RIZZETTO M, CANESE MG, GERIN JL, et al. Transmission of the hepatitis B virus-associated delta antigen to chimpanzees[J]. J Infect Dis, 1980, 141(5): 590-602. DOI: 10.1093/infdis/141.5.590.
[3]	LAI MM. The molecular biology of hepatitis delta virus[J]. Annu Rev Biochem, 1995, 64: 259-286. DOI: 10.1146/annurev.bi.64.070195.001355.
[4]	RADJEF N, GORDIEN E, IVANIUSHINA V, et al. Molecular phylogenetic analyses indicate a wide and ancient radiation of African hepatitis delta virus, suggesting a deltavirus genus of at least seven major clades[J]. J Virol, 2004, 78(5): 2537-2544. DOI: 10.1128/jvi.78.5.2537-2544.2004.
[5]	DI BISCEGLIE AM, NEGRO F. Diagnosis of hepatitis delta virus infection[J]. Hepatology, 1989, 10(6): 1014-1016. DOI: 10.1002/hep.1840100621.
[6]	YURDAYD_IN C, IDILMAN R, BOZKAYA H, et al. Natural history and treatment of chronic delta hepatitis[J]. J Viral Hepat, 2010, 17(11): 749-756. DOI: 10.1111/j.1365-2893.2010.01353.x.
[7]	ROMEO R, DEL NINNO E, RUMI M, et al. A 28-year study of the course of hepatitis Delta infection: a risk factor for cirrhosis and hepatocellular carcinoma[J]. Gastroenterology, 2009, 136(5): 1629-1638. DOI: 10.1053/j.gastro.2009.01.052.
[8]	FATTOVICH G, GIUSTINA G, CHRISTENSEN E, et al. Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B. The European Concerted Action on Viral Hepatitis (Eurohep)[J]. Gut, 2000, 46(3): 420-426. DOI: 10.1136/gut.46.3.420.
[9]	PALOM A, RODRÍGUEZ-TAJES S, NAVASCUÉS CA, et al. Long-term clinical outcomes in patients with chronic hepatitis delta: the role of persistent viraemia[J]. Aliment Pharmacol Ther, 2020, 51(1): 158-166. DOI: 10.1111/apt.15521.
[10]	MIAO Z, ZHANG S, OU X, et al. Estimating the global prevalence, disease progression, and clinical outcome of hepatitis delta virus infection[J]. J Infect Dis, 2020, 221(10): 1677-1687. DOI: 10.1093/infdis/jiz633.
[11]	STOCKDALE AJ, KREUELS B, HENRION M, et al. The global prevalence of hepatitis D virus infection: Systematic review and meta-analysis[J]. J Hepatol, 2020, 73(3): 523-532. DOI: 10.1016/j.jhep.2020.04.008.
[12]	CHEN HY, SHEN DT, JI DZ, et al. Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis[J]. Gut, 2019, 68(3): 512-521. DOI: 10.1136/gutjnl-2018-316601.
[13]	WHO Guidelines Approved by the Guidelines Review Committee. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection[M]. Geneva, World Health Organization, 2015.
[14]	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. DOI: 10.1007/s12072-015-9675-4.
[15]	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. DOI: 10.1016/j.jhep.2017.03.021.
[16]	TERRAULT NA, LOK A SF, 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.
[17]	MENTHA N, CLÉMENT S, NEGRO F, et al. A review on hepatitis D: From virology to new therapies[J]. J Adv Res, 2019, 17: 3-15. DOI: 10.1016/j.jare.2019.03.009.
[18]	COLLER KE, BUTLER EK, LUK KC, et al. Development and performance of prototype serologic and molecular tests for hepatitis delta infection[J]. Sci Rep, 2018, 8(1): 2095. DOI: 10.1038/s41598-018-20455-5.
[19]	WU S, ZHANG Y, TANG Y, et al. Molecular epidemiology and clinical characteristics of hepatitis delta virus (HDV) infected patients with elevated transaminases in Shanghai, China[J]. BMC Infect Dis, 2020, 20(1): 565. DOI: 10.1186/s12879-020-05275-1.
[20]	RIZZETTO M. Hepatitis D[M]//JOHNSON LR. Encyclopedia of Gastroenterology. New York, Elsevier, 2004: 334-337.
[21]	KAMAL H, WESTMAN G, FALCONER K, et al. Long-term study of hepatitis delta virus infection at secondary care centers: the impact of viremia on liver-related outcomes[J]. Hepatology, 2020, 72(4): 1177-1190. DOI: 10.1002/hep.31214.
[22]	ROMEO R, FOGLIENI B, CASAZZA G, et al. High serum levels of HDV RNA are predictors of cirrhosis and liver cancer in patients with chronic hepatitis delta[J]. PLoS One, 2014, 9(3): e92062. DOI: 10.1371/journal.pone.0092062.
[23]	WRANKE A, SERRANO BC, HEIDRICH B, et al. Antiviral treatment and liver-related complications in hepatitis delta[J]. Hepatology, 2017, 65(2): 414-425. DOI: 10.1002/hep.28876.
[24]	WEDEMEYER H, YURDAYDIN C, HARDTKE S, et al. Peginterferon alfa-2a plus tenofovir disoproxil fumarate for hepatitis D (HIDIT-Ⅱ): a randomised, placebo controlled, phase 2 trial[J]. Lancet Infect Dis, 2019, 19(3): 275-286. DOI: 10.1016/S1473-3099(18)30663-7.
[25]	BREMER B, ANASTASIOU OE, HARDTKE S, et al. Residual low HDV viraemia is associated HDV RNA relapse after PEG-IFNa-based antiviral treatment of hepatitis delta: Results from the HIDIT-Ⅱ study[J]. Liver Int, 2021, 41(2): 295-299. DOI: 10.1111/liv.14740.
[26]	FARCI P, ROSKAMS T, CHESSA L, et al. Long-term benefit of interferon alpha therapy of chronic hepatitis D: regression of advanced hepatic fibrosis[J]. Gastroenterology, 2004, 126(7): 1740-1749. DOI: 10.1053/j.gastro.2004.03.017.
[27]	KESKIN O, WEDEMEYER H, TVZVN A, et al. Association between level of hepatitis D virus RNA at week 24 of pegylated interferon therapy and outcome[J]. Clin Gastroenterol Hepatol, 2015, 13(13): 2342-2349. e1-2. DOI: 10.1016/j.cgh.2015.05.029.
[28]	ERHARDT A, GERLICH W, STARKE C, et al. Treatment of chronic hepatitis delta with pegylated interferon-alpha2b[J]. Liver Int, 2006, 26(7): 805-810. DOI: 10.1111/j.1478-3231.2006.01279.x.
[29]	KARACA C, SOYER OM, BARAN B, et al. Efficacy of pegylated interferon-α treatment for 24 months in chronic delta hepatitis and predictors of response[J]. Antivir Ther, 2013, 18(4): 561-566. DOI: 10.3851/IMP2381.
[30]	YURDAYDIN C, KESKIN O, KALKAN Ç, et al. Interferon treatment duration in patients with chronic delta hepatitis and its effect on the natural course of the disease[J]. J Infect Dis, 2018, 217(8): 1184-1192. DOI: 10.1093/infdis/jix656.
[31]	KOH C, DA BL, GLENN JS. HBV/HDV coinfection: A challenge for therapeutics[J]. Clin Liver Dis, 2019, 23(3): 557-572. DOI: 10.1016/j.cld.2019.04.005.
[32]	YURDAYDIN C, ABBAS Z, BUTI M, et al. Treating chronic hepatitis delta: The need for surrogate markers of treatment efficacy[J]. J Hepatol, 2019, 70(5): 1008-1015. DOI: 10.1016/j.jhep.2018.12.022.
[33]	LE GAL F, GAULT E, RIPAULT MP, et al. Eighth major clade for hepatitis delta virus[J]. Emerg Infect Dis, 2006, 12(9): 1447-1450. DOI: 10.3201/eid1209.060112.
[34]	LE GAL F, BRICHLER S, DRUGAN T, et al. Genetic diversity and worldwide distribution of the deltavirus genus: A study of 2, 152 clinical strains[J]. Hepatology, 2017, 66(6): 1826-1841. DOI: 10.1002/hep.29574.
[35]	SU CW, HUANG YH, HUO TI, et al. Genotypes and viremia of hepatitis B and D viruses are associated with outcomes of chronic hepatitis D patients[J]. Gastroenterology, 2006, 130(6): 1625-1635. DOI: 10.1053/j.gastro.2006.01.035.
[36]	GOMES-GOUVÊA MS, SOARES M, BENSABATH G, et al. Hepatitis B virus and hepatitis delta virus genotypes in outbreaks of fulminant hepatitis (Labrea black fever) in the western Brazilian Amazon region[J]. J Gen Virol, 2009, 90(Pt 11): 2638-2643. DOI: 10.1099/vir.0.013615-0.
[37]	ROULOT D, BRICHLER S, LAYESE R, et al. Origin, HDV genotype and persistent viremia determine outcome and treatment response in patients with chronic hepatitis delta[J]. J Hepatol, 2020, 73(5): 1046-1062. DOI: 10.1016/j.jhep.2020.06.038.
[38]	WANG W, LEMPP FA, SCHLUND F, et al. Assembly and infection efficacy of hepatitis B virus surface protein exchanges in 8 hepatitis D virus genotype isolates[J]. J Hepatol, 2021, 75(2): 311-323. DOI: 10.1016/j.jhep.2021.03.025.
[39]	HSU SC, SYU WJ, SHEEN IJ, et al. Varied assembly and RNA editing efficiencies between genotypes Ⅰ and Ⅱ hepatitis D virus and their implications[J]. Hepatology, 2002, 35(3): 665-672. DOI: 10.1053/jhep.2002.31777.
[40]	SALDANHA J, DI BLASI F, BLAS C, et al. Detection of hepatitis delta virus RNA in chronic liver disease[J]. J Hepatol, 1989, 9(1): 23-28. DOI: 10.1016/0168-8278(89)90071-8.
[41]	MADEJÓN A, CASTILLO I, BARTOLOMÉ J, et al. Detection of HDV-RNA by PCR in serum of patients with chronic HDV infection[J]. J Hepatol, 1990, 11(3): 381-384. DOI: 10.1016/0168-8278(90)90225-g.
[42]	CHEN PJ, KALPANA G, GOLDBERG J, et al. Structure and replication of the genome of the hepatitis delta virus[J]. Proc Natl Acad Sci U S A, 1986, 83(22): 8774-8778. DOI: 10.1073/pnas.83.22.8774.
[43]	SAIKI RK, SCHARF S, FALOONA F, et al. Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia[J]. Science, 1985, 230(4732): 1350-1354. DOI: 10.1126/science.2999980.
[44]	HAFF LA. Improved quantitative PCR using nested primers[J]. PCR Methods Appl, 1994, 3(6): 332-337. DOI: 10.1101/gr.3.6.332.
[45]	WITTWER CT, HERRMANN MG, MOSS AA, et al. Continuous fluorescence monitoring of rapid cycle DNA amplification[J]. Biotechniques, 1997, 22(1): 130-131, 134-138. DOI: 10.2144/97221bi01.
[46]	NAVARRO E, SERRANO-HERAS G, CASTAÑO MJ, et al. Real-time PCR detection chemistry[J]. Clin Chim Acta, 2015, 439: 231-250. DOI: 10.1016/j.cca.2014.10.017.
[47]	YAMASHIRO T, NAGAYAMA K, ENOMOTO N, et al. Quantitation of the level of hepatitis delta virus RNA in serum, by real-time polymerase chain reaction--and its possible correlation with the clinical stage of liver disease[J]. J Infect Dis, 2004, 189(7): 1151-1157. DOI: 10.1086/382133.
[48]	LE GAL F, GORDIEN E, AFFOLABI D, et al. Quantification of hepatitis delta virus RNA in serum by consensus real-time PCR indicates different patterns of virological response to interferon therapy in chronically infected patients[J]. J Clin Microbiol, 2005, 43(5): 2363-2369. DOI: 10.1128/JCM.43.5.2363-2369.2005.
[49]	LE GAL F, BRICHLER S, SAHLI R, et al. First international external quality assessment for hepatitis delta virus RNA quantification in plasma[J]. Hepatology, 2016, 64(5): 1483-1494. DOI: 10.1002/hep.28772.
[50]	WANG Y, GLENN JS, WINTERS MA, et al. A new dual-targeting real-time RT-PCR assay for hepatitis D virus RNA detection[J]. Diagn Microbiol Infect Dis, 2018, 92(2): 112-117. DOI: 10.1016/j.diagmicrobio.2018.05.016.
[51]	HOMS M, GIERSCH K, BLASI M, et al. Relevance of a full-length genomic RNA standard and a thermal-shock step for optimal hepatitis delta virus quantification[J]. J Clin Microbiol, 2014, 52(9): 3334-3338. DOI: 10.1128/JCM.00940-14.
[52]	OLIVERO A, ABATE M L, NIRO G, et al. A novel approach for hepatitis delta virus viremia quantification by droplet digital PCR assay[J]. J Hepatol, 2016, 64(2): S354. DOI: 10.1016/s0168-8278(16)00518-3.
[53]	NOTOMI T, OKAYAMA H, MASUBUCHI H, et al. Loop-mediated isothermal amplification of DNA[J]. Nucleic Acids Res, 2000, 28(12): E63. DOI: 10.1093/nar/28.12.e63.
[54]	WANG C, SHEN X, LU J, et al. Development of a reverse transcription-loop-mediated isothermal amplification (RT-LAMP) system for rapid detection of HDV genotype 1[J]. Lett Appl Microbiol, 2013, 56(3): 229-235. DOI: 10.1111/lam.12039.
[55]	SOROKA M, WASOWICZ B, RYMASZEWSKA A. Loop-Mediated Isothermal Amplification (LAMP): The better sibling of PCR?[J]. Cells, 2021, 10(8). DOI: 10.3390/cells10081931.
[56]	SCHAPER M, RODRIGUEZ-FRIAS F, JARDI R, et al. Quantitative longitudinal evaluations of hepatitis delta virus RNA and hepatitis B virus DNA shows a dynamic, complex replicative profile in chronic hepatitis B and D[J]. J Hepatol, 2010, 52(5): 658-664. DOI: 10.1016/j.jhep.2009.10.036.
[57]	KARATAYL_I E, ALTUNOĜLU YÇ, KARATAYL_I SC, et al. A one step real time PCR method for the quantification of hepatitis delta virus RNA using an external armored RNA standard and intrinsic internal control[J]. J Clin Virol, 2014, 60(1): 11-15. DOI: 10.1016/j.jcv.2014.01.021.
[58]	CHUDY M, HANSCHMANN KM, BOZDAYI M, et al. Collaborative study to establish a World Health Organization international standard for hepatitis D virus RNA for nucleic acid amplification technique (NAT)-based assays[R]. Geneva: World Health Organization, 2013.
[59]	SCHELLER L, HILGARD G, ANASTASIOU O, et al. Poor clinical and virological outcome of nucleos(t)ide analogue monotherapy in HBV/HDV co-infected patients[J]. Medicine (Baltimore), 2021, 100(28): e26571. DOI: 10.1097/MD.0000000000026571.