Skip to main content
Log in

Potential use of serum HBV RNA in antiviral therapy for chronic hepatitis B in the era of nucleos(t)ide analogs

  • Review
  • Published:
Frontiers of Medicine Aims and scope Submit manuscript

Abstract

Although the efficacy of nucleos(t)ide analogue (NA) has been confirmed for treatment of chronic hepatitis B, long-term therapy has been recommended due to the high frequency of off-therapy viral DNA rebound and disease relapse. In this review, the RNA virion-like particles of hepatitis B virus (HBV) are integrated into the life cycle of HBV replication, and the potential significance of serum HBV RNA is systematically described. The production of HBV RNA virion-like particles should not be blocked by NA; in this regard, serum HBV RNA is found to be a suitable surrogate marker for the activity of intrahepatic covalently closed circular DNA (cccDNA), particularly among patients receiving NA therapy. Therefore, the concept of virological response is redefined as persistent loss of serum HBV DNA and HBV RNA. In contrast to hepatitis B surface antigen (HBsAg) that can originate from either the cccDNA or the integrated HBV DNA fragment, serum HBV RNA, with pregenomic RNA origination, can only be transcribed from cccDNA. Therefore, the loss of serum HBV RNA would likely be a promising predicator for safe drug discontinuation. The clinical status of consistent loss of serum HBV RNA accompanied with low serum HBsAg levels might be implicated as a “para-functional cure,” a status nearly close to the functional cure of chronic hepatitis B, to distinguish the “functional cure” characterized as serum HBsAg loss with or without anti-HBs seroconversion.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Trépo C, Chan HL, Lok A. Hepatitis B virus infection. Lancet 2014; 384(9959): 2053–2063

    Article  PubMed  Google Scholar 

  2. WHO guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. Geneva: World Health Organization, 2015. Available from: URL: http://www.who.int/hepatitis/publications/hepatitis-b-guidelines-policy

  3. Lu FM, Zhuang H. Management of hepatitis B in China. Chin Med J (Engl) 2009; 122(1): 3–4

    Google Scholar 

  4. Petersen J, Thompson AJ, Levrero M. Aiming for cure in HBV and HDV infection. J Hepatol 2016; 65(4): 835–848

    Article  PubMed  Google Scholar 

  5. Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, Gane E, Fried MW, Chow WC, Paik SW, Chang WY, Berg T, Flisiak R, McCloud P, Pluck N; Peginterferon Alfa-2a HBeAg-Positive Chronic Hepatitis B Study Group. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005; 352(26): 2682–2695

    Article  CAS  PubMed  Google Scholar 

  6. Wei L, Kao JH. Benefits of long-term therapy with nucleos(t)ide analogues in treatment-naïve patients with chronic hepatitis B. Curr Med Res Opin 2017; 33(3): 495–504

    Article  CAS  PubMed  Google Scholar 

  7. Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, Chen DS, Chen HL, Chen PJ, Chien RN, Dokmeci AK, Gane E, Hou JL, Jafri W, Jia J, Kim JH, Lai CL, Lee HC, Lim SG, Liu CJ, Locarnini S, Al Mahtab M, Mohamed R, Omata M, Park J, Piratvisuth T, Sharma BC, Sollano J, Wang FS, Wei L, Yuen MF, Zheng SS, Kao JH. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 2016; 10(1): 1–98

    Article  CAS  PubMed  Google Scholar 

  8. Lampertico P, Agarwal K, Berg T, Buti M, Janssen HLA, Papatheodoridis G, Zoulim F, Tacke F; European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol 2017; 67(2): 370–398

    Article  Google Scholar 

  9. Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH; American Association for the Study of Liver Diseases. AASLD guidelines for treatment of chronic hepatitis B. Hepatology 2016; 63(1): 261–283

    Article  PubMed  Google Scholar 

  10. Chinese Society of Infectious Diseases, Chinese Medical Association; Hou JL, Wei L. The guideline of prevention and treatment for chronic hepatitis B: a 2015 update. Chin J Hepatol (Zhonghua Gan Zang Bing Za Zhi) 2015; 23(12): 888–905 (in Chinese)

    Google Scholar 

  11. Jansen L, Kootstra NA, van Dort KA, Takkenberg RB, Reesink HW, Zaaijer HL. 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 Infect Dis 2016; 213(2): 224–232

    Article  CAS  PubMed  Google Scholar 

  12. Wang J, Shen T, Huang X, Kumar GR, Chen X, Zeng Z, Zhang R, Chen R, Li T, Zhang T, Yuan Q, Li PC, Huang Q, Colonno R, Jia J, Hou J, McCrae MA, Gao Z, Ren H, Xia N, Zhuang H, Lu F. Serum hepatitis B virus RNA is encapsidated pregenome RNA that may be associated with persistence of viral infection and rebound. J Hepatol 2016; 65(4): 700–710

    Article  CAS  PubMed  Google Scholar 

  13. Köck J, Theilmann L, Galle P, Schlicht HJ. Hepatitis B virus nucleic acids associated with human peripheral blood mononuclear cells do not originate from replicating virus. Hepatology 1996; 23(3): 405–413 (PubMed: 8617418)

    PubMed  Google Scholar 

  14. Rokuhara A, Matsumoto A, Tanaka E, Umemura T, Yoshizawa K, Kimura T, Maki N, Kiyosawa K. Hepatitis B virus RNA is measurable in serum and can be a new marker for monitoring lamivudine therapy. J Gastroenterol 2006; 41(8): 785–790

    Article  CAS  PubMed  Google Scholar 

  15. Huang YW, Chayama K, Tsuge M, Takahashi S, Hatakeyama T, Abe H, Hu JT, Liu CJ, Lai MY, Chen DS, Yang SS, Kao JH. Differential effects of interferon and lamivudine on serum HBV RNA inhibition in patients with chronic hepatitis B. Antivir Ther 2010; 15(2): 177–184

    Article  CAS  PubMed  Google Scholar 

  16. Huang YW, Takahashi S, Tsuge M, Chen CL, Wang TC, Abe H, Hu JT, Chen DS, Yang SS, Chayama K, Kao JH. On-treatment low serum HBV RNA level predicts initial virological response in chronic hepatitis B patients receiving nucleoside analogue therapy. Antivir Ther 2015; 20(4): 369–375

    Article  CAS  PubMed  Google Scholar 

  17. van Bömmel F, Bartens A, Mysickova A, Hofmann J, Krüger DH, Berg T, Edelmann A. Serum hepatitis B virus RNA levels as an early predictor of hepatitis B envelope antigen seroconversion during treatment with polymerase inhibitors. Hepatology 2015; 61(1): 66–76

    Article  PubMed  Google Scholar 

  18. Tsuge M, Chayama K. Availability of monitoring serum HBV DNA plus RNA during nucleot(s)ide analogue therapy. J Gastroenterol 2013; 48(6): 779–780

    Article  PubMed  Google Scholar 

  19. Hatakeyama T, Noguchi C, Hiraga N, Mori N, Tsuge M, Imamura M, Takahashi S, Kawakami Y, Fujimoto Y, Ochi H, Abe H, Maekawa T, Kawakami H, Yatsuji H, Aisaka Y, Kohno H, Aimitsu S, Chayama K. Serum HBV RNA is a predictor of early emergence of the YMDD mutant in patients treated with lamivudine. Hepatology 2007; 45(5): 1179–1186

    Article  CAS  PubMed  Google Scholar 

  20. Tsuge M, Murakami E, Imamura M, Abe H, Miki D, Hiraga N, Takahashi S, Ochi H, Nelson Hayes C, Ginba H, Matsuyama K, Kawakami H, Chayama K. Serum HBV RNA and HBeAg are useful markers for the safe discontinuation of nucleotide analogue treatments in chronic hepatitis B patients. J Gastroenterol 2013; 48(10): 1188–1204

    Article  CAS  PubMed  Google Scholar 

  21. Summers J, O’Connell A, Millman I. Genome of hepatitis B virus: restriction enzyme cleavage and structure of DNA extracted from Dane particles. Proc Natl Acad Sci USA 1975; 72(11): 4597–4601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yan H, Zhong G, Xu G, He W, Jing Z, Gao Z, Huang Y, Qi Y, Peng B, Wang H, Fu L, Song M, Chen P, Gao W, Ren B, Sun Y, Cai T, Feng X, Sui J, Li W. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. eLife 2012; 1: e00049

    Article  PubMed  PubMed Central  Google Scholar 

  23. Sureau C, Salisse J. A conformational heparan sulfate binding site essential to infectivity overlaps with the conserved hepatitis B virus a-determinant. Hepatology 2013; 57(3): 985–994

    Article  CAS  PubMed  Google Scholar 

  24. Cornberg M, Wong VW, Locarnini S, Brunetto M, Janssen HL, Chan HL. The role of quantitative hepatitis B surface antigen revisited. J Hepatol 2017; 66(2): 398–411

    Article  CAS  PubMed  Google Scholar 

  25. Yang HC, Kao JH. Persistence of hepatitis B virus covalently closed circular DNA in hepatocytes: molecular mechanisms and clinical significance. Emerg Microbes Infect 2014; 3(9): e64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tuttleman JS, Pourcel C, Summers J. Formation of the pool of covalently closed circular viral DNA in hepadnavirus-infected cells. Cell 1986; 47(3): 451–460

    Article  CAS  PubMed  Google Scholar 

  27. Zhang YY, Zhang BH, Theele D, Litwin S, Toll E, Summers J. Single-cell analysis of covalently closed circular DNA copy numbers in a hepadnavirus-infected liver. Proc Natl Acad Sci USA 2003; 100(21): 12372–12377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yang W, Summers J. Illegitimate replication of linear hepadnavirus DNA through nonhomologous recombination. J Virol 1995; 69(7): 4029–4036

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Bill CA, Summers J. Genomic DNA double-strand breaks are targets for hepadnaviral DNA integration. Proc Natl Acad Sci USA 2004; 101(30): 11135–11140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Li X, Zhang J, Yang Z, Kang J, Jiang S, Zhang T, Chen T, Li M, Lv Q, Chen X, McCrae MA, Zhuang H, Lu F. The function of targeted host genes determines the oncogenicity of HBV integration in hepatocellular carcinoma. J Hepatol 2014; 60(5): 975–984

    Article  PubMed  Google Scholar 

  31. Wang HP, Rogler CE. Topoisomerase I-mediated integration of hepadnavirus DNA in vitro. J Virol 1991; 65(5): 2381–2392

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Mason WS, Gill US, Litwin S, Zhou Y, Peri S, Pop O, Hong ML, Naik S, Quaglia A, Bertoletti A, Kennedy PT. HBV DNA integration and clonal hepatocyte expansion in chronic hepatitis B patients considered immune tolerant. Gastroenterology 2016; 151(5): 986–998.e4

    Article  CAS  PubMed  Google Scholar 

  33. Rivkina MB, Lunin VG, Mahov AM, Tikchonenko TI, Kukain RA. Nucleotide sequence of integrated hepatitis B virus DNA and human flanking regions in the genome of the PLC/PRF/5 cell line. Gene 1988; 64(2): 285–296

    Article  CAS  PubMed  Google Scholar 

  34. Kaplan PM, Ford EC, Purcell RH, Gerin JL. Demonstration of subpopulations of Dane particles. J Virol 1976; 17(3): 885–893

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Sakamoto Y, Yamada G, Mizuno M, Nishihara T, Kinoyama S, Kobayashi T, Takahashi T, Nagashima H. Full and empty particles of hepatitis B virus in hepatocytes from patients with HBsAgpositive chronic active hepatitis. Lab Invest 1983; 48(6): 678–682

    CAS  PubMed  Google Scholar 

  36. Ning X, Nguyen D, Mentzer L, Adams C, Lee H, Ashley R, Hafenstein S, Hu J. Secretion of genome-free hepatitis B virus—single strand blocking model for virion morphogenesis of para-retrovirus. PLoS Pathog 2011; 7(9): e1002255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Luckenbaugh L, Kitrinos KM, Delaney WE 4th, Hu J. Genome-free hepatitis B virion levels in patient sera as a potential marker to monitor response to antiviral therapy. J Viral Hepat 2015; 22(6): 561–570

    Article  CAS  PubMed  Google Scholar 

  38. Littlejohn M, Locarnini S, Yuen L. Origins and evolution of hepatitis B virus and hepatitis D virus. Cold Spring Harb Perspect Med 2016; 6(1): a021360

    Article  PubMed  PubMed Central  Google Scholar 

  39. Huang CR, Lo SJ. Hepatitis D virus infection, replication and crosstalk with the hepatitis B virus. World J Gastroenterol 2014; 20(40): 14589–14597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Li M, Hongyan C, Huaxing Z, Wei L, Daru L. Locked nucleic acid couples with Fok I nucleases to target and cleave hepatitis B virus’s gene in vitro. Yi Chuan 2016; 38(4): 350–359

    PubMed  Google Scholar 

  41. Zhu Y, Yamamoto T, Cullen J, Saputelli J, Aldrich CE, Miller DS, Litwin S, Furman PA, Jilbert AR, Mason WS. Kinetics of hepadnavirus loss from the liver during inhibition of viral DNA synthesis. J Virol 2001; 75(1): 311–322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Dandri M, Locarnini S. New insight in the pathobiology of hepatitis B virus infection. Gut 2012; 61(Suppl 1): i6–i17

    Article  CAS  PubMed  Google Scholar 

  43. Nguyen T, Locarnini S. Hepatitis: monitoring drug therapy for hepatitis B—a global challenge? Nat Rev Gastroenterol Hepatol 2009; 6(10): 565–567

    Article  CAS  PubMed  Google Scholar 

  44. Werle-Lapostolle B, Bowden S, Locarnini S, Wursthorn K, Petersen J, Lau G, Trepo C, Marcellin P, Goodman Z, Delaney WE 4th, Xiong S, Brosgart CL, Chen SS, Gibbs CS, Zoulim F. Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy. Gastroenterology 2004; 126(7): 1750–1758

    Article  CAS  PubMed  Google Scholar 

  45. Wong DK, Yuen MF, Ngai VW, Fung J, Lai CL. One-year entecavir or lamivudine therapy results in reduction of hepatitis B virus intrahepatic covalently closed circular DNA levels. Antivir Ther 2006; 11(7): 909–916

    CAS  PubMed  Google Scholar 

  46. Wursthorn K, Lutgehetmann M, Dandri M, Volz T, Buggisch P, Zollner B, Longerich T, Schirmacher P, Metzler F, Zankel M, Fischer C, Currie G, Brosgart C, Petersen J. Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B. Hepatology 2006; 44(3): 675–684

    Article  CAS  PubMed  Google Scholar 

  47. Durantel D, Zoulim F. New antiviral targets for innovative treatment concepts for hepatitis B virus and hepatitis delta virus. J Hepatol 2016; 64(1 Suppl): S117–S131

    Article  CAS  PubMed  Google Scholar 

  48. Nassal M. HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B. Gut 2015; 64(12): 1972–1984

    Article  CAS  PubMed  Google Scholar 

  49. Petersen J, Thompson AJ, Levrero M. Aiming for cure in HBV and HDV infection. J Hepatol 2016; 65(4): 835–848

    Article  PubMed  Google Scholar 

  50. Yip TC, Wong VW, Tse YK, Chan HL, Wong GL. Hepatitis B surface antigen seroclearance in a cohort of 154, 740 patients with chronic hepatitis B: a 15-year follow-up study. Hepatol Int 2017; 11: S75

    Google Scholar 

  51. Liu ZR, Liu F, Wang L, Liu YD, Zhang M, Li T. Clinical characteristics and outcomes of patients with recurrent chronic hepatitis B after nucleos(t)ide analog withdrawal with stringent cessation criteria: a prospectivecohort study. Hepatol Res 2017; 47(10): 1000–1007

    Article  CAS  PubMed  Google Scholar 

  52. Petersen J, Buggisch P, Hinrichsen H, Berg T, Wedemeyer H, Cornberg M, Stoehr A. Stopping long-term NA-therapy before HBsAg loss in HBeAg negative patients: follow-up of long-term responders. J Hepatol 2013; 58: S313–S314

    Google Scholar 

  53. Lai CL, Wong D, Ip P, Kopaniszen M, Seto WK, Fung J, Huang FY, Lee B, Cullaro G, Chong CK, Wu R, Cheng C, Yuen J, Ngai V, Yuen MF. Reduction of covalently closed circular DNA with longterm nucleos(t)ide analogue treatment in chronic hepatitis B. J Hepatol 2017; 66(2): 275–281

    Article  CAS  PubMed  Google Scholar 

  54. Jiang S, Yang Z, Li W, Li X, Wang Y, Zhang J, Xu C, Chen PJ, Hou J, McCrae MA, Chen X, Zhuang H, Lu F. Re-evaluation of the carcinogenic significance of hepatitis B virus integration in hepatocarcinogenesis. PLoS One 2012; 7(9): e40363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Freitas N, Cunha C, Menne S, Gudima SO. Envelope proteins derived from naturally integrated hepatitis B virus DNA support assembly and release of infectious hepatitis delta virus particles. J Virol 2014; 88(10): 5742–5754

    Article  PubMed  PubMed Central  Google Scholar 

  56. Wooddell CI, Yuen MF, Chan HL, Gish RG, Locarnini SA, Chavez D, Ferrari C, Given BD, Hamilton J, Kanner SB, Lai CL, Lau JYN, Schluep T, Xu Z, Lanford RE, Lewis DL. RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg. Sci Trans Med 2017; 9(409): eaan0241

    Article  Google Scholar 

  57. Wang J, Du M, Huang H, Chen R, Niu J, Jiang J, Zhuang H, Lu F. Reply to: “Serum HBV pgRNA as a clinical marker for cccDNA activity”: Consistent loss of serum HBV RNA might predict the “para-functional cure” of chronic hepatitis B. J Hepatol 2017; 66(2): 462–463

    Article  CAS  PubMed  Google Scholar 

  58. Yip TC, Chan HL, Wong VW, Tse YK, Lam KL, Wong GL. Impact of age and gender on risk of hepatocellular carcinoma after hepatitis B surface antigen seroclearance. J Hepatol 2017; 67(5): 902–908

    Article  CAS  PubMed  Google Scholar 

  59. Liu J, Yang HI, Lee MH, Lu SN, Jen CL, Batrla-Utermann R, Wang LY, You SL, Hsiao CK, Chen PJ, Chen CJ; R.E.V.E.A.L.-HBV Study Group. Spontaneous seroclearance of hepatitis B seromarkers and subsequent risk of hepatocellular carcinoma. Gut 2014; 63(10): 1648–1657

    Article  CAS  PubMed  Google Scholar 

  60. Giersch K, Allweiss L, Volz T, Dandri M, Lütgehetmann M. Serum HBV pgRNA as a clinical marker for cccDNA activity. J Hepatol 2017; 66(2): 460–462

    Article  CAS  PubMed  Google Scholar 

  61. Hu P, Jia S, Zhang W, Gong G, Li Y, Chen X, Jiang J, Xie Q, Dou X, Sun Y, Li Y, Liu Y, Liu G, Mao D, Chi X, Tang H, Li X, Xie Y, Chen X, Jiang J, Zhao P, Hou J, Gao Z, Fan H, Ding J, Ren H. A multi-center randomized study on the efficacy and safety of switching to peginterferon alpha-2a (40KD) for 48 or 96 weeks in HBeAg positive CHB patients with a prior NUC history for 1 to 3 years: an interim analysis of NEW SWITCH study. Hepatology 2014; 60: 1273A–1274A

    Google Scholar 

  62. Ning Q, Han M, Sun Y, Jiang J, Tan D, Hou J, Tang H, Sheng J, Zhao M. Switching from entecavir to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: a randomised open-label trial (OSST trial). J Hepatol 2014; 61(4): 777–784

    Article  CAS  PubMed  Google Scholar 

  63. Chen EQ, Feng S, Wang ML, Liang LB, Zhou LY, Du LY, Yan LB, Tao CM, Tang H. Serum hepatitis B core-related antigen is a satisfactory surrogate marker of intrahepatic covalently closed circular DNA in chronic hepatitis B. Sci Rep 2017; 7(1): 173

    Article  PubMed  PubMed Central  Google Scholar 

  64. Hu J, Liu K. Complete and incomplete hepatitis B virus particles: formation, function, and application. Viruses 2017; 9(3): E56

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 81672013 and 81471938), the National S&T Major Project for Infectious Diseases (Nos. 2017ZX10302201 and 2017ZX10202202), and the 111 project (No. B07001).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Fengmin Lu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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. Front. Med. 11, 502–508 (2017). https://doi.org/10.1007/s11684-017-0590-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11684-017-0590-z

Keywords

Navigation