Hepatitis B virus infection, structure, genotypes, and epidemiology - A review HBV infection

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Bader S Alotaibi https://orcid.org/0000-0001-6878-257X


Hepatitis b virus, Replication, Sub genotypes, Chronic hepatitis, HBV vaccine


There are currently 250 million people infected with the hepatitis B virus (HBV) worldwide, despite the availability of a prophylactic vaccine for many years and the use of efficient and well-tolerated viral suppressive drugs since 1998. In this review, I go through the most recent developments in the structure, and epidemiology and biology of the virus, look at changes in the way the disease is currently being treated, and investigate novel, cutting-edge treatments that are being developed for the treatment of HBV infection. Genotypes and serological subtypes have a strong and statistically significant association, and in some circumstances, serological subtypes can be utilized to distinguish between sub genotypes. geographic distribution of certain genotypes and subgenotypes varies and plays a crucial role in the clinical manifestation of infection as well as the response to antiviral medication. Thanks to advancements in genetics, the prospect for vaccinations, and tailored management to target the integration of virus with host. HBV persistence occurs due to covalently closed circular DNA can rarely be removed by current pharmacological therapies. Alternative treatment approaches, such as those built on silencing of viral. According to reports, HBV DNA levels can be inhibited and conversion of HBeAg to antibody to HBe Ag can be induced by antiviral medication like nucleotide analog (NUC), which can prevent liver-related death. Additionally, there is a critical need for the creation of global archives of standardized HBV reagents and protocols that can be accessible by all HBV researchers. The plan for HBV cure research presented in this position paper will make a significant contribution to the objective of eradicating HBV infection globally.

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1. World Health Organization. Hepatitis B. Available at: www.who.int/topics/hepatitis/factsheets/en. Accessed June 22, 2016. 
2. WHO position paper on hepatitis B vaccines - October 2009. Wkly Epidemiol Rec. 2009;84:405-420. 
3. Fricker ZP, Reddy KR. When (and when not) to treat patients with HBV infection. Clin Gastroenterol Hepatol. 2019;17(13):2644-2647. https://doi.org/10.1016/j.cgh.2019.05.039
4. Madihi S, Syed H, Lazar F, et al. A systematic review of the current hepatitis B viral infection and hepatocellular carcinoma situation in Mediterranean countries. Biomed Res Int. 2020;2020:7027169. https://doi.org/10.1155/2020/7027169
5. Fonseca MA, Ling JZ, Al-Siyabi O, et al. The efficacy of hepatitis B treatments in achieving HBsAg seroclearance: a systematic review and meta-analysis. J Viral Hepat. 2020;27(7):650-662. https://doi.org/10.1111/jvh.13283
6. Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat. 2004;11(2):97107. https://doi.org/10.1046/j.1365-2893.2003.00487.x
7. Beasley RP, Hwang LY, Lin CC, et al. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet. 1981;2:11291133.
8. Fujiwara K, Yokosuka O, Ehata T, et al. The two different states of hepatitis B virus DNA in asymptomatic carriers: Beantigenpositive versus antiHBepositive asymptomatic carriers. Dig Dis Sci. 1998;43:368376. 
9. 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. Lancet. 2015;386(10003):1546-1555. https://doi.org/10.1016/
10. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and causespecific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. 
Lancet. 2015;385(9963):117-171. 
11. Franco E, Bagnato B, Marino MG, et al. Hepatitis B: epidemiology and prevention in developing countries. World J Hepatol. 2012;4(3):74-80. https://doi.org/10.4254/wjh.v4.i3.68
12. Lee HM, Banini BA. Updates on chronic HBV: current challenges and future goals. Curr Treat Options Gastroenterol. 2019;17(2):271-291. https://doi.org/10.1007/s11938-019-00236-3
13. Liang TJ. Hepatitis B: the virus and disease. Hepatology 2009;49(5 Suppl): S13-21. https://doi.org/10.4324/9780203853856-2
14. Tripathi N, Mousa OY. Hepatitis B 2020. StatPearls, Treasure Island; 2020. https://doi.org/10.5772/intechopen.82772 
15. Datta S, Chatterjee S, Veer V, et al. Molecular biology of the hepatitis B virus for clinicians. J Clin Exp Hepatol. 2012;2(4):353-365.
16. Lai CL, Ratziu V, Yuen MF, et al. Viral hepatitis B. Lancet. 2003;362(9401):2089-2094.
17. Bartenschlager R, Schaller H. The amino-terminal domain of the hepadnaviral P-gene encodes the terminal protein (genome-linked protein) believed to prime reverse transcription. Embo J. 1988;7(13):4185-4192. https://doi.org/10.1002/j.1460-2075.1988.
18. Seeger C, Mason WS. Hepatitis B virus biology. Microbiol Mol Biol Rev. 2018;64(1):51-68. https://doi.org/10.1201/9781351074759-1
19. Yang HC, Kao JH. Persistence of hepatitis B virus covalently closed circular DNA in hepatocytes: molecular mechanisms and clinical significance. Emerg Microbes Infect. 2000;3(9):e64-139. https://doi.org/10.1038/emi.2014.64
20. Gerlich WH. Medical virology of hepatitis B: how it began and where we are now. Virol J. 2013;10(1):239. https://doi.org/10.1186/1743-422x-10-239
21. Taylor JM. Structure and replication of hepatitis delta virus RNA. Curr Top Microbiol Immunol. 2006;307:1-23. https://doi.org/10.1007/0-387-35103-5_3
22. Pourkarim MR, Amini-Bavil-Olyaee S, Lemey P, et al. Are hepatitis B virus ‘subgenotypes’ defined accurately? J Clin Virol. 2010;47(4):356-360. https://doi.org/10.1016/j.jcv.2010.01.015
23. Pourkarim MR, Amini-Bavil-Olyaee S, Lemey P, et al. HBV subgenotype misclassification expands quasi-subgenotype A3. Clin Microbiol Infect. 2011;17(6):947-949. https://doi.org/10.1111/j.1469-0691.2010.03374.x
24. Shi W, Zhu C, Zheng W, et al. Subgenotype reclassification of genotype B hepatitis B virus. BMC Gastroenterol. 2012;12(1):116.https://doi.org/10.1186/1471-230x-12-116
25. Shi W, Zhu C, Zheng W, et al. Subgenotyping of genotype C hepatitis B virus: correcting misclassifications and identifying a novel subgenotype. PLoS One. 2012;7(10):e47271. https://doi.org/10.1371/journal.pone.0047271
26. Yousif M, Kramvis A. Genotype D of hepatitis B virus and its subgenotypes: an update. Hepatol Res. 2013;43(4):355-364. https://doi.org/10.1111/j.1872-034x.2012.01090.x
27. Andernach IE, Hunewald OE, Muller CP. Bayesian inference of the evolution of HBV/E. PLoS One. 2013;8(11):e81690. https://doi.org/10.1371/journal.pone.0081690
28. Kramvis A, Kew MC. Epidemiology of hepatitis B virus in Africa, its genotypes and clinical associations of genotypes. Hepatol Res. 2007;37(1):S9-S19. https://doi.org/10.1111/j.1872-034x.2007.00098.x
29. Panduro A, Maldonado-Gonzalez M, Fierro NA, et al. Distribution of HBV genotypes F and H in Mexico and Central America. Antivir Ther. 2013;18(3):475-484. https://doi.org/10.3851/imp2605
30. Olinger CM, Jutavijittum P, Hubschen JM, et al. Possible new hepatitis B virus genotype, southeast Asia. Emerg Infect Dis. 2008;14(11):1777-1780. https://doi.org/10.3201/eid1411.080437
31. Tatematsu K, Tanaka Y, Kurbanov F, et al. A genetic variant of hepatitis B virus divergent from known human and ape genotypes isolated from a Japanese patient and provisionally assigned to new genotype J. J Virol. 2009;83(20):10538-10547. https://doi.
32. Margolis HS, Alter MJ, Hadler SC. Hepatitis B: evolving epidemiology and implications for control. Semin Liver Dis. 1991;11(2):84-92. https://doi.org/10.1055/s-2008-1040427
33. 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. Lancet. 2015;386(10003):1546-1555. https://doi.org/10.1016/
34. The World Health Organization. Hepatitis B. https://www.who.int/news-room/fact-sheets/detail/hepatitis-b (Accessed on March 13, 2022).35. Alter MJ, Hadler SC, Margolis HS, et al. The changing epidemiology of hepatitis B in the United States. Need for alternative 
vaccination strategies. JAMA. 1990;263(9):1218-1222. https://doi.org/10.1001/jama.1990.03440090052025
36. Easley RP, Hwang LY, Lin CC, et al. Incidence of hepatitis B virus infections in preschool children in Taiwan. J Infect Dis. 1982;146(2):198-204. https://doi.org/10.1093/infdis/146.2.198
37. Lin CL, Kao JH, Chen BF, et al. Application of hepatitis B virus genotyping and phylogenetic analysis in intrafamilial transmission of hepatitis B virus. Clin Infect Dis 2005;41(11):1576. https://doi.org/10.1086/497837
38. Ahmed MM, Huang TH, Xie QD. A sensitive and rapid assay for investigating vertical transmission of hepatitis B virus via male germ line using EGFP Vector as reporter. J Biomed Biotechnol. 2008;2008:495436. https://doi.org/10.1155/2008/495436
39. Ahmed MM, Huang TH, Xie QD. An improved experimental model for studying vertical transmission of hepatitis B virus via human spermatozoa. J Virol Methods. 2008;151(1):116. https://doi.org/10.1016/j.jviromet.2008.03.014
40. World Health Organization. Guidelines on assessing donor suitability for blood donation. http://iacld.ir/DL/elm/whoblooddonorselectionguidelinesonassessingdonorsuitabilityforblooddonation.pdf (Accessed on December 07, 2015).
41. Goh KT. Prevention and control of hepatitis B virus infection in Singapore. Ann Acad Med Singapore 1997; 26:671.
42. Centers for Disease Control. Surveillance for viral hepatitis - United States, 2013 http://www.cdc.gov/hepatitis/statistics/2013surveillance/commentary.htm#hepatitisB (Accessed on October 02, 2015).
43. Iqbal K, Klevens RM, Kainer MA, et al. Epidemiology of Acute Hepatitis B in the United States From Population-Based Surveillance, 2006-2011. Clin Infect Dis. 2015;61(4):584. https://doi.org/10.1093/cid/civ332
44. World Health Organization. Hepatitis B fact sheet. http://www.who.int/mediacentre/factsheets/fs204/en/ (Accessed on December 07, 2015).
45. Nelson PK, Mathers BM, Cowie B, et al. Global epidemiology of hepatitis B and hepatitis C in people who inject drugs: results of systematic reviews. Lancet 2011;378(9791):571. https://doi.org/10.1016/s0140-6736(11)61097-0
46. Perry JL, Pearson RD, Jagger J. Infected health care workers and patient safety: a double standard. Am J Infect Control. 2006;34(5):313-319. https://doi.org/10.1016/j.ajic.2006.01.004
47. Thomas HC. Best practice in the treatment of chronic hepatitis B: a summary of the European Viral Hepatitis Educational Initiative (EVHEI). J Hepatol. 2007;47(4):588-597. https://doi.org/10.1016/j.jhep.2007.07.017
48. Tong S, Revill P. Overview of hepatitis B viral replication and genetic variability. J. Hepatol. 2016;64(1):S4-S16. https://doi.org/10.1016/j.jhep.2016.01.027
49. Testoni B, Levrero M, Zoulim F. Challenges to a cure for HBV infection. Semin Liver Dis. 2017;37(3):231-242. https://doi.org/10.1055/s-0037-1606212
50. Gish RG. Chronic hepatitis B: virology, natural history, current management and a glimpse at future opportunities. Antivir Res. 2015;121:47-58. https://doi.org/10.1016/j.antiviral.2015.06.008
51. Coffin CS, Zhou K, Terrault NA. New and old biomarkers for diagnosis and management of chronic hepatitis B virus infection. Gastroenterology. 2019;156(2):355-368. https://doi.org/10.1053/j.gastro.2018.11.037
52. Revill PA. A global scientific strategy to cure hepatitis B. Lancet Gastroenterol Hepatol. 2019;4:545-558.
53. Hong X. Characterization of hepatitis B precore/core-related antigens. J Virol. 2021. https://doi.org/doi.org/10.1128/JVI.01695-20
54. Gerlich WH, Glebe D, Kramvis A, et al. Peculiarities in the designations of hepatitis B virus genes, their products, and their antigenic specificities: a potential source of misunderstandings. Virus Genes 2020;56(2):109-119. https://doi.org/10.1007/
55. Seeger C, Mason WS. Hepatitis B virus biology. Microbiol Mol Biol Rev. 2000;64:51-68.
56. Stadelmayer B. Full-length 5’RACE identifies all major HBV transcripts in HBV-infected hepatocytes and patient serum. J Hepatol. 2020;73(1):40-51. https://doi.org/10.1016/j.jhep.2020.01.028
57. Wang J. 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. https://doi.org/10.1016/j.jhep.2016.05.029
58. Bai L. Extracellular hepatitis B virus RNAs are heterogeneous in length and circulate as capsidantibody complexes in addition to virions in chronic hepatitis B patients. J Virol. 2018;92(24). https://doi.org/10.1128/jvi.00798-18
59. van Bommel F. 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. https://doi.org/10.1002/hep.28349
60. van Bommel F. 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. https://doi.org/10.1002/hep.28349
61. Testoni B. Serum hepatitis B core-related antigen (HBcrAg) correlates with covalently closed circular DNA transcriptional activity in chronic hepatitis B patients. J Hepatol. 2019;70(4):615-625. https://doi.org/10.1016/j.jhep.2018.11.030
62. Testoni B. Serum hepatitis B core-related antigen (HBcrAg) correlates with covalently closed circular DNA transcriptional activity in chronic hepatitis B patients. J Hepatol. 2019;70(4):615-625. https://doi.org/10.1016/j.jhep.2018.11.030
63. Wong GL, Wong VW, Chan HL. Virus and host testing to manage chronic hepatitis B. Clin Infect Dis. 2016;62(Suppl 4):S298-305. https://doi.org/10.1093/cid/ciw02464. Chen EQ. 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. https://doi.org/10.1038/s41598-017-00111-0
65. Pfefferkorn M. Quantification of large and middle proteins of hepatitis B virus surface antigen (HBsAg) as a novel tool for the identification of inactive HBV carriers. Gut. 2018;67(11):2045-2053. https://doi.org/10.1136/gutjnl-2017-313811
66. Pfefferkorn M. Composition of HBsAg is predictive of HBsAg loss during treatment in patients with HBeAg-positive chronic hepatitis B. J Hepatol. 2021;74(2):283-292. https://doi.org/10.1016/j.jhep.2020.08.039
67. Hassemer M. Comparative characterization of hepatitis B virus surface antigen derived from different hepatitis B virus genotypes. Virology. 2017;502:1-12. https://doi.org/10.1016/j.virol.2016.12.003
68. Bengsch B, Chang KM. Evolution in our understanding of hepatitis B virus virology and immunology. Clin Liver Dis. 2016;20(4):629-644. https://doi.org/10.1016/j.cld.2016.06.001
69. Ghany MG. Serum alanine aminotransferase flares in chronic hepatitis B infection: the good and the bad. Lancet Gastroenterol. Hepatol. 2020;5(4):406-417. https://doi.org/10.1016/s2468-1253(19)30344-9
70. World Health Organization. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. 2015. https://www.who.int/publications/i/item/9789241549059.
71. Polaris Observatory Collaborators. Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study. Lancet Gastroenterol Hepatol. 2018;3:383-403.
72. Yeh ML, Huang JF, Dai CY, et al. Pharmacokinetics and pharmacodynamics of pegylated interferon for the treatment of hepatitis B. Expert Opin Drug Metab Toxicol. 2019;15:779-785. https://doi.org/10.1111/jvh.13111
73. Indolfi G, Bailey H, Serranti D, et al. Treatment and monitoring of children with chronic hepatitis C in the Pre-DAA era: A European survey of 38 paediatric specialists. J Viral Hepat. 2019;26:961-968. https://doi.org/10.1111/jvh.13111
74. Jonas MM, Mizerski J, Badia IB, et al. International Pediatric Lamivudine Investigator Group. Clinical trial of lamivudine in children with chronic hepatitis B. N Engl J Med. 2002;346:1706-1713.
75. Robinson DM, Scott LJ, Plosker GL. Entecavir: a review of its use in chronic hepatitis B. Drugs. 2006;66:1605-1622.
76. Jonas MM, Chang MH, Sokal E, et al. Randomized, controlled trial of entecavir versus placebo in children with hepatitis B envelope antigen-positive chronic hepatitis B. Hepatology. 2016;63(2):377-387. https://doi.org/10.1002/hep.28015
77. Grim SA, Romanelli F. Tenofovir disoproxil fumarate. Ann Pharmacother. 2003;37:849-859.
78. Murray KF, Szenborn L, Wysocki J, et al. Randomized, placebo-controlled trial of tenofovir disoproxil fumarate in adolescents with chronic hepatitis B. Hepatology. 2012;56(2):2018-2026. https://doi.org/10.1002/hep.25818
79. Yan H, Zhong G, Xu G, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife. 2014;33(3):388-396. https://doi.org/10.1159/000371692
80. Yan H, Peng B, He W, et al. Molecular determinants of hepatitis B and D virus entry restriction in mouse sodium taurocholate cotransporting polypeptide. J Virol. 2013;87(14):79777991. https://doi.org/10.1128/jvi.03540-12
81. Liu J, Zhang E, Ma Z, et al. Enhancing virus-specific immunity in vivo by combining therapeutic vaccination and PD-L1 blockade in chronic hepadnaviral infection. PLoS Pathog. 2014;10(1):e1003856. https://doi.org/10.1371/journal.ppat.1003856
82. Bohne F, Chmielewski M, Ebert G, et al. T cells redirected against hepatitis B virus surface proteins eliminate infected hepatocytes. Gastroenterology. 2008;134(1):239-247. https://doi.org/10.1053/j.gastro.2007.11.002

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