Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Clinical significance and molecular characteristics of common hepatitis B virus variants

Anna SF Lok, MD
Section Editor
Rafael Esteban, MD
Deputy Editor
Jennifer Mitty, MD, MPH


Viral DNA and especially RNA genomes are inherently variable due to errors introduced during replication. These errors are in the range of 1 mutation in 1,000 to 100,000 nucleotides per replication cycle for RNA viruses, and approximately 1 mutation in 100,000,000 nucleotides per replication cycle for DNA viruses [1,2]. The higher mutation rate among RNA viruses is related to the lack of proofreading functions of RNA polymerases and reverse transcriptases. As a result, mutations in viral genomic sequences are generated naturally during viral replication and should be viewed as a normal biological event.

Hepatitis B virus (HBV), a member of the Hepadnaviridae family, replicates asymmetrically via reverse transcription of an RNA intermediate, making it prone to mutations [3]. The estimated mutation rate of the hepadnavirus genome is about 2 x 10(4) base substitutions/site/year, about 100 times higher than that of other DNA viruses but about 100 to 1,000 times lower than that of other RNA viruses [4]. Although mutations can occur randomly along the HBV genome, the overlapping open reading frames limit the number and location of viable mutations. Because chronic HBV infection frequently persists for decades, many variants may exist within the same host at any given time and each variant may have multiple base changes.

Selection by the host for the fittest variant occurs after the random mutation process. Fitness may be defined at the cellular level (viruses that replicate most efficiently in a cell type will predominate) or at the extra-cellular level (viruses that avoid immune elimination will become dominant) [5]. Thus, the accumulation of viral variants depends upon the rate at which the variants are generated and the advantage they confer to the virus.

The genetically different viral species concomitantly present in a single cell or in a single individual are termed quasi-species [1]. Interpretation of the clinical significance of HBV mutations is complicated by the lack of standardized nomenclature, differences in sensitivities of assays used in their detection, and the presence of mutations in more than one region of the HBV genome even in the same species [6,7]. Despite these difficulties, in vivo analyses of naturally occurring viral variants and in vitro mutagenesis studies have identified some mutations that have a role in viral latency, pathogenesis of liver disease, immune escape, and resistance to antiviral therapy. This topic review will summarize the clinical relevance and molecular characteristics of common HBV variants.


The precore/core region of the HBV genome encodes the nucleocapsid protein (HBcAg) and HBeAg [8,9]. The core open reading frame has two transcripts with heterogeneous 5' ends and two in-phase initiation codons. HBeAg is translated from the precore mRNA, producing a precursor polypeptide comprising the precore and the entire core region. The precore polypeptide is translocated into the endoplasmic reticulum by a signal peptide. Cleavage of the amino and carboxy termini results in a secretory protein, HBeAg. HBcAg is translated from the pregenomic RNA. Both HBcAg and HBeAg contain B- and T-cell epitopes, of which some are shared. (See "Characteristics of the hepatitis B virus and pathogenesis of infection".)

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Oct 12, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Carman W, Thomas H, Domingo E. Viral genetic variation: hepatitis B virus as a clinical example. Lancet 1993; 341:349.
  2. Domingo E, Sabo D, Taniguchi T, Weissmann C. Nucleotide sequence heterogeneity of an RNA phage population. Cell 1978; 13:735.
  3. Summers J, Mason WS. Replication of the genome of a hepatitis B--like virus by reverse transcription of an RNA intermediate. Cell 1982; 29:403.
  4. Girones R, Miller RH. Mutation rate of the hepadnavirus genome. Virology 1989; 170:595.
  5. Oldstone MB. Molecular anatomy of viral persistence. J Virol 1991; 65:6381.
  6. Blum HE, Liang TJ, Galun E, Wands JR. Persistence of hepatitis B viral DNA after serological recovery from hepatitis B virus infection. Hepatology 1991; 14:56.
  7. Hasegawa K, Huang J, Rogers SA, et al. Enhanced replication of a hepatitis B virus mutant associated with an epidemic of fulminant hepatitis. J Virol 1994; 68:1651.
  8. Uy A, Bruss V, Gerlich WH, et al. Precore sequence of hepatitis B virus inducing e antigen and membrane association of the viral core protein. Virology 1986; 155:89.
  9. Ou JH, Laub O, Rutter WJ. Hepatitis B virus gene function: the precore region targets the core antigen to cellular membranes and causes the secretion of the e antigen. Proc Natl Acad Sci U S A 1986; 83:1578.
  10. Yuh CH, Chang YL, Ting LP. Transcriptional regulation of precore and pregenomic RNAs of hepatitis B virus. J Virol 1992; 66:4073.
  11. Buckwold VE, Xu Z, Chen M, et al. Effects of a naturally occurring mutation in the hepatitis B virus basal core promoter on precore gene expression and viral replication. J Virol 1996; 70:5845.
  12. Scaglioni PP, Melegari M, Wands JR. Biologic properties of hepatitis B viral genomes with mutations in the precore promoter and precore open reading frame. Virology 1997; 233:374.
  13. Carman WF, Jacyna MR, Hadziyannis S, et al. Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet 1989; 2:588.
  14. Akahane Y, Yamanaka T, Suzuki H, et al. Chronic active hepatitis with hepatitis B virus DNA and antibody against e antigen in the serum. Disturbed synthesis and secretion of e antigen from hepatocytes due to a point mutation in the precore region. Gastroenterology 1990; 99:1113.
  15. Brunetto MR, Giarin MM, Oliveri F, et al. Wild-type and e antigen-minus hepatitis B viruses and course of chronic hepatitis. Proc Natl Acad Sci U S A 1991; 88:4186.
  16. Ganem D, Varmus HE. The molecular biology of the hepatitis B viruses. Annu Rev Biochem 1987; 56:651.
  17. Tong SP, Li JS, Vitvitski L, Trépo C. Replication capacities of natural and artificial precore stop codon mutants of hepatitis B virus: relevance of pregenome encapsidation signal. Virology 1992; 191:237.
  18. Milich DR, Jones JE, Hughes JL, et al. Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero? Proc Natl Acad Sci U S A 1990; 87:6599.
  19. Raimondo G, Tanzi E, Brancatelli S, et al. Is the course of perinatal hepatitis B virus infection influenced by genetic heterogeneity of the virus? J Med Virol 1993; 40:87.
  20. Twu JS, Schloemer RH. Transcription of the human beta interferon gene is inhibited by hepatitis B virus. J Virol 1989; 63:3065.
  21. Milich DR, Chen MK, Hughes JL, Jones JE. The secreted hepatitis B precore antigen can modulate the immune response to the nucleocapsid: a mechanism for persistence. J Immunol 1998; 160:2013.
  22. Jung MC, Diepolder HM, Spengler U, et al. Activation of a heterogeneous hepatitis B (HB) core and e antigen-specific CD4+ T-cell population during seroconversion to anti-HBe and anti-HBs in hepatitis B virus infection. J Virol 1995; 69:3358.
  23. Ferrari C, Penna A, Bertoletti A, et al. Cellular immune response to hepatitis B virus-encoded antigens in acute and chronic hepatitis B virus infection. J Immunol 1990; 145:3442.
  24. Frelin L, Wahlström T, Tucker AE, et al. A mechanism to explain the selection of the hepatitis e antigen-negative mutant during chronic hepatitis B virus infection. J Virol 2009; 83:1379.
  25. Guidotti LG, Matzke B, Pasquinelli C, et al. The hepatitis B virus (HBV) precore protein inhibits HBV replication in transgenic mice. J Virol 1996; 70:7056.
  26. Scaglioni PP, Melegari M, Wands JR. Posttranscriptional regulation of hepatitis B virus replication by the precore protein. J Virol 1997; 71:345.
  27. Hadziyannis S. Hepatitis E antigen negative chronic hepatitis B: From clinical recognition to pathogenesis and treatment. Viral Hepatitis Rev 1995; 1:7.
  28. Santantonio T, Jung MC, Miska S, et al. Prevalence and type of pre-C HBV mutants in anti-HBe positive carriers with chronic liver disease in a highly endemic area. Virology 1991; 183:840.
  29. Okamoto H, Yotsumoto S, Akahane Y, et al. Hepatitis B viruses with precore region defects prevail in persistently infected hosts along with seroconversion to the antibody against e antigen. J Virol 1990; 64:1298.
  30. Chu CJ, Keeffe EB, Han SH, et al. Hepatitis B virus genotypes in the United States: results of a nationwide study. Gastroenterology 2003; 125:444.
  31. Ogata N, Miller RH, Ishak KG, Purcell RH. The complete nucleotide sequence of a pre-core mutant of hepatitis B virus implicated in fulminant hepatitis and its biological characterization in chimpanzees. Virology 1993; 194:263.
  32. Laskus T, Rakela J, Tong MJ, et al. Naturally occurring hepatitis B virus mutants with deletions in the core promoter region. J Hepatol 1994; 20:837.
  33. Fukuda R, Nguyen XT, Ishimura N, et al. X gene and precore region mutations in the hepatitis B virus genome in persons positive for antibody to hepatitis B e antigen: comparison between asymptomatic "healthy" carriers and patients with severe chronic active hepatitis. J Infect Dis 1995; 172:1191.
  34. Uchida T, Shimojima M, Gotoh K, et al. "Silent" hepatitis B virus mutants are responsible for non-A, non-B, non-C, non-D, non-E hepatitis. Microbiol Immunol 1994; 38:281.
  35. Lindh M, Furuta Y, Ljunggren KK, et al. Detection of hepatitis B virus precore TAG mutant by an amplification-created restriction site method. J Infect Dis 1995; 171:194.
  36. Takahashi K, Ohta Y, Kanai K, et al. Clinical implications of mutations C-to-T1653 and T-to-C/A/G1753 of hepatitis B virus genotype C genome in chronic liver disease. Arch Virol 1999; 144:1299.
  37. Grandjacques C, Pradat P, Stuyver L, et al. Rapid detection of genotypes and mutations in the pre-core promoter and the pre-core region of hepatitis B virus genome: correlation with viral persistence and disease severity. J Hepatol 2000; 33:430.
  38. Hussain M, Chu CJ, Sablon E, Lok AS. Rapid and sensitive assays for determination of hepatitis B virus (HBV) genotypes and detection of HBV precore and core promoter variants. J Clin Microbiol 2003; 41:3699.
  39. Minamitani S, Nishiguchi S, Kuroki T, et al. Detection by ligase chain reaction of precore mutant of hepatitis B virus. Hepatology 1997; 25:216.
  40. Ballard AL, Boxall EH. Colourimetric point mutation assay: for detection of precore mutants of hepatitis B. J Virol Methods 1997; 67:143.
  41. Okamoto H, Tsuda F, Akahane Y, et al. Hepatitis B virus with mutations in the core promoter for an e antigen-negative phenotype in carriers with antibody to e antigen. J Virol 1994; 68:8102.
  42. Lok AS, Akarca US, Greene S. Predictive value of precore hepatitis B virus mutations in spontaneous and interferon-induced hepatitis B e antigen clearance. Hepatology 1995; 21:19.
  43. Chu CM, Yeh CT, Lee CS, et al. Precore stop mutant in HBeAg-positive patients with chronic hepatitis B: clinical characteristics and correlation with the course of HBeAg-to-anti-HBe seroconversion. J Clin Microbiol 2002; 40:16.
  44. Kidd-Ljunggren K, Oberg M, Kidd AH. Hepatitis B virus X gene 1751 to 1764 mutations: implications for HBeAg status and disease. J Gen Virol 1997; 78 ( Pt 6):1469.
  45. Chan HL, Leung NW, Hussain M, et al. Hepatitis B e antigen-negative chronic hepatitis B in Hong Kong. Hepatology 2000; 31:763.
  46. Chan HL, Hussain M, Lok AS. Different hepatitis B virus genotypes are associated with different mutations in the core promoter and precore regions during hepatitis B e antigen seroconversion. Hepatology 1999; 29:976.
  47. Takahashi K, Aoyama K, Ohno N, et al. The precore/core promoter mutant (T1762A1764) of hepatitis B virus: clinical significance and an easy method for detection. J Gen Virol 1995; 76 ( Pt 12):3159.
  48. Kurosaki M, Enomoto N, Asahina Y, et al. Mutations in the core promoter region of hepatitis B virus in patients with chronic hepatitis B. J Med Virol 1996; 49:115.
  49. Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: 2000--summary of a workshop. Gastroenterology 2001; 120:1828.
  50. Zarski JP, Marcellin P, Cohard M, et al. Comparison of anti-HBe-positive and HBe-antigen-positive chronic hepatitis B in France. French Multicentre Group. J Hepatol 1994; 20:636.
  51. Brunetto MR, Oliveri F, Rocca G, et al. Natural course and response to interferon of chronic hepatitis B accompanied by antibody to hepatitis B e antigen. Hepatology 1989; 10:198.
  52. Fattovich G, Brollo L, Alberti A, et al. Long-term follow-up of anti-HBe-positive chronic active hepatitis B. Hepatology 1988; 8:1651.
  53. Naoumov NV, Schneider R, Grötzinger T, et al. Precore mutant hepatitis B virus infection and liver disease. Gastroenterology 1992; 102:538.
  54. Shindo M, Hamada K, Koya S, et al. The clinical significance of core promoter and precore mutations during the natural course and interferon therapy in patients with chronic hepatitis B. Am J Gastroenterol 1999; 94:2237.
  55. Schalm SW, Thomas HC, Hadziyannis SJ. Chronic hepatitis B. Prog Liver Dis 1990; 9:443.
  56. Lindh M, Andersson AS, Gusdal A. Genotypes, nt 1858 variants, and geographic origin of hepatitis B virus--large-scale analysis using a new genotyping method. J Infect Dis 1997; 175:1285.
  57. Lok AS, Akarca U, Greene S. Mutations in the pre-core region of hepatitis B virus serve to enhance the stability of the secondary structure of the pre-genome encapsidation signal. Proc Natl Acad Sci U S A 1994; 91:4077.
  58. Rodriguez-Frias F, Buti M, Jardi R, et al. Hepatitis B virus infection: precore mutants and its relation to viral genotypes and core mutations. Hepatology 1995; 22:1641.
  59. Lindh M, Hannoun C, Dhillon AP, et al. Core promoter mutations and genotypes in relation to viral replication and liver damage in East Asian hepatitis B virus carriers. J Infect Dis 1999; 179:775.
  60. Orito E, Mizokami M, Sakugawa H, et al. A case-control study for clinical and molecular biological differences between hepatitis B viruses of genotypes B and C. Japan HBV Genotype Research Group. Hepatology 2001; 33:218.
  61. Fang ZL, Ling R, Wang SS, et al. HBV core promoter mutations prevail in patients with hepatocellular carcinoma from Guangxi, China. J Med Virol 1998; 56:18.
  62. Baptista M, Kramvis A, Kew MC. High prevalence of 1762(T) 1764(A) mutations in the basic core promoter of hepatitis B virus isolated from black Africans with hepatocellular carcinoma compared with asymptomatic carriers. Hepatology 1999; 29:946.
  63. Gaglio P, Singh S, Degertekin B, et al. Impact of the hepatitis B virus genotype on pre- and post-liver transplantation outcomes. Liver Transpl 2008; 14:1420.
  64. Bonino F, Brunetto MR. Hepatitis B virus heterogeneity, one of many factors influencing the severity of hepatitis B. J Hepatol 1993; 18:5.
  65. Yuen MF, Tanaka Y, Ng IO, et al. Hepatic necroinflammation and fibrosis in patients with genotypes Ba and C, core-promoter and precore mutations. J Viral Hepat 2005; 12:513.
  66. Yuen MF, Sablon E, Yuan HJ, et al. Relationship between the development of precore and core promoter mutations and hepatitis B e antigen seroconversion in patients with chronic hepatitis B virus. J Infect Dis 2002; 186:1335.
  67. Yuen MF, Tanaka Y, Mizokami M, et al. Role of hepatitis B virus genotypes Ba and C, core promoter and precore mutations on hepatocellular carcinoma: a case control study. Carcinogenesis 2004; 25:1593.
  68. Kao JH, Chen PJ, Lai MY, Chen DS. Basal core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers. Gastroenterology 2003; 124:327.
  69. Chou YC, Yu MW, Wu CF, et al. Temporal relationship between hepatitis B virus enhancer II/basal core promoter sequence variation and risk of hepatocellular carcinoma. Gut 2008; 57:91.
  70. Chu CJ, Keeffe EB, Han SH, et al. Prevalence of HBV precore/core promoter variants in the United States. Hepatology 2003; 38:619.
  71. Tseng TC, Liu CJ, Yang HC, et al. Higher proportion of viral basal core promoter mutant increases the risk of liver cirrhosis in hepatitis B carriers. Gut 2015; 64:292.
  72. Qu LS, Zhu J, Liu TT, et al. Effect of combined mutations in the enhancer II and basal core promoter of hepatitis B virus on development of hepatocellular carcinoma in Qidong, China. Hepatol Res 2014; 44:1186.
  73. Lyu H, Lee D, Chung YH, et al. Synergistic effects of A1896, T1653 and T1762/A1764 mutations in genotype c2 hepatitis B virus on development of hepatocellular carcinoma. J Viral Hepat 2013; 20:219.
  74. Yin J, Xie J, Liu S, et al. Association between the various mutations in viral core promoter region to different stages of hepatitis B, ranging of asymptomatic carrier state to hepatocellular carcinoma. Am J Gastroenterol 2011; 106:81.
  75. Yang HI, Yeh SH, Chen PJ, et al. Associations between hepatitis B virus genotype and mutants and the risk of hepatocellular carcinoma. J Natl Cancer Inst 2008; 100:1134.
  76. Sato S, Suzuki K, Akahane Y, et al. Hepatitis B virus strains with mutations in the core promoter in patients with fulminant hepatitis. Ann Intern Med 1995; 122:241.
  77. Kosaka Y, Takase K, Kojima M, et al. Fulminant hepatitis B: induction by hepatitis B virus mutants defective in the precore region and incapable of encoding e antigen. Gastroenterology 1991; 100:1087.
  78. Omata M, Ehata T, Yokosuka O, et al. Mutations in the precore region of hepatitis B virus DNA in patients with fulminant and severe hepatitis. N Engl J Med 1991; 324:1699.
  79. Liang TJ, Hasegawa K, Rimon N, et al. A hepatitis B virus mutant associated with an epidemic of fulminant hepatitis. N Engl J Med 1991; 324:1705.
  80. Karayiannis P, Alexopoulou A, Hadziyannis S, et al. Fulminant hepatitis associated with hepatitis B virus e antigen-negative infection: importance of host factors. Hepatology 1995; 22:1628.
  81. Jardi R, Rodriguez F, Buti M, et al. Mutations in the basic core promoter region of hepatitis B virus. Relationship with precore variants and HBV genotypes in a Spanish population of HBV carriers. J Hepatol 2004; 40:507.
  82. Peng XM, Huang GM, Li JG, et al. High level of hepatitis B virus DNA after HBeAg-to-anti-HBe seroconversion is related to coexistence of mutations in its precore and basal core promoter. World J Gastroenterol 2005; 11:3131.
  83. Brunetto MR, Giarin M, Saracco G, et al. Hepatitis B virus unable to secrete e antigen and response to interferon in chronic hepatitis B. Gastroenterology 1993; 105:845.
  84. Oliveri F, Santantonio T, Bellati G, et al. Long term response to therapy of chronic anti-HBe-positive hepatitis B is poor independent of type and schedule of interferon. Am J Gastroenterol 1999; 94:1366.
  85. Lampertico P, Del Ninno E, Manzin A, et al. A randomized, controlled trial of a 24-month course of interferon alfa 2b in patients with chronic hepatitis B who had hepatitis B virus DNA without hepatitis B e antigen in serum. Hepatology 1997; 26:1621.
  86. Fattovich G, McIntyre G, Thursz M, et al. Hepatitis B virus precore/core variation and interferon therapy. Hepatology 1995; 22:1355.
  87. Erhardt A, Reineke U, Blondin D, et al. Mutations of the core promoter and response to interferon treatment in chronic replicative hepatitis B. Hepatology 2000; 31:716.
  88. Kao JH, Wu NH, Chen PJ, et al. Hepatitis B genotypes and the response to interferon therapy. J Hepatol 2000; 33:998.
  89. Marrone A, Zampino R, Luongo G, et al. Low HBeAg serum levels correlate with the presence of the double A1762T/G1764A core promoter mutation and a positive response to interferon in patients with chronic hepatitis B virus infection. Intervirology 2003; 46:222.
  90. Sonneveld MJ, Zoutendijk R, Hansen BE, Janssen HL. Pegylated interferon results in higher serological, but not virological, response rates when compared to continuous entecavir. Antivir Ther 2012; 17:1605.
  91. Sonneveld MJ, Rijckborst V, Zeuzem S, et al. Presence of precore and core promoter mutants limits the probability of response to peginterferon in hepatitis B e antigen-positive chronic hepatitis B. Hepatology 2012; 56:67.
  92. Chen RY, Edwards R, Shaw T, et al. Effect of the G1896A precore mutation on drug sensitivity and replication yield of lamivudine-resistant HBV in vitro. Hepatology 2003; 37:27.
  93. Lok AS, Hussain M, Cursano C, et al. Evolution of hepatitis B virus polymerase gene mutations in hepatitis B e antigen-negative patients receiving lamivudine therapy. Hepatology 2000; 32:1145.
  94. Tacke F, Gehrke C, Luedde T, et al. Basal core promoter and precore mutations in the hepatitis B virus genome enhance replication efficacy of Lamivudine-resistant mutants. J Virol 2004; 78:8524.
  95. Bhatnagar PK, Papas E, Blum HE, et al. Immune response to synthetic peptide analogues of hepatitis B surface antigen specific for the a determinant. Proc Natl Acad Sci U S A 1982; 79:4400.
  96. Brown SE, Stanley C, Howard CR, et al. Antibody responses to recombinant and plasma derived hepatitis B vaccines. Br Med J (Clin Res Ed) 1986; 292:159.
  97. Szmuness W, Stevens CE, Harley EJ, et al. Hepatitis B vaccine in medical staff of hemodialysis units: efficacy and subtype cross-protection. N Engl J Med 1982; 307:1481.
  98. Chisari FV, Ferrari C. Hepatitis B virus immunopathogenesis. Annu Rev Immunol 1995; 13:29.
  99. Pircher H, Moskophidis D, Rohrer U, et al. Viral escape by selection of cytotoxic T cell-resistant virus variants in vivo. Nature 1990; 346:629.
  100. Waters JA, Kennedy M, Voet P, et al. Loss of the common "A" determinant of hepatitis B surface antigen by a vaccine-induced escape mutant. J Clin Invest 1992; 90:2543.
  101. Oon CJ, Chen WN, Goo KS, Goh KT. Intra-familial evidence of horizontal transmission of hepatitis B virus surface antigen mutant G145R. J Infect 2000; 41:260.
  102. Hsu HY, Chang MH, Ni YH, Chen HL. Survey of hepatitis B surface variant infection in children 15 years after a nationwide vaccination programme in Taiwan. Gut 2004; 53:1499.
  103. Bréchot C, Thiers V, Kremsdorf D, et al. Persistent hepatitis B virus infection in subjects without hepatitis B surface antigen: clinically significant or purely "occult"? Hepatology 2001; 34:194.
  104. Carman WF, Van Deursen FJ, Mimms LT, et al. The prevalence of surface antigen variants of hepatitis B virus in Papua New Guinea, South Africa, and Sardinia. Hepatology 1997; 26:1658.
  105. Grethe S, Monazahian M, Böhme I, Thomssen R. Characterization of unusual escape variants of hepatitis B virus isolated from a hepatitis B surface antigen-negative subject. J Virol 1998; 72:7692.
  106. Hou J, Karayiannis P, Waters J, et al. A unique insertion in the S gene of surface antigen--negative hepatitis B virus Chinese carriers. Hepatology 1995; 21:273.
  107. Kato J, Hasegawa K, Torii N, et al. A molecular analysis of viral persistence in surface antigen-negative chronic hepatitis B. Hepatology 1996; 23:389.
  108. Conjeevaram HS, Lok AS. Occult hepatitis B virus infection: a hidden menace? Hepatology 2001; 34:204.
  109. Poch O, Sauvaget I, Delarue M, Tordo N. Identification of four conserved motifs among the RNA-dependent polymerase encoding elements. EMBO J 1989; 8:3867.
  110. Johnson MS, McClure MA, Feng DF, et al. Computer analysis of retroviral pol genes: assignment of enzymatic functions to specific sequences and homologies with nonviral enzymes. Proc Natl Acad Sci U S A 1986; 83:7648.
  111. Kohlstaedt LA, Wang J, Friedman JM, et al. Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science 1992; 256:1783.
  112. Rossner MT. Review: hepatitis B virus X-gene product: a promiscuous transcriptional activator. J Med Virol 1992; 36:101.
  113. Yoo YD, Ueda H, Park K, et al. Regulation of transforming growth factor-beta 1 expression by the hepatitis B virus (HBV) X transactivator. Role in HBV pathogenesis. J Clin Invest 1996; 97:388.
  114. Hsia CC, Yuwen H, Tabor E. Hot-spot mutations in hepatitis B virus X gene in hepatocellular carcinoma. Lancet 1996; 348:625.