Chapter 31 : Hepatitis B Virus

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Hepatitis B Virus, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555815981/9781555814250_Chap31-1.gif /docserver/preview/fulltext/10.1128/9781555815981/9781555814250_Chap31-2.gif


The goal of chemoprevention for chronic hepatitis B (CHB) must be to improve the quality and the outcomes of care for patients with CHB. This chapter focuses on the human hepatitis B virus (HBV). HBV is an enveloped, 3.2-kb double-stranded DNA virus which may be classified into eight major genotypes (A to H) based on a nucleotide diversity of 8% or more. HBV infection is usually diagnosed using specific serologic assays. During the course of infection, the viral proteins HBsAg, HBcAg, and HBeAg stimulate the immune system to produce the corresponding antibodies anti-HBs, anti-HBc, and anti-HBe. Once HBV DNA becomes detectable, replication increases exponentially to peak at levels of >10 copies/ml in serum. In adult-acquired acute HBV infection, in which the host is able to control the virus, viral replication then declines, preceding the onset of clinical hepatitis. The risk of fulminant hepatic failure (FHF) may be higher in patients acutely infected with basal core promoter (BCP) or precore variants, coinfected with other hepatitis viruses, or with underlying liver disease. The major complications of CHB are cirrhosis, hepatic decompensation, and HCC. The current challenge in CHB is to identify patients at risk for progressive liver disease, so that therapy may be offered early to alter the natural history. The major risk factors for progression to cirrhosis are viral load, the presence of fibrosis on liver biopsy, and elevated serum alanine aminotransferase (ALT).

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31

Key Concept Ranking

Duck hepatitis B virus
Highly Active Antiretroviral Therapy
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of FIGURE 1

(A) Electron micrograph of the various forms found in the blood of HBV-infected persons. The 42-nm virions, both full and empty, can be seen. Within the empty particles, the 27- to 32-nm core structure can be visualized. The excess 22-nm subviral particles and filamentous forms of HBsAg are also present. (B) The circular double-stranded DNA genome of HBV showing the four main ORFs. The minus (–) and plus (+) DNA strands are marked. The HBV Pol and capped mRNA oligomer at the 5′ end of the minus and plus strands, respectively, as well as DR1 and DR2 are shown. The space between DR1 and DR2 is the “cohesive overlap region.” The plus strand is typically incomplete.

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 2

(A) Biosynthesis of the precore/core, Pol, envelope, and X proteins from the various HBV transcripts. The two major genomic 3.5-kb transcripts are the larger precore mRNA from which the precore protein (HBeAg) is made and the smaller pgmRNA that encodes the core and Pol and is the template for reverse transcription. The single 2.4-kb RNA makes LHBs, while the various 2.1-kb mRNAs translate MHBs and SHBs. The HBx protein is translated from the 0.7-kb mRNA. (B) Functional domains of the Pol-reverse transcriptase of HBV. (C) HBV DNA genome showing the overlapping ORFs and, in particular, how the Pol-envelope overlap can affect each of the proteins during the emergence of NA drug resistance.

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 3

Replication cycle of HBV. Following attachment, penetration, and uncoating, the viral nucleocapsid is released into the cytosol and transported to the nuclear pore. The genomic DNA is delivered into the nucleus, where it is converted into cccDNA and the viral minichromosome is generated. Transcription of the viral minichromosome produces the genomic and subgenomic HBV mRNA transcripts. Translation of the pgRNA in the cytosol produces the core and Pol proteins, and in association with HSP60 all are selectively packaged into a replication complex. Within the nucleocapsid, reverse transcription begins. The envelope proteins (pre-S1, pre-S2, and S) are translated at the rough ER and then bud into the lumen of the intermediate compartment. Approximately 50% of the pre-S1-enriched ER membrane areas envelope core particles. The HBV virions, small particles, and tubules are then secreted into the extracellular space by the constitutive pathway. The nucleocapsids can also be transported to the nucleus via an intracellular conversion pathway, increasing the copy number of cccDNA molecules.

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 4

Diagrammatic representation of the epsilon (ε) stem-loop structure of HBV. This is a highly conserved structure within the eight genotypes of HBV. The positions of base changes for genotype A-2 (Ae) are shown, as are the common translational precore mutations of G1896A (precore stop codon: UAG) and G1899A.

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 5

Location of the primary mutations associated with LMV and LdT resistance as well as ADV, TDF, and ETV resistance, in the major catalytic domains of the HBV Pol gene. a.a., amino acids.

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 6

Natural history of CHB, showing relationships between serology, biochemistry, molecular virology (serum and liver compartment), and immunologic parameters of the innate and adaptive arms. (Adapted from reference .)

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 7

The host immune response directed against HBV requires coordinated action of both innate immunity and cellular and humoral adaptive immunity, to affect both noncytolytic and cytolytic activity. The pathways of noncytolytic clearance are highlighted (see text). The key cytokines involved are IFN-γ, TNF-α, and IFN-α/β. IFN-γ and TNF-α, secreted by antigen-specific CTL or by the antigen-nonspecific macrophages and T cells that they activate, abolish HBV gene expression and replication in the livers of transgenic mice without killing the hepatocytes. These cytokines activate two independent virocidal pathways. The first pathway eliminates HBV nucleocapsid particles and their cargo of replicating viral genomes, by preventing capsid assembly in a proteasome- and kinase-dependent manner. The second pathway destabilizes the viral RNA by an SSB/La-dependent mechanism. IFN-γ and TNF-α induce proteolytic cleavage of the La autoantigen, which normally protects several HBV RNA endoribonuclease cleavage sites from cellular RNases. Type I IFN (IFN-α/β) also inhibits HBV replication at a posttranscriptional level. IFN-β has been shown to activate hepatocellular mechanisms that prevent the formation of replication-competent HBV capsids. The molecular mechanism(s) that mediates this inhibition has not yet been defined; type I IFN-inducible genes with known antiviral activity, including those for double-stranded RNA-dependent protein kinase and interferon regulatory factor 1, have been implicated. Type I IFNs have also been shown to inhibit transcription of HBV RNAs in some models.

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 8

Global prevalence of HBsAg. The WHO clarifies areas as being of high, medium, or low endemicity for HBV if the prevalence rate of HBsAg is >8, 2 to 7, or <2%, respectively.

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 9

HBV DNA level predicts the risk of cirrhosis (light gray bars) and HCC (dark gray bars). Elevated serum HBV DNA level (>10 copies/ml) is a strong predictor of risk for both cirrhosis and HCC. (Adapted from references and .)

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 10

Impact of universal vaccination on the incidence of HCC in Taiwan. A universal vaccination program was implemented in Taiwan in July 1984. Subsequently, the incidence of HCC was found to decline ( < 0.01 for the comparison of values before July 1990 with those after July 1990). (Adapted from reference .)

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Alward, W. L.,, B. J. McMahon,, D. B. Hall,, W. L. Hey-ward,, D. P. Francis, and, T. R. Bender. 1985. The long-term serological course of asymptomatic hepatitis B virus carriers and the development of primary hepatocellular carcinoma. J. Infect. Dis. 151:604609.
2. Angus, P.,, R. Vaughan,, S. Xiong,, H. Yang,, W. Delaney,, C. Gibbs,, C. Brosgart,, D. Colledge,, R. Edwards,, A. Ayres,, A. Bartholomeusz, and, S. Locarnini. 2003. Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase. Gastroenterology 125:292297.
3. Bartenschlager, R.,, and H. Schaller. 1992. Hepadnaviral assembly is initiated by polymerase binding to the encapsidation signal in the viral RNA genome. EMBO J. 11:34133420.
4. Bartholomeusz, A.,, and S. Schaefer. 2004. Hepatitis B virus genotypes: comparison of genotyping methods. Rev. Med. Virol. 14:316.
5. Bartholomeusz, A.,, B. G. Tehan, and, D. K. Chalmers. 2004. Comparisons of the HBV and HIV polymerase, and antiviral resistance mutations. Antivir. Ther. 9:149160.
6. Beasley, R. P. 1988. Hepatitis B virus. The major etiology of hepatocellular carcinoma. Cancer 61:19421956.
7. Beasley, R. P.,, C. C. Lin,, C. S. Chien,, C. J. Chen, and, L. Y. Hwang. 1982. Geographic distribution of HBsAg carriers in China. Hepatology 2:553556.
8. Beck, J.,, and M. Nassal. 2007. Hepatitis B virus replication. World J Gastroenterol. 13:4864.
9. Bell, S. J.,, A. Lau,, A. Thompson,, K. J. Watson,, B. Demediuk,, G. Shaw,, R. Y. Chen,, A. Ayres,, L. Yuen,, A. Bartholomeusz,, S. A. Locarnini, and, P. V. Desmond. 2005. Chronic hepatitis B: recommendations for therapy based on the natural history of disease in Australian patients. J. Clin. Virol. 32:122127.
10. Besisik, F.,, C. Karaca,, F. Akyuz,, S. Horosanli,, D. Onel,, S. Badur,, M. S. Sever,, A. Danalioglu,, K. Demir,, S. Kaymakoglu,, Y. Cakaloglu, and, A. Okten. 2003. Occult HBV infection and YMDD variants in hemodialysis patients with chronic HCV infection. J. Hepatol. 38:506510.
11. Biswas, R.,, E. Tabor,, C. C. Hsia,, D. J. Wright,, M. E. Laycock,, E. W. Fiebig,, L. Peddada,, R. Smith,, G. B. Schreiber,, J. S. Epstein,, G. J. Nemo, and, M. P. Busch. 2003. Comparative sensitivity of HBV NATs and HBsAg assays for detection of acute HBV infection. Transfusion 43:788798.
12. Bock, C. T.,, P. Schranz,, C. H. Schroder, and, H. Zentgraf. 1994. Hepatitis B virus genome is organized into nucleosomes in the nucleus of the infected cell. Virus Genes 8:215229.
13. Bodsworth, N.,, B. Donovan, and, B. N. Nightingale. 1989. The effect of concurrent human immunodeficiency virus infection on chronic hepatitis B: a study of 150 homosexual men. J. Infect. Dis. 160:577582.
14. Bowden, S. 2002. Laboratory Diagnosis of Hepatitis B Infection. International Medical Press, London, United Kingdom.
15. Bowden, S. 2006. Serological and molecular diagnosis. Semin. Liver Dis. 26:97103.
16. Brook, M. G.,, P. Karayiannis, and, H. C. Thomas. 1989. Which patients with chronic hepatitis B virus infection will respond to alpha-interferon therapy? A statistical analysis of predictive factors. Hepatology 10:761763.
17. Brunetto, M. R.,, F. Oliveri,, B. Coco,, G. Leandro,, P. Colombatto,, J. M. Gorin, and, F. Bonino. 2002. Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated and untreated patients: a long term cohort study. J. Hepatol. 36:263270.
18. Bruss, V.,, J. Hagelstein,, E. Gerhardt, and, P. R. Galle. 1996. Myristylation of the large surface protein is required for hepatitis B virus in vitro infectivity. Virology 218:396399.
19. Buster, E. H.,, B. E. Hansen,, M. Buti,, J. Delwaide,, C. Niederau,, P. P. Michielsen,, R. Flisiak,, P. E. Zondervan,, S. W. Schalm, and, H. L. Janssen. 2007. Peginterferon alpha-2b is safe and effective in HBeAg-positive chronic hepatitis B patients with advanced fibrosis. Hepatology 46:388394.
20. Carman, W. F. 1997. The clinical significance of surface antigen variants of hepatitis B virus. J. Viral. Hepat. 4(Suppl. 1):1120.
21. Carman, W. F.,, C. Trautwein,, F. J. van Deursen,, K. Colman,, E. Dornan,, G. Mc-Intyre,, J. Waters,, V. Kliem,, R. Muller,, H. C. Thomas, and, M. P. Manns. 1996. Hepatitis B virus envelope variation after transplantation with and without hepatitis B immune globulin prophylaxis. Hepatology 24:489493.
22. Carman, W. F.,, A. R. Zanetti,, P. Karayiannis,, J. Waters,, G. Manzillo,, E. Tanzi,, A. J. Zuckerman, and, H. C. Thomas. 1990. Vaccine-induced escape mutant of hepatitis B virus. Lancet 336:325329.
23. Chan, H. L.,, J. L. Tang,, W. Tam, and, J. J. Sung. 2001. The efficacy of thymosin in the treatment of chronic hepatitis B virus infection: a meta-analysis. Aliment. Pharmacol. Ther. 15:18991905.
24. Chan, H. L.,, S. W. Tsang,, M. L. Wong,, C. H. Tse,, N. W. Leung,, F. K. Chan, and, J. J. Sung. 2002. Genotype B hepatitis B virus is associated with severe icteric flare-up of chronic hepatitis B virus infection in Hong Kong. Am. J. Gastroenterol. 97:26292633.
25. Chang, M.-H.,, C.-J. Chen,, M.-S. Lai,, H.-M. Hsu,, T.-C. Wu,, M.-S. Kong,, D.-C. Liang,, W.-Y. Shau, and D.-S. Chen for the Taiwan Childhood Hepatoma Study Group. 1997. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N. Engl. J. Med. 336:18551859.
26. Chang, T. T.,, R. G. Gish,, R. de Man,, A. Gadano,, J. Sollano,, Y. C. Chao,, A. S. Lok,, K. H. Han,, Z. Goodman,, J. Zhu,, A. Cross,, D. DeHertogh,, R. Wilber,, R. Colonno, and, D. Apelian. 2006. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N. Engl. J. Med. 354:10011010.
27. Chen, C. J.,, H. I. Yang,, J. Su,, C. L. Jen,, S. L. You,, S. N. Lu,, G. T. Huang, and, U. H. Iloeje. 2006. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 295:6573.
28. Chen, G.,, W. Lin,, F. Shen,, U. H. Iloeje,, W. T. London, and, A. A. Evans. 2006. Past HBV viral load as predictor of mortality and morbidity from HCC and chronic liver disease in a prospective study. Am. J. Gastroenterol. 101:17971803.
29. Chen, H. L.,, C. J. Chang,, M. S. Kong,, F. C. Huang,, H. C. Lee,, C. C. Lin,, C. C. Liu,, I. H. Lee,, T. C. Wu,, S. F. Wu,, Y. H. Ni,, H. Y. Hsu,, D. S. Chen, and, M. H. Chang. 2004. Pediatric fulminant hepatic failure in endemic areas of hepatitis B infection: 15 years after universal hepatitis B vaccination. Hepatology 39:5863.
30. Chen, H. S.,, M. C. Kew,, W. E. Hornbuckle,, B. C. Tennant,, P. J. Cote,, J. L. Gerin,, R. H. Purcell, and, R. H. Miller. 1992. The precore gene of the woodchuck hepatitis virus genome is not essential for viral replication in the natural host. J. Virol. 66:56825684.
31. Chen, R. Y.,, R. Edwards,, T. Shaw,, D. Colledge,, W. E. Delaney IV,, H. Isom,, S. Bowden,, P. Desmond, and, S. A. Locarnini. 2003. Effect of the G1896A precore mutation on drug sensitivity and replication yield of lamivudine-resistant HBV in vitro. Hepatology 37:2735.
32. Chien, R.-N.,, Y.-F. Liaw, and M. Atkins for the Asian Hepatitis Lamivudine Trial Group. 1999. Pretherapy alanine transaminase level as a determinant for hepatitis B e antigen seroconversion during lamivudine therapy in patients with chronic hepatitis B. Hepatology 30:770774.
33. Chisari, F. V.,, and C. Ferrari. 1995. Hepatitis B virus immunopathogenesis. Annu. Rev. Immunol. 13:2960.
34. Chu, C. J.,, M. Hussain, and, A. S. Lok. 2002. Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C. Gastroenterology 122:17561762.
35. Chu, C. J.,, E. B. Keeffe,, S. H. Han,, R. P. Perrillo,, A. D. Min,, C. Soldevila-Pico,, W. Carey,, R. S. Brown, Jr.,, V. A. Luketic,, N. Terrault, and, A. S. Lok. 2003. Prevalence of HBV precore/core promoter variants in the United States. Hepatology 38:619628.
36. Colonno, R. J.,, R. Rose,, C. J. Baldick,, S. Levine,, K. Pokornowski,, C. F. Yu,, A. Walsh,, J. Fang,, M. Hsu,, C. Mazzucco,, B. Eggers,, S. Zhang,, M. Plym,, K. Klesczewski, and, D. J. Tenney. 2006. Entecavir resistance is rare in nucleoside naive patients with hepatitis B. Hepatology 44:16561665.
37. Cooksley, G. 2003. The treatment of hepatitis B e antigen-positive chronic hepatitis B with pegylated interferon. J. Hepatol. 39(Suppl. 1):S143S145.
38. Deguchi, M.,, N. Yamashita,, M. Kagita,, S. Asari,, Y. Iwatani,, T. Tsuchida,, K. Iinuma, and, I. K. Mushahwar. 2004. Quantitation of hepatitis B surface antigen by an automated chemiluminescent microparticle immunoassay. J. Virol. Methods 115:217222.
39. Delaney, W. E., IV,, S. Locarnini, and, T. Shaw. 2001. Resistance of hepatitis B virus to antiviral drugs: current aspects and directions for future investigation. Antivir. Chem. Chemother. 12:135.
40. Delaney, W. E.,, IV, H. Yang,, C. E. Westland,, K. Das,, E. Arnold,, C. S. Gibbs,, M. D. Miller, and, S. Xiong. 2003. The hepatitis B virus polymerase mutation rtV173L is selected during lamivudine therapy and enhances viral replication in vitro. J. Virol. 77:1183311841.
41. Dienstag, J. L.,, R. D. Goldin,, E. J. Heathcote,, H. W. Hann,, M. Woessner,, S. L. Stephenson,, S. Gardner,, D. F. Gray, and, E. R. Schiff. 2003. Histological outcome during long-term lamivudine therapy. Gastroenterology 124:105117.
42. Durantel, D.,, S. Carrouee-Durantel,, B. Werle-Lapostolle,, M. N. Brunelle,, C. Pichoud,, C. Trepo, and, F. Zoulim. 2004. A new strategy for studying in vitro the drug susceptibility of clinical isolates of human hepatitis B virus. Hepatology 40:855864.
43. Durantel, S.,, B. Werle,, D. Durantel,, C. Pichoud,, G. Currie,, S. Xiong,, C. Brosgart,, C. Trepo, and, F. Zoulim. 2004. Different profiles of response to adefovir dipivoxil and factors that may influence response in patients with chronic hepatitis B. Hepatology 40:654A.
44. Elsevier. 2003. Proceedings of the European Association for the Study of the Liver (EASL) International Consensus Conference on Hepatitis B. September 14–16, 2002. Geneva, Switzerland. J. Hepatol. 39(Suppl. 1):S1S235.
45. Entecavir Review Team. Briefing document for NDA 21-797, and NDA 21-798, ETV oral solution 0.05 mg/ml. http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4094B1_02_FDA-Background-Memo.pdf.
46. Fattovich, G.,, L. Brollo,, A. Alberti,, P. Pontisso,, G. Giustina, and, G. Realdi. 1988. Long-term follow-up of anti-HBe-positive chronic active hepatitis B. Hepatology 8:16511654.
47. Fattovich, G.,, L. Brollo,, G. Giustina,, F. Noventa,, P. Pontisso,, A. Alberti,, G. Realdi, and, A. Ruol. 1991. Natural history and prognostic factors for chronic hepatitis type B. Gut 32:294298.
48. Fattovich, G.,, G. Giustina,, S. W. Schalm,, S. Hadziyannis,, J. Sanchez-Tapias,, P. Almasio,, E. Christensen,, K. Krogsgaard,, F. Degos,, M. Carneiro de Moura, et al., for The EUROHEP Study Group on Hepatitis B Virus and Cirrhosis. 1995. Occurrence of hepatocellular carcinoma and decompensation in western European patients with cirrhosis type B. Hepatology 21:7782.
49. Feld, J.,, J. Y. Lee, and, S. Locarnini. 2003. New targets and possible new therapeutic approaches in the chemotherapy of chronic hepatitis B. Hepatology 38:545553.
50. Feld, J. J.,, and E. J. Heathcote. 2006. Hepatitis B e antigen-positive chronic hepatitis B: natural history and treatment. Semin. Liver Dis. 26:116129.
51. Ferri, C.,, M. Sebastiani,, D. Giuggioli,, M. Cazzato,, G. Longombardo,, A. Antonelli,, R. Puccini,, C. Michelassi, and, A. L. Zignego. 2004. Mixed cryoglobulinemia: demographic, clinical, and serologic features and survival in 231 patients. Semin. Arthritis Rheum. 33:355374.
52. Fitzsimons, D.,, G. Francois,, A. Hall,, B. McMahon,, A. Meheus,, A. Zanetti,, B. Duval,, W. Jilg,, W. O. Bocher,, S. N. Lu,, U. Akarca,, D. Lavanchy,, S. Goldstein,, J. Banatvala, and, P. V. Damme. 2005. Long-term efficacy of hepatitis B vaccine, booster policy, and impact of hepatitis B virus mutants. Vaccine 23:41584166.
53. Flink, H. J.,, M. van Zonneveld,, B. E. Hansen,, R. A. de Man,, S. W. Schalm, and H. L. A. Janssen for the HBV 99-01 Study Group. 2006. Treatment with Peginterferon α-2b for HBeAg-positive chronic hepatitis B: HBsAg loss is associated with HBV genotype. Am. J. Gastroenterol. 101:297303.
54. Fried, M.,, Y.-F. Liaw, and, K. Luo. 2005. Role of baseline and on-treatment quantitative HBeAg levels in predicting response to Peginterferon alfa-2a (40kD) (Pegasys) monotherapy in a large, multinational trial of patients with chronic hepatitis B. Hepatology 42:268A.
55. Fung, S. K.,, P. Andreone,, S. H. Han,, K. Rajender Reddy,, A. Regev,, E. B. Keeffe,, M. Hussain,, C. Cursaro,, P. Richtmyer,, J. A. Marrero, and, A. S. Lok. 2005. Adefovir-resistant hepatitis B can be associated with viral rebound and hepatic decompensation. J. Hepatol. 43:937943.
56. Gane, E. J.,, P. W. Angus,, S. Strasser,, D. H. Crawford,, J. Ring,, G. P. Jeffrey, and, G. W. McCaughan. 2007. Lamivudine plus low-dose hepatitis B immunoglobulin to prevent recurrent hepatitis B following liver transplantation. Gastroenterology 132:931937.
57. Ganem, D.,, and R. Schneider. 2001. Hepadnaviridae: the viruses and their replication, p. 2923–2970. In D. M. Knipe,, P. M. Howley,, D. E. Griffin,, R. A. Lamb,, M. A. Martin,, B. Roizman, and, S. E. Straus (ed.), Fields Virology, 4th ed., vol. 2. Lippincott Williams & Wilkins, Philadelphia, PA.
58. Girones, R.,, and R. H. Miller. 1989. Mutation rate of the hepadnavirus genome. Virology 170:595597.
59. Gish, R.,, T. T. Chang,, R. de Man,, A. Gadano,, J. Sollano,, K. H. Han,, A. Lok,, J. Zhu, and, L. Fernandes. 2005. Entecavir results in substantial virologic and biochemical improvement through 96 weeks of treatment in HBeAg(+) chronic hepatitis B patients (Study ETV-022). Hepatology 42:267A.
60. Guidotti, L. G.,, R. Rochford,, J. Chung,, M. Shapiro,, R. Purcell, and, F. V. Chisari. 1999. Viral clearance without destruction of infected cells during acute HBV infection. Science 284:825829.
61. Günther, S.,, L. Fischer,, I. Pult,, M. Sterneck, and, H. Will. 1999. Naturally occurring variants of hepatitis B virus. Adv. Virus Res. 52:25137.
62. Gust, I. D. 1996. Epidemiology of hepatitis B infection in the Western Pacific and South East Asia. Gut 38(Suppl. 2):S18S23.
63. Hadziyannis, S.,, I. Sevastianos,, I. Rapt, and, N. Tassopoulos. 2006. Sustained biochemical and virological remission after discontinuation of 4 to 5 years of adefovir dipivoxil (ADV) treatment in HBeAg-negative chronic hepatitis B. Hepatology 44:231A.
64. Hadziyannis, S. J.,, and G. V. Papatheodoridis. 2006. Hepatitis B e antigen-negative chronic hepatitis B: natural history and treatment. Semin. Liver Dis. 26:130141.
65. Hadziyannis, S. J.,, N. C. Tassopoulos,, E. J. Heathcote,, T. T. Chang,, G. Kitis,, M. Rizzetto,, P. Marcellin,, S. G. Lim,, Z. Goodman,, J. Ma,, S. Arterburn,, S. Xiong,, G. Currie, and, C. L. Brosgart. 2005. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N. Engl. J. Med. 352:26732681.
66. Hammer, S. M.,, M. S. Saag,, M. Schechter,, J. S. Montaner,, R. T. Schooley,, D. M. Jacobsen,, M. A. Thompson,, C. C. Carpenter,, M. A. Fischl,, B. G. Gazzard,, J. M. Gatell,, M. S. Hirsch,, D. A. Katzenstein,, D. D. Richman,, S. Vella,, P. G. Yeni, and, P. A. Volberding. 2006. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society—USA panel. Top. HIV Med. 14:827843.
67. Han, S. H. 2004. Extrahepatic manifestations of chronic hepatitis B. Clin. Liver Dis. 8:403418.
68. Hsu, Y. S.,, R. N. Chien,, C. T. Yeh,, I. S. Sheen,, H. Y. Chiou,, C. M. Chu, and, Y. F. Liaw. 2002. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology 35:15221527.
69. Hu, Z.,, Z. Zhang,, E. Doo,, O. Coux,, A. L. Goldberg, and, T. J. Liang. 1999. Hepatitis B virus X protein is both a substrate and a potential inhibitor of the proteasome complex. J. Virol. 73:72317240.
70. Hunt, C. M.,, J. M. McGill,, M. I. Allen, and, L. D. Condreay. 2000. Clinical relevance of hepatitis B viral mutations. Hepatology 31:10371044.
71. Iloeje, U. H.,, H. I. Yang,, J. Su,, C. L. Jen,, S. L. You, and, C. J. Chen. 2006. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 130:678686.
72. Isogawa, M.,, M. D. Robek,, Y. Furuichi, and, F. V. Chisari. 2005. Toll-like receptor signaling inhibits hepatitis B virus replication in vivo. J. Virol. 79:72697272.
73. Janssen, H. L.,, and G. K. Lau. 2005. Chronic hepatitis B: HBeAg seroconversion after pegylated interferon and nucleos(t)ide analogs. Hepatology 42:1459. (Author’s reply, 42:14591460.)
74. Kakimi, K.,, L. G. Guidotti,, Y. Koezuka, and, F. V. Chisari. 2000. Natural killer T cell activation inhibits hepatitis B virus replication in vivo. J. Exp. Med. 192:921930.
75. Kann, M. 1998. Hepadnaviridae: structure and molecular virology, p. 77–105. In A. J. Zuckerman and, H. C. Thomas (ed.), Viral Hepatitis, 2nd ed. Churchill Livingstone, New York, NY.
76. Kao, J. H.,, and D. S. Chen. 2003. Clinical relevance of hepatitis B virus genotypes Ba and Bj in Taiwan. Gastroenterology 125:19161917. (Author’s reply, 125:19171918.)
77. Kao, J. H.,, P. J. Chen,, M. Y. Lai, and, D. S. Chen. 2000. Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B. Gastroenterology 118:554559.
78. Kao, J. H.,, P. J. Chen,, M. Y. Lai, and, D. S. Chen. 2004. Hepatitis B virus genotypes and spontaneous hepatitis B e antigen seroconversion in Taiwanese hepatitis B carriers. J. Med. Virol. 72:363369.
79. Koike, K.,, T. Tsutsumi,, H. Fujie,, Y. Shintani, and, M. Kyoji. 2002. Molecular mechanism of viral hepatocarcinogenesis. Oncology 62(Suppl. 1):2937.
80. Krogsgaard, K., the Long-Term Follow-up Investigator Group, Executive Team on Anti-Viral Treatment. 1998. The long-term effect of treatment with interferon-α2a in chronic hepatitis B. J. Viral Hepat. 5:389397.
81. Kumar, M.,, S. Satapathy,, R. Monga,, K. Das,, S. Hissar,, C. Pande,, B. C. Sharma, and, S. K. Sarin. 2007. A randomized controlled trial of lamivudine to treat acute hepatitis B. Hepatology 45:97101.
82. Lai, C. L.,, J. Dienstag,, E. Schiff,, N. W. Leung,, M. Atkins,, C. Hunt,, N. Brown,, M. Woessner,, R. Boehme, and, L. Condreay. 2003. Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B. Clin. Infect. Dis. 36:687696.
83. Lai, C. L.,, N. Leung,, E. K. Teo,, M. Tong,, F. Wong,, H. W. Hann,, S. Han,, T. Poynard,, M. Myers,, G. Chao,, D. Lloyd, and, N. A. Brown. 2005. A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B. Gastroenterology 129:528536.
84. Lampertico, P.,, M. Vigano,, E. Manenti,, M. Iavarone,, G. Lunghi, and, M. Colombo. 2005. Adefovir rapidly suppresses hepatitis B in HBeAg-negative patients developing genotypic resistance to lamivudine. Hepatology 42:14141419.
85. Laras, A.,, J. Koskinas,, E. Dimou,, A. Kostamena, and, S. J. Hadziyannis. 2006. Intrahepatic levels and replicative activity of covalently closed circular hepatitis B virus DNA in chronically infected patients. Hepatology 44:694702.
86. Lau, G. K.,, T. Piratvisuth,, K. X. Luo,, P. Marcellin,, S. Thongsawat,, G. Cooksley,, E. Gane,, M. W. Fried,, W. C. Chow,, S. W. Paik,, W. Y. Chang,, T. Berg,, R. Flisiak,, P. McCloud, and, N. Pluck. 2005. Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N. Engl. J. Med. 352:26822695.
87. Lau, G. K.,, H. H. Yiu,, D. Y. Fong,, H. C. Cheng,, W. Y. Au,, L. S. Lai,, M. Cheung,, H. Y. Zhang,, A. Lie,, R. Ngan, and, R. Liang. 2003. Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients undergoing chemotherapy. Gastroenterology 125:17421749.
88. Lavanchy, D. 2004. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J. Viral. Hepat. 11:97107.
89. Lee, Y. S.,, D. J. Suh,, Y. S. Lim,, S. W. Jung,, K. M. Kim,, H. C. Lee,, Y. H. Chung,, W. Yoo, and, S. O. Kim. 2006. Increased risk of adefovir resistance in patients with lamivudine-resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy. Hepatology 43:13851391.
90. Leemans, W. F.,, H. J. Flink,, H. L. Janssen,, H. G. Niesters,, S. W. Schalm, and, R. A. de Man. 2006. The effect of pegylated interferon-alpha on the treatment of lamivudine resistant chronic HBeAg positive hepatitis B virus infection. J. Hepatol. 44:507511.
91. Liaw, Y. F.,, N. Leung,, R. Guan,, G. K. Lau,, I. Merican,, G. McCaughan,, E. Gane,, J. H. Kao, and, M. Omata. 2005. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2005 update. Liver Int. 25:472489.
92. Liaw, Y. F.,, I. S. Sheen,, T. J. Chen,, C. M. Chu, and, C. C. Pao. 1991. Incidence, determinants and significance of delayed clearance of serum HBsAg in chronic hepatitis B virus infection: a prospective study. Hepatology 13:627631.
93. Liaw, Y. F.,, J. J. Sung,, W. C. Chow,, G. Farrell,, C. Z. Lee,, H. Yuen,, T. Tanwandee,, Q. M. Tao,, K. Shue,, O. N. Keene,, J. S. Dixon,, D. F. Gray, and, J. Sabbat. 2004. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N. Engl. J. Med. 351:15211531.
94. Liaw, Y. F.,, D. I. Tai,, C. M. Chu, and, T. J. Chen. 1988. The development of cirrhosis in patients with chronic type B hepatitis: a prospective study. Hepatology 8:493496.
95. Lim, S. G.,, Y. Cheng,, S. Guindon,, B. L. Seet,, L. Y. Lee,, P. Hu,, S. Wasser,, F. J. Peter,, T. Tan,, M. Goode, and, A. G. Rodrigo. 2007. Viral quasispecies evolution during hepatitis B e antigen seroconversion. Gastroenterology 133:951958.
96. Lim, S. G.,, T. M. Ng,, N. Kung,, Z. Krastev,, M. Volfova,, P. Husa,, S. S. Lee,, S. Chan,, M. L. Shiffman,, M. K. Washington,, A. Rigney,, J. Anderson,, E. Mondou,, A. Snow,, J. Sorbel,, R. Guan, and, F. Rousseau. 2006. A double-blind placebo-controlled study of emtricitabine in chronic hepatitis B. Arch. Intern. Med. 166:4956.
97. Lin, C. L.,, L. Y. Liao,, C. S. Wang,, P. J. Chen,, M. Y. Lai,, D. S. Chen, and, J. H. Kao. 2005. Basal core-promoter mutant of hepatitis B virus and progression of liver disease in hepatitis B e antigen-negative chronic hepatitis B. Liver Int. 25:564570.
98. Lin, S. M.,, I. S. Sheen,, R. N. Chien,, C. M. Chu, and, Y. F. Liaw. 1999. Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection. Hepatology 29:971975.
99. Livingston, S. E.,, J. P. Simonetti,, B. J. McMahon,, L. R. Bulkow,, K. J. Hurlburt,, C. E. Homan,, M. M. Snowball,, H. H. Cagle,, J. L. Williams, and, V. P. Chulanov. 2007. Hepatitis B virus genotypes in Alaska Native people with hepatocellular carcinoma: preponderance of genotype F. J. Infect. Dis. 195:511.
100. Lo, K. J.,, Y. T. Tsai,, S. D. Lee,, T. C. Wu,, J. Y. Wang,, G. H. Chen,, C. L. Yeh,, B. N. Chiang,, S. H. Yeh,, A. Goudeau,, P. Coursaget, and, M. Tong. 1985. Immunoprophylaxis of infection with hepatitis B virus in infants born to hepatitis B surface antigen-positive carrier mothers. J. Infect. Dis. 152:817822.
101. Locarnini, S. 2005. Molecular virology and the development of resistant mutants: implications for therapy. Semin. Liver Dis. 25(Suppl. 1):919.
102. Locarnini, S.,, A. Hatzakis,, J. Heathcote,, E. B. Keeffe,, T. J. Liang,, D. Mutimer,, J. M. Pawlotsky, and, F. Zoulim. 2004. Management of antiviral resistance in patients with chronic hepatitis B. Antivir. Ther. 9:679693.
103. Lok, A. S. 2002. Chronic hepatitis B. N. Engl. J. Med. 346:16821683.
104. Lok, A. S.,, U. Akarca, and, S. Greene. 1994. Mutations in the pre-core region of hepatitis B virus serve to enhance the stability of the secondary structure of the pregenome encapsidation signal. Proc. Natl. Acad. Sci. USA 91:40774081.
105. Lok, A. S.,, C. L. Lai,, P. C. Wu,, E. K. Leung, and, T. S. Lam. 1987. Spontaneous hepatitis B e antigen to antibody seroconversion and reversion in Chinese patients with chronic hepatitis B virus infection. Gastroenterology 92:18391843.
106. Lok, A. S.,, and B. J. McMahon. 2007. Chronic hepatitis B. Hepatology 45:507539.
107. Mahoney, F. J.,, K. Stewart,, H. Hu,, P. Coleman, and, M. J. Alter. 1997. Progress toward the elimination of hepatitis B virus transmission among health care workers in the United States. Arch. Intern. Med. 157:26012605.
108. Maini, M. K.,, C. Boni,, C. K. Lee,, J. R. Larrubia,, S. Reignat,, G. S. Ogg,, A. S. King,, J. Herberg,, R. Gilson,, A. Alisa,, R. Williams,, D. Vergani,, N. V. Naoumov,, C. Ferrari, and, A. Bertoletti. 2000. The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection. J. Exp. Med. 191:12691280.
109. Manesis, E. K.,, and S. J. Hadziyannis. 2001. Interferon alpha treatment and retreatment of hepatitis B e antigen-negative chronic hepatitis B. Gastroenterology 121:101109.
110. Marcellin, P.,, G. K. Lau,, F. Bonino,, P. Farci,, S. Hadziyannis,, R. Jin,, Z. M. Lu,, T. Piratvisuth,, G. German-idis,, C. Yurdaydin,, M. Diago,, S. Gurel,, M. Y. Lai,, P. Button, and, N. Pluck. 2004. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N. Engl. J. Med. 351:12061217.
111. Maruyama, T.,, S. Iino,, K. Koike,, K. Yasuda, and, D. R. Milich. 1993. Serology of acute exacerbation in chronic hepatitis B virus infection. Gastroenterology 105:11411151.
112. Maruyama, T.,, A. McLachlan,, S. Iino,, K. Koike,, K. Kurokawa, and, D. R. Milich. 1993. The serology of chronic hepatitis B infection revisited. J. Clin. Investig. 91:25862595.
113. Mast, E. E.,, M. J. Alter, and, H. S. Margolis. 1999. Strategies to prevent and control hepatitis B and C virus infections: a global perspective. Vaccine 17:17301733.
114. Maynard, J. E. 1990. Hepatitis B: global importance and need for control. Vaccine 8(Suppl. 1):S18S20; discussion, S21S23.
115. McCaffrey, A. P.,, H. Nakai,, K. Pandey,, Z. Huang,, F. H. Salazar,, H. Xu,, S. F. Wieland,, P. L. Marion, and, M. A. Kay. 2003. Inhibition of hepatitis B virus in mice by RNA interference. Nat. Biotechnol. 21:639644.
116. McClary, H.,, R. Koch,, F. V. Chisari, and, L. G. Guidotti. 2000. Relative sensitivity of hepatitis B virus and other hepatotropic viruses to the antiviral effects of cytokines. J. Virol. 74:22552264.
117. McMahon, B. J.,, D. L. Bruden,, K. M. Petersen,, L. R. Bulkow,, A. J. Parkinson,, O. Nainan,, M. Khristova,, C. Zanis,, H. Peters, and, H. S. Margolis. 2005. Antibody levels and protection after hepatitis B vaccination: results of a 15-year follow-up. Ann. Intern. Med. 142:333341.
118. McMahon, M. A.,, B. L. Jilek,, T. P. Brennan,, L. Shen,, Y. Zhou,, M. Wind-Rotolo,, S. Xing,, S. Bhat,, B. Hale,, R. Hegarty,, C. R. Chong,, J. O. Liu,, R. F. Siliciano, and, C. L. Thio. 2007. The HBV drug entecavir—effects on HIV-1 replication and resistance. N. Engl. J. Med. 356:26142621.
119. Milich, D.,, and T. J. Liang. 2003. Exploring the biological basis of hepatitis B e antigen in hepatitis B virus infection. Hepatology 38:10751086.
120. Milich, D. R.,, J. E. Jones,, J. L. Hughes,, J. Price,, A. K. Raney, and, A. McLachlan. 1990. Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero? Proc. Natl. Acad. Sci. USA 87:65996603.
121. Milich, D. R.,, A. McLachlan,, F. V. Chisari,, S. B. Kent, and, G. B. Thorton. 1986. Immune response to the pre-S(1) region of the hepatitis B surface antigen (HBsAg): a pre-S(1)-specific T cell response can bypass nonresponsiveness to the pre-S(2) and S regions of HBsAg. J. Immunol. 137:315322.
122. Milich, D. R.,, G. B. Thornton,, A. R. Neurath,, S. B. Kent,, M. L. Michel,, P. Tiollais, and, F. V. Chisari. 1985. Enhanced immunogenicity of the pre-S region of hepatitis B surface antigen. Science 228:11951199.
123. Newbold, J. E.,, H. Xin,, M. Tencza,, G. Sherman,, J. Dean,, S. Bowden, and, S. Locarnini. 1995. The covalently closed duplex form of the hepadnavirus genome exists in situ as a heterogeneous population of viral mini-chromosomes. J. Virol. 69:33503357.
124. Ni, Y. H.,, L. M. Huang,, M. H. Chang,, C. J. Yen,, C. Y. Lu,, S. L. You,, J. H. Kao,, Y. C. Lin,, H. L. Chen,, H. Y. Hsu, and, D. S. Chen. 2007. Two decades of universal hepatitis B vaccination in Taiwan: impact and implication for future strategies. Gastroenterology 132:12871293.
125. Niederau, C.,, T. Heintges,, S. Lange,, G. Goldmann,, C. M. Niederau,, L. Mohr, and, D. Haussinger. 1996. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N. Engl. J. Med. 334:14221427.
126. Ocama, P.,, C. K. Opio, and, W. M. Lee. 2005. Hepatitis B virus infection: current status. Am. J. Med. 118:1413.
127. Okamoto, H.,, F. Tsuda,, Y. Akahane,, Y. Sugai,, M. Yoshiba,, K. Moriyama,, T. Tanaka,, Y. Miyakawa, and, M. Mayumi. 1994. Hepatitis B virus with mutations in the core promoter for an e antigen-negative phenotype in carriers with antibody to e antigen. J. Virol. 68:81028110.
128. Papatheodoridis, G. V.,, E. Dimou,, K. Dimakopoulos,, S. Manolakopoulos,, I. Rapti,, G. Kitis,, D. Tzourmakliotis,, E. Manesis, and, S. J. Hadziyannis. 2005. Outcome of hepatitis B e antigen-negative chronic hepatitis B on long-term nucleos(t)ide analog therapy starting with lamivudine. Hepatology 42:121129.
129. Papatheodoridis, G. V.,, E. Manesis, and, S. J. Hadziyannis. 2001. The long-term outcome of interferon-alpha treated and untreated patients with HBeAg-negative chronic hepatitis B. J. Hepatol. 34:306313.
130. Park, B. K.,, Y. N. Park,, S. H. Ahn,, K. S. Lee,, C. Y. Chon,, Y. M. Moon,, C. Park, and, K. H. Han. 2007. Long-term outcome of chronic hepatitis B based on histological grade and stage. J. Gastroenterol. Hepatol. 22:383388.
131. Park, N. H.,, J. W. Shin,, J. H. Park,, S. J. Bang,, D. H. Kim, and, K. R. Joo. 2005. Monitoring of HBeAg levels may help to predict the outcomes of lamivudine therapy for HBeAg positive chronic hepatitis B. J. Viral. Hepat. 12:216221.
132. Pawlotsky, J. M. 2002. Molecular diagnosis of viral hepatitis. Gastroenterology 122:15541568.
133. Perrillo, R.,, C. Tamburro,, F. Regenstein,, L. Balart,, H. Bodenheimer,, M. Silva,, E. Schiff,, C. Bodicky,, B. Miller,, C. Denham,, C. Brodeur,, K. Roach, and, J. Albrecht. 1995. Low-dose, titratable interferon alfa in decompensated liver disease caused by chronic infection with hepatitis B virus. Gastroenterology 109:908916.
134. Perrillo, R. P. 2005. Current treatment of chronic hepatitis B: benefits and limitations. Semin. Liver Dis. 25(Suppl. 1):2028.
135. Perrillo, R. P.,, E. R. Schiff,, G. L. Davis,, H. C. Bodenheimer, Jr.,, K. Lindsay,, J. Payne,, J. L. Dienstag,, C. O’Brien,, C. Tamburro,, I. M. Jacobson,, R. Sampliner,, D. Feit,, J. Lefkowitch,, M. Kuhns,, C. Meschievitz,, B. Sanghvi,, J. Albrecht,, A. Gibes, and The Hepatitis Interventional Therapy Group. 1990. A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. N. Engl. J. Med. 323:295301.
136. Poland, G. A. 1998. Hepatitis B immunization in health care workers. Dealing with vaccine nonresponse. Am. J. Prev. Med. 15:7377.
137. Poland, G. A.,, and R. M. Jacobson. 2004. Clinical practice: prevention of hepatitis B with the hepatitis B vaccine. N. Engl. J. Med. 351:28322838.
138. Rabe, B.,, A. Vlachou,, N. Pante,, A. Helenius, and, M. Kann. 2003. Nuclear import of hepatitis B virus capsids and release of the viral genome. Proc. Natl. Acad. Sci. USA 100:98499854.
139. Raimondo, G.,, T. Pollicino,, I. Cacciola, and, G. Squadrito. 2007. Occult hepatitis B virus infection. J. Hepatol. 46:160170.
140. Rapti, I.,, E. Dimou,, P. Mitsoula, and, S. J. Hadziyannis. 2007. Adding-on versus switching-to adefovir therapy in lamivudine-resistant HBeAg-negative chronic hepatitis B. Hepatology 45:307313.
141. Realdi, G.,, G. Fattovich,, S. Hadziyannis,, S. W. Schalm,, P. Almasio,, J. Sanchez-Tapias,, E. Christensen,, G. Giustina, and F. Noventa for The Investigators of the European Concerted Action on Viral Hepatitis (EUROHEP). 1994. Survival and prognostic factors in 366 patients with compensated cirrhosis type B: a multicenter study. J. Hepatol. 21:656666.
142. Richman, D. D. 2000. The impact of drug resistance on the effectiveness of chemotherapy for chronic hepatitis B. Hepatology 32:866867.
143. Rossner, M. T. 1992. Review: hepatitis B virus X-gene product: a promiscuous transcriptional activator. J. Med. Virol. 36:101117.
144. Saldanha, J.,, W. Gerlich,, N. Lelie,, P. Dawson,, K. Heermann, and, A. Heath. 2001. An international collaborative study to establish a World Health Organization international standard for hepatitis B virus DNA nucleic acid amplification techniques. Vox Sang. 80:6371.
145. Schaefer, S. 2007. Hepatitis B virus taxonomy and hepatitis B virus genotypes. World J. Gastroenterol. 13:1421.
146. Schiff, E.,, C.-L. Lai,, S. Hadziyannis,, P. Neuhaus,, N. Terrault,, M. Colombo,, H. Tillmann,, D. Samuel,, S. Zeuzem,, J.-P. Villeneuve,, S. Arterburn,, K. Borroto-Esoda,, C. Brosgart, and, S. Chuck for the Adefovir Dipivoxil Study 435 International Investigators Group. 2007. Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B: final long-term results. Liver Transplant. 13:349360.
147. Schlicht, H.,, R. Bartenschlager, and, H. Schaller. 1991. Biosynthesis and enzymatic functions of the hepadnaviral reverse transcriptase, p. 171–180. In A. McLachlan (ed.), Molecular Biology of the Hepatitis B Viruses. CRC Press, Boca Raton, FL.
148. Schreiber, G. B.,, M. P. Busch,, S. H. Kleinman, and J. J. Korelitz for The Retrovirus Epidemiology Donor Study. 1996. The risk of transfusion-transmitted viral infections. N. Engl. J. Med. 334:16851690.
149. Shaw, T.,, and S. Locarnini. 2004. Entecavir for the treatment of chronic hepatitis B. Expert Rev. Anti-Infect. Ther. 2:853871.
150. Sherlock, S. 1987. The natural history of hepatitis B. Postgrad. Med. J. 63(Suppl. 2):711.
151. Sherman, M.,, C. Yurdaydin,, J. Sollano,, M. Silva,, Y. F. Liaw,, J. Cianciara,, A. Boron-Kaczmarska,, P. Martin,, Z. Goodman,, R. Colonno,, A. Cross,, G. Denisky,, B. Kreter, and, R. Hindes. 2006. Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B. Gastroenterology 130:20392049.
152. Starzl, T. E.,, A. J. Demetris, and, D. Van Thiel. 1989. Liver transplantation (1). N. Engl. J. Med. 321:10141022.
153. Stephan, W.,, A. M. Prince, and, B. Brotman. 1984. Modulation of hepatitis B infection by intravenous application of an immunoglobulin preparation that contains antibodies to hepatitis B e and core antigens but not to hepatitis B surface antigen. J. Virol. 51:420424.
154. Stevens, C. E.,, R. P. Beasley,, J. Tsui, and, W. C. Lee. 1975. Vertical transmission of hepatitis B antigen in Taiwan. N. Engl. J. Med. 292:771774.
155. Stevens, C. E.,, P. T. Toy,, M. J. Tong,, P. E. Taylor,, G. N. Vyas,, P. V. Nair,, M. Gudavalli, and, S. Krugman. 1985. Perinatal hepatitis B virus transmission in the United States. Prevention by passive-active immunization. JAMA 253:17401745.
156. Stuyver, L.,, S. De Gendt,, C. Van Geyt,, F. Zoulim,, M. Fried,, R. F. Schinazi, and, R. Rossau. 2000. A new genotype of hepatitis B virus: complete genome and phylogenetic relatedness. J. Gen. Virol. 81:6774.
157. Stuyver, L. J.,, S. A. Locarnini,, A. Lok,, D. D. Richman,, W. F. Carman,, J. L. Dienstag, and, R. F. Schinazi. 2001. Nomenclature for antiviral-resistant human hepatitis B virus mutations in the polymerase region. Hepatology 33:751757.
158. Sugiyama, M.,, Y. Tanaka,, T. Kato,, E. Orito,, K. Ito,, S. K. Acharya,, R. G. Gish,, A. Kramvis,, T. Shimada,, N. Izumi,, M. Kaito,, Y. Miyakawa, and, M. Mizokami. 2006. Influence of hepatitis B virus genotypes on the intra- and extracellular expression of viral DNA and antigens. Hepatology 44:915924.
159. Sumi, H.,, O. Yokosuka,, N. Seki,, M. Arai,, F. Imazeki,, T. Kurihara,, T. Kanda,, K. Fukai,, M. Kato, and, H. Saisho. 2003. Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease. Hepatology 37:1926.
160. Tenney, D. J.,, S. M. Levine,, R. E. Rose,, A. W. Walsh,, S. P. Weinheimer,, L. Discotto,, M. Plym,, K. Pokornowski,, C. F. Yu,, P. Angus,, A. Ayres,, A. Bartholomeusz,, W. Sievert,, G. Thompson,, N. Warner,, S. Locarnini, and, R. J. Colonno. 2004. Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to lamivudine. Antimicrob. Agents Chemother. 48:34983507.
161. Thibault, V.,, C. Aubron-Olivier,, H. Agut, and, C. Katlama. 2002. Primary infection with a lamivudine-resistant hepatitis B virus. AIDS 16:131133.
162. Thimme, R.,, S. Wieland,, C. Steiger,, J. Ghrayeb,, K. A. Reimann,, R. H. Purcell, and, F. V. Chisari. 2003. CD8+ T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J. Virol. 77:6876.
163. Thio, C. L.,, and S. Locarnini. 2007. Treatment of HIV/HBV coinfection: clinical and virologic issues. AIDS Rev. 9:4053.
164. Thio, C. L.,, E. C. Seaberg,, R. Skolasky, Jr.,, J. Phair,, B. Visscher,, A. Munoz, and, D. L. Thomas. 2002. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet 360:19211926.
165. Thompson, A. J. V.,, D. S. Preiss,, X. Chen,, P. Revill,, P. Desmond,, K. Visvanathan, and, S. A. Locarnini. 2006. Hepatocyte interleukin-1 receptor and toll-like receptor signalling: effects on HBV replication in vitro. Hepatology 44:537A.
166. Tillmann, H. L.,, J. Hadem,, L. Leifeld,, K. Zachou,, A. Canbay,, C. Eisenbach,, I. Graziadei,, J. Encke,, H. Schmidt,, W. Vogel,, A. Schneider,, U. Spengler,, G. Gerken,, G. N. Dalekos,, H. Wedemeyer, and, M. P. Manns. 2006. Safety and efficacy of lamivudine in patients with severe acute or fulminant hepatitis B, a multicenter experience. J. Viral Hepat. 13:256263.
167. Torresi, J.,, L. Earnest-Silveira,, G. Deliyannis,, K. Edgtton,, H. Zhuang,, S. A. Locarnini,, J. Fyfe,, T. Sozzi, and, D. C. Jackson. 2002. Reduced antigenicity of the hepatitis B virus HBsAg protein arising as a consequence of sequence changes in the overlapping polymerase gene that are selected by lamivudine therapy. Virology 293:305313.
168. Trojan, J.,, M. Stuermer,, G. Teuber,, A. Berger, and, D. Faust. 2007. Treatment of patients with lamivudine-resistant and adefovir dipivoxil-resistant chronic hepatitis B virus infection: is tenofovir the answer? Gut 56:436437. (Author’s reply, 56: 437.)
169. Tron, F.,, F. Degos,, C. Brechot,, A. M. Courouce,, A. Goudeau,, F. N. Marie,, P. Adamowicz,, P. Saliou,, A. Laplanche,, J. P. Benhamou, and, M. Girard. 1989. Randomized dose range study of a recombinant hepatitis B vaccine produced in mammalian cells and containing the S and Pre-S2 sequences. J. Infect. Dis. 160:199204.
170. Truant, R.,, J. Antunovic,, J. Greenblatt,, C. Prives, and, J. A. Cromlish. 1995. Direct interaction of the hepatitis B virus HBx protein with p53 leads to inhibition by HBx of p53 response element-directed transactivation. J. Virol. 69:18511859.
171. Van Bommel, F.,, A. Schernick,, U. Hopf, and, T. Berg. 2003. Tenofovir disoproxil fumarate exhibits strong antiviral effect in a patient with lamivudine-resistant severe hepatitis B reactivation. Gastroenterology 124:586587.
172. van Bommel, F.,, B. Zollner,, C. Sarrazin,, U. Spengler,, D. Huppe,, B. Moller,, H. H. Feucht,, B. Wiedenmann, and, T. Berg. 2006. Tenofovir for patients with lamivudine-resistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy. Hepatology 44:318325.
173. van Zonneveld, M.,, P. Honkoop,, B. E. Hansen,, H. G. Niesters,, S. D. Murad,, R. A. de Man,, S. W. Schalm, and, H. L. Janssen. 2004. Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B. Hepatology 39:804810.
174. Verhelst, D.,, M. Monge,, J. L. Meynard,, B. Fouqueray,, B. Mougenot,, P. M. Girard,, P. Ronco, and, J. Rossert. 2002. Fanconi syndrome and renal failure induced by tenofovir: a first case report. Am. J. Kidney Dis. 40:13311333.
175. Villeneuve, J. P.,, L. D. Condreay,, B. Willems,, G. Pomier-Layrargues,, D. Fenyves,, M. Bilodeau,, R. Leduc,, K. Peltekian,, F. Wong,, M. Margulies, and, E. J. Heathcote. 2000. Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B. Hepatology 31:207210.
176. Visvanathan, K.,, N. A. Skinner,, A. J. Thompson,, S. M. Riordan,, V. Sozzi,, R. Edwards,, S. Rodgers,, J. Kurtovic,, J. Chang,, S. Lewin,, P. Desmond, and, S. Locarnini. 2007. Regulation of Toll-like receptor-2 expression in chronic hepatitis B by the precore protein. Hepatology 45:102110.
177. Volz, T.,, M. Lutgehetmann,, P. Wachtler,, A. Jacob,, A. Quaas,, J. M. Murray,, M. Dandri, and, J. Petersen. 2007. Impaired intrahepatic hepatitis B virus productivity contributes to low viremia in most HBeAg-negative patients. Gastroenterology 133:843852.
178. Wachs, M. E.,, W. J. Amend,, N. L. Ascher,, P. N. Bretan,, J. Emond,, J. R. Lake,, J. S. Melzer,, J. P. Roberts,, S. J. Tomlanovich,, F. Vincenti, and, P. Stock. 1995. The risk of transmission of hepatitis B from HBsAg(–), HBcAb(+), HBIgM(–) organ donors. Transplantation 59:230234.
179. Wang, X. W.,, K. Forrester,, H. Yeh,, M. A. Feitelson,, J. R. Gu, and, C. C. Harris. 1994. Hepatitis B virus X protein inhibits p53 sequence-specific DNA binding, transcriptional activity, and association with transcription factor ERCC3. Proc. Natl. Acad. Sci. USA 91:22302234.
180. Wang, X. W.,, M. K. Gibson,, W. Vermeulen,, H. Yeh,, K. Forrester,, H. W. Sturzbecher,, J. H. Hoeijmakers, and, C. C. Harris. 1995. Abrogation of p53-induced apoptosis by the hepatitis B virus X gene. Cancer Res. 55:60126016.
181. Warner, N.,, S. Locarnini, and, D. Colledge. 2004. Molecular modeling of entecavir resistant mutations in the hepatitis B polymerase selected during therapy. Hepatology 40:245A.
182. Wasley, A.,, J. T. Miller, and, L. Finelli. 2007. Surveillance for acute viral hepatitis—United States, 2005. Morb. Mortal. Wkly. Rep. Surveill. Summ. 56:124.
183. Webster, G. J.,, S. Reignat,, D. Brown,, G. S. Ogg,, L. Jones,, S. L. Seneviratne,, R. Williams,, G. Dusheiko, and, A. Bertoletti. 2004. Longitudinal analysis of CD8+ T cells specific for structural and nonstructural hepatitis B virus proteins in patients with chronic hepatitis B: implications for immunotherapy. J. Virol. 78:57075719.
184. Webster, G. J.,, S. Reignat,, M. K. Maini,, S. A. Whalley,, G. S. Ogg,, A. King,, D. Brown,, P. L. Amlot,, R. Williams,, D. Vergani,, G. M. Dusheiko, and, A. Bertoletti. 2000. Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms. Hepatology 32:11171124.
185. Werle-Lapostolle, B.,, S. Bowden,, S. Locarnini,, K. Wursthorn,, J. Petersen,, G. Lau,, C. Trepo,, P. Marcellin,, Z. Goodman,, W. E. Delaney IV,, S. Xiong,, C. L. Brosgart,, S. S. Chen,, C. S. Gibbs, and, F. Zoulim. 2004. Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy. Gastroenterology 126:17501758.
186. Whalley, S. A.,, J. M. Murray,, D. Brown,, G. J. Webster,, V. C. Emery,, G. M. Dusheiko, and, A. S. Perelson. 2001. Kinetics of acute hepatitis B virus infection in humans. J. Exp. Med. 193:847854.
187. Wieland, S.,, R. Thimme,, R. H. Purcell, and, F. V. Chisari. 2004. Genomic analysis of the host response to hepatitis B virus infection. Proc. Natl. Acad. Sci. USA 101:66696674.
188. Wieland, S. F.,, and F. V. Chisari. 2005. Stealth and cunning: hepatitis B and hepatitis C viruses. J. Virol. 79:93699380.
189. Will, H.,, W. Reiser,, T. Weimer,, E. Pfaff,, M. Buscher,, R. Sprengel,, R. Cattaneo, and, H. Schaller. 1987. Replication strategy of human hepatitis B virus. J. Virol. 61:904911.
190. Wong, D. K.,, A. M. Cheung,, K. O’Rourke,, C. D. Naylor,, A. S. Detsky, and, J. Heathcote. 1993. Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis. Ann. Intern. Med. 119:312323.
191. Wursthorn, K.,, M. Lutgehetmann,, M. Dandri,, T. Volz,, P. Buggisch,, B. Zollner,, T. Longerich,, P. Schirmacher,, F. Metzler,, M. Zankel,, C. Fischer,, G. Currie,, C. Brosgart, and, J. Petersen. 2006. Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B. Hepatology 44:675684.
192. Yap, I.,, and S. H. Chan. 1996. A new pre-S containing recombinant hepatitis B vaccine and its effect on nonresponders: a preliminary observation. Ann. Acad. Med. Singap. 25:120122.
193. Yeo, W.,, and P. J. Johnson. 2006. Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy. Hepatology 43:209220.
194. Yim, H. J.,, M. Hussain,, Y. Liu,, S. N. Wong,, S. K. Fung, and, A. S. Lok. 2006. Evolution of multi-drug resistant hepatitis B virus during sequential therapy. Hepatology 44:703712.
195. Yim, H. J.,, and A. S. Lok. 2006. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in 2005. Hepatology 43:S173S181.
196. Ying, R. S.,, C. Zhu,, X. G. Fan,, N. Li,, X. F. Tian,, H. B. Liu, and, B. X. Zhang. 2007. Hepatitis B virus is inhibited by RNA interference in cell culture and in mice. Antivir. Res. 73:2430.
197. Yu, M. W.,, S. H. Yeh,, P. J. Chen,, Y. F. Liaw,, C. L. Lin,, C. J. Liu,, W. L. Shih,, J. H. Kao,, D. S. Chen, and, C. J. Chen. 2005. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men. J. Natl. Cancer Inst. 97:265272.
198. Yuen, M. F.,, H. J. Yuan,, D. K. Wong,, J. C. Yuen,, W. M. Wong,, A. O. Chan,, B. C. Wong,, K. C. Lai, and, C. L. Lai. 2005. Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications. Gut 54:16101614.
199. Zakaria, S.,, R. Fouad,, O. Shaker,, S. Zaki,, A. Hashem,, S. S. El-Kamary, and, G. Esmat. 2007. Changing patterns of acute viral hepatitis at a major urban referral center in Egypt. Clin. Infect. Dis. 44:e30e36.
200. Zoulim, F.,, J. Saputelli, and, C. Seeger. 1994. Woodchuck hepatitis virus X protein is required for viral infection in vivo. J. Virol. 68:20262030.
201. Zoulim, F.,, and C. Seeger. 1994. Reverse transcription in hepatitis B viruses is primed by a tyrosine residue of the polymerase. J. Virol. 68:613.


Generic image for table

Taxonomy of

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31
Generic image for table

Overview of the eight genotypes of HBV

Citation: Thompson A, Bell S, Locarnini S. 2009. Hepatitis B Virus, p 673-707. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch31
Generic image for table

Profile of serologic markers for HBV infection