Hepatitis B virus DNA in the sera of HBsAg carriers: A marker of active hepatitis B virus replication in the liver

Bonino, Ferruccio; Hoyer, Bill H.; Nelson, Judith E.; Engle, Ronald E.; Verme, G; Gerin, John L.

doi:10.1002/hep.1840010503

Cited by 278 publications

(110 citation statements)

References 33 publications

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“…Furthermore, our findings confirm and expand results of investigations using the conventional hybridisation assay for the detection of HBV DNA. These earlier studies showed that viral replication, as demonstrated by the presence of viral DNA in the circulation, is correlated with the presence of HBeAg and with symptomatic liver disease [Bonino et al, 1981;Berninger et al, 1982;Scotto et al, 1983;Zyzik et al, 19861. Our data fit well into this pattern. All HBeAg-positive individuals tested were indeed also DNA positive, although they were apparently asymptomatic.…”

Section: Discussionmentioning

confidence: 99%

“…The hepatitis B e antigen (HBeAg) is a clearly better but also indirect marker for the presence of virus in the blood. By far the best diagnostic parameter in this respect is the viral DNA, which can be detected by a sensitive direct hybridisation assay [Bonino et al, 1981;Berninger et al, 19821. The introduction of this test was one of the major improvements for the diagnosis of hepatitis B.…”

Section: Introductionmentioning

confidence: 99%

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Detection of hepatitis B virus in serum using amplification of viral DNA by means of the polymerase chain reaction

Sumazaki

Motz

Wolf

et al. 1989

Journal of Medical Virology

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A new assay was developed for the detection of hepatitis B virus (HBV) in human serum using amplification of a short viral DNA sequence by means of the polymerase chain reaction. As little as 0.4 fg viral DNA, corresponding to about 130 genome equivalents, per ml serum could be detected after the amplification procedure. This assay detected viral DNA in a number of patients with proven or suspected chronic HBV infection who were all negative for HBV DNA in the conventional hybridisation assay. We found HBV DNA in all of six HBeAg-positive and in three of eight HBeAg-negative HBsAg carriers, as well as in all of 11 patients with chronic liver disease with antibodies against the HBV core antigen (anti-HBc) as the sole marker for HBV infection, and in three of five apparently healthy individuals showing only anti HBc. Thus, this method is an important improvement for the diagnosis of persistent HBV infections, especially in patients where a definitive serological diagnosis is not possible.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Detection of hepatitis B virus in serum using amplification of viral DNA by means of the polymerase chain reaction

Sumazaki

Motz

Wolf

et al. 1989

Journal of Medical Virology

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“…3 In the early 1980s it became apparent that HBV could replicate in the absence of HBeAg. [4][5][6] Patients from the Mediterranean area, although negative for HBeAg and positive for antibodies to HBeAg (anti-HBe), were reported to have CHB with replicating HBV. 7 The term anti-HBe-positive or HBeAgnegative CHB was then proposed 4 and subsequently became widely accepted.…”

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confidence: 99%

Hepatitis B e antigen-negative chronic hepatitis B

2001

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Thirty years ago, the diagnosis of chronic hepatitis B (CHB) was thought to require the presence of hepatitis B e antigen (HBeAg), as a reliable and sensitive marker of hepatitis B virus (HBV) replication. 1 Individuals positive for hepatitis B surface antigen (HBsAg) but negative for HBeAg were considered to have nonreplicative HBV infection, and if their liver enzymes were normal or nearly normal they were referred to as asymptomatic or healthy HBsAg or HBV carriers. 2 If, on the other hand, they displayed elevated serum aminotransferases and liver histology indicative of chronic hepatitis, they were generally thought to be suffering from other superimposed or complicating conditions such as hepatitis D virus infection, alcohol-induced, metabolic, autoimmune, drug-induced, or other forms of chronic liver disease. 3 In the early 1980s it became apparent that HBV could replicate in the absence of HBeAg. [4][5][6] Patients from the Mediterranean area, although negative for HBeAg and positive for antibodies to HBeAg (anti-HBe), were reported to have CHB with replicating HBV. 7 The term anti-HBe-positive or HBeAgnegative CHB was then proposed 4 and subsequently became widely accepted. In 1989 the molecular basis of this form of CHB was discovered 8,9 with the identification of HBV mutations preventing HBeAg formation from an otherwise normally replicating HBV. 10,11 With time, it became apparent that HBeAg-negative CHB, initially viewed as an atypical and rare form of CHB mainly restricted in the Mediterranean area, had a much wider geographical distribution and that its frequency was increasing. 12 Its molecular virology and immunology were found to be more complex than initially thought, 13 whereas the selection of precore HBV mutants was shown to be largely determined by the HBV genotype. 14 Mutations abolishing or diminishing HBeAg formation were identified along with changes in other parts of the HBV genome. 14 More recently, the new nucleoside analog, lamivudine, has been used to treat a sizeable number of patients with HBeAg-negative CHB, and important information on its efficacy and the development of resistance has been collected. [15][16][17][18] DEFINITION AND NOMENCLATUREThe term HBeAg-negative CHB defines the condition as disease caused by strains of HBV that are not producing HBeAg. 12 It does not specify the mutations responsible for the lack of HBeAg, i.e., a precore stop-codon mutation, 10 a double basic core promoter (BCP) mutation, or other, 14 and it says nothing about the level of HBV replication. The alternative term "precore mutant CHB," used by some investigators, also does not specify the nature of the precore mutation. In clinical practice, the term HBeAg-negative CHB is appropriate for patients with chronic HBV infection who test negative for HBeAg, are usually positive for anti-HBe, have increased alanine aminotransferase (ALT) levels and display detectable HBV DNA in serum by classical hybridization techniques. 12 Despite the fact that the identification of the underlying mutations in ...

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“…The following connections have been found. (i) When hepatitis B e antigen (HBeAg), which is part of HBcAg (Ohori et al, 1979; Mackay et al, 1981), is detectable in serum, Dane particles, HBV-specific DNA polymerase and DNA are demonstrable in the serum (Nordenfelt & Kjellen, 1975;Imai et al, 1976;Ohori et al, 1980) and HBcAg and HBV DNA in liver tissues (Bonino et al, 1981;Hadziyannis et al, 1983). (ii) The localization of HBcAg in hepatocytes varies even in the same tissue (Gudat et al, 1975;Yamada & Nakane, 1977; Huang & Neurath, 1979).…”

mentioning

confidence: 99%

Relationship between the Replication of Hepatitis B Virus and the Localization of Virus Nucleocapsid Antigen (HBcAg) in Hepatocytes

Akiba¹,

Nakayama

Miyazaki

et al. 1987

Journal of General Virology

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SUMMARYAccording to the localization of hepatitis B virus (HBV) core antigen (HBcAg), detected by the avidin biotin complex method, infected hepatocytes were classified into three types, i.e. those having nuclear (type I), nuclear and cytoplasmic (type II) or only cytoplasmic (type III) antigen. HBcAg-positive hepatocytes of all specimens (three) from non-specific reactive hepatitis and of most (five of seven) from chronic persistent hepatitis (CPH) patients were only type I; the other two CPH samples and all (seven) chronic active hepatitis samples were composed of a mixture of types I, II and III. Linear correlations between the frequency of type I, as well as that of all types (I, II and III) of the HBcAg-positive hepatocytes, and the amount of HBV DNA in serum were found. The relative HBV production of HBcAg-positive hepatocytes (serum HBV DNA amount/frequency of HBcAg-positive cells) was 0.11 in type I and 0-07 in all hepatocytes including types I, II and III. HBV core particles and complete HBV particles were found in type I hepatocytes. On the other hand, these particles were not found in a predominantly type III liver specimen. These results suggest that type I hepatocytes are more involved in the propagation of HBV than types II and III.Several immunological, histological and biochemical studies on the relationship between the expression of hepatitis B virus (HBV)-related antigens, especially of HBV core antigen (HBcAg), and viral replication have been performed using serum and liver tissues from patients with type B hepatitis. The following connections have been found. (i) When hepatitis B e antigen (HBeAg), which is part of HBcAg (Ohori et al., 1979; Mackay et al., 1981), is detectable in serum, Dane particles, HBV-specific DNA polymerase and DNA are demonstrable in the serum (Nordenfelt & Kjellen, 1975;Imai et al., 1976;Ohori et al., 1980) and HBcAg and HBV DNA in liver tissues (Bonino et al., 1981;Hadziyannis et al., 1983). (ii) The localization of HBcAg in hepatocytes varies even in the same tissue (Gudat et al., 1975;Yamada & Nakane, 1977; Huang & Neurath, 1979). However, because conflicting results have been obtained in studies of the localization of HBcAg and the presence of HBV DNA in hepatocytes, valid conclusions about the correlation between HBV replication and HBcAg expression in hepatocytes can not yet be drawn (Blum et al., 1984;Burrell et al., 1985).In the present study, we have examined staining conditions for the detection of HBcAg, and classified the HBcAg-positive hepatocytes with respect to the localization of this antigen in liver tissues from patients whose sera were positive for HBeAg. The amount of HBV DNA in serum was determined and electron microscopic observations were made. These results are discussed with regard to virus replication in the three types of hepatocyte. t Present address:

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Hepatitis B virus DNA in the sera of HBsAg carriers: A marker of active hepatitis B virus replication in the liver

Cited by 278 publications

References 33 publications

Detection of hepatitis B virus in serum using amplification of viral DNA by means of the polymerase chain reaction

Detection of hepatitis B virus in serum using amplification of viral DNA by means of the polymerase chain reaction

Hepatitis B e antigen-negative chronic hepatitis B

Relationship between the Replication of Hepatitis B Virus and the Localization of Virus Nucleocapsid Antigen (HBcAg) in Hepatocytes

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