The Risk Of Transmission Of Hepatitis B From Hbsag(-), Hbcab(+), Hbigm(-) Organ Donors

Wachs, Michael; Amend, W; Ascher, Nancy L.; Bretan, Peter N.; Emond, Jean C.; Lake, John R.; Melzer, Juliet S.; Roberts, John P.; Tomlanovich, S.; Vincenti, Flavio; Stock, Peter G.

doi:10.1097/00007890-199501000-00014

Cited by 187 publications

(218 citation statements)

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“…32,39,40 These findings are consistent with our earlier reports of SOI continuing for life after termination of acute WHV hepatitis, 30,32,37 along with documented infectivity and liver pathogenic competence of the silently carried virus. 30,32 The current results also agree with the data from the limited studies of apparently healthy individuals reactive for anti-HBc alone or anti-HBc and anti-HBs, which showed presence of HBV cccDNA and HBV RNA in their liver 8,41 and transmission of HBV by liver grafts [15][16][17][18][19][20][21] or blood [42][43][44] to virusnaïve recipients.…”

Section: Discussionsupporting

confidence: 90%

“…This outcome was consistent with the earlier findings of anti-HBc along with HBV DNA in serum and peripheral blood mononuclear cells (PBMC) 12 and a vigorous cytotoxic T-lymphocyte response to HBV antigens in apparently completely healthy individuals years after recovery from acute hepatitis B. 13,14 Moreover, transmission of HBV from blood and organ donors with isolated anti-HBc to virus-naïve individuals 5,[15][16][17][18][19][20][21] and reactivation of the infection in anti-HBc-positive persons 22,23 have been reported. Also, it is perceived that occult HBV infection with or without anti-HBc is associated with an increased risk of developing hepatocellular carcinoma.…”

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confidence: 89%

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Persistence of isolated antibodies to woodchuck hepatitis virus core antigen is indicative of occult infection

et al. 2004

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Antibodies against virus nucleocapsid (anticore) normally accompany hepadnaviral hepatitis but they may also occur in the absence of symptoms and other serological indicators of the infection. This situation can be encountered following a clinically and serologically unapparent exposure to hepatitis B virus (HBV) or after recovery from hepatitis B. In this study, woodchucks inoculated with woodchuck hepatitis virus (WHV) were investigated to determine the relationship between anticore detection and the molecular status of virus replication in a primary WHV surface antigen (WHsAg)-negative infection or long-after resolution of WHV hepatitis. Serial, parallel samples of sera, peripheral blood mononuclear cells (PBMC) and liver tissue, collected for more than 5 years after inoculation with virus, were examined for WHV DNA by highly sensitive polymerase chain reaction (PCR)/nucleic acid hybridization assays. Sera were also tested for WHV DNA after DNase treatment and for WHV DNA and WHsAg after concentration in sucrose. Liver and PBMC were examined for WHV covalently closed circular DNA and viral RNA transcripts by PCR-based techniques to assess virus replication status. The study showed that anticore antibodies existing in the absence of other serological markers are a reliable indicator of occult WHV infection. This state can be accompanied by traces of circulating particles behaving as intact virions and by intermittent minimal-to-mild liver inflammation. In conclusion, the long-term presence of anticore antibodies alone is a consequence of sustained restimulation of the immune system by virus nucleocapsid produced during low-level hepadnaviral assembly. ( A ntibodies to hepatits B virus (HBV) core antigen (anti-HBc) coexist with HBV surface antigen (HBsAg) in symptomatic infection and can persist along with antibodies to HBsAg (anti-HBs) or without them for life after recovery from hepatitis B. 1,2 They may also occur in the pre-acute phase of hepatitis prior to the appearance of HBsAg. 3 Absence of anti-HBc is rare in HBV infection and has been attributed to aberrant immunological response to the virus or to infection with viral variants. The detection of anti-HBc as the only serological marker of HBV exposure ("isolated anti-core" or "anti-core alone") has been found in up to 10%-20% of blood donors in endemic areas. 4,5 Since anti-HBc-like reactivity was occasionally seen after HBV vaccination, this result has raised doubts as to the reliability of antiHBc testing. 6,7 However, individuals with isolated antiHBc showed the highest rates of HBV DNA detection by specific polymerase chain reaction (PCR) assays, 5,8 -11 suggesting ongoing low-level HBV infection despite the absence of classical serological markers. This outcome was consistent with the earlier findings of anti-HBc along with HBV DNA in serum and peripheral blood mononuclear cells (PBMC) 12 and a vigorous cytotoxic T-lymphocyte response to HBV antigens in apparently completely healthy individuals years after recovery from

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Section: Discussionsupporting

confidence: 90%

supporting

confidence: 89%

Persistence of isolated antibodies to woodchuck hepatitis virus core antigen is indicative of occult infection

et al. 2004

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“…This assumption is based on a growing number of observations indicating that HBV infection can appear in recipients of organs from HBV serologically negative donors, [7][8][9][10][11][12] and that hepatocellular carcinoma (HCC) with integrated HBV genomic sequences can arise in HBVseronegative patients 13-15 and animals. 16,17 There is also the likelihood that some individuals who develop subclinical infection after exposure to HBV become serologically silent carriers of virus and a potential source of infection to nonimmune humans.…”

mentioning

confidence: 99%

Occult lifelong persistence of infectious hepadnavirus and residual liver inflammation in woodchucks convalescent from acute viral hepatitis

Michalak

Pardoe²,

Coffin³

et al. 1999

Hepatology

133

322

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Traces of hepatitis B virus (HBV) genome can persist for years following recovery from hepatitis B. To determine overall duration, molecular characteristics, and pathological implications of this serologically undetectable form of hepadnaviral carriage, we have analyzed the expression of transcriptionally active virus genomes, their infectivity, and examined liver alterations during the natural lifespan of woodchucks convalescent from acute infection with HBVrelated woodchuck hepatitis virus (WHV). In this study, we document lifelong persistence of scanty amounts of replicating virus both in the liver and lymphatic system after spontaneous resolution of an episode of experimental hepadnaviral hepatitis. Antibodies to virus nucleocapsid (core) were found to be the most reliable immunovirological marker coexisting with occult infection. In the majority of convalescent woodchucks, serial liver biopsies showed protracted minimal to mild necroinflammation with periods of normal morphology; however, hepatocellular carcinoma (HCC) ultimately developed in 2 of 9 animals studied. Inocula derived from lymphoid cells of convalescent animals induced classical acute hepatitis in virus-naive woodchucks that progressed to chronic hepatitis and HCC in 1 of the animals, demonstrating infectivity and pathogenic competence of the carried virus. Our results reveal that low levels of infectious WHV and residual hepatic inflammation usually continue for life after resolution of hepatitis and that this recovery does not avert HCC development. They also demonstrate that, in addition to the liver, the lymphatic system is the site of the occult lifelong maintenance of replicating hepadnavirus. (HEPATOLOGY 1999;29:928-938.)Current evidence indicates that carriage of minute quantities of hepatitis B virus (HBV) genome can continue for years following complete clinical and serological recovery from acute hepatitis B. 1-5 In these convalescent patients, HBV DNA have been detected both in serum and in circulating lymphomononuclear cells, often despite the presence of neutralizing antibodies to virus envelope (hepatitis B surface antigen) 2,3,5 and a vigorous polyclonal HBV-specific cytotoxic T-cell response. 3,4,6 In addition, traces of hepatitis B surface antigen and HBV-DNA-reactive particles with physicochemical properties of intact virions have been detected in the circulation of some of the recovered individuals. 2 These findings imply that HBV eradication does not coincide with the rise of antivirusspecific humoral and cellular immune responses and with clinical resolution of acute hepatitis.It is expected that this serologically undetectable persistence of HBV may have important epidemiological and pathogenic implications, whose range has yet to be established. This assumption is based on a growing number of observations indicating that HBV infection can appear in recipients of organs from HBV serologically negative donors, [7][8][9][10][11][12] and that hepatocellular carcinoma (HCC) with integrated HBV genomic sequences can arise in ...

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“…1 However, there are clearly documented cases of reactivation of latent viral infection following chemotherapy and immunosuppressive treatment, as well as de novo infection in patients receiving organs from HBsAg-negative donors with serological evidence of previous hepatitis B virus (HBV) infection. [2][3][4][5][6][7] In this setting, the reactivated infection is not entirely unexpected, because most patients who have cleared HBsAg from the serum still have detectable HBV DNA in the liver using the polymerase chain reaction (PCR) methodology. [8][9][10][11][12][13][14] In fact, HBV DNA can also be found in bodily secretions and peripheral blood mononuclear cells from patients with acute and chronic HBV infection after sustained loss of serum HBsAg.…”

mentioning

confidence: 99%

Molecular basis for persistent hepatitis B virus infection in the liver after clearance of serum hepatitis B surface antigen

Mason¹,

Xu²,

Guo³

et al. 1998

Hepatology

195

144

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The clearance of the hepatitis B surface antigen (HBsAg) from serum usually indicates a resolution of biochemical and histological hepatitis in patients with chronic hepatitis B. 1 However, there are clearly documented cases of reactivation of latent viral infection following chemotherapy and immunosuppressive treatment, as well as de novo infection in patients receiving organs from HBsAg-negative donors with serological evidence of previous hepatitis B virus (HBV) infection. [2][3][4][5][6][7] In this setting, the reactivated infection is not entirely unexpected, because most patients who have cleared HBsAg from the serum still have detectable HBV DNA in the liver using the polymerase chain reaction (PCR) methodology. [8][9][10][11][12][13][14] In fact, HBV DNA can also be found in bodily secretions and peripheral blood mononuclear cells from patients with acute and chronic HBV infection after sustained loss of serum HBsAg. [15][16][17] Taken together, these studies suggest that following the loss of HBsAg from serum, HBV persists in a state of low-level replication or in a replication-competent state that can be reactivated to form infectious particles.The natural biology of the latent virus may be further investigated by assessing the transcriptional activity and the molecular form of the persistent HBV DNA. Using in situ hybridization, we were unable to detect hepatic HBV RNA in patients who had cleared serum HBsAg, and other investigators had little success using reverse-transcription (RT) PCR studies because of the inability to completely eradicate tissue HBV DNA. 11 Furthermore, the molecular form of the persistent HBV DNA has proved difficult to define because of the minute quantities of virus found in patients with resolved hepatitis.During chronic infection, HBV DNA can be detected in four predominant molecular forms. Following infection by the intact Dane particle, the partially double-stranded HBV-DNA genome becomes a covalently closed circular (CCC) DNA molecule that acts as a template for transcription of mRNA and the RNA pregenome. The reverse transcription of the RNA pregenome and second-strand HBV DNA synthesis results in low-molecular-weight replicative intermediates, whereas the HBV DNA that integrates into the host' s genome can be detected as high-molecular-weight species on Southern blot. 18,19 Similar to retroviral integration at the site of the long terminal repeats, HBV DNA generally inserts into DNA flanked by the direct repeat regions, which share sequence homology with the U5 region of murine leukemia virus long terminal repeats. [20][21][22] The genomic organization of the HBV direct repeat region provides a potential strategy for the detection of replicating virus when only minute quantities of HBV DNA are present (Fig. 1). Using PCR primers flanking the direct repeat region, the CCC HBV DNA can be amplified using PCR. In contrast, the HBV DNA within the Dane particle is incomplete, and integrated HBV DNA is usually, but not always, disrupted in the direct repeat region (Fig. 1). Th...

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The Risk Of Transmission Of Hepatitis B From Hbsag(-), Hbcab(+), Hbigm(-) Organ Donors

Cited by 187 publications

References 0 publications

Persistence of isolated antibodies to woodchuck hepatitis virus core antigen is indicative of occult infection

Persistence of isolated antibodies to woodchuck hepatitis virus core antigen is indicative of occult infection

Occult lifelong persistence of infectious hepadnavirus and residual liver inflammation in woodchucks convalescent from acute viral hepatitis

Molecular basis for persistent hepatitis B virus infection in the liver after clearance of serum hepatitis B surface antigen

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