Chronic hepatitis B(CHB) is a major global health problem affecting an estimated 350 million people with more than 786000 individuals dying annually due to complications, such as cirrhosis, liver failure and hepatocel...Chronic hepatitis B(CHB) is a major global health problem affecting an estimated 350 million people with more than 786000 individuals dying annually due to complications, such as cirrhosis, liver failure and hepatocellular carcinoma(HCC). Liver transplantation(LT) is considered gold standard for treatment of hepatitis B virus(HBV)-related liver failure and HCC. However, post-transplant viral reactivation can be detrimental to allograft function, leading to poor survival. Prophylaxis with high-dose hepatitis B immunoglobulin(HBIG) and anti-viral drugs have achieved remarkable progress in LT by suppressingviral replication and improving long-term survival. The combination of lamivudine(LAM) plus HBIG has been for many years the most widely used. However, life-long HBIG use is both cumbersome and costly, whereas long-term use of LAM results in resistant virus. Recently, in an effort to develop HBIG-free protocols, high potency nucleos(t)ide analogues, such as Entecavir or Tenofovir, have been tried either as monotherapy or in combination with low-dose HBIG with excellent results. Current focus is on novel antiviral targets, especially for covalently closed circular DNA(ccc DNA), in an effort to eradicate HBV infection instead of viral suppression. However, there are several other molecular mechanisms through which HBV may reactivate and need equal attention. The purpose of this review is to address post-LT HBV reactivation, its risk factors, underlying molecular mechanisms, and recent advancements and future of anti-viral therapy.展开更多
Hepatitis B virus (HBV) is a highly pathogenic virus that causes chronic liver diseases in millions of people globally. In addition to a symptomatic, serologically evident infection, occult persistent HBV carriage has...Hepatitis B virus (HBV) is a highly pathogenic virus that causes chronic liver diseases in millions of people globally. In addition to a symptomatic, serologically evident infection, occult persistent HBV carriage has been identified since nucleic acid amplification assays of enhanced sensitivity became introduced for detection of hepadnaviral genomes and their replicative intermediates. Current evidence indicates that occult HBV infection is a common and long-term consequence of resolution of acute hepatitis B. This form of residual infection is termed as secondary occult infection (SOI). The data from the woodchuck model of HBV infection indicate that exposure to small amounts of hepadnavirus can also cause primary occult infection (POI) where virus genome, but no serological makers of exposure to virus, are detectable, and the liver may not be involved. However, virus replicates at low levels in the lymphatic system in both these forms. We briefly summarize the current understanding of the nature and characteristics of occult hepadnaviral persistence as well as of its documented and expected pathological consequences.展开更多
Recent discovery of occult hepatitis C virus (HCV) infection persisting after spontaneous or antiviral therapy-induced resolution of hepatitis C was made possible by the introduction of nucleic acid amplification assa...Recent discovery of occult hepatitis C virus (HCV) infection persisting after spontaneous or antiviral therapy-induced resolution of hepatitis C was made possible by the introduction of nucleic acid amplification assays capable of detecting HCV RNA at sensitivities superseding those offered by clinical tests. Although individuals with this seemingly silent HCV infection are usually anti-HCV antibody reactive and have normal liver function tests, occult HCV infection has also been reported in anti-HCV-negative individuals with persistently elevated liver enzymes of unknown etiology. Studies have shown that HCV RNA can persist for years in serum, lymphomononuclear cells and liver in the absence of clinical symptoms, although histological evidence of a mild inflammatory liver injury can be occasionally encountered. Furthermore, while HCV RNA can be detected in circulating lymphoid cells in approximately 30% of cases, a short-term culture under stimulatory conditions augments HCV replication in these cells allowing detection of virus in otherwise HCV-negative cases. HCV infects different immune cell subsets, including CD4+ and CD8+ T lymphocytes, B cells and monocytes. Studies employing clonal sequencing and single-stranded conformational polymorphism analyses have revealed unique HCV variants residing in immune cells, further strengthening the notion of HCV lymphotropism. Overall, the data accumulated suggest that occult HCV infection is a common consequence of resolution of symptomatic hepatitis C and that examination of the cells of the immune system is an effective approach to diagnosis of HCV infection and its long-term persistence. Further work is required to fully realize pathogenic and epidemiological consequences of occult HCV persistence.展开更多
Woodchuck hepatitis virus (WHV) is molecularly and pathogenically closely related to hepatitis B virus (HBV).Both viruses display tropism towards hepatocytes and cells of the immune system and cause similar liver path...Woodchuck hepatitis virus (WHV) is molecularly and pathogenically closely related to hepatitis B virus (HBV).Both viruses display tropism towards hepatocytes and cells of the immune system and cause similar liver pathology,where acute hepatitis can progress to chronic hepatitis and to hepatocellular carcinoma (HCC).Two forms of occult hepadnaviral persistence were identified in the woodchuck-WHV model:secondary occult infection (SOI) and primary occult infection (POI).SOI occurs after resolution of a serologically apparent infection with hepatitis or after subclinical serologically evident virus exposure.POI is caused by small amounts of virus and progresses without serological infection markers,but the virus genome and its replication are detectable in the immune system and with time in the liver.SOI can be accompanied by minimal hepatitis,while the hallmark of POI is normal liver morphology.Nonetheless,HCC develops in about 20% of animals with SOI or POI within 3 to 5 years.The virus persists throughout the lifespan in both SOI and POI at serum levels rarely greater than 100 copies/mL,causes hepatitis and HCC when concentrated and administered to virus-na(i)ve woodchucks.SOI is accompanied by virusspecific T and B cell immune responses,while only virusspecific T cells are detected in POI.SOI coincides with protection against reinfection,while POI does not and hepatitis develops after challenge with liver pathogenic doses >1000 virions.Both SOI and POI are associated with virus DNA integration into the liver and the immune system genomes.Overall,SOI and POI are two distinct forms of silent hepadnaviral persistence that share common characteristics.Here,we review findings from the woodchuck model and discuss the relevant observations made in human occult HBV infection (OBI).展开更多
基金the Canadian Cancer Society, Environment-Cancer Fundthe Canadian Institutes of Health Research for operating research grant support
文摘Chronic hepatitis B(CHB) is a major global health problem affecting an estimated 350 million people with more than 786000 individuals dying annually due to complications, such as cirrhosis, liver failure and hepatocellular carcinoma(HCC). Liver transplantation(LT) is considered gold standard for treatment of hepatitis B virus(HBV)-related liver failure and HCC. However, post-transplant viral reactivation can be detrimental to allograft function, leading to poor survival. Prophylaxis with high-dose hepatitis B immunoglobulin(HBIG) and anti-viral drugs have achieved remarkable progress in LT by suppressingviral replication and improving long-term survival. The combination of lamivudine(LAM) plus HBIG has been for many years the most widely used. However, life-long HBIG use is both cumbersome and costly, whereas long-term use of LAM results in resistant virus. Recently, in an effort to develop HBIG-free protocols, high potency nucleos(t)ide analogues, such as Entecavir or Tenofovir, have been tried either as monotherapy or in combination with low-dose HBIG with excellent results. Current focus is on novel antiviral targets, especially for covalently closed circular DNA(ccc DNA), in an effort to eradicate HBV infection instead of viral suppression. However, there are several other molecular mechanisms through which HBV may reactivate and need equal attention. The purpose of this review is to address post-LT HBV reactivation, its risk factors, underlying molecular mechanisms, and recent advancements and future of anti-viral therapy.
基金operating research grants from the Canadian Institutes of Health Research, Canada and the Canada Research Chair Program, and the Canada Foundation for Innovation
文摘Hepatitis B virus (HBV) is a highly pathogenic virus that causes chronic liver diseases in millions of people globally. In addition to a symptomatic, serologically evident infection, occult persistent HBV carriage has been identified since nucleic acid amplification assays of enhanced sensitivity became introduced for detection of hepadnaviral genomes and their replicative intermediates. Current evidence indicates that occult HBV infection is a common and long-term consequence of resolution of acute hepatitis B. This form of residual infection is termed as secondary occult infection (SOI). The data from the woodchuck model of HBV infection indicate that exposure to small amounts of hepadnavirus can also cause primary occult infection (POI) where virus genome, but no serological makers of exposure to virus, are detectable, and the liver may not be involved. However, virus replicates at low levels in the lymphatic system in both these forms. We briefly summarize the current understanding of the nature and characteristics of occult hepadnaviral persistence as well as of its documented and expected pathological consequences.
文摘Recent discovery of occult hepatitis C virus (HCV) infection persisting after spontaneous or antiviral therapy-induced resolution of hepatitis C was made possible by the introduction of nucleic acid amplification assays capable of detecting HCV RNA at sensitivities superseding those offered by clinical tests. Although individuals with this seemingly silent HCV infection are usually anti-HCV antibody reactive and have normal liver function tests, occult HCV infection has also been reported in anti-HCV-negative individuals with persistently elevated liver enzymes of unknown etiology. Studies have shown that HCV RNA can persist for years in serum, lymphomononuclear cells and liver in the absence of clinical symptoms, although histological evidence of a mild inflammatory liver injury can be occasionally encountered. Furthermore, while HCV RNA can be detected in circulating lymphoid cells in approximately 30% of cases, a short-term culture under stimulatory conditions augments HCV replication in these cells allowing detection of virus in otherwise HCV-negative cases. HCV infects different immune cell subsets, including CD4+ and CD8+ T lymphocytes, B cells and monocytes. Studies employing clonal sequencing and single-stranded conformational polymorphism analyses have revealed unique HCV variants residing in immune cells, further strengthening the notion of HCV lymphotropism. Overall, the data accumulated suggest that occult HCV infection is a common consequence of resolution of symptomatic hepatitis C and that examination of the cells of the immune system is an effective approach to diagnosis of HCV infection and its long-term persistence. Further work is required to fully realize pathogenic and epidemiological consequences of occult HCV persistence.
基金The studies were supported by operating grants MA-9256,MT-11262,RO-15174 and MOP-14818 from the Canadian Institutes of Health Researchformerly the Medical Research Council of Canada
文摘Woodchuck hepatitis virus (WHV) is molecularly and pathogenically closely related to hepatitis B virus (HBV).Both viruses display tropism towards hepatocytes and cells of the immune system and cause similar liver pathology,where acute hepatitis can progress to chronic hepatitis and to hepatocellular carcinoma (HCC).Two forms of occult hepadnaviral persistence were identified in the woodchuck-WHV model:secondary occult infection (SOI) and primary occult infection (POI).SOI occurs after resolution of a serologically apparent infection with hepatitis or after subclinical serologically evident virus exposure.POI is caused by small amounts of virus and progresses without serological infection markers,but the virus genome and its replication are detectable in the immune system and with time in the liver.SOI can be accompanied by minimal hepatitis,while the hallmark of POI is normal liver morphology.Nonetheless,HCC develops in about 20% of animals with SOI or POI within 3 to 5 years.The virus persists throughout the lifespan in both SOI and POI at serum levels rarely greater than 100 copies/mL,causes hepatitis and HCC when concentrated and administered to virus-na(i)ve woodchucks.SOI is accompanied by virusspecific T and B cell immune responses,while only virusspecific T cells are detected in POI.SOI coincides with protection against reinfection,while POI does not and hepatitis develops after challenge with liver pathogenic doses >1000 virions.Both SOI and POI are associated with virus DNA integration into the liver and the immune system genomes.Overall,SOI and POI are two distinct forms of silent hepadnaviral persistence that share common characteristics.Here,we review findings from the woodchuck model and discuss the relevant observations made in human occult HBV infection (OBI).
