AIM： To analysis the factors that predict the response to entecavir therapy in chronic hepatitis patients with hepatitis B virus （HBV） genotype C. METHODS： Fifty patients [hepatitis B e antigen （HBeAg）- negative...AIM： To analysis the factors that predict the response to entecavir therapy in chronic hepatitis patients with hepatitis B virus （HBV） genotype C. METHODS： Fifty patients [hepatitis B e antigen （HBeAg）- negative：HBeAg-positive = 26：24] with HBV genotype C, who received nalve entecavir therapy for 〉 2 years, were analyzed. Patients who showed HBV DNA levels ≥ 3.0 log viral copies/mL after 2 years of entecavir ther- apy were designated as slow-responders, while those that showed 〈 3.0 log copies/mL were termed rapid- responders. Quantitative hepatitis B surface antigen （HBsAg） levels （qHBsAg） were determined by the Archi- tect HBsAg QT immunoassay. Hepatitis B core-related antigen was detected by enzyme immunoassay. Pre-C and Core promoter mutations were determined using by polymerase chain reaction （PCR）. Drug-resistance muta- tions were detected by the PCR-Invader method. RESULTS： At year 2, HBV DNA levels in all patients in the HBeAg-negative group were 〈 3.0 log copies/mL. In contrast, in the HBeAg-positive group, 41.7% were slow-responders, while 58.3% were rapid-responders. No entecavir-resistant mutants were detected in the slow-responders. When the pretreatment factors were compared between the slow- and rapid-responders; the median qHBsAg in the slow-responders was 4.57 log IU/mL, compared with 3.63 log IU/mL in the rapid- responders （P 〈 0.01）. When the pretreatment factors predictive of HBV DNA-negative status at year 2 in all 50 patients were analyzed, HBeAg-negative status, low HBV DNA levels, and low qHBsAg levels were signifi- cant （P 〈 0.01）. Multivariate analysis revealed that the low qHBsAg level was the most significant predictive factor （P = 0.03）. CONCLUSION： Quantitation of HBsAg could be a use- ful indicator to predict response to entecavir therapy.展开更多
Hepatitis D virus(HDV) is a defective RNA virus which requires the help of hepatitis B virus(HBV) virus for its replication and assembly of new virions. HDV genome contains only one actively transcribed open reading f...Hepatitis D virus(HDV) is a defective RNA virus which requires the help of hepatitis B virus(HBV) virus for its replication and assembly of new virions. HDV genome contains only one actively transcribed open reading frame which encodes for two isoforms of hepatitis delta antigen. Post-translational modifications of small and large delta antigens(S-HDAg and L-HDAg) involving phosphorylation and isoprenylation respectively con- fer these antigens their specific properties. S-HDAg is required for the initiation of the viral genome replica- tion, whereas L-HDAg serves as a principal inhibitor of replication and is essential for the assembly of new virion particles. Immune mediation has usually been implicated in HDV-associated liver damage. The patho- genesis of HDV mainly involves interferon-α signaling inhibition, HDV-specific T-lymphocyte activation and cytokine responses, and tumor necrosis factor-alpha and nuclear factor kappa B signaling. Due to limited protein coding capacity, HDV makes use of host cel- lular proteins to accomplish their life cycle processes, including transcription, replication, post-transcriptional and translational modifications. This intimate host- pathogen interaction significantly alters cell proteome and is associated with an augmented expression of pro-inflammatory, growth and anti-apoptotic factorswhich explains severe necroinflammation and increased cell survival and an early progression to hepatocellular carcinoma in HDV patients. The understanding of the process of viral replication, HBV-HDV interactions, and etio-pathogenesis of the severe course of HDV infection is helpful in identifying the potential therapeutic targets in the virus life cycle for the prophylaxis and treatment of HDV infection and complications.展开更多
Over the last decade, the standard of care for the treat- ment of chronic hepatitis C has been the combination of pegylated-interferon-alfa （PEG-IFN） and ribavirin （RBV） which results in sustained virological resp...Over the last decade, the standard of care for the treat- ment of chronic hepatitis C has been the combination of pegylated-interferon-alfa （PEG-IFN） and ribavirin （RBV） which results in sustained virological response （SVR） rates of 75%-85% in patients with genotypes 2 or 3 but only of 40%-50% in patients with genotype 1. Cur- rently, there are rapid and continuous developments of numerous new agents against hepatitis C virus （HCV）, which are the focus of this review. Boceprevir and tela- previr, two first-generation NS3/4A HCV protease inhibi- tors, have been recently licensed in several countries around the world to be used in combination with PEG- IFN and RBV for the treatment of genotype 1 patients. Boceprevir or telaprevir based triple regimens, com- pared with the PEG-IFN/RBV combination, improve the SVR rates by 25%-31% in treatment-naTve genotype 1 patients, by 40%-64% in prior relapsers, by 33%-45% in prior partial responders and by 24%-28% in prior null responders. At the same time, the application of response-guided treatment algorithms according to the on-treatment virological response results in shortening of the total therapy duration to only 24 wk in 45%-55% of treatment-na＇ive patients. There are, however, several challenges with the use of the new triple combinations in genotype 1 patients, such as the need for immediate results of HCV RNA testing using sensitive quantitative assays, new and more frequent adverse events （anemia and dysgeusia for boceprevir; pruritus, rash and anemia for telaprevir）, new drug interactions and increasing dif- ficulties in compliance. Moreover, the SVR rates are still poor in very difficult to treat subgroups of genotype 1 patients, such as null responders with cirrhosis, while there is no benefit for patients who cannot tolerate PEG- IFN/RBV or who are infected with non-1 HCV genotype. Many newer anti-HCV agents of different classes and numerous combinations are currently under evaluation with encouraging results. Preliminary data suggest that the treatment of chronic HCV patients with well toler- ated combinations of oral agents without PEG-IFN is feasible and may lead to a universal HCV cure over the next 5-10 years.展开更多
AIM:To investigate histological and immunohistochemical differences in hepatitis between autoimmune hepatitis(AIH)and primary biliary cirrhosis(PBC)with AIH features.METHODS:Liver needle biopsies of 41 PBC with AIH fe...AIM:To investigate histological and immunohistochemical differences in hepatitis between autoimmune hepatitis(AIH)and primary biliary cirrhosis(PBC)with AIH features.METHODS:Liver needle biopsies of 41 PBC with AIH features and 43 AIH patients were examined.The activity of periportal and lobular inflammation was scored0(none or minimal activity)to 4(severe),and the degree of hepatitic rosette formation and emperipolesis was semiquantatively scored 0-3.The infiltration of mononuclear cells positive for CD20,CD38,CD3,CD4,and CD8 and positive for immunoglobulins(IgG,IgM,and IgA)at the periportal areas(interface hepatitis)and in the hepatic lobules(lobular hepatitis)were semiquantitatively scored in immunostained liver sections(score 0-6).Serum aspartate aminotransferase(AST),immunoglobulins,and autoantibodies at the time of liver biopsy were correlated with the histological and immunohistochemical scores of individual lesions.RESULTS:Lobular hepatitis,hepatitic rosette formation,and emperipolesis were more extensive and frequent in AIH than in PBC.CD3+,CD4+,and CD8+cell infiltration scores were higher in the hepatic lobules and at the interface in AIH but were also found in PBC.The degree of mononuclear cell infiltration correlated well with the degree of interface and lobular hepatitis in PBC,but to a lesser degree in AIH.CD20+cells were mainly found in the portal tracts and,occasionally,at the interface in both diseases.Elevated AST correlated well with the hepatocyte necroinflammation and mononuclear cell infiltration,specifically CD38+cells in PBC.No correlation existed between autoantibodies and inflammatory cell infiltration in PBC or AIH.While most AIH cases were IgG-predominant at the interface,PBC cases were divided into IgM-predominant,IgM/IgGequal,and IgG-predominant types,with the latter sharing several features with AIH.CONCLUSION:These results suggest that the hepatocellular injuries associated with interface and lobular hepatitis in AIH and PBC with interface hepatitis may not be identical.展开更多
Several case reports deal with the relationship between hepatitis C virus （HCV） infection and pulmonary or he- patic sarcoidosis. Most publications describe interferon m-induced sarcoidosis. However, HCV infection p...Several case reports deal with the relationship between hepatitis C virus （HCV） infection and pulmonary or he- patic sarcoidosis. Most publications describe interferon m-induced sarcoidosis. However, HCV infection per se is also suggested to cause sarcoqdosis. The present case report describes a case of biopsy-verified lung and liver sarcoidosis and HCV infection, and the out- come of antiviral therapy. In March 2009, a 25-year-old man presented with moderately elevated liver enzymes without any clinical symptoms. The patient was posi- tive for HCV antibodies and HCV RNA of genotype lb. Four months later the patient became dyspnoic and pulmonary sarcoidosis was diagnosed by lung biopsy and radiography. A short course of corticosteroid treat- ment relieved symptoms. Three months later, liver biopsy showed noncaseating granulomas consisting of epithelioid histiocytes and giant cells with a small amount of peripheral lymphocyte infiltration, without any signs of fibrosis. Chronic HCV infection with co- existence of pulmonary and hepatic sarcoidosis was diagnosed. Antiviral therapy with peginterferon ~ and ribavirin at standard doses was started, which lasted 48 wk, and sustained viral response was achieved. A second liver biopsy showed disappearance of granulo- mas and chest radiography revealed normalization of mediastinal and perihilar glands. The hypothesis that HCV infection perse may have triggered systemic sar- coidosis was proposed. Successful treatment of HCV infection led to continuous remission of pulmonary and hepatic sarcoidosis. Further studies are required to un- derstand the relationship between systemic sarcoidosis and HCV infection.展开更多
基金Supported by A grant from the Japanese Ministry of Health and Welfare
文摘AIM： To analysis the factors that predict the response to entecavir therapy in chronic hepatitis patients with hepatitis B virus （HBV） genotype C. METHODS： Fifty patients [hepatitis B e antigen （HBeAg）- negative：HBeAg-positive = 26：24] with HBV genotype C, who received nalve entecavir therapy for 〉 2 years, were analyzed. Patients who showed HBV DNA levels ≥ 3.0 log viral copies/mL after 2 years of entecavir ther- apy were designated as slow-responders, while those that showed 〈 3.0 log copies/mL were termed rapid- responders. Quantitative hepatitis B surface antigen （HBsAg） levels （qHBsAg） were determined by the Archi- tect HBsAg QT immunoassay. Hepatitis B core-related antigen was detected by enzyme immunoassay. Pre-C and Core promoter mutations were determined using by polymerase chain reaction （PCR）. Drug-resistance muta- tions were detected by the PCR-Invader method. RESULTS： At year 2, HBV DNA levels in all patients in the HBeAg-negative group were 〈 3.0 log copies/mL. In contrast, in the HBeAg-positive group, 41.7% were slow-responders, while 58.3% were rapid-responders. No entecavir-resistant mutants were detected in the slow-responders. When the pretreatment factors were compared between the slow- and rapid-responders; the median qHBsAg in the slow-responders was 4.57 log IU/mL, compared with 3.63 log IU/mL in the rapid- responders （P 〈 0.01）. When the pretreatment factors predictive of HBV DNA-negative status at year 2 in all 50 patients were analyzed, HBeAg-negative status, low HBV DNA levels, and low qHBsAg levels were signifi- cant （P 〈 0.01）. Multivariate analysis revealed that the low qHBsAg level was the most significant predictive factor （P = 0.03）. CONCLUSION： Quantitation of HBsAg could be a use- ful indicator to predict response to entecavir therapy.
文摘Hepatitis D virus(HDV) is a defective RNA virus which requires the help of hepatitis B virus(HBV) virus for its replication and assembly of new virions. HDV genome contains only one actively transcribed open reading frame which encodes for two isoforms of hepatitis delta antigen. Post-translational modifications of small and large delta antigens(S-HDAg and L-HDAg) involving phosphorylation and isoprenylation respectively con- fer these antigens their specific properties. S-HDAg is required for the initiation of the viral genome replica- tion, whereas L-HDAg serves as a principal inhibitor of replication and is essential for the assembly of new virion particles. Immune mediation has usually been implicated in HDV-associated liver damage. The patho- genesis of HDV mainly involves interferon-α signaling inhibition, HDV-specific T-lymphocyte activation and cytokine responses, and tumor necrosis factor-alpha and nuclear factor kappa B signaling. Due to limited protein coding capacity, HDV makes use of host cel- lular proteins to accomplish their life cycle processes, including transcription, replication, post-transcriptional and translational modifications. This intimate host- pathogen interaction significantly alters cell proteome and is associated with an augmented expression of pro-inflammatory, growth and anti-apoptotic factorswhich explains severe necroinflammation and increased cell survival and an early progression to hepatocellular carcinoma in HDV patients. The understanding of the process of viral replication, HBV-HDV interactions, and etio-pathogenesis of the severe course of HDV infection is helpful in identifying the potential therapeutic targets in the virus life cycle for the prophylaxis and treatment of HDV infection and complications.
文摘Over the last decade, the standard of care for the treat- ment of chronic hepatitis C has been the combination of pegylated-interferon-alfa （PEG-IFN） and ribavirin （RBV） which results in sustained virological response （SVR） rates of 75%-85% in patients with genotypes 2 or 3 but only of 40%-50% in patients with genotype 1. Cur- rently, there are rapid and continuous developments of numerous new agents against hepatitis C virus （HCV）, which are the focus of this review. Boceprevir and tela- previr, two first-generation NS3/4A HCV protease inhibi- tors, have been recently licensed in several countries around the world to be used in combination with PEG- IFN and RBV for the treatment of genotype 1 patients. Boceprevir or telaprevir based triple regimens, com- pared with the PEG-IFN/RBV combination, improve the SVR rates by 25%-31% in treatment-naTve genotype 1 patients, by 40%-64% in prior relapsers, by 33%-45% in prior partial responders and by 24%-28% in prior null responders. At the same time, the application of response-guided treatment algorithms according to the on-treatment virological response results in shortening of the total therapy duration to only 24 wk in 45%-55% of treatment-na＇ive patients. There are, however, several challenges with the use of the new triple combinations in genotype 1 patients, such as the need for immediate results of HCV RNA testing using sensitive quantitative assays, new and more frequent adverse events （anemia and dysgeusia for boceprevir; pruritus, rash and anemia for telaprevir）, new drug interactions and increasing dif- ficulties in compliance. Moreover, the SVR rates are still poor in very difficult to treat subgroups of genotype 1 patients, such as null responders with cirrhosis, while there is no benefit for patients who cannot tolerate PEG- IFN/RBV or who are infected with non-1 HCV genotype. Many newer anti-HCV agents of different classes and numerous combinations are currently under evaluation with encouraging results. Preliminary data suggest that the treatment of chronic HCV patients with well toler- ated combinations of oral agents without PEG-IFN is feasible and may lead to a universal HCV cure over the next 5-10 years.
基金Supported by Primary Biliary Cirrhosis Subdivision of Intrac-table Hepatobiliary Diseases Study Group of Japan(Chairman,Hirohito TsubouchiDepartment of Human and Environmental Sciences,Graduate School of Medical and Dental Sciences,Ka-goshima University,Kagoshima,Japan)
文摘AIM:To investigate histological and immunohistochemical differences in hepatitis between autoimmune hepatitis(AIH)and primary biliary cirrhosis(PBC)with AIH features.METHODS:Liver needle biopsies of 41 PBC with AIH features and 43 AIH patients were examined.The activity of periportal and lobular inflammation was scored0(none or minimal activity)to 4(severe),and the degree of hepatitic rosette formation and emperipolesis was semiquantatively scored 0-3.The infiltration of mononuclear cells positive for CD20,CD38,CD3,CD4,and CD8 and positive for immunoglobulins(IgG,IgM,and IgA)at the periportal areas(interface hepatitis)and in the hepatic lobules(lobular hepatitis)were semiquantitatively scored in immunostained liver sections(score 0-6).Serum aspartate aminotransferase(AST),immunoglobulins,and autoantibodies at the time of liver biopsy were correlated with the histological and immunohistochemical scores of individual lesions.RESULTS:Lobular hepatitis,hepatitic rosette formation,and emperipolesis were more extensive and frequent in AIH than in PBC.CD3+,CD4+,and CD8+cell infiltration scores were higher in the hepatic lobules and at the interface in AIH but were also found in PBC.The degree of mononuclear cell infiltration correlated well with the degree of interface and lobular hepatitis in PBC,but to a lesser degree in AIH.CD20+cells were mainly found in the portal tracts and,occasionally,at the interface in both diseases.Elevated AST correlated well with the hepatocyte necroinflammation and mononuclear cell infiltration,specifically CD38+cells in PBC.No correlation existed between autoantibodies and inflammatory cell infiltration in PBC or AIH.While most AIH cases were IgG-predominant at the interface,PBC cases were divided into IgM-predominant,IgM/IgGequal,and IgG-predominant types,with the latter sharing several features with AIH.CONCLUSION:These results suggest that the hepatocellular injuries associated with interface and lobular hepatitis in AIH and PBC with interface hepatitis may not be identical.
基金Supported by A grant from the Estonian Science Foundation,No.7650a grant from the University of Tartu,No. SF0180081s07
文摘Several case reports deal with the relationship between hepatitis C virus （HCV） infection and pulmonary or he- patic sarcoidosis. Most publications describe interferon m-induced sarcoidosis. However, HCV infection per se is also suggested to cause sarcoqdosis. The present case report describes a case of biopsy-verified lung and liver sarcoidosis and HCV infection, and the out- come of antiviral therapy. In March 2009, a 25-year-old man presented with moderately elevated liver enzymes without any clinical symptoms. The patient was posi- tive for HCV antibodies and HCV RNA of genotype lb. Four months later the patient became dyspnoic and pulmonary sarcoidosis was diagnosed by lung biopsy and radiography. A short course of corticosteroid treat- ment relieved symptoms. Three months later, liver biopsy showed noncaseating granulomas consisting of epithelioid histiocytes and giant cells with a small amount of peripheral lymphocyte infiltration, without any signs of fibrosis. Chronic HCV infection with co- existence of pulmonary and hepatic sarcoidosis was diagnosed. Antiviral therapy with peginterferon ~ and ribavirin at standard doses was started, which lasted 48 wk, and sustained viral response was achieved. A second liver biopsy showed disappearance of granulo- mas and chest radiography revealed normalization of mediastinal and perihilar glands. The hypothesis that HCV infection perse may have triggered systemic sar- coidosis was proposed. Successful treatment of HCV infection led to continuous remission of pulmonary and hepatic sarcoidosis. Further studies are required to un- derstand the relationship between systemic sarcoidosis and HCV infection.
