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从EB、HCV、HCMV感染者二对半全阴性而HBV DNA（PCR）阳性重谈治疗性复合HBV系列疫苗
今天周日上网开中华网上的传染病科网上诊室，收到一位可能是HCV、EB、HCV混合重叠感染者的二个咨询（先前似有一此姓HCV病友曾联系IFN治疗HCV感染一事），使我今日再从病毒感染相互间的关系谈HBV感染的复制，甚至至可从此而类推到细菌与病毒间之关系谈HBV感染的复制，进一步谈治疗性复合HBV系列疫苗可取之处。
咨询者： 叶先生 性别：男 年龄：54岁 咨询主题： 两对半与DNA 05-26 09:21 咨询内容： 金博士： 我两对半都是阴性，从未有过阳性，最后一次验是去年四月。今年五月无意间验了HBV-DNA却是阳性，并且定量是2.7乘十的五次方。请问在两对半阴性的情况下有可能HCV-DNA阳性吗？还有这个定量是高还是低？（我简直怀疑是医院搞错了血样。）还有E B 病毒对肝炎指标的化验有没有影响？我以前验过有EB病毒。请答复，谢谢！
咨询者： 叶先生 性别：男 年龄：54岁 咨询主题： 丙肝治疗 05-26 09:36 咨询内容： 金医生： 请问你有没有亲自治疗过慢性丙肝病人而成功治愈的病例？如果我想到你处来正规治疗，不知可否？ 以上问题，烦请答复，谢谢！
一般认为HBV与HDV、HCV或别的其他病毒混合重叠感染致肝损伤加重，而且多认为HDV和HCV抑制HBV复制，但亦有认为HBV抑制HCV复制。其实关于HCV感染者伴有血清HBV抗原指标阴性而HBV DNA阳性的报道早在1997年便有报道，而且认为此变异的HBV有促进HCV复制作用，而且发现混凝土合感染者干扰素治疗效果差。 （详细可参见下述参考文献）。
事实上有些病毒感染相互间可能产生相互抑制复制效应，有的是通过重新激活机体非特异性免疫功能所致（即人与病毒之间交互谈话、Host-virus cross-talk），有的则病毒间相互抑制（“狗哎狗”效应）（详细可参见下述参考文献），如HCV病毒蛋白抑制HBV复制早有文献报道和研究结果认证，即感染HCV后HBV复制反而减轻，故有viral cross-talk（病毒间的交互谈话）之说（详细可参见下述参考文献）。临床上不少病人HBV感染后再感染甲肝、丁肝或别的肝炎病毒而致HBV复制受抑甚至HBV消除（但肝损伤可能更加严重），我们医生便此一现象称之为“以毒攻毒”，并有人试利用一些没有明显毒性的病毒来感染HBV病人而“以毒攻毒”治疗HBV感染的，而麻疹疫苗（类似活麻疹疫苗的减毒或灭活的病毒疫苗）用于治疗HBV感染便是此理。而推而远之，有人利用有些细菌与病毒间亦有相互抑制的关系而研究出治疗HBV感染的新方法，多机理多是通过重新激活机体非特异性免疫功能所致，如细菌壁结构成份（特别是其多糖部分）如OK-432、BCG、胞必佳、高聚生、沙培林、A型链球菌甘露聚糖 (多抗甲素)、短小棒状杆菌菌苗 （短棒菌苗，丙酸杆菌，可化舒，Propionibacteriumacnes,COPARVAX）、 冻干麻疹活疫苗、卡介苗 (Vaccine Calmette-Guerin， 结核活菌苗，BCG)及核酸多糖（PNS）、伤寒杆菌脂多糖 、灵菌素（ Prodigiosin ，神灵杆菌脂多糖，灵杆菌素) 、亮菌甲素(假密环菌甲素)、 乌苯美司 （Ubenimex， 抑氨肽酶素，抑氨须酶B，BST了BESTATIN）、西佐糖（ Sizofiran， 裂裥多糖，裂褶多糖，Sonifilan,Schizofilan）等。
有鉴于HBV清除有赖于机体免疫功能的激活尤其是HBV特异性免疫功能的激活（上述病毒间或细菌或别的微生物与HBV间的复制抑制是多为随带性、即随机、BYSTANDER性的），故有效的特效/特异性HBV的激活将更有助于HBV清除，我们正在设计中的治疗性复合HBV系列疫苗其疫苗的多位点性（S区、前S2区、前S1 区、C/E区、DNA多聚酶区、X区），并有多种微生物抗原作为免疫佐剂、加上激活全部免疫系统细胞，并有意识地诱导一种非胞溶性（不损伤肝细胞）而抗HBV免疫机制，其所引导发的HBV特异性免疫是强力和多克隆，因此可以说我们正在设计中的治疗性复合HBV系列疫苗是一有望根治HBV感染的治疗方法。
J Med Virol 1997 Aug;52(4):399-405
Hepatitis C virus is frequently coinfected with serum marker-negative hepatitis B virus: probable replication promotion of the former by the latter as demonstrated by in vitro cotransfection.
Uchida T, Kaneita Y, Gotoh K, Kanagawa H, Kouyama H, Kawanishi T, Mima S.
Department of Pathology, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan.
Patients with hepatitis C have been reported occasionally to be coinfected with serum marker-negative (silent) hepatitis B virus (HBV). The frequency and significance of such coinfection were investigated. Thirty patients with hepatitis C virus (HCV) infections (10 acute, 10 chronic, 10 cirrhotic) were selected randomly; the acute cases were without serum hepatitis B surface antigen (HBsAg) and anti-hepatitis B core IgM, and the chronic cases were without HBsAg. A nested polymerase chain reaction for the X open reading frame was used to amplify HBV DNA in serum, and immunoperoxidase staining was carried out on liver biopsy specimens. Nucleotide sequencing was carried out to characterize the amplified HBV DNAs. In order to clarify the possibility that the silent HBV mutant promotes HCV replication in the liver, the full-length HCV RNA and the cloned silent HBV DNA dimer were cotransfected into an established cell line, HuH-7, and the amount of secreted HCV RNA was quantified serially. The target HBV DNA was amplified in 26 (86.7%) of the 30 patients. Subsequent direct nucleotide sequencing in 9 selected patients revealed an 8-nucleotide deletion, characteristic of a silent HBV mutant. Immunostaining revealed hepatitis B surface antigen in 15 (50.0%). Cotransfected silent HBV DNA augmented the secretion of HCV RNA by up to 5-fold in comparison with HCV RNA transfection alone. In conclusion, HCV is coinfected frequently with the silent HBV mutant and the latter probably promotes the replication of the former in the liver.
PMID: 9260688 [PubMed - indexed for MEDLINE]
J Hepatol 1995;22(1 Suppl):38-41
The interaction between hepatitis B virus and hepatitis C virus in acute and chronic liver disease.
Alberti A, Pontisso P, Chemello L, Fattovich G, Benvegnu L, Belussi F, De Mitri MS.
Clinica Medica II, University of Padua, Italy.
Infections by the hepatitis B or C virus are extremely common causes of acute and chronic liver disease, and coexistence of the two viruses in the same patient is not rare. Evidence has been found that such interaction may play an important role in fulminant hepatitis and in the development of hepatocellular carcinoma in cirrhotic patients. Liver disease activity and prognosis have been reported to be generally more serious in the presence of double infection, although an inverse relationship in the replicative levels of the two agents has been noted, suggesting viral interference, particularly in cases of chronic hepatitis. Thus, the two viruses seem to inhibit each other at the molecular level, while cytopathic effects appear to be enhanced. Further studies are needed to explain the mechanisms of these apparently contrasting effects. Publication Types: Review Review, Tutorial
PMID: 7602074 [PubMed - indexed for MEDLINE]
J Virol 1998 Dec;72(12):10138-47
Host cell-virus cross talk: phosphorylation of a hepatitis B virus envelope protein mediates intracellular signaling.
Rothmann K, Schnolzer M, Radziwill G, Hildt E, Moelling K, Schaller H.
Zentrum fur Molekulare Biologie Heidelberg, D-69124 Heidelberg, Germany.
Phosphorylation of cytosolic pre-S domains of the duck hepatitis B virus (DHBV) large envelope protein (L) was identified as a regulatory modification involved in intracellular signaling. By using biochemical and mass spectrometric analyses of phosphopeptides obtained from metabolically radiolabeled L protein, a single phosphorylation site was identified at serine 118 as part of a PX(S/T)P motif, which is strongly preferred by ERK-type mitogen-activated protein kinases (MAP kinases). ERK2 specifically phosphorylated L at serine 118 in vitro, and L phosphorylation was inhibited by a coexpressed MAP kinase-specific phosphatase. Furthermore, L phosphorylation and ERK activation were shown to be induced in parallel by various stimuli. Functional analysis with transfected cells showed that DHBV L possesses the ability to activate gene expression in trans and, by using mutations eliminating (S-->A) or mimicking (S-->D) serine phosphorylation, that this function correlates with L phosphorylation. These mutations had, however, no major effects on virus production in cell culture and in vivo, indicating that L phosphorylation and transactivation are not essential for hepadnavirus replication and morphogenesis. Together, these data suggest a role of the L protein in intracellular host-virus cross talk by varying the levels of pre-S phosphorylation in response to the state of the cell.
PMID: 9811754 [PubMed - indexed for MEDLINE]
New Biol 1991 Dec;3(12):1177-81
Man versus pathogen: can we talk? Molecular cross-talk between epithelial cells and pathogenic microorganisms sponsored by the American Society for Cell Biology and the European Molecular Biology Organization, Arolla, Switzerland, August 18-23, 1991.
Finlay BB. Biotechnology Laboratory, University of British Columbia, Vancouver, Canada.
Publication Types: Congresses
PMID: 1812963 [PubMed - indexed for MEDLINE]
Proc Natl Acad Sci U S A 1996 May 14;93(10):4589-94
Viral cross talk: intracellular inactivation of the hepatitis B virus during an unrelated viral infection of the liver.
Guidotti LG, Borrow P, Hobbs MV, Matzke B, Gresser I, Oldstone MB, Chisari FV.
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Hepatitis B virus (HBV) infection is thought to be controlled by virus-specific cytotoxic T lymphocytes (CTL). We have recently shown that HBV-specific CTL can abolish HBV replication noncytopathically in the liver of transgenic mice by secreting tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) after antigen recognition. We now demonstrate that hepatocellular HBV replication is also abolished noncytopathically during lymphocytic choriomeningitis virus (LCMV) infection, and we show that this process is mediated by TNF-alpha and IFN-alpha/beta produced by LCMV-infected hepatic macrophages. These results confirm the ability of these inflammatory cytokines to abolish HBV replication; they elucidate the mechanism likely to be responsible for clearance of HBV in chronically infected patients who become superinfected by other hepatotropic viruses; they suggest that pharmacological activation of intrahepatic macrophages may have therapeutic value in chronic HBV infection; and they raise the possibility that conceptually similar events may be operative in other viral infections as well.
PMID: 8643448 [PubMed - indexed for MEDLINE]
Liver 1999 Aug;19(4):348-53
Comment in: Liver. 2000 Apr;20(2):188.
Clearance of HCV RNA in a chronic hepatitis C virus-infected patient during acute hepatitis B virus superinfection.
Wietzke P, Schott P, Braun F, Mihm S, Ramadori G.
Department of Medicine, Division of Gastroenterology and Endocrinology, Georg-August-Universitat, Gottingen, Germany. The routes of hepatitis B virus and hepatitis C virus transmission are quite similar and coexistence of both viruses in one patient is not a rare phenomenon. Until now, the natural course of liver diseases induced by coinfections has not been well documented and the mechanisms of interaction between the two viruses and the human host have not been fully clarified. We report the case of a patient suffering from chronic hepatitis due to hepatitis C virus who developed an acute hepatitis B virus superinfection. Serum hepatitis C virus ribonucleic acid became undetectable by reverse transcriptase/polymerase chain reaction at diagnosis of acute hepatitis B virus infection. At the same time, there was a striking increase in the serum concentrations of the antibodies against C22 and C33c hepatitis C virus antigens. Four months after clinical resolution of the acute hepatitis, hepatitis B surface antigen was undetectable in serum and three months later antibodies against hepatitis B surface antigen appeared. Two years after acute hepatitis B virus infection, the patient has had no relapse of markers for viral replication of hepatitis B virus. Transaminases are within the reference range and hepatitis C virus ribonucleic acid is undetectable in both serum and liver tissue. We hypothesize that acute hepatitis B virus infection stimulated a specific humoral response against hepatitis C virus as well as triggering non-specific defense mechanisms which finally eliminated both viruses.
PMID: 10459635 [PubMed - indexed for MEDLINE]
Gastroenterol Hepatol 2002 May;25(5):295-8
[Study of hepatitis B virus replication and infection by other hepatitis viruses in patients with chronic hepatitis B virus infection] [Article in Spanish]
Buti M, Costa X, Valdes A, Cotrina M, Rodriguez Frias F, Jardi R, Esteban R, Guardia J.
Servicio de Hepatologia. Laboratorio de Bioquimica. Hospital Universitario Vall d'Hebron. Barcelona. Spain.
Aim: To study hepatitis B virus (HBV) replication in a series of patients with HBV infection and to analyze the frequency of associated hepatitis C virus (HCV) and hepatitis D (HDV) infection.Patients and method: Serological markers of HBV, HCV and HDV, transaminase values and HBV DNA were studied in serum samples from 463 patients with chronic HBV infection.Results: Three hundred ninety-six (85.5%) were classified as hepatitis B, 33 (7.1%) as hepatitis B and C, 17 (3.6%) as hepatitis B and D and 17 (3.6%) as hepatitis B, C and D. Sixty-seven percent of patients with hepatitis B and 33% of those with chronic hepatitis B were asymptomatic HBsAg carriers. HVB DNA was identified in 27.7% of patients with hepatitis B, in 24% of those with hepatitis B and C, in 11.7% of those with hepatitis B and D and in 29.4% of those with hepatitis B, C and D. HBV DNA and elevated transaminase levels were found in 63% of HBeAg-positive patients and in only 16% of those who were anti-HBe-positive. These latter were considered candidates for antiviral treatment.Conclusions: In our environment, most patients with HBV infection are asymptomatic HBsAg carriers. Viral replication and elevated alanine aminotransferase levels were found in 22% of the patients. Consequently, these patients are candidates for antiviral treatment. Between 3.6% and 7.1% of patients with hepatitis B presented coinfection with HCV or HDV, or both. No significant differences were found in HBV replication among the different groups.
PMID: 11985798 [PubMed - in process]
Mod Pathol 1999 Jun;12(6):599-603
Intrahepatic expression of hepatitis B virus antigens: effect of hepatitis C virus infection.
Guido M, Thung SN, Fattovich G, Cusinato R, Leandro G, Cecchetto A, Cesaro S, Panese P, Rugge M.
Cattedra di Istochimica ed Immunohistochimica Patologica, Universita di Padova- U.O. Anatomia Patologica ULLS 15, Ospedale di Cittadella, Italy.
Coinfection with hepatitis B and C viruses (HBV, HCV) is not uncommon, but the expression of HBV antigens in the liver of patients with concomitant HCV infection has not been investigated. This study aimed to evaluate the effects of concomitant HCV infection on the intrahepatic expression of HBV antigens in chronic hepatitis. HBV surface and core antigens (HBsAg, HBcAg) were immunohistochemically evaluated and semiquantitatively scored in liver biopsy specimens from patients with chronic hepatitis, comprising 17 cases with dual HBV/HCV infection and 25 with HBV infection alone. The prevalence of HBV Ag expression proved significantly lower in the group with dual infection. In the presence of active HBV replication (HBV DNA-positive serum) the prevalence of HBsAg and HBcAg immunoreaction was similar in the two groups, though a significantly lower percentage of cells expressed HBcAg in the group of coinfected patients. HBV Ag was not detected at all among HBV DNA-negative/HCV RNA-positive cases. In conclusion, these observations suggest that HCV might influence HBV antigen expression in the liver and that either partial or complete suppression might occur.
PMID: 10392636 [PubMed - indexed for MEDLINE]
J Mol Med 2002 Mar;80(3):187-95
Inhibition of duck hepatitis B virus replication by intrahepatic expression of an antiviral resistance gene.
Kundgen R, Thoma C, Kock J, Wilting J, Koch K, Offensperger WB, Blum E, von Weizsacker F.
Department of Medicine II, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany.
Resistance genes coding for inhibitors of hepadnaviral replication, such as ribozymes, antisense RNA, and dominant negative mutants have been shown to be effective in transfected hepatoma cells. In vivo studies, however, are not available to date. Here we expanded the use of the duck hepatitis B virus (DHBV) model for studying antiviral resistance genes in vivo. Animals were experimentally infected by intravenous injection of DHBV-positive serum in ovo. The use of recombinant human adenovirus type 5 and avian adenovirus CELO for gene transfer was evaluated. Adenovirus type 5 transduced more than 95% and CELO less than 1% of embryonic hepatocytes in vivo. Adenovirus type 5 interfered with DHBV replication (viral cross-talk), but this effect was moderate and did not preclude analysis of specific antiviral effects. Thus adenoviral transfer of a dominant negative mutant prior to DHBV infection (intracellular immunization) yielded 100-fold suppression of viral replication compared to the green fluorescent protein marker gene. Neither gene was toxic. These data demonstrate that a prototype anthepadnaviral resistance gene is functional in vivo. Duck embryos represent a useful model for evaluating gene therapeutic strategies in vivo without the need for large scale preparations of gene delivery vehicles.
PMID: 11894145 [PubMed - in process]
J Cell Physiol 2002 Jun;191(3):249-56
Molecular biology and immunoregulation of human neurotropic JC virus in CNS.
Sweet TM, Valle LD, Khalili K.
Center for Neurovirology and Cancer Biology, Temple University, Philadelphia, Pennsylvania 19122, USA.
The human polyomavirus, JC virus (JCV), provides an excellent model system to investigate the reciprocal interaction of the immune and nervous systems. Infection with JCV occurs during childhood and the virus remains in the latent state with no apparent clinical symptoms. However, under immunosuppressed conditions, the virus enters the lytic cycle and upon cytolytic destruction of glial cells, causes the fatal demyelinating disease of the central nervous system (CNS), named progressive multifocal leukoencephalopathy (PML). In this short review, we discuss the molecular pathogenesis of PML by highlighting the role of the immune system in modulating JCV gene activation and replication, and the latency/reactivation of this virus upon immunosuppression. Further, due to the higher incidence of PML among AIDS patients, we further elaborate on the cross-talk between JCV and HIV-1 by direct and indirect pathways that lead to enhanced expression of the JCV genome. Copyright 2002 Wiley-Liss, Inc.
PMID: 12012320 [PubMed - in process]
Vopr Virusol 2002 Jan-Feb;47(1):12-5
[Acute hepatitis C in the presence of chronic HBV infection] [Article in Russian]
Shkurko TV, Cheshik SG, Braginskii DM.
Acute HCV superinfection was studied in 23 patients with chronic hepatitis B virus infection. HBsAg, anti-HCV (C-100, core, NS3, NS5) were detected in patients' sera at first investigation. Predominant replication of HBV DNA was detected in the sera of 68% patients and HCV RNA in only 24% patients. The clinical course of acute hepatitis C in patients with chronic HBV infection in general corresponded to HCV monoinfection except for more pronounced biochemical shifts and shorter intoxication. The role of HBV and HCV in infectious process is discussed.
PMID: 11852776 [PubMed - indexed for MEDLINE]
J Biomed Sci 2001 Nov-Dec;8(6):492-503
Hepatitis B viral polymerase fusion proteins are biologically active and can interact with the hepatitis C virus core protein in vivo.
Chen KL, Chen CM, Shih CM, Huang HL, Lee YH, Chang C, Lo SJ.
Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan, ROC.
Hepadnaviruses and retroviruses are evolutionarily related families because they both require a process of reverse transcription for genome replication. However, hepadnaviruses produce polymerase (pol) and core proteins separately, while retroviruses synthesize a gag-pol fusion protein that is subsequently cleaved by a virally encoded protease to release a functional polymerase. To test whether an additional sequence at the N-terminus of pol in hepatitis B virus (HBV) interferes with its function, we created two plasmids expressing core-pol fusion proteins, core144-pol and core31-pol. Secreted particles obtained from HuH-7 cells, which were cotransfected with a core-pol fusion protein-expressing plasmid and a core-expressing plasmid, showed a positive signal of HBV DNA by the endogenous polymerase assay, indicating that the core-pol fusion proteins retain DNA priming, polymerization and RNase H activities. The fusion protein was detected in the cytoplasm of transfected cells and in secreted virions by immunoprecipitation. Furthermore, we found by immunofluorescence staining that the HBV core-pol fusion protein colocalized with the hepatitis C virus (HCV) core protein in cytoplasm and in lipid droplets. Immunoprecipitation studies showed that the anti-HCV core complex contained the HBV core-pol fusion protein while the anti-HBV pol complex contained the HCV core protein, which supports the hypothesis that the HCV core protein can form a complex with the HBV core-pol fusion protein. Copyright 2001 National Science Council, ROC and S. Karger AG, Basel
PMID: 11702013 [PubMed - indexed for MEDLINE]
Antiviral Res 2001 Nov;52(2):117-23
Role of silent hepatitis B virus in chronic hepatitis B surface antigen(-) liver disease.
Chemin I, Jeantet D, Kay A, Trepo C.
INSERM U271, 151 Cours A Thomas, 69003 Lyon, France. chemin@lyon151.inserm.fr
Despite a number of studies documenting hepatitis B virus (HBV) infection in the absence of hepatitis B surface antigen (HBsAg) a causal relationship between silent HBV infection and liver disease remain difficult to establish. In particular, both the prevalence and clinical significance of this observation are poorly understood. Why is HBV replication apparently so low in these patients? A number of studies have tried to elucidate the mechanism of HBsAg negative infections, and considerable data documenting HBV infectivity or reinfection in the absence of detectable HBsAg support the hypothesis that in some of these cases, HBV is undergoing low-level replication in the liver and this, in several situations including: (1) chronic liver disease, alcoholic liver disease, hepatocellular carcinoma; (2) viral reactivation following cancer chemotherapy or immunosuppression and (3) transmission via transfusion or from human serum to chimpanzees. In a recent study including 50 patients with chronic liver disease of unknown etiology we could detect serum HBV DNA by nested polymerase chain reaction (PCR) in 15/50 patients (50% at the cirrhosis stage) in the absence of HBsAg; in the liver of the 15 patients both HBcAg and/or HBsAg can be detected at very low-level. Viral host factors allowing HBV persistence in the absence of HBsAg can depend on several mechanisms. Coinfections with HCV can explain only a proportion of HBsAg(-) HBV infections. Secondly, HBV mutations in the core promotor region leading to a minimal viral replication, or mutations in the HBsAg-encoding region might explain the absence of serological recognition. Finally, it is possible that in some cases host immune mechanisms can maintain HBV infection in a latent state until transmission to another individual who subsequently develops a more active infection especially when immunosuppressive therapy is employed. Existence of HBsAg(-) HBV infections should be taken into account by the use of sensitive PCR tests for prevention of viral transmission in the settings of blood donations and organ transplants. Publication Types: Review Review, Tutorial
PMID: 11672821 [PubMed - indexed for MEDLINE]
Hepatology 2001 Aug;34(2):404-10
Role of hepatitis B, C, and D viruses in dual and triple infection: influence of viral genotypes and hepatitis B precore and basal core promoter mutations on viral replicative interference.
Jardi R, Rodriguez F, Buti M, Costa X, Cotrina M, Galimany R, Esteban R, Guardia J.
Department of Biochemistry, Hospital Universitario Vall d'Hebron, Barcelona, Spain. rjardi@hg.vhebron.es
The interactions among hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis delta virus (HDV) were studied by measuring HBV-DNA and HCV-RNA levels and by determining the influence of viral genotypes and mutations in HBV basal core promoter (BCP) and precore regions. We included 65 consecutive patients, 25 HBV/HCV, 18 HBV/HDV, and 22 HBV/HCV/HDV. Controls consisted of 55 patients with chronic HBV and 55 with chronic HCV infection. HBV-DNA and HCV-RNA levels were lower in coinfections than in single infections (P <.05). HBV/HCV coinfection was associated with lower HBV viremia (8.2 x 10(4) copies/mL) and lower HCV-RNA levels (7 x 10(5) IU/mL), than the corresponding control group (P <.05), with more marked decrease in HBV replication (P <.05). Moreover, in HBV/HCV coinfection and in triple coinfection we observed an inverse relationship between HBV-DNA and HCV-RNA levels (P <.05). HBV/HDV coinfection was associated with lower HBV viremia (2.5 x 10(4) copies/mL) than that found in HBV infection (P <.05). Patients with triple coinfection showed lower HBV-DNA and HCV-RNA levels than control groups (P <.05). Prevalence of precore mutations was lower in HCV coinfections (P <.05). No significant association was observed between HCV-RNA levels and HBV precore mutations, BCP mutations or HBV genotypes, or between HBV-DNA levels and HCV genotypes (P <.05). In conclusion, HCV exhibited stronger inhibitory action in the reciprocal inhibition seen in HBV/HCV coinfection. HDV was the dominant virus in HBV/HDV coinfection and in triple coinfection, and had a greater unfavorable influence on HCV than on HBV replication. The reciprocal inhibition of viral replication seemed to be little influenced by the inherent genomic factors studied.
PMID: 11481626 [PubMed - indexed for MEDLINE]
J Gastroenterol Hepatol 2001 Jun;16(6):636-40
Comment in: J Gastroenterol Hepatol. 2001 Jun;16(6):597-8.
Influence of hepatitis C virus on the profiles of patients with chronic hepatitis B virus infection.
Dai CY, Yu ML, Chuang WL, Lin ZY, Chen SC, Hsieh MY, Wang LY, Tsai JF, Chang WY.
Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, Republic of China.
BACKGROUND: Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the most common causes of chronic liver disease, cirrhosis and hepatocellular carcinoma. The influence of HCV infection on the clinicopathological and virological profiles of chronic HBV infection was investigated. METHODS: A total of 100 chronic HBV carriers with histopathological diagnoses by liver biopsy were studied. Hepatitis B e antigen (HBeAg) and anti-HCV antibody were tested. Serum HCV-RNA was detected by using a nested reverse transcription-PCR assay. A branched DNA (bDNA) assay was used to detect HBV-DNA and quantitate the serum levels. RESULTS: Eighteen (18%) of 100 patients were positive for anti-HCV and HCV-RNA. Patients with concurrent HCV and HBV infection were significantly older than those without HCV infection (P < 0.05). The positive rates of HBeAg and HBV-DNA as well as the serum levels of HBV-DNA in patients with concurrent HCV and HBV infection were significantly lower than those without concurrent HCV and HBV infection (P < 0.01, P < 0.05, and P < 0.001, respectively). By using multivariate analysis, the factors of seroconversion of HBeAg and decreasing level of HBV-DNA were significantly correlated to concurrent HCV and HBV infection in chronic HBV carriers. The factors of increasing age and concurrent HCV and HBV infection were significantly correlated to seroconversion of HBeAg. CONCLUSIONS: The concurrent HCV and HBV infection in chronic HBV carriers might result in a suppression of HBV replication that presented with a lower level of serum HBV-DNA and HBeAg seroconversion. Nevertheless, neither more obvious increase in biochemical parameters nor histopathological progression to more advanced liver diseases was observed.
PMID: 11422616 [PubMed - indexed for MEDLINE]
J Hepatol 2000 Nov;33(5):785-90
Hepatitis B virus DNA in sera and liver tissue of HBsAg negative patients with chronic hepatitis C.
Kazemi-Shirazi L, Petermann D, Muller C.
Universitatsklinik fur Innere Medizin IV, Klinische Abteilung fur Gastroenterologie und Hepatologie, University of Vienna, Austria.
BACKGROUND/AIMS: Hepatitis B virus (HBV) DNA has been detected in HBsAg-negative patients with hepatitis C. We determined the rate and explored the clinical significance of HBsAg negative HBV coinfections in Austrian patients with chronic hepatitis C. METHODS: Sera (n=82, group I) or liver tissue (n=16, group II) from 98 HBsAg negative Austrian patients with chronic hepatitis C were examined for HBV DNA by nested polymerase chain reaction (PCR). For control purposes, sera from 15 patients with chronic HBV infection (8 HBsAg positive, 7 HBsAg negative, all HBV PCR positive) were examined. RESULTS: HBV DNA was detected in 22% of sera and 19% of liver tissue specimens of patients with chronic hepatitis C. No significant difference in mean aminotransferase values, markers of HBV infection, inflammatory disease activity, or degree of hepatic fibrosis was observed in patients with or without HBV DNA. Anti-HBc alone as a marker of past HBV infection was more frequent in chronic hepatitis C patients compared to control individuals. Negative HCV PCR was more common (p=0.009) among patients with positive HBV PCR in serum. When examining repeat sera for HBV DNA, positive results were obtained in previously negative, but also negative results in previously positive patients. CONCLUSIONS: Coinfection with HBV can be demonstrated by PCR in a considerable number of HBsAg negative Austrian patients with chronic hepatitis C. HBV infection seems to suppress HCV replication even in HBsAg negative patients with dual infection. HBV coinfection in HCV infected patients cannot be excluded by negative HBsAg status alone. Repeat PCR examinations are needed to exclude dual infections.
PMID: 11097488 [PubMed - indexed for MEDLINE]
Hepatology 2000 Nov;32(5):1106-10
Virologic and clinical expressions of reciprocal inhibitory effect of hepatitis B, C, and delta viruses in patients with chronic hepatitis.
Sagnelli E, Coppola N, Scolastico C, Filippini P, Santantonio T, Stroffolini T, Piccinino F.
Institute of Infectious Diseases, Second University of Naples, Naples, Italy. evangelista.sagnelli@unina2.it
We studied 648 hepatitis B surface antigen (HBsAg)- and/or anti-hepatitis C virus (HCV)-positive patients to evaluate the virologic and clinical characteristics of multiple hepatitis viral infection. We defined as Case B-C an HBsAg/anti-HCV positive patient and as Case b-C an anti-HCV/anti-HBc-positive, HBsAg/anti-HBs-negative patient. For each Case B-C we scheduled as Control-B an HBsAg positive and anti-HCV negative patient and as Control-C an HBsAg/anti-HBs/anti-hepatitis B core antigen (HBc)-negative and anti-HCV-positive patient. Control group C was used as the control also for Case group b-C. Serum HBV DNA by molecular hybridization was found more frequently in Control group B (54% of 161 patients) than in Case group B-C (35.7% of 84, P <.01). The prevalence of HBV wild type was similar in Case group B-C (14. 3%) and in Control group B (17.4%), whereas the e-minus strain was less frequent in Case group B-C (10.7% vs. 33%; P <.01). HBV DNA by polymerase chain reaction (PCR) was detected in 40.8% of 71 patients in Case group b-C. HCV RNA was detected more frequently in Control group C (90.7% of 130 patients) than in Case group B-C (65.2% of 69, P <.0001). Moderate or severe chronic hepatitis or cirrhosis were more frequent in Case group B-C (62.9% of 65 patients) than in Control group B (46.7% of 90, P <.05) or C (40.8% of 98, P <.005), and in Case group b-C (71.1% of 76) than in Control group C. Thus, in multiple hepatitis we observed a reciprocal inhibition of the viral genomes and a more severe liver disease. In Case group b-C, serum HBV DNA was frequent and the clinical presentation was severe.
PMID: 11050062 [PubMed - indexed for MEDLINE]
Intervirology 2000;43(2):71-6
High frequency of HCV infection in individuals with isolated antibody to hepatitis B core antigen.
Berger A, Doerr HW, Rabenau HF, Weber B.
Institut fur Medizinische Virologie, Universitatskliniken Frankfurt, Germany.
Although isolated antibody to hepatitis B core antigen (anti-HBc) is frequently nonspecific or may be the only serological marker of past self-limiting hepatitis B, where antibodies against the surface antigen have disappeared, isolated anti-HBc seropositivity is frequently associated with chronic hepatitis B in HIV- and HCV-infected individuals. Of 5,520 samples that tested positive for anti-HBc (IMx and AxSYM CORE, Abbott, Delkenheim, Germany) at the Institute of Virology, University Clinic Frankfurt during the time interval from January 1994 to February 1996, 643 (11.6%) were isolated anti-HBc-reactive in the IMx and AxSYM CORE assays (inhibition values >90%). There was a statistically significant association between isolated anti-HBc seropositivity and HCV and HIV/HCV coinfection (p < 0.05). A total of 190 samples were available for further testing. Six (3.2%) of 190 isolated anti-HBc-positive samples were considered false-positive since they were only positive in the AxSYM or IMx CORE assay and a linear decrease of the measured signal could not be observed in dilution series. Of 184 serum samples tested with nested PCR using primers of the S genome region, only 6 (3.3%) were HBV DNA-positive. Anti-HBc-IgM antibody could be detected in 3 (1.6 %) of the tested samples using the IMx CORE-M. With the more sensitive VIDAS HBc IgM specific IgM antibody was detected in 15 (8.5%) of 177 samples at concentrations ranging from 10 to >200 Paul Ehrlich Institute U/ml. HIV or HCV coinfection was present in 28.1% and 37.5% of isolated anti-HBc-positive individuals, respectively. We conclude from our observations that only a limited proportion of anti-HBc-isolated individuals are potentially infectious, however anti-HBc-IgM which is detectable in any form of liver disease associated with HBV infection was present in more than 8% of the individuals. Of isolated anti-HBc-positive sera 37% were positive for anti-HCV, suggesting that anti-HCV antibody testing should be performed in isolated anti-HBc-positive individuals. Copyright 2000 S. Karger AG, Basel
PMID: 10971123 [PubMed - indexed for MEDLINE]
Southeast Asian J Trop Med Public Health 1999 Dec;30(4):741-9
Coinfections with hepatitis g and/or c virus in hepatitis B-related chronic liver disease.
Pramoolsinsap C, Sirikulchayanonta V, Busakorn W, Poovorawan Y, Hirsch P, Theamboonlers A, Lerdverasirikul P.
Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Concurrent infections with HGV and/or HCV (HGV/HCV) were investigated in 196 patients with HBV-related chronic liver disease (115 chronic hepatitis, 31 liver cirrhosis, 50 hepatocellular carcinoma), and in 100 HBsAg carriers. Coinfections were detected in 18 (9.2%) patients with HGV (10) or HCV (5) or both agents (3), but in none of the HBsAg carriers. Patients with coinfection were more frequently exposed to blood transfusions (55.6% vs 5.6%) and also were more commonly anti-HBe positive. Serum levels of HBV-DNA were lower in patients with HCV coinfection than in those coinfected with HGV. Interferon was administered to 39 patients with chronic active hepatitis including 7 patients with HGV/HCV coinfection. Sustained clearance of HBV-DNA was observed in 10 (25.6%) patients who were solely infected with HBV. These patients were significantly younger and had much lower histological scores than non-responders. Patients with HCV coinfection had significantly higher pre-treatment histological scores than those without HCV. After interferon treatment, a significant reduction in histological scores was observed in all patients except those coinfected with HGV/HCV. None of the 7 patients with coinfection had sustained clearance of HBV-DNA or HCV-RNA, and only one had cleared HGV-RNA. These results suggest that parenteral exposure is a risk factor for HGV/HCV coinfection in chronic HBV infection. HGV infection shows no significant impact on chronic HBV infection. HCV coinfection appears to inhibit HBV replication, but causes more severe chronic hepatitis and increases resistance to interferon therapy.
PMID: 10928369 [PubMed - indexed for MEDLINE]
Vopr Virusol 2000 May-Jun;45(3):32-5
[Acute hepatitis B in anti-HCV-positive patients] [Article in Russian]
Shkurko TV, Cheshik SG.
Seventy-six anti-HCV-positive patients with acute hepatitis B were observed. HBsAg, anti-HBc IgM, and anti-HCV were detected in the sera of all patients. During the acute phase of illness, HBV DNA was present in the sera of 90.8% patients, but not HCV RNA. The clinical picture of acute hepatitis B in anti-HCV-positive patients corresponded to HBV monoinfection with prolonged intoxication and a more benign biochemical course. Out of 10 patients observed during 2 years chronic mixed HBV/HCV hepatitis was diagnosed in 1 patient, in 8 patients only HCV infection was diagnosed, and in 6 cases HCV RNA was detected. Virus interference may be responsible for successive alternative dominant replication of HBV and HCV.
PMID: 10867993 [PubMed - indexed for MEDLINE]
Antivir Ther 1998;3(Suppl 3):137-42
Coinfection by hepatitis B virus and hepatitis C virus.
Pontisso P, Gerotto M, Benvegnu L, Chemello L, Alberti A.
Department of Clinical and Experimental Medicine, University of Padova, Italy. patrizia@ux1.unipd.it
Coinfection by hepatotropic viruses can occur due to the fact that hepatitis B virus (HBV) and hepatitis C virus (HCV) share similar routes of transmission. Different clinical features of liver disease can be observed in infected patients, ranging from fulminant, acute and chronic hepatitis to hepatocellular carcinoma (HCC). The relative role of the infecting viruses in determining the final clinical picture is not yet well defined. Several reports indicate that clinical and pathological severity of liver disease among coinfected patients is increased and in patients with HCC, co-occurrence of both viruses is a common event. The potential mechanism of tumour development still remains speculative, although direct and indirect roles for both HBV and HCV have been proposed. At the molecular level, reciprocal interference of virus replication has been repeatedly described and the extent of interference is influenced by the infecting HCV genotype, genotype 1 of HCV having more efficient inhibitory activity on HBV than genotype 2. Sequence similarities between an arginine-rich nucleocapsid motif of both viruses could support these clinical observations. Concerning response rates to interferon therapy, no satisfactory results have been achieved to date, although identification of effective therapeutic schemes, based on virological status of both viruses are warranted. Publication Types: Review Review, Tutorial
PMID: 10726063 [PubMed - indexed for MEDLINE]
J Viral Hepat 2000 Jan;7(1):15-22
Replication status and histological features of patients with triple (B, C, D) and dual (B, C) hepatic infections.
Mathurin P, Thibault V, Kadidja K, Ganne-Carrie N, Moussalli J, El Younsi M, Di Martino V, Lunel F, Charlotte F, Vidaud M, Opolon P, Poynard T.
Service d'HepatoGastroenterologie, France.
In patients with multiple hepatotropic viral infections (B and C, or B, C and D), the reciprocal influence of each virus remains controversial. The aims of this study were twofold: first, to determine the impact of multiple infection on the replication status of B, C and D viruses and on histological features; and second, to compare patients with multiple infection to patients infected only with the hepatitis C virus (HCV). We retrospectively included 50 patients with multiple infection and 50 control HCV patients, who were matched on independent factors associated with fibrosis, such as age, gender, alcohol consumption and duration of infection. The replication status of hepatitis B virus (HBV), HCV and hepatitis D virus (HDV), and histological lesions, were determined. In patients with multiple infection, HCV RNA was present less frequently (44% vs 98%, P < 0.001) and the prevalence of cirrhosis was higher (35% vs 8%, P < 0.001). Among patients with triple infection (n = 16), HBV replication was observed in 25%, HCV RNA was detectable in only two (P < 0.0001) and HCV viremia was significantly lower than in the matched HCV patients (0 vs 54.7, P < 0.0001). Among patients with dual infection (n = 34), HCV RNA was present less frequently in those with serological markers of active HBV infection than in those without (30% vs 79%, P = 0.01). Hence, multiple infection is associated with a decrease of HCV replication. Cirrhosis seems to be more frequently observed in patients with multiple infection. In patients with triple infection, serum HCV RNA and markers of HBV replication were absent in 80%, suggesting that HDV acts as a dominant virus. In patients with dual infection, HBV and HCV exert an alternative, dominant replication.
PMID: 10718938 [PubMed - indexed for MEDLINE]
Zhonghua Liu Xing Bing Xue Za Zhi 1999 Jun;20(3):141-3
[Study of superinfection of HBV and HCV] [Article in Chinese]
Chen X, Xuan M, Wu D.
Taishan Medical College, Shandong Province.
OBJECTIVES: To understand the situation in hepatitis B patients coinciding with HCV and to explore its influence on HCV on the replication of HBV. METHODS: Using ELISA, 712 hepatitis B patients were tested for serum anti-HCV and markers of HBV. RESULTS: Of the 712 patients, anti-HCV positive rate was 14.47% with the highest 48.98% in patients with severe hepatitis and the lowest 3.25% in patients with acute hepatitis. Markedly different anti-HCV positive rates (P < 0.001) in patients of different clinical stages were discovered. The more severe the case with longer the course, the higher the anti-HCV positive rates. In patients with superinfection of HBV and HCV, serum HBsAg, HBeAg and anti-HBcIgM positive rates were lower than those in patients with hepatitis B (P < 0.001, P < 0.001 and P < 0.05) but the anti-HBe positive rates were higher. All the differences showed an obvious statistical significance. CONCLUSION: Hepatitis B coinciding with HCV infection is responsible for the deterioration of the disease and towards its formation of its chronic phase as well as for the inhibition of HBV replication.
PMID: 10682522 [PubMed - indexed for MEDLINE]
Liver Transpl 2000 Jan;6(1):92-6
Clinical and virologic outcomes of hepatitis B and C viral coinfection after liver transplantation: effect of viral hepatitis D.
Taniguchi M, Shakil AO, Vargas HE, Laskus T, Demetris AJ, Gayowski T, Dodson SF, Fung JJ, Rakela J.
Division of Gastroenterology and Hepatology, University of Pittsburgh School of Medicine and Thomas E. Starzl Transplantation Institute, Pittsburgh, PA 15213-2582, USA.
Hepatitis B (HBV) and C viral (HCV) dual-infection-associated liver disease is an uncommon indication for liver transplantation. The clinical and virologic outcomes in such patients have not been well studied. We retrospectively studied 13 patients with hepatitis B surface antigen (HBsAg) and antibody to HCV positivity who underwent orthotopic liver transplantation (OLT) and survived at least 30 days post-OLT. Antibody to hepatitis delta virus (HDV) was negative in 8 patients (group I) and positive in 5 patients (group II). Eleven of the 13 patients received standard hepatitis B immune prophylaxis, and they all remained HBsAg negative. All group I patients were HCV RNA positive after transplantation; in contrast, all group II patients were HCV RNA negative. Serum alanine aminotransferase levels were elevated in 88% (7 of 8) of the patients in group I compared with 20% (1 of 5 patients) in group II. None of the patients had graft loss from chronic rejection or recurrent hepatitis. Three patients had unsuspected hepatocellular carcinoma in the explant. We conclude that among liver transplant recipients with HBV and HCV coinfection, HDV infection is associated with the suppression of HCV replication and mild inflammatory activity after OLT.
PMID: 10648584 [PubMed - indexed for MEDLINE]
Blood 1999 Dec 15;94(12):4046-52
Dual or single hepatitis B and C virus infections in childhood cancer survivors: long-term follow-up and effect of interferon treatment.
Utili R, Zampino R, Bellopede P, Marracino M, Ragone E, Adinolfi LE, Ruggiero G, Capasso M, Indolfi P, Casale F, Martini A, Di Tullio MT.
Institute of Medical Therapy, Chair of Infectious Diseases, Pediatric Oncologic Service, 2nd University of Naples, Medical School, Naples, Italy. utili@unina.it
We conducted a long-term prospective study of 89 cancer survivor children who had acquired hepatitis B virus (HBV) and/or hepatitis C virus (HCV) during treatment for neoplasia, the aim being to evaluate the natural history of the diseases and the effect of interferon (IFN) treatment. Patients were followed up for a median period of 13 years (range, 8 to 20); 46 were infected by HBV, 11 by HCV, and 32 coinfected by HBV and HCV. A spontaneous clearance of hepatitis B surface antigen (HBsAg) occurred more frequently in coinfected patients (19%) than in the HBV-infected (2%; P =.004), with an annual seroconversion rate of 2.1% and 0.2%, respectively (P =.008). Loss of hepatitis Be antigen (HBeAg) occurred in 44% of coinfected and in 28% of HBV-infected patients. Clearance of serum HCV-RNA was observed in 34% and 9%, respectively, of coinfected and HCV-infected patients. Seventeen HBV-infected, 4 HCV-infected, and 16 coinfected patients received alpha-IFN treatment. In the HBV group, 6 patients (35%) cleared serum HBV DNA and seroconverted to anti-HBe; in the HCV-group, none cleared HCV-RNA. In the coinfected group, 1 patient cleared both HBV DNA and HCV-RNA, 6 patients cleared serum HCV-RNA alone, and 1 only HBV DNA and HBeAg. Overall, the diseases showed a mild histological course with no evidence of liver cirrhosis. A reciprocal interference on viral replication between HBV and HCV may occur in coinfected patients. Treatment seems to be effective for selected cases and is justified in view of the uncertain prognosis of the disease in these patients.
PMID: 10590048 [PubMed - indexed for MEDLINE]
J Gastroenterol 1999 Aug;34(4):481-5
Suppression of hepatitis C virus by hepatitis B virus in coinfected patients at the National University Hospital of Singapore.
Wang YM, Ng WC, Lo SK.
Department of Medicine, National University of Singapore, Singapore. This study was carried out to compare hepatitis B virus (HBV) and hepatitis C virus (HCV) replicative states and to determine possible interference between HBV and HCV. One thousand and sixty-one consecutive patients seen at The Gastroenterology Division of the National University Hospital of Singapore between 1988 and 1995 were screened for HBV and HCV serological markers. Anti-HCV was tested using a second-generation enzyme-linked immunosorbent assay (ELISA) method. HCV-RNA was detected by a reverse-transcription polymerase chain reaction method (RT-PCR). Data were analyzed by either paired t-test or chi2 test. Two hundred and twenty-four patients were infected with HBV alone, while 117 patients were infected with HCV only. Thirty-one patients were coinfected with HBV and HCV. HCV-RNA was detected in 104 of the 117 HCV patients (88.9%), and in 12 of 29 coinfected patients (41.4%). Serum anti-HCV levels in the coinfected patients were lower than those in the HCV-infected patients. A significant difference for anti-HCV reactivity and HCV-RNA positivity was observed between HCV-infected patients and coinfected patients (P < 0.01). In contrast, HBV-DNA and hepatitis B envelope antigen (HBeAg) positive rates were similar in HBV carriers and patients coinfected with HBV and HCV. These results show a possible interaction between HBV and HCV life cycles, and suggest that HCV replication may be negatively affected by HBV.
PMID: 10452681 [PubMed - indexed for MEDLINE]
J Med Virol 1999 Jul;58(3):201-7
Serologically silent hepatitis B virus coinfection in patients with hepatitis C virus-associated chronic liver disease: clinical and virological significance.
Fukuda R, Ishimura N, Niigaki M, Hamamoto S, Satoh S, Tanaka S, Kushiyama Y, Uchida Y, Ihihara S, Akagi S, Watanabe M, Kinoshita Y.
2nd Department of Internal Medicine, Shimane Medical University, Japan.
Frequent coinfection of surface antigen-negative hepatitis B virus (silent HBV) in hepatitis C virus (HCV)-associated chronic liver disease (CLD) has been reported. The clinical and virological significance of silent HBV infection was investigated in 65 patients with HCV-associated CLD who subsequently received interferon (IFN) therapy. HBV DNA was detected in 34 (52.3%) patients by a nested polymerase chain reaction (PCR). Virologically, all of the 34 patients were found to have HBV with an eight-nucleotide deletion in the core promoter. Coinfection of silent HBV was more frequent with HCV genotype 1b than in 2a (64.3% vs. 28.6%, P<.01). With HCV genotype 1b, the serum RNA level was significantly higher (> or =10(6) copies per milliliter vs. < or =10(5) copies per milliliter) in patients with silent HBV than those without coinfection (P<.01). Clinically, silent HBV was associated with a higher level of serum alanine aminotransferase (158.5+/-104.8 vs. 121.8+/-78.6 IU/I; mean +/- SD) and a greater histological activity of hepatitis as evaluated by histological activity index score (9.4+/-3.8 vs. 8.6+/-4.5; mean +/- SD), although it was not statistically significant. Silent HBV was also associated with poor efficacy of IFN therapy (P<.01). The results suggest that silent HBV has some promoting effect for HCV replication, at least for HCV genotype 1b, and may affect the histological activity of hepatitis and IFN response in HCV-associated CLD.
PMID: 10447413 [PubMed - indexed for MEDLINE]
Arkh Patol 1998 Nov-Dec;60(6):37-41
[An evaluation of the degree of the morphological activity and the stage of the process in patients with chronic liver diseases caused by coinfection with the hepatitis B, C and/or D viruses] [Article in Russian]
Siutkin VE, Lopatkina TN, Popova IV. I. M.
Sechenov Moscow Medical Academy.
In order to determine the differences in histological grade of activity and the stage of fibrosis in patients with chronic liver diseases due to multiple hepatitis virus infection and single infection of HBV and HCV we assessed the 68 liver biopsies samples according to Knodell and Scheuer scoring systems. Retrospectively, 216 liver biopsies reports from consecutive patients with chronic viral hepatitis were analysed. Histological activity index (HAI) in HBV/HCV coinfection was higher than in a single HCV infection; it did not differ in groups of HBV/HBC and HBV. The difference was due to the interface hepatitis; lobular activity and portal inflammation were the same. In HDV superinfection HAI was high due to both portal-periportal and lobular hepatitis. HAI depended mainly upon the presence of HBV replication; in patients with chronic hepatitis C with HBV-DNA HAI was also higher than in single HCV group. No difference in HAI between triple and dual hepatitis virus infection was found. In patients with HBV/HCV coinfection and especially with HDV superinfection the advanced stages occurred more than often than in patients with single infections.
PMID: 9949904 [PubMed - indexed for MEDLINE]
J Gastroenterol Hepatol 1998 Jan;13(1):52-6
Histological changes of concurrent hepatitis C virus infection in asymptomatic hepatitis B virus patients.
Lau GK, Wu PC, Lo CK, Lau V, Lam SK.
Department of Medicine, The University of Hong Kong, Hong Kong. gkklau@hkstar.com
In chimpanzees and in vitro cell culture studies, hepatitis C infection has been shown to suppress hepatitis B virus expression. In addition, hepatitis C infection can cause much more severe liver disease in patients chronically infected with hepatitis B virus. The aims of the present study were to determine the prevalence of hepatitis C infection in asymptomatic chronic hepatitis B Hong Kong Chinese patients and the histological changes and hepatic expression of hepatitis B virus and hepatitis C virus. Five hundred and seventy-one Hong Kong Chinese asymptomatic chronic hepatitis B patients were studied. Only four (0.7%) were hepatitis C virus antibody positive; they were also all positive for hepatitis C viral RNA in serum by reverse transcription-polymerase chain reaction (RT-PCR). Portal lymphoid aggregates and bile duct damage was noted in the liver sections of three of the four patients. Hepatic expression of hepatitis B surface antigen was detected in three patients; none had detectable hepatitis B core antigen. By branched DNA assay, serum hepatitis B DNA could not be detected in any of the four patients, but three had hepatitis C RNA. By in situ RT-PCR, hepatitis C RNA was detected in the cytoplasm of three of the four patients. These findings suggest that hepatitis C coinfection in asymptomatic chronic hepatitis B patients is uncommon in Hong Kong Chinese and active hepatitis B viral replication is absent in these patients.
PMID: 9737572 [PubMed - indexed for MEDLINE]
J Clin Microbiol 1998 Jul;36(7):2084-6
Low-level viremia and intracellular expression of hepatitis B surface antigen (HBsAg) in HBsAg carriers with concurrent hepatitis C virus infection.
Chu CM, Yeh CT, Liaw YF.
Liver Research Unit, Chang Gung Memorial Hospital and Medical College, Taipei, Taiwan. gi31208108@adm.cgmh.com.tw
Assays of hepatitis B virus (HBV) replication and antigen expression in HBV surface antigen (HBsAg) carriers with concurrent hepatitis C or D virus (HCV or HDV) infection revealed that HCV and HDV can suppress HBV replication but that HCV also substantially suppresses HBV surface protein expression. HBsAg carriers with concurrent HCV infection thus have low-level viremia and intracellular HBsAg.
PMID: 9650968 [PubMed - indexed for MEDLINE]
Arch Virol 1998;143(4):797-802
Effects of GB virus-C/hepatitis G virus on hepatitis B and C viremia in multiple hepatitis virus infections.
Kao JH, Chen PJ, Lai MY, Chen W, Chen DS.
Department of Internal Medicine, National Taiwan University College of Medicine, Taipei.
We found that patients with dual HBV and GBV-C/HGV infection had comparable serum HBV DNA positivity and mean virus concentration compared with age-matched HBV carriers, and those with triple infection had a significantly lower HBV DNA positivity. Serum HCV RNA positivity and mean virus titer were similar between HCV carriers with or without GBV-C/HGV co-infection, and those with GBV-C/HGV co-infection seemed to have a lower serum ALT level. These data suggest that GBV-C/HGV infection exerts no significant suppression on levels of chronic hepatitis B or hepatitis C viremia.
PMID: 9638149 [PubMed - indexed for MEDLINE]
Acta Med Okayama 1998 Apr;52(2):113-8
Relationship of serum markers of hepatitis B and C virus replication in coinfected patients.
Tsuji H, Shimomura H, Fujio K, Wato M, Kondo J, Hasui T, Ishii Y, Fujioka S, Tsuji T.
First Department of Internal Medicine, Okayama University Medical School, Japan.
To evaluate viral interference between hepatitis B and C, we studied coinfected patients serologically and molecular biologically. Twenty-seven patients positive for hepatitis B surface antigen (HBsAg) and anti-hepatitis C virus (HCV) antibody, were classified into Groups BC-L and BC-H according to DNA-polymerase activity (less or greater than 100 cpm, respectively). Patients with hepatitis B or C alone were also enrolled as controls. HCV-RNA was detected more often in Group BC-L than in Group BC-H. Genotype 1b of HCV was determined in 75% of Group BC-H, 87.5% of Group BC-L, and 70.7% of hepatitis C-only patients. Activity of DNA-polymerase in coinfected patients was lower in patients positive for HCV-RNA as compared with those negative. HBsAg titers tended to be lower in coinfected patients than in patients with hepatitis B virus (HBV) alone. In conclusion, in coinfection, HBV may suppress the replication of HCV and HCV appears to reduce the expression of HBsAg and probably suppresses HBV replication.
PMID: 9588227 [PubMed - indexed for MEDLINE]
J Viral Hepat 1998 Mar;5(2):123-30
Hepatitis G virus infection in hepatitis C virus-positive patients co-infected or not with hepatitis B virus and/or human immunodeficiency virus.
Thiers V, Pol S, Persico T, Carnot F, Zylberberg H, Berthelot P, Brechot C, Nalpas B.
Centre de Biologie Moleculaire Specialisee, Institut Pasteur, Paris, France.
This was a retrospective study to evaluate the prevalence and impact of hepatitis G virus (HGV) infection in hepatitis C virus (HCV)-positive drug addicts, according to the serological status of hepatitis B virus (HBV) and human immunodeficiency virus (HIV) coinfection. Two hundred and thirty-five randomly selected intravenous drug addicted patients (147 French, 88 Italian) were studied. All patients were positive for antibodies to HCV (anti-HCV). HGV RNA positivity was measured by reverse transcriptase-polymerase chain reaction (RT-PCR). Comparisons of HCV RNA positivity rate, and biological and histopathological variables, were made between HGV RNA-positive and negative patients, according to their HBV and HIV status. HGV prevalence was around 30% in both French and Italian groups. No clear association between HGV infection and a particular HCV genotype was observed. The rate of HCV RNA positivity did not differ between HGV-positive and HGV-negative patients after stratification for hepatitis B surface antigen (HBsAg) and HIV positivity. Histological severity of the underlying chronic hepatitis did not differ according to the HGV status; however, in HIV-positive HBsAg-negative patients, the hepatitis activity was moderately increased in HGV-positive patients. A striking negative influence of HBsAg positivity on HCV replication was observed in HIV-negative patients; an HCV RNA-positive rate of 25% was found in HBsAg-positive patients vs 86% in HBsAg-negative patients; similar significant results were observed in HIV-positive patients, although to a lesser extent. The underlying chronic hepatitis was significantly more severe in HBsAg-positive than in HBsAg-negative HIV-negative patients. Hence, HGV infection is highly prevalent in anti-HCV positive drug addicts but the co-infection with HCV does not seem to influence HCV replication nor to worsen the underlying chronic hepatitis, in HIV-negative patients at least. Reciprocal influence between HBV, HCV and HIV appears rather complex, HBsAg carriage seeming to exert per se a negative effect on HCV replication, particularly in HIV-negative patients, suggesting that interactions between hepatitis viruses should always be analysed in the light of HIV status.
PMID: 9572037 [PubMed - indexed for MEDLINE]
J Hepatol 1998 Jan;28(1):27-33
Characteristics of patients with dual infection by hepatitis B and C viruses.
Zarski JP, Bohn B, Bastie A, Pawlotsky JM, Baud M, Bost-Bezeaux F, Tran van Nhieu J, Seigneurin JM, Buffet C, Dhumeaux D.
Departement d'Hepato-Gastroenterologie, C.H.U. de Grenoble - BP 217, France.
BACKGROUND/AIMS: The purpose of this study was to compare the epidemiological, biochemical, virological and histological characteristics of patients with chronic hepatitis B and C with those of patients suffering from chronic hepatitis C alone. METHODS: Twenty-three patients with chronic hepatitis C, who were anti-HCV positive and HBs antigen positive, were studied and subdivided into two groups according to the presence or absence of HBV DNA replication. They were compared to 69 age- and sex-matched patients with chronic hepatitis who were anti-HCV positive and HBs antigen negative. All patients were HCV RNA positive by PCR, anti-HIV negative and anti-HDV negative. HBV DNA and HCV RNA were detected in serum by means of a branched DNA assay and PCR. The HCV serotypes were determined by the Chiron Riba HCV serotyping SIA technique. The histological characteristics included the Knodell score. RESULTS: Epidemiological, biochemical and virological parameters were not different between the two groups. Only the prevalence of cirrhosis was greater in chronic hepatitis B and C patients than in patients with chronic hepatitis C alone (p = 0.01). Among chronic hepatitis B and C patients, HCV RNA level was significantly lower in HBV DNA positive than in HBV DNA negative patients (p = 0.01). Indeed, histological lesions were more severe in HBV DNA positive than in HBV DNA negative patients, including prevalence of cirrhosis (p = 0.01), Knodell score (p = 0.05) and, among the latter, piecemeal necrosis (p = 0.01) and fibrosis (p = 0.05). The characteristics of patients with dual infection did not differ according to the mode of contamination and duration of HBV disease, except for a shorter duration in patients contaminated by drug abuse than in other patients. CONCLUSIONS: These results suggest that HBV DNA replication inhibits HCV RNA replication in patients with chronic active hepatitis B and C but increases the severity of histological lesions.
PMID: 9537860 [PubMed - indexed for MEDLINE]
Arch Virol 1997;142(3):535-44
Impaired response to alpha interferon in patients with an inapparent hepatitis B and hepatitis C virus coinfection.
Zignego AL, Fontana R, Puliti S, Barbagli S, Monti M, Careccia G, Giannelli F, Giannini C, Buzzelli G, Brunetto MR, Bonino F, Gentilini P.
Institute of Internal Medicine, University of Florence, Italy.
The possibility of hepatitis B virus (HBV) infection in HBsAg-negative patients has been shown. However, an "inapparent" coinfection by HBV in hepatitis C virus (HCV)-positive patients generally is not taken into account in clinical practice. Mechanisms responsible for resistance to interferon (IFN) have not been completely clarified. The aim of this study was to investigate whether an "inapparent" coinfection by HBV in anti-HCV-positive chronic liver disease patients may influence IFN response. Fourteen anti-HCV positive, HBsAg-negative but serum HBV DNA-positive patients by PCR and 111 anti-HCV-positive, HBsAg-negative and HBV DNA (PCR)-negative patients with chronic hepatitis were treated with 3 MU of recombinant alpha-2a IFN 3 times weekly for 12 months. Serum HBV DNA and HCV RNA were determined before treatment, after 6-12 months and in coincidence with ALT flare-up by PCR. HBV PCR was performed using primers specific for the S region of the HBV genome and HCV PCR with primers localised in the 5'NC region of HCV genome. IgM anti-HBc was tested using IMx Core-M Abbott assay. By the end of treatment, ALT values had become normal in 4/14 HBV DNA-positive patients (28%), but all "responders" (4/4) relapsed between 2 and 5 months after therapy. All but one patient were HCV RNA-positive before treatment, 6 were also both HBV DNA and HCV RNA-positive during ALT flare-ups. In 5 patients, only HBV DNA and in 3 patients, only HCV RNA was detected when transaminase values increased. All patients remained HBsAg-negative and anti-HCV-positive. IgM anti-HBc was detected both before treatment and during ALT elevation in 3 patients and only during ALT relapse in 3 others. Of the 111 anti-HCV positive, HBsAg-negative and HBV DNA (PCR)-negative patients with chronic hepatitis, a biochemical response to IFN treatment was observed in 54% of the cases. Relapse of ALT values was observed in 47% of the cases during a follow-up of 1 year after treatment. "Inapparent" HBV/HCV coinfection may be implicated in cases of resistance to IFN treatment. In addition, HBV replication may persist in patients in whom HCV replication was inhibited by IFN treatment. The pathogenic role of HBV in liver disease was confirmed by detection of IgM anti-HBc in some cases; the appearance of these antibodies only after IFN treatment suggests that IFN may exert a selective role in favour of HBV. Further studies will show the effect of different treatment schedules. HBV DNA and/or IgM anti-HBc detection with very sensitive methods may be important both as a prognostic factor and as a tool for better understanding interviral relationships and mechanisms involved in multiple hepatitis virus infections.
PMID: 9349299 [PubMed - indexed for MEDLINE]
Arch Virol 1997;142(3):445-51
Multiple hepatitis virus infections in chronic HBsAg carriers in Naples. Sagnelli E, Felaco FM, Filippini P, Scolastico C, Rapicetta M, Stroffolini T, Piccinino F.
Clinic of Tropical Diseases, Second University of Naples, Italy.
In order to determine the prevalence of multiple infections with hepatitis viruses in chronic HBsAg carriers in Naples, to assess the interaction between HBV, HDV and HCV infections and to evaluate the influence of multiple virus hepatitis infections on the clinical presentation, we studied 198 HBsAg chronic carriers observed consecutively from 1971 to 1988 at our Liver Unit. Of the 198 HBsAg chronic carriers, 171 had undergone percutaneous liver biopsy. The presence of HBcAg or HDAg in the liver biopsy was considered a marker of HBV or HDV replication, respectively; the presence of anti-HCV was considered a marker of HCV infection. Anti-HCV was observed in 13.6% of the 22 subjects with normal liver, in 27.7% of the 47 patients with minimal chronic hepatitis, in 40% of the 50 with mild chronic hepatitis, in 70.6% of the 17 with moderate hepatitis, in 66.7% of the 3 with severe chronic hepatitis and in 65.6% of the 32 with active cirrhosis. Anti-HCV positive cases were antiHD positive more frequently than the anti-HCV negative (59.2% vs. 43%, p = 0.05). HDV infection exerted a clear inhibition on the HBV genome. Among the 171 HBsAg chronic carriers, the finding of an active chronic hepatitis (moderate chronic hepatitis + severe chronic hepatitis + active cirrhosis) is less frequent in subjects with HBV replication alone than in those with HDV replication or HCV infection. Patients with both HBV replication and HCV infection and those with both HDV replication and HCV infection showed a very high prevelance of active chronic hepatitis.
PMID: 9349290 [PubMed - indexed for MEDLINE]
Cancer 1997 Dec 1;80(11):2060-7
Does dual infection by hepatitis B and C viruses play an important role in the pathogenesis of hepatocellular carcinoma in Japan?
Shiratori Y, Shiina S, Zhang PY, Ohno E, Okudaira T, Payawal DA, Ono-Nita SK, Imamura M, Kato N, Omata M.
Department of Internal Medicine (II), University of Tokyo, Japan.
BACKGROUND: There are contradictory data concerning the synergistic effect of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection on the progression from chronic hepatitis to hepatocellular carcinoma (HCC). METHODS: To clarify the role of coinfection with HBV and HCV in the progression and pathogenesis of HCC, viral and clinicopathologic features were studied in 368 consecutive HCC patients at the University of Tokyo from 1991-1995. RESULTS: Approximately 83% of patients (305 patients) were seropositive for the HCV antibody ("C-viral") and approximately 10% (37 patients) were positive for the hepatitis B surface antigen ("B-viral"). Positivity for both (dual infection) was found in only 2% of patients, and negativity for both in 5%. The incidence of dual infection in HCC patients was Similar to that in 549 patients with chronic hepatitis (1%) and 119 patients with cirrhosis (1%). Of the six HCC patients with dual infection, five patients were positive for the HBV early antigen and HBV DNA was less than measurable, whereas HCV RNA was detected and ranged from 10(3)-10(6) copies/50 microL of serum by competitive reverse transcriptase-polymerase chain reaction, and the clinical features resembled those of "C-viral" HCC. The remaining patient was early antigen positive and had HBV DNA by slot blot analysis, but the serum HCV RNA level was less than measurable. These data indicate that mutually exclusive viral replication occurred in patients with persistent coinfection. To further clarify further the possible involvement of HBV infection in "C-viral" HCC, HBV core antibody (HBcAb) was tested in 192 patients and was found to be positive in 111 and negative in 81. The serum HCV RNA level and clinicopathologic features (such as age and the severity of liver disease) were similar among the "C-viral" HCC patients irrespective of the presence or absence of HBcAb. CONCLUSIONS: Based on these results, coinfection was found to be much less prevalent than generally is claimed, and even in a few HCC patients with the coinfection the mutually exclusive viral replication was noted, suggesting that coinfection plays little if any role in the development of HCC.
PMID: 9392327 [PubMed - indexed for MEDLINE]
Eur J Clin Microbiol Infect Dis 1997 Jun;16(6):445-51
Viral replication in patients with concomitant hepatitis B and C virus infections.
Crespo J, Lozano JL, Carte B, de las Heras B, de la Cruz F, Pons-Romero F.
Gastroenterology and Hepatology Unit, University Hospital Marques de Valdecilla, Faculty of Medicine, Cantabria, Spain.
The aim of this study was to assess the implications of dual infection with hepatitis B virus (HBV) and hepatitis C virus (HCV). The HBV and HCV status in 100 patients with chronic hepatitis was analysed. HBV DNA was studied using liquid hybridization and the polymerase chain reaction (PCR). HCV viremia was measured using qualitative and quantitative PCR. The HCV genotype was determined by PCR. Patients were divided into three groups according to their HCV-RNA and HBsAg status: group I consisted of 40 patients with chronic hepatitis caused by HBV; group II, 40 patients with chronic hepatitis caused by HCV; and group III, 20 patients infected with both viruses. The HBV-DNA level was higher in group I than in group III (66.4 vs. 11.5 pg/ml; p < 0.05). Quantification of HCV viremia revealed mean values of 36.9 copies x 10(5)/ml in group II and 5.5 copies/ml x 10(5) in group III (p < 0.05). The mean aminotransferase level and histological activity were higher in group III. HCV genotype lb was the predominant type. The data suggest that there is reciprocal inhibition of viral replication in patients with dual HBV and HCV infection. Liver disease appears to be more severe in patients with chronic hepatitis B and C.
PMID: 9248747 [PubMed - indexed for MEDLINE]
J Med Virol 1997 Apr;51(4):313-8
Relevance of inapparent coinfection by hepatitis B virus in alpha interferon-treated patients with hepatitis C virus chronic hepatitis.
Zignego AL, Fontana R, Puliti S, Barbagli S, Monti M, Careccia G, Giannelli F, Giannini C, Buzzelli G, Brunetto MR, Bonino F, Gentilini P.
Istituto Medicina Interna, University of Florence, Italy.
The aim of the study was to investigate whether an "inapparent" coinfection by hepatitis B virus (HBV) in anti-HCV-positive chronic liver disease patients may influence interferon (IFN) response. Fourteen anti-HCV-positive, hepatitis B surface antigen (HBsAg)-negative but serum HBV-DNA-positive patients and 111 anti-HCV-positive, HBsAg-negative, and HBV-DNA-negative patients with chronic hepatitis were treated with 3 MU of recombinant alpha-2a IFN 3/week for 1.2 months. Serum HBV-DNA and HCV-RNA were determined before treatment, after 6-12 months, and at the time of alanine aminotransferase (ALT) flare-up by HBV polymerase chain reaction (PCR) and HCV PCR, respectively. IgM anti-HBc were tested using the IMx Core-M assay (Abbott Laboratories, North Chicago, IL). By the end of treatment, ALT values had become normal in 4/14 HBV-DNA-positive patients (28%), but all "responders" (4/4) relapsed. IgM anti-HBc was detected both before treatment and during ALT elevation in three patients and only during ALT relapse in another three. In the remaining 111 patients, a biochemical response to IFN treatment was observed in 54% and relapse of ALT values in 47%. "Inapparent" HBV/HCV coinfection may be implicated in cases of resistance to IFN. HBV replication and HBV-related liver damage may persist in patients in whom HCV replication was inhibited by current doses of IFN, as suggested also by the presence of IgM anti-HBc in some cases. Further studies will show the effect of different treatment schedules. HBV-DNA and/or IgM anti-HBc detection with very sensitive methods may be important both as a prognostic factor and as a tool for better understanding of intervirus relationships and mechanisms involved in multiple hepatitis virus infections.
PMID: 9093946 [PubMed - indexed for MEDLINE]
: World J Surg 1997 Jan;21(1):78-84; discussion 85
De novo hepatitis B and C viral infection after liver transplantation.
Cavallari A, De Raffele E, Bellusci R, Miniero R, Vivarelli M, Galli S, Luchetti R, Fruet F, Giordano E, Mazziotti A, Conte R, Sprovieri G.
Istituto di Clinica Chirurgica II, Universita di Bologna, Policlinico S Orsola, Via Massarenti 9, 40138 Bologna, Italy.
Hepatitis B (HBV) and hepatitis C (HCV) viral infections often recur after orthotopic liver transplantation (OLT), but viral infections acquired with OLT have not been widely investigated. The aim of the study was to evaluate the incidence, evolution, and diagnostic problems of de novo HBV and HCV infections in liver transplant recipients with long-term follow-up. Altogether 121 transplant recipients entered the study. HBV, HDV, and HCV infections were diagnosed by means of serology and the polymerase chain reaction (PCR). Three patients became hepatitis B surface antigen (HBsAg)-positive after OLT, all of whom showed signs of persistent viral replication. Twelve patients became anti-HCV-positive after OLT: After clearance of passive antibodies, active anti-HCV seroconversion was usually delayed. The viral genome was detected in 9 of 12 patients, with fluctuations of viremia during their follow-up. The other three patients, who were HBsAg-positive before and after OLT, were repeatedly HCV-RNA-negative despite persistent anti-HCV reactivity. Four pre-OLT HBsAg-positive patients had evidence of HBV-related liver transplant disease. The remaining 8 of 12 patients experienced repeated alanine aminotransferase increases more than two times normal after transplant. De novo infections due to primary hepatotropic viruses were frequent after OLT in our experience. Early diagnosis of infection, especially when the HCV is involved, may be problematic and should be taken into account in patients showing persistent aminotransferase abnormalities. Monitoring viral markers and accurate evaluation of biopsy specimens are mandatory. The interference between HBV and HCV might play a role in the replicative cycle of one or both viruses in co-infected patients.
PMID: 8943182 [PubMed - indexed for MEDLINE]
Zhonghua Yi Xue Za Zhi 1996 May;76(5):345-8
[Immunohistochemical double labelling studies on liver tissues superinfected with hepatitis C virus and hepatitis B virus] [Article in Chinese]
Lang Z, Meng X, Guo X.
Youan Hospital, Beijing.
OBJECTIVE: To explore the relatiship between hepatitis C virus (HCV) and hepatitis B virus (HBV) replication in liver tissue of patients superinfected with HCV and HBV. METHODS: The expresion and distribution of HCVAg and HBVAg in paraffin-embeded liver tissue from 25 autopsy cases were studied with immunohistochemical double labelling techniques using monoclonal anti-HCV NS3 and anti-HCV NS5 as well as polyclonal anti-HBs and anti-HBc. RESULTS: HBsAg and HCV NS3 or NS5 antigen were detected at the same section in 11 and 12 cases, and HBcAg and HCV NS3 or NS5 antigen in each 10 cases, respectively. Nearly all of the specimens with single labelling stained positive tissue for HC-VAg or HBVAg were also those positive with double labelling studies for HCVAg and HBVAg. The distribution of HCV and HBV infected hepatocytes was characterized as diffuse and single or cluster scattered in liver lobular. There were no differences in expression related to replication such as membranous, cytoplasmic type of HBsAg or cytoplasmic type of HBcAg and the cases positive for HCV NS3Ag or HCV NS5Ag between the group of HCV superinfected with HBV and the group infected with single HCV or HBV (chi 2 = 0.154 and 0.198, P > 0.05). CONCLUSION: The results suggested that there was no interference or suppression each other in liver tissues superinfected with HCV and HBV.
PMID: 9206196 [PubMed - indexed for MEDLINE]
J Med Virol 1996 May;49(1):66-9
Chronic delta hepatitis: is the prognosis worse when associated with hepatitis C virus and human immunodeficiency virus infections?
Buti M, Jardi R, Allende H, Cotrina M, Rodriguez F, Viladomiu L, Esteban R, Guardia J.
Department of Hepatology, Hospital General Universitario Valle Hebron, Barcelona, Spain.
Eighty-six patients were followed for 6.5 years to study the epidemiological, virological, and histological course of chronic delta hepatitis and the relationship of this disease with HIV and HCV infection. Patients were classified into four groups according to simultaneous HCV and/or HIV infection: group 1, HDV infection (20 cases); group 2, HDV and HCV infection (11 cases); group 3, HDV and HIV infection (12 cases), and group 4, HDV, HCV, and HIV infection (43 cases). All but 14 patients were asymptomatic at presentation. Liver histology showed chronic active hepatitis in 53 cases and cirrhosis in 19 cases. During followup, 52 patients remained asymptomatic, 34 developed hepatic dysfunction, 28 died, and 1 received a liver transplant. Among the 28 patients who died, 4 had HDV infection; 3 HDV and HCV infection; 3 HDV and HIV infection; and 18 HDV, HCV, and HIV infection. Death was due to liver failure in 16 (57%), AIDS in 10 (36%), and was unrelated to liver disease in 2 (8%) cases. There results demonstrate that chronic delta hepatitis is a severe disease, especially among drug users with HIV and HCV infection. The high morbidity and mortality of chronic delta hepatitis justifies the use of antiviral therapy to modify the natural course of the disease.
PMID: 8732862 [PubMed - indexed for MEDLINE]
J Med Virol 1996 Feb;48(2):157-60
Hepatitis C genotypes in patients with dual hepatitis B and C virus infection.
Pontisso P, Gerotto M, Ruvoletto MG, Fattovich G, Chemello L, Tisminetzky S, Baralle F, Alberti A.
Clinica Medica 2, Universita di Padova, Italy.
In patients with chronic hepatitis B and C virus (HBV, HCV) infection, an inverse relationship in the replicative activity of the two viruses has been reported. In the present study the genotype of HCV was evaluated in 34 consecutive cases found with hepatitis B surface antigen (HBsAg) and anti-HCV in the serum, in order to identify its possible influence in determining the pattern of HBV/HCV interaction. Nineteen patients were HCV-RNA positive and could be genotyped: 8 were infected by HCV-1 (3 by HCV-1a and 5 by HCV-1b), 10 by HCV-2, and only 1 by HCV-3. Among these, 3 were HBV-DNA positive, compared to 10 of 15 HCV-RNA-negative patients (P = 0.003), and all 3 were coinfected with HCV-2. Mean alanine aminotransferase (ALT) levels were similar between patients infected with HCV-1 and HCV-2. Among 7 patients with cirrhosis 5 were infected by HCV-2, while 6 of 12 of those without cirrhosis had HCV-1 infection. In conclusion, HBV replication was inhibited more efficiently by HCV-1 than by HCV-2. Cirrhosis was frequently found in patients with dual HBV and HCV-2 infection.
PMID: 8835349 [PubMed - indexed for MEDLINE]
Dig Dis Sci 1995 Jul;40(7):1583-8
Suppression of hepatitis C virus (HCV) replication by hepatitis D virus (HDV) in HIV-infected hemophiliacs with chronic hepatitis B and C.
Eyster ME, Sanders JC, Battegay M, Di Bisceglie AM.
Department of Medicine, Pennsylvania State University School of Medicine, Hershey, USA.
Most hemophiliacs who are coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) have high serum levels of HCV RNA. To study the impact of multiple hepatitis virus infections, we evaluated all eight chronic carriers of hepatitis B surface antigen (HBsAg) from a previously studied cohort of 99 hemophiliacs with chronic HIV and HCV infections. Stored serum or plasma samples were tested for antibody to hepatitis D virus (anti-HDV) by ELISA; qualitatively for HCV RNA, HBV DNA, and HDV RNA by the polymerase chain reaction (PCR); and quantitively for HIV RNA, HCV RNA, and hepatitis B virus (HBV) DNA by a quantitative branched DNA signal amplification assay. HCV RNA was detected in only one of five patients with HDV infections on a cross-sectional study, and this individual had low levels (< 3.5 x 10(5) genome eq/ml) of HCV RNA. In contrast, all three without HDV infections had high levels (> 1.5 x 10(7) genome eq/ml) of HCV RNA. HIV RNA was present in all eight patients. There was no correlation between the level of HIV RNA and the presence of hepatitis viruses. Three of the eight patients (38%) died of liver failure and another has hypersplenism with hypoprothrombinemia. We conclude that HDV infection appears to suppress HCV replication and that liver failure is common in adult HIV-infected hemophiliacs with chronic HCV and HBV infections. These findings have implications for the therapy of HCV-infected hemophiliacs who are HBsAg positive.
PMID: 7628288 [PubMed - indexed for MEDLINE]
J Med Virol 1995 Jul;46(3):258-64
Long-term follow-up of hepatitis B virus and hepatitis C virus replicative levels in chronic hepatitis patients coinfected with both viruses.
Ohkawa K, Hayashi N, Yuki N, Masuzawa M, Kato M, Yamamoto K, Hosotsubo H, Deguchi M, Katayama K, Kasahara A, et al.
First Department of Medicine, Osaka University School of Medicine, Japan.
Dual infection with hepatitis B and C viruses is often encountered in endemic areas of both viruses. However, understanding of the clinical and virological implications is limited. The aim of this study was to investigate the role of each virus in liver injury and the interaction between the two viruses in dual infection with hepatitis B and C viruses. Three patients who had chronic infection with both hepatitis B and C viruses were examined, and a longitudinal study of both serum hepatitis B virus DNA and hepatitis C virus RNA levels over 4 years was undertaken. The results were correlated with serum alanine aminotransferase levels. Serum alanine aminotransferase values showed a relationship with hepatitis B virus replicative levels, but not with hepatitis C virus replicative levels in all 3 patients. Serial changes of replicative levels of both viruses were studied, and it was found that hepatitis C virus replicative levels were enhanced after the decline of hepatitis B virus replication in 1 of the 3 patients. In the remaining 2 patients, a transient rise of hepatitis C virus replicative levels in association with a decrease of hepatitis B virus replication was also observed during part of the follow-up period. These findings indicate that hepatitis B virus may play a dominant etiological role in liver injury, and that a suppressive action between hepatitis B and C viruses may occur in dual infection with both viruses.
PMID: 7561800 [PubMed - indexed for MEDLINE]
J Med Virol 1995 Feb;45(2):236-9
Dominant replication of either virus in dual infection with hepatitis viruses B and C.
Koike K, Yasuda K, Yotsuyanagi H, Moriya K, Hino K, Kurokawa K, Iino S.
First Department of Internal Medicine, University of Tokyo, Japan.
To characterize the state of dual infection with hepatitis B virus (HBV) and hepatitis C virus (HCV), HBV-DNA and HCV-RNA levels were determined by spot hybridization or polymerase chain reaction in the sera of patients who were positive for both hepatitis B surface antigen and HCV antibody. Among 27 patients who showed evidence of double infection, 21 (77.8%) had detectable levels of only either HBV or HCV genome in their sera, 2 (7.4%) showed none of the viral genomes, and 4 (14.8%) had both HBV-DNA and HCV-RNA. In the 4 patients with both HBV-DNA and HCV-RNA, the titers of HCV-RNA or HBV-DNA were lower than those in the patients with HCV-RNA or HBV-DNA alone. In some patients with chronic hepatitis, the viruses appeared to replicate in turn in the course of the disease. These results indicate that the viruses show alternating dominance in replication in most of the patients who have dual infection with HBV and HCV, probably due to interference of the viruses.
PMID: 7539830 [PubMed - indexed for MEDLINE]
J Infect Dis 1994 Dec;170(6):1582-5
Absence of precore stop mutant in chronic dual (B and C) and triple (B, C, and D) hepatitis virus infection.
Yeh CT, Chiu CT, Tsai SL, Hong ST, Chu CM, Liaw YF.
Liver Unit, Chang Gung Memorial Hospital, Taipei, Taiwan.
Sequences of hepatitis B virus (HBV) precore regions from 7 patients with HBV and hepatitis C virus (HCV) dual infection and 2 with HBV, HCV, and hepatitis D virus (HDV) triple infection were analyzed. Two patients, 1 with only acute HBV infection and 1 with only chronic HBV infection, were also included for comparison. All patients had antibodies against HBV e antigen (anti-HBe) except 1 with chronic hepatitis B and C. No precore stop mutation at codon 28 (TGG to TAG mutation) was found in 21 cloned sequences from the 7 patients with HBV and HCV infection, nor in 11 cloned sequences from 2 patients with HBV, HCV, and HDV infection. However, mutations in other positions of the precore region were observed in 2 patients with hepatitis B and C. In both cases, precore sequences with mutations in different positions were obtained from the same serum sample. No mutations were observed in other positions of the precore region in the 2 patients with hepatitis B, C, and D. The presence of anti-HBe in these patients was probably due to the low level of HBV replication and not to the presence of the precore stop mutant.
PMID: 7995999 [PubMed - indexed for MEDLINE]
Dig Dis Sci 1994 Dec;39(12):2650-5
Hepatitis delta virus RNA in serum of patients with chronic delta hepatitis.
Simpson LH, Battegay M, Hoofnagle JH, Waggoner JG, Di Bisceglie AM.
Liver Diseases Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
We studied 28 patients with chronic delta hepatitis for the presence of hepatitis delta virus (HDV) RNA in serum. The hot start polymerase chain reaction (PCR) method, in which the reaction begins at 60-80 degrees C, showed a higher sensitivity than conventional PCR reaction. Additionally, the presence of hepatitis B (HBV) and C virus (HCV) infections were determined by PCR. HDV RNA was detected in 26 patients (93%), HBV DNA in 22 (79%), and HCV RNA in only one. Detection of HDV RNA correlated very well with detection of hepatitis delta antigen by immunostaining in the liver. In six patients HDV RNA was detectable despite the absence of HBV DNA in serum, suggesting that high levels of HBV are not required for HDV replication. Of 29 control patients with chronic hepatitis B without antibody to HDV, none had detectable HDV RNA, while all had HBV DNA in serum. Detection of HDV RNA with PCR proved highly sensitive and specific, demonstrating that virtually all patients with chronic HDV infection had ongoing viral replication.
PMID: 7995191 [PubMed - indexed for MEDLINE]
Liver 1994 Oct;14(5):241-4
Inapparent "wild-type" and "e-minus variant" HBV infection in patients with HCV-related chronic hepatitis.
Sardo MA, Rodino G, Brancatelli S, Pernice M, Campo S, Squadrito G, Russo F, Raimondo G.
Dipartimento di Medicina Interna, Universita di Messina, Italy.
We analysed DNA extracted from liver biopsy specimens and serum samples from 42 HCV-RNA-positive/HBsAg-negative subjects with chronic hepatitis. Twenty-eight of them were anti-HBs/anti-HBc-positive (group A), while 14 were negative for all HBV markers (group B). HBV sequences were found in hepatic DNA of 12 cases (11 of group A, one of group B), but in the serum of only two cases of group A. Sequencing analysis of pre-core region of HBV-DNA showed the presence of wild-type HBV in three cases, HBeAg-defective HBV in three cases, and the coexistence of both viral populations in six cases. These results indicate that HBV and HCV infection may coexist in HBsAg-negative chronic hepatitis, particularly in anti-HBs/anti-HBc-positive patients. However, HBV replication appears suppressed in these cases, and this state of latency may involve both wild and HBeAg-defective HBV types.
PMID: 7997082 [PubMed - indexed for MEDLINE]
Zhonghua Liu Xing Bing Xue Za Zhi 1994 Oct;15(5):275-7
[Superinfection of hepatitis viruses] [Article in Chinese]
Chen Z, Liu X, Li LY.
Air Force Fuzhou Hospital, Fuzhou.
Using ELISA method, anti-HAV-IgM and anti-HCV were determined in 493 blood donors and 192 patients with HBV infection. The positive rate of anti-HCV in blood donors was 1.62%. The superinfection rates of HBV and HAV, HBV and HCV, HBV, HAV and HCV in patients with HBV infection were 16.7%, 3.13% and 0.52%, respectively. The incidence of hepatitis B viral replication marker was found to be lower in patients with superinfection of types A and B and/or C hepatitis viruses than in those with HBV infection alone. The prolonged course was found to be longer and the degree severer in patients with superinfection of types A and B and/or C hepatitis viruses than in those with HAV or HBV or HCV infection alone. The results suggest that those patients with superinfection of types A and B and/or C hepatitis viruses showed poor prognosis and prolonged course, and many patients with chronic Type A hepatitis resulted from superinfection HBV and/or HCV.
PMID: 7532107 [PubMed - indexed for MEDLINE]
J Hepatol 1994 Oct;21(4):509-14
Comment in: J Hepatol. 1995 Nov;23(5):630-1. J Hepatol. 1995 Oct;23(4):480.
Hepatitis C virus antibody and hepatitis C virus replication in chronic hepatitis B patients.
Ohkawa K, Hayashi N, Yuki N, Hagiwara H, Kato M, Yamamoto K, Eguchi H, Fusamoto H, Masuzawa M, Kamada T.
First Department of Medicine, Osaka University School of Medicine, Japan.
We assessed hepatitis C virus infection in 156 chronic hepatitis B patients using second-generation hepatitis C virus antibody (anti-HCV). Active virus replication was further investigated in anti-HCV-positive cases by means of polymerase chain reaction assay for the detection of serum hepatitis C virus RNA. Anti-HCV prevalence was higher in patients negative for hepatitis B e antigen (HBeAg) (10/48, 21%) than in HBeAg-positive patients (10/108, 9%) (p < 0.05), and the reactivity (cut-off index) in anti-HCV enzyme-linked immunosorbent assay of the positive cases was significantly higher in HBeAg-negative patients (4.1 +/- 0.1) than in -positive ones (3.6 +/- 0.6) (p < 0.05). The prevalence of hepatitis C virus RNA in anti-HCV-positive cases was also higher in the HBeAg-negative group (9/10, 90%) than in the -positive group (3/10, 30%) (p < 0.01). Viremia was found in association with high reactivity in anti-HCV ELISA (cut-off index > 3.5) in both groups. Nine (90%) of 10 such cases were viremic in the HBeAg-negative group compared with three (43%) of seven in the HBeAg-positive group (p < 0.05). These results suggest that hepatitis C virus replication may be influenced by hepatitis B virus replicative states, indicating possible interference between hepatitis B and C viruses.
PMID: 7529271 [PubMed - indexed for MEDLINE]
Am J Gastroenterol 1994 Aug;89(8):1147-51
Comment in: Am J Gastroenterol. 1994 Aug;89(8):1139-41.
Prevalence and significance of hepatitis C viremia in chronic active hepatitis B.
Crespo J, Lozano JL, de la Cruz F, Rodrigo L, Rodriguez M, San Miguel G, Artinano E, Pons-Romero F.
Gastroenterology and Hepatology Unit, Hospital Universitario Marques de Valdecilla, Santander, Spain.
OBJECTIVES: To assess the prevalence and significance of HCV infection in patients with chronic active hepatitis B. METHODS: We studied clinical and histological activity in 132 patients with chronic active hepatitis B, 17 of whom were co-infected by HCV. Serum HBV-DNA was determined by dot-blot hybridization and polymerase chain reaction (PCR) and serum HCV-RNA was determined by ELISA-2, RIBA-2, and reverse transcription PCR (RT-PCR). RESULTS: HBV-DNA was detected by dot-blot in five of 17 (29.4%) patients in the HCV-RNA-positive group and in 64 of 115 (55.6%) in the HCV-RNA-negative group (p < 0.05). The low levels of HBV replication (assessed by PCR) were similar in both groups. Mean levels of serum AST, ALT, and gamma-globulin, as well as mean scores of liver damage, were significantly higher among HCV-RNA-positive patients than among HCV-RNA-negative patients. CONCLUSIONS: 1) Concomitant HCV infection occurs frequently in patients with chronic active hepatitis B; 2) co-infection of HBV and HCV is more common in the absence of HBV-DNA detected by dot-blot hybridization; 3) liver disease seems to be more severe in patients with concomitant HBV and HCV infection, even though the number of replicative HBV patients was lower in the group of HCV-infected patients. This suggests that the role of HCV is probably important as the cause of persistent liver disease. 4) The detection of HBV-DNA by dot-blot and HCV-RNA by PCR could help to establish whether HBV, HCV, or both contribute to liver injury.
PMID: 8053425 [PubMed - indexed for MEDLINE]
J Hepatol 1994 Aug;21(2):159-66
Coinfection of hepatitis C virus in patients with chronic hepatitis B infection.
Sato S, Fujiyama S, Tanaka M, Yamasaki K, Kuramoto I, Kawano S, Sato T, Mizuno K, Nonaka S.
Third Department of Internal Medicine, Kumamoto University School of Medicine, Japan.
Enzyme-linked immunosorbent assays for detecting antibodies against hepatitis C virus and the polymerase chain reaction were tested in 82 chronic hepatitis B surface antigen carriers for their accuracy in diagnosing patients coinfected with hepatitis B and C viruses. To clarify the role of each virus in chronic hepatitis, serologic assays against hepatitis B virus were also tested. Thirteen (14.9%), 14 (17.1%) and 15 (18.3%) patients were anti-HCV positive using C100 (HCV1), JCC, and a second generation test (HCV2), respectively. HCV RNA was detected by polymerase chain reaction in 9 of 18 anti-HCV-positive cases. Although HCV1 assays were not sufficient, either the JCC or HCV2 assay detected all polymerase chain reaction-positive cases. Fifteen of 18 specimens that were positive in at least one of the three ELISA were seronegative for the hepatitis B e antigen. As judged by HBV DNA polymerase activity, titers of hepatitis B surface antigen and immunoglobulin A antibody against hepatitis B core antigen (IgA anti-HBc), activity of hepatitis B virus replication and immune response against hepatitis B virus in patients with coinfection was decreased to the level of hepatitis B virus asymptomatic carriers. These results show that hepatitis C virus appears to be the primary cause of active hepatitis in most patients with hepatitis B and hepatitis C virus coinfection.
PMID: 7527435 [PubMed - indexed for MEDLINE]
Gastroenterology 1994 Jul;107(1):322-3
Comment on: Gastroenterology. 1993 Nov;105(5):1529-33.
Viral replication in patients with multiple hepatitis virus infections.
Garcia-Samaniego J, Soriano V, Bravo R, Gonzalez-Lahoz J, Munoz F.
Publication Types: Comment Letter
PMID: 8020685 [PubMed - indexed for MEDLINE]
Med Microbiol Immunol (Berl) 1994 Jul;183(3):159-67
Correlation between hepatitis B viremia and the clinical and histological activity of chronic delta hepatitis.
Lozano JL, Crespo J, de la Cruz F, Casafont F, Lopez-Arias MJ, Martin-Ramos L, Pons-Romero F.
Gastroenterology and Hepatology Unit, University Hospital Marques de Valdecilla, Faculty of Medicine, Santander, Spain.
To analyze the serological, clinical and histological significance of hepatitis B virus (HBV) replication among a group of patients with chronic delta hepatitis (CDH), we have studied the clinical and the histological activity in 49 patients with CDH. The HBV-DNA was analyzed by dot-blot and polymerase chain reaction (PCR). Concomitant infection with hepatitis C virus (HCV) was analyzed by reverse transcriptase (RT)-PCR, HDV replication by dot-blot, and human immunodeficiency virus (HIV) infection by enzyme-linked immunosorbent assay. The subjects were divided into three groups according to HBV-DNA status: group I: 14 patients HBV-DNA dot-blot positive; group II: 29 patients HBV-DNA positive only by PCR, and group III: 6 patients HBV-DNA negative by dot-blot and PCR. We have found HBV-DNA by dot-blot in 28.5% of patients, and by PCR in 87.7%. Also 22 patients were anti-HCV positive (86.3% had HCV-RNA by RT-PCR). The first group (HBV-DNA dot-blot positive) had significantly higher serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) than those in the second and third groups. Likewise, serum ALT and AST were significantly higher in the second group (HBV-DNA positive by PCR) than in those of the third group. Histological inflammatory activity was significantly higher in the group of patients with HBV-DNA detectable by dot-blot. The prevalence of serum HDV-RNA and IgM anti-HDV were similar in the three groups. These results were similar in the anti-HCV-positive and -negative patients. In conclusion, these data suggest that: (1) persistence of HBV replication is a major determinant of severe liver damage in chronic delta hepatitis, and (2) HCV and HIV infections do not influence the natural history of CDH.
PMID: 7997189 [PubMed - indexed for MEDLINE]
J Viral Hepat 1994;1(2):131-7
Influence of human immunodeficiency virus infection on hepatitis delta virus superinfection in chronic HBsAg carriers.
Pol S, Wesenfelder L, Dubois F, Roingeard P, Carnot F, Driss F, Brechot C, Goudeau A, Berthelot P.
Unite d'Hepatologie, Hopital Necker, Paris, France.
It is generally agreed that hepatitis B virus (HBV) replication is reduced by hepatitis delta virus infection (HDV) and augmented by human immunodeficiency virus (HIV) infection. However, the precise nature of the interactions between HBV, HDV and HIV is controversial. The aim of this study was to evaluate the impact of HIV infection on HBV and HDV replication, and on histological scores during delta virus superinfection in HDV-positive, chronic carriers of hepatitis B surface antigen (HBsAg). We studied 38 men and six women, 15 of whom were HIV-positive and all of whom had at least one marker of HDV infection. Serum hepatitis B e antigen (HBeAg), HBV DNA, HDV RNA, anti-delta antigen antibodies (anti-HD) IgM, anti-HD IgG and hepatitis delta antigen (HDAg) were tested for in the serum and liver, respectively; anti-hepatitis C virus (HCV) antibodies were detected using a second-generation recombinant immunoblot assay. Histological specimens were scored blindly according to Knodell's classification for periportal and intralobular necrosis, portal inflammation and fibrosis. HBV DNA was detected more frequently in the HIV-positive patients than in those who were HIV-negative (25 vs 0%; P = 0.01), while markers of HDV replication (serum anti-HD IgM, serum HDV RNA and liver HDAg) were as frequent in the HIV-positive patients (69%, 40% and 50%, respectively) as in those who were HIV-negative (75%, 52% and 30%, respectively; P > 0.05). By contrast, 31% of the HIV-positive patients were serum HDAg-positive compared to only 6% of the HIV-negative patients (P = 0.001). HDV antigenaemia and anti-HD antibodies usually fluctuated in the HIV-positive patients during follow-up. The mean Knodell score was similar in the HIV-positive (11.5 +/- 3.2) and HIV-negative (10.7 +/- 2) subgroups, as was the mean semi-quantitative index of hepatic necrosis, inflammation and fibrosis. Our results provide evidence that in HDV-positive patients: (1) HIV infection counters the inhibitory effect of HDV superinfection on HBV replication; (2) serum anti-HD IgM. HDV RNA and liver HDAg are not more frequent in HIV-positive than in HIV-negative patients, suggesting that HIV infection has no effect on HDV replication (although the significance of the increased frequency of HD antigenaemia remains unclear); (3) the histological severity of liver disease is not influenced by HIV status.
PMID: 8790568 [PubMed - indexed for MEDLINE]
Gastroenterology 1993 Nov;105(5):1529-33
Comment in: Gastroenterology. 1994 Jul;107(1):322-3.
Clinical and virological profiles in patients with multiple hepatitis virus infections.
Pontisso P, Ruvoletto MG, Fattovich G, Chemello L, Gallorini A, Ruol A, Alberti A.
Istituto di Medicina Clinica, Universita di Padova, Italy.
BACKGROUND: The "in vivo" interplay between hepatitis B virus (HBV) and hepatitis C virus (HCV) both in terms of replication activity and cytopathic effect on liver cells is poorly understood. The aim of the study was to investigate their reciprocal influence in patients with HBV and HCV coinfection. METHODS: HBV and HCV genomic sequences in the serum and liver of 55 patients with chronic liver disease who were positive for anti-HCV and for markers of HBV were studied. RESULTS: Twenty-five hepatitis B surface antigen-positive patients, without markers of hepatitis D virus (HDV) infection, showed an inverse relation between seropositivity for HCV RNA and for HBV DNA (P < 0.001). HCV genomic sequences were detected in the liver of all patients positive for HBV DNA but negative for HCV RNA in serum. The biochemical activity and the histological severity of liver disease were lower in HCV RNA-positive/HBV DNA-negative patients, compared with HCV RNA (serum)-negative/HBV DNA-positive cases (P < 0.005). Nine of 10 patients with concurrent HDV infection were negative for serum and liver HCV RNA. None of 20 hepatitis B surface antigen-negative/HCV RNA-positive patients with antibodies to HBV had HBV DNA detectable in serum or liver. CONCLUSIONS: Our findings indicate a reciprocal inverse relation between HBV and HCV replication. Patients positive for antibody to HCV with antibodies to HBV usually have no evidence of HBV DNA persistence in the liver.
PMID: 8224658 [PubMed - indexed for MEDLINE]
J Virol 1993 Oct;67(10):5823-32
Suppression of hepatitis B virus expression and replication by hepatitis C virus core protein in HuH-7 cells.
Shih CM, Lo SJ, Miyamura T, Chen SY, Lee YH.
Institute of Biochemistry, National Yang-Ming Medical College, Taipei, Taiwan, Republic of China.
Hepatitis B and C viruses (HBV and HCV, respectively) are associated with acute and chronic liver diseases and hepatocellular carcinoma. To elucidate the molecular status of superinfection with these two hepatitis viruses, we cotransfected the full-length or truncated version of HCV structural genes (core and envelope 1) together with the cloned HBV DNA into a human hepatoma cell line (HuH-7). Expression of HBV-specific major transcripts (3.5 and 2.1 kb), as well as HBV antigens (hepatitis B surface antigen and hepatitis B e and core antigens), was reduced about two- to fourfold by the presence of the HCV structural genes. In addition, the secretion of HBV viral particles, including the viral nucleocapsid and mature virion, was drastically suppressed about 20-fold. Analysis of the intracellular HBV core protein-associated nucleic acid indicated that the encapsidated HBV pregenomic RNA was similarly reduced about 14-fold. Deletion analysis of the HCV structural genes demonstrated that the core gene alone or the fragment containing the core protein's N-terminal 122 amino acid residues conferred the same level of suppressive activity as the full-length structural genes. By indirect immunofluorescence, we found that the core protein of HCV was located in the cytoplasm of transfected HuH-7 cells at day 3 posttransfection and was targeted to the nucleus at day 6. Thus, the kinetics of the suppressive effect exerted by HCV constructs matched the timing of core protein entrance into the nucleus. Our results substantiate the clinical finding that HBV markers are suppressed by superinfection with HCV and further imply that this inhibitory effect may occur in the processes of transcription and encapsidation of HBV pregenomic RNA and may be mediated by the core protein of HCV. The deduced amino acid sequence of the HCV core protein has revealed that it is a basic protein which contains a putative DNA-binding motif (SPRG), as well as triplicate nuclear localization signals and several putative protein kinase A and C recognition sites. These characteristics imply that the HCV core protein can also function as a gene-regulatory protein.
PMID: 8396658 [PubMed - indexed for MEDLINE]
Gastroenterol Jpn 1992 Oct;27(5):617-23
Hepatitis type C virus infection in patients with type B chronic liver disease.
Doi T, Yamada G, Endo H, Nishimoto H, Takahashi M, Miyamoto R, Fujiki S, Shimomura H, Mizuno M, Tsuji T.
First Department of Internal Medicine, Okayama University Medical School, Japan.
Anti-c100-3 (Ortho) was determined in the sera of 152 patients with HBs antige