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HBV Replication (hbv + replication)
Selected AbstractsHigh risk of hepatitis B-virus reactivation after hematopoietic cell transplantation in hepatitis B core antibody-positive patientsEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 4 2009Kosei Matsue Abstract We investigated the serological changes in hepatitis B virus (HBV)-related markers in 55 and 26 hepatitis B surface antigen (HBsAg)-negative patients undergoing allogeneic and autologous stem cell transplantation, respectively, over the past 4 yr. Five of the 17 allogeneic and one of the five autologous patients with pretransplant anti-hepatitis B core antigen antibodies (anti-HBc) were HBsAg-positive after transplantation, whereas none of the patients negative for anti-HBc were HBsAg-positive in both groups. All patients who became HBsAg-positive received steroid-containing immunosuppressive therapy for chronic graft versus host disease (GVHD) or myeloma. Four of the six patients developed flare of HBV hepatitis, and two patients did not. One patient developed fulminant hepatitis treated with lamivudine and plasma exchange. Other five patients received entecavir from the detection of HBsAg. Although HBV-DNA levels became below the limit of detection in all patients, HBsAg positivity remained in three patients after 6 months of treatment. We concluded that anti-HBc positivity is a risk factor for reactivation of HBV after both autologous and allogeneic transplantation, and HBV-related markers should be monitored regularly in these patients. We also stress the efficacy of pre-emptive use of antiviral agents in controlling HBV replication and limiting hepatic injury due to reactivation of HBV in these patients. [source] Betulinic acid-mediated inhibitory effect on hepatitis B virus by suppression of manganese superoxide dismutase expressionFEBS JOURNAL, Issue 9 2009Dachun Yao The betulinic acid (BetA) purified from Pulsatilla chinensis (PC) has been found to have selective inhibitory effects on hepatitis B virus (HBV). In hepatocytes from HBV-transgenic mice, we showed that BetA substantially inhibited HBV replication by downregulation of manganese superoxide dismutase (SOD2) expression, with subsequent reactive oxygen species generation and mitochondrial dysfunction. Also, the HBV X protein (HBx) is suppressed and translocated into the mitochondria followed by cytochrome c release. Further investigation revealed that SOD2 expression was suppressed by BetA-induced cAMP-response element-binding protein dephosphorylation at Ser133, which subsequently prevented SOD2 transcription through the cAMP-response element-binding protein-binding motif on the SOD2 promoter. SOD2 overexpression abolished the inhibitory effect of BetA on HBV replication, whereas SOD2 knockdown mimicked this effect, indicating that BetA-mediated HBV clearance was due to modulation of the mitochondrial redox balance. This observation was further confirmed in HBV-transgenic mice, where both BetA and PC crude extracts suppressed SOD2 expression, with enhanced reactive oxygen species generation in liver tissues followed by substantial HBV clearance. We conclude that BetA from PC could be a good candidate for anti-HBV drug development. [source] Serum hepatitis B surface antigen and hepatitis B e antigen titers: Disease phase influences correlation with viral load and intrahepatic hepatitis B virus markers,,HEPATOLOGY, Issue 6 2010Alexander J.V. Thompson Although threshold levels for hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) titers have recently been proposed to guide therapy for chronic hepatitis B (CHB), their relationship to circulating hepatitis B virus (HBV) DNA and intrahepatic HBV replicative intermediates, and the significance of emerging viral variants, remains unclear. We therefore tested the hypothesis that HBsAg and HBeAg titers may vary independently of viral replication in vivo. In all, 149 treatment-naïve CHB patients were recruited (HBeAg-positive, n = 71; HBeAg-negative, n = 78). Quantification of HBeAg and HBsAg was performed by enzyme immunoassay. Virological characterization included serum HBV DNA load, HBV genotype, basal core promoter (BCP)/precore (PC) sequence, and, in a subset (n = 44), measurement of intrahepatic covalently closed circular DNA (cccDNA) and total HBV DNA, as well as quantitative immunohistochemical (IHC) staining for HBsAg. In HBeAg-positive CHB, HBsAg was positively correlated with serum HBV DNA and intrahepatic cccDNA and total HBV DNA (r = 0.69, 0.71, 0.76, P < 0.01). HBeAg correlated with serum HBV DNA (r = 0.60, P < 0.0001), although emerging BCP/PC variants reduced HBeAg titer independent of viral replication. In HBeAg-negative CHB, HBsAg correlated poorly with serum HBV DNA (r = 0.28, P = 0.01) and did not correlate with intrahepatic cccDNA nor total HBV DNA. Quantitative IHC for hepatocyte HBsAg confirmed a relationship with viral replication only in HBeAg-positive patients. Conclusion: The correlation between quantitative HBsAg titer and serum and intrahepatic markers of HBV replication differs between patients with HBeAg-positive and HBeAg-negative CHB. HBeAg titers may fall independent of viral replication as HBeAg-defective variants emerge prior to HBeAg seroconversion. These findings provide new insights into viral pathogenesis and have practical implications for the use of quantitative serology as a clinical biomarker. (HEPATOLOGY 2010) [source] Hepatitis B virus X protein affects S phase progression leading to chromosome segregation defects by binding to damaged DNA binding protein 1,HEPATOLOGY, Issue 5 2008Silvia Martin-Lluesma Chronic hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC), but its role in the transformation process remains unclear. HBV encodes a small protein, known as HBx, which is required for infection and has been implicated in hepatocarcinogenesis. Here we show that HBx induces lagging chromosomes during mitosis, which in turn leads to formation of aberrant mitotic spindles and multinucleated cells. These effects require the binding of HBx to UV-damaged DNA binding protein 1 (DDB1), a protein involved in DNA repair and cell cycle regulation, and are unexpectedly attributable to HBx interfering with S-phase progression and not directly with mitotic events. HBx also affects S-phase and induces lagging chromosomes when expressed from its natural viral context and, consequently, exhibits deleterious activities in dividing, but not quiescent, hepatoma cells. Conclusion: In addition to its reported role in promoting HBV replication, the binding of HBx to DDB1 may induce genetic instability in regenerating hepatocytes and thereby contribute to HCC development, thus making this HBV,host protein interaction an attractive target for new therapeutic intervention. (HEPATOLOGY 2008.) [source] Interferon-inducible expression of APOBEC3 editing enzymes in human hepatocytes and inhibition of hepatitis B virus replication,HEPATOLOGY, Issue 6 2006Marianne Bonvin Hypermutations in hepatitis B virus (HBV) DNA by APOBEC3 cytidine deaminases have been detected in vitro and in vivo, and APOBEC3G (A3G) and APOBEC3F (A3F) have been shown to inhibit the replication of HBV in vitro, but the presumably low or even absent hepatic expression of these enzymes has raised the question as to their physiological impact on HBV replication. We show that normal human liver expresses the mRNAs of APOBEC3B (A3B), APOBEC3C (A3C), A3F, and A3G. In primary human hepatocytes, interferon alpha (IFN-,) stimulated the expression of these cytidine deaminases up to 14-fold, and the mRNAs of A3G, A3F, and A3B reached expression levels of 10%, 3%, and 3%, respectively, relative to GAPDH mRNA abundance. On transfection, the full-length protein A3BL inhibited HBV replication in vitro as efficiently as A3G or A3F, whereas the truncated splice variant A3BS and A3C had no effect. A3BL and A3BS were detected predominantly in the nucleus of uninfected cells; however, in HBV-expressing cells both proteins were found also in the cytoplasm and were associated with HBV viral particles, similarly to A3G and A3F. Moreover, A3G, A3F, and A3BL, but not A3BS, induced extensive G-to-A hypermutations in a fraction of the replicated HBV genomes. In conclusion, the editing enzymes A3BL, A3F, and most markedly A3G, which are expressed in liver and up-regulated by IFN-, in hepatocytes, are candidates to contribute to the noncytolytic clearance of HBV. (HEPATOLOGY 2006;43:1364,1374.) [source] Impact of the hepatitis B virus genotype and genotype mixtures on the course of liver disease in Vietnam,HEPATOLOGY, Issue 6 2006Nguyen L. Toan Eight genotypes (A-H) of hepatitis B virus (HBV) have been identified. However, the impact of different genotypes on the clinical course of hepatitis B infection remains controversial. We investigated the frequency and clinical outcome of HBV genotypes and genotype mixtures in HBV-infected patients from Vietnam, Europe, and Africa. In addition, we analyzed the effects of genotype mixtures on alterations in in vitro viral replication. In Asian patients, seven genotypes (A-G) were detected, with A, C, and D predominating. In European and African patients, only genotypes A, C, D, and G were identified. Genotype mixtures were more frequently encountered in African than in Asian (P = .01) and European patients (P = .06). In Asian patients, the predominant genotype mixtures included A/C and C/D, compared to C/D in European and A/D in African patients. Genotype A was more frequent in asymptomatic compared with symptomatic patients (P < .0001). Genotype C was more frequent in patients with hepatocellular carcinoma (HCC; P = .02). Genotype mixtures were more frequently encountered in patients with chronic hepatitis in comparison to patients with acute hepatitis B (P = .015), liver cirrhosis (P = .013), and HCC (P = .002). Viral loads in patients infected with genotype mixtures were significantly higher in comparison to patients with a single genotype (P = .019). Genotype mixtures were also associated with increased in vitro HBV replication. In conclusion, infection with mixtures of HBV genotypes is frequent in Asia, Africa, and Europe. Differences in the replication-phenotype of single genotypes compared to genotype-mixtures suggest that co-infection with different HBV-genotypes is associated with altered pathogenesis and clinical outcome. (HEPATOLOGY 2006;43:1375,1384.) [source] Incubation phase of acute hepatitis B in man: Dynamic of cellular immune mechanismsHEPATOLOGY, Issue 5 2000George J.M. Webster After hepatitis B virus (HBV) infection, liver injury and viral control have been thought to result from lysis of infected hepatocytes by virus-specific cytotoxic T cells. Patients are usually studied only after developing significant liver injury, and so the viral and immune events during the incubation phase of disease have not been defined. During a single-source outbreak of HBV infection, we identified patients before the onset of symptomatic hepatitis. The dynamics of HBV replication, liver injury, and HBV-specific CD8+ and CD4+ cell responses were investigated from incubation to recovery. Although a rise in alanine transaminase (ALT) levels was present at the time of the initial fall in HBV-DNA levels, maximal reduction in virus level occurred before significant liver injury. Direct ex vivo quantification of HBV-specific CD4+ and CD8+ cells, by using human leukocyte antigen (HLA) class I tetramers and intracellular cytokine staining, showed that adaptive immune mechanisms are present during the incubation phase, at least 4 weeks before symptoms. The results suggest that the pattern of reduction in HBV replication is not directly proportional to tissue injury during acute hepatitis B in humans. Furthermore, because virus-specific immune responses and significant reductions in viral replication are seen during the incubation phase, it is likely that the immune events central to viral control occur before symptomatic disease. [source] Combination therapy with lamivudine and famciclovir for chronic hepatitis B,infected Chinese patients: A viral dynamics studyHEPATOLOGY, Issue 2 2000George Ka Lau M.D. In vitro studies have shown that lamivudine and penciclovir (the active metabolite of famciclovir) act synergistically to inhibit hepatitis B virus (HBV) replication. We compared the effectiveness of HBV viral suppression by lamivudine monotherapy versus lamivudine plus famciclovir combination therapy in Chinese patients with chronic HBV infection. Twenty-one Chinese hepatitis B e antigen (HBeAg)-positive patients, with detectable HBV DNA (Digene Hybrid Capture II), were randomized to receive either lamivudine 150 mg/d orally (group 1, 9 patients) or lamivudine 150 mg/d plus famciclovir 500 mg 3 times a day orally (group 2, 12 patients) for 12 weeks, with a follow-up period of at least 16 weeks. Serial serum HBV-DNA levels were determined and a mathematical model with provision for incomplete inhibition of virus production during therapy was applied to analyze the dynamics of viral clearance. The mean antiviral efficacy was significantly greater in group 2 than in group 1 (0.988 ± 0.012 vs. 0.94 ± 0.03, P = .0012). HBV DNA returned to pretreatment level within 16 weeks after the end of initial treatment in 4 patients (66.7%) in group 1 and none in group 2 (P = .08), who remained HBeAg positive and received no further treatment after week 12. Hence, in Chinese chronic HBeAg-positive patients, combination therapy using lamivudine and famciclovir was superior to lamivudine monotherapy in inhibiting HBV replication. Further studies of longer duration are needed to define whether combination therapy will increase the HBeAg seroconversion rate and decrease the rate of emergence of lamivudine-resistant variants. [source] Long-term outcome of tenofovir disoproxil fumarate use against hepatitis B in an HIV-coinfected cohortHIV MEDICINE, Issue 5 2009G Alvarez-Uria Objectives Tenofovir disoproxil fumarate (TDF) is active against hepatitis B virus (HBV) and HIV. However, the long-term efficacy of tenofovir disoproxil fumarate (TDF) is not well known and the appearance of resistance is a major concern. We have studied the efficacy of TDF against HBV in patients treated at an Infectious Diseases Unit. Methods We carried out a retrospective observational study of the efficacy of TDF against HBV replication in a cohort of 52 HIV-coinfected patients who received TDF for at least 6 months. Results The median duration of follow-up of TDF treatment was 34 months. Forty-one patients (79%) were positive for HBV envelope antigen (HBeAg) and 35 had received previous lamivudine monotherapy for a median duration of 32 months. Virological breakthrough was observed in nine cases (17%). At the end of the follow-up period, HBV DNA levels were <1000 copies/mL in 42 patients (81%) and <200 copies/mL in 31 patients (60%). There were no significant differences between the lamivudine-naïve and lamivudine-experienced groups. In the lamivudine-experienced group, the duration of previous lamivudine monotherapy was associated with failure to achieve HBV DNA levels <200 copies/mL (P=0.036). Adding lamivudine or emtricitabine to TDF did not improve virological suppression. In 39 patients who achieved <200 HBV DNA copies/mL during TDF treatment, virological breakthrough was seen only in two patients (5%) after a median follow-up duration of 39.7 months. Conclusions TDF was able to control HBV replication in most HIV-coinfected patients after a median follow-up duration of 34 months, regardless of previous lamivudine treatment. However, a sizeable proportion of patients developed virological breakthrough. [source] Chronic hepatitis B virus infection in Asian countriesJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 12 2000I Merican Of the estimated 50 million new cases of hepatitis B virus (HBV) infection diagnosed annually, 5,10% of adults and up to 90% of infants will become chronically infected, 75% of these in Asia where hepatitis B is the leading cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC). In Indonesia, 4.6% of the population was positive for HBsAg in 1994 and of these, 21% were positive for HBeAg and 73% for anti-HBe; 44% and 45% of Indonesian patients with cirrhosis and HCC, respectively, were HBsAg positive. In the Philippines, there appear to be two types of age-specific HBsAg prevalence, suggesting different modes of transmission. In Thailand, 8,10% of males and 6,8% of females are HBsAg positive, with HBsAg also found in 30% of patients with cirrhosis and 50,75% of those with HCC. In Taiwan, 75,80% of patients with chronic liver disease are HBsAg positive, and HBsAg is found in 34% and 72% of patients with cirrhosis and HCC, respectively. In China, 73% of patients with chronic hepatitis and 78% and 71% of those with cirrhosis and HCC, respectively, are HBsAg positive. In Singapore, the prevalence of HBsAg has dropped since the introduction of HBV vaccination and the HBsAg seroprevalence of unvaccinated individuals over 5 years of age is 4.5%. In Malaysia, 5.24% of healthy volunteers, with a mean age of 34 years, were positive for HBsAg in 1997. In the highly endemic countries in Asia, the majority of infections are contracted postnatally or perinatally. Three phases of chronic HBV infection are recognized: phase 1 patients are HBeAg positive with high levels of virus in the serum and minimal hepatic inflammation; phase 2 patients have intermittent or continuous hepatitis of varying degrees of severity; phase 3 is the inactive phase during which viral concentrations are low and there is minimal inflammatory activity in the liver. In general, patients who clear HBeAg have a better prognosis than patients who remain HBeAg-positive for prolonged periods of time. The outcome after anti-HBe seroconversion depends on the degree of pre-existing liver damage and any subsequent HBV reactivation. Without pre-existing cirrhosis, there may be only slight fibrosis or mild chronic hepatitis, but with pre-existing cirrhosis, further complications may ensue. HBsAg-negative chronic hepatitis B is a phase of chronic HBV infection during which a mutation arises resulting in the inability of the virus to produce HBeAg. Such patients tend to have more severe liver disease and run a more rapidly progressive course. The annual probability of developing cirrhosis varies from 0.1 to 1.0% depending on the duration of HBV replication, the severity of disease and the presence of concomitant infections or drugs. The annual incidence of hepatic decompensation in HBV-related cirrhosis varies from 2 to 10% and in these patients the 5-year survival rate drops dramatically to 14,35%. The annual risk of developing HCC in patients with cirrhosis varies between 1 and 6%; the overall reported annual detection rate of HCC in surveillance studies, which included individuals with chronic hepatitis B and cirrhosis, is 0.8,4.1%. Chronic hepatitis B is not a static disease and the natural history of the disease is affected by both viral and host factors. The prognosis is poor with decompensated cirrhosis and effective treatment options are limited. Prevention of HBV infection thorough vaccination is still, therefore, the best strategy for decreasing the incidence of hepatitis B-associated cirrhosis and HCC. [source] Occult hepatitis B infection in patients infected with HIV: Report of two cases of hepatitis B reactivation and prevalence in a hospital cohortJOURNAL OF MEDICAL VIROLOGY, Issue 2 2010B. Bloquel Abstract Patients co-infected with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) are particularly at risk of hepatitis B reactivation. Two cases of patients infected with HIV with isolated anti-HBc antibodies who had experienced an HBV reactivation are described. In the two cases HBV reactivation occurred after withdrawal of anti-retroviral treatment with anti-HBV activity from the patients' highly active antiretroviral therapy (HAART), in accordance with HIV genotypic resistance profiles. Consequently, plasma samples from 383 patients infected with HIV were tested to assess the prevalence of occult HBV infection in the Infectious Diseases Department Unit of Nancy Hospital by investigating serological patterns and HBV replication. Forty-five percent (172/383) of patients had had previous contact with HBV. Isolated anti-HBc antibodies were observed in 48 patients (48/383, 12%) and, among these, 2 were HBV-DNA positive. Since 75% (288/383) of the patients were treated with HAART, including at least one drug active against HBV, occult HBV infection was perhaps unrecognized. In cases of HIV infection, all patients should be screened for HBV infection and the knowledge of HBV status as well as the monitoring of HBV viral load are essential in preventing HBV reactivation. Consideration should be given to the continuation of drugs with anti-HBV activity in co-infected patients receiving HAART, as cessation of therapy is associated with a risk of HBV reactivation. At least, close monitoring of the HBV viral load is warranted in such situations. J. Med. Virol. 82:206,212, 2010. © 2009 Wiley-Liss, Inc. [source] Fatal liver failure with the emergence of hepatitis B surface antigen variants with multiple stop mutations after discontinuation of lamivudine therapyJOURNAL OF MEDICAL VIROLOGY, Issue 3 2006Ji-Ming Zhang Abstract Treatment of chronic hepatitis B virus (HBV) infection with lamivudine is effective and well-tolerated. However, discontinuation of the treatment is associated frequently with acute exacerbation of liver diseases. A patient suffering from acute liver failure after discontinuation of lamivudine treatment is described. The patient was treated with lamivudine for 4 months and ceased the treatment without consulting. After receiving lamivudine, the patient developed anti-HBs and became negative for hepatitis B surface antigens (HBsAg). However, HBV DNA reappeared to a level of 6.47,×,105 copies/ml. The patient died due to acute liver failure. Sequencing of HBV isolates revealed that mutations including G145R and stop codons occurred within the HBsAg coding region. In conclusion, HBV replication resumed after the uncontrolled cessation of lamivudine treatment in this patient and may have triggered the process leading to liver failure. Anti-HBs antibody appeared and may be the selective force for the emergence of HBV mutants. J. Med. Virol. 78:324,328, 2006. © 2006 Wiley-Liss, Inc. [source] The correlation of hepatocyte nuclear factor 4 alpha and 3 beta with hepatitis B virus replication in the liver of chronic hepatitis B patientsJOURNAL OF VIRAL HEPATITIS, Issue 8 2009Y. Long Summary., Hepatocyte nuclear factors 4 alpha (HNF4,) and 3 beta (HNF3,) are members of a group of liver-enriched transcription factors (LETFs) that play important roles in regulating the replication of hepatitis B virus (HBV). Using cell culture and animal models, we showed that HNF4, supports HBV replication in nonhepatic cells and HNF3, inhibits HBV replication. However, the expression of HNF4, and HNF3, in the liver tissue of chronic HBV-infected patients and the relationship between the levels of HNF4, and HNF3, and HBV replication are unclear. In this study, liver biopsy specimens from 86 chronic HBV-infected patients were collected. The expression levels of HNF4,, HNF3,, hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) were detected by an immunohistochemical technique and the level of HBV DNA was checked by in situ hybridization with serial sections from liver biopsy tissue samples. We show here that samples with higher levels of HNF4, expression also have higher levels of HBsAg, HBcAg and HBV DNA. In contrast, in samples with higher levels of HNF3, expression, levels of HBsAg, HBcAg and HBV DNA were lower. There was a positive correlation between HNF4, expression and HBV replication, and a negative correlation between HNF3, expression and HBV replication, in the liver of chronic HBV-infected patients. This suggests that HNF4, and HNF3, likely participate in HBV replication in patients with HBV infection, or that HBV replication may somehow influence the expression of HNF4, and HNF3, in the liver. [source] Suppression of p38 mitogen-activated protein kinase inhibits hepatitis B virus replication in human hepatoma cell: the antiviral role of nitric oxideJOURNAL OF VIRAL HEPATITIS, Issue 7 2008W.-W. Chang Summary., The role of the p38 mitogen-activated protein kinase (MAPK) pathway in hepatitis B virus (HBV) replication was investigated in this study. After transient transfection with HBV plasmid, p38 MAPK, but not JNK or ERK1/2, was significantly phosphorylated in human hepatoma cell Huh7. Interestingly, HBV proteins and RNA synthesis were significantly inhibited by a specific inhibitor of p38 MAPK, SB203580, in a dose-dependent manner. Intracellular core-associated DNA, extracellular virion-associated DNA and covalently closed circular DNA were also significantly inhibited by SB203580. Further results showed the antiviral role of nitric oxide (NO) on the suppression of HBV replication and downregulation of p38 MAPK phosphorylation. In conclusion, these results suggested that suppression of phosphorylation of p38 MAPK by inhibitor or NO could inhibit intracellular HBV replication. [source] Inhibition of hepatitis B virus replication in 2.2.15 cells by expressed shRNAJOURNAL OF VIRAL HEPATITIS, Issue 3 2005X.-R. Ren Summary., Hepatitis B virus (HBV) infection is a worldwide health problem. To determine whether RNA interference (RNAi) could inhibit ongoing HBV replication in 2.2.15 cells, we constructed shRNA-producing vector pU6P based on the mouse U6 RNA promoter and cloned 12 targeted sequences against HBV into the vector, resulting in a series of pU6-siHBV vectors. The recombinant vectors were transfected into 2.2.15 cells, HBsAg and HBeAg in cultured media were assayed using enzyme-linked immunosorbent assay at various days after transfection. The amount of HBV DNA in the culture medium was quantitated by real-time polymerase chain reaction. HBsAg and HBeAg expression were inhibited by 72.8 ± 5.4% (P = 0.00003) and 55.8 ± 6.2% (P = 0.000026), respectively, 4 days after transfection with pU6-siHBV5. The greatest inhibition of HBV DNA was decreased by approximately 1.9-fold (P = 0.013) on day 6 post transfection with pU6-siHBV11 compared with that of empty vector. No change was found for HBV protein expression and DNA replication on pU6-siGFP (negative control) transfected cells. Our data demonstrate that the transfection of HBV-targeted shRNA-producing vector in 2.2.15 cells could inhibit the HBV protein expression and HBV DNA replication specifically. RNAi may be considered as a potential antiviral approach for human HBV infection. [source] Tenofovir plus lamivudine as rescue therapy for adefovir-resistant chronic hepatitis B in hepatitis B e antigen-positive patients with liver cirrhosisLIVER INTERNATIONAL, Issue 6 2008Won Hyeok Choe Abstract Background/Aims: There is no consensus on the management of patients with adefovir (ADV)-resistant hepatitis B virus (HBV) infection. The aim of this study was to investigate whether tenofovir disoproxil fumarate (TDF) combined with lamivudine (LMV) is effective and safe in patients with resistance to or non-response to ADV. Methods: Six patients with HBV-related cirrhosis, viral breakthrough during LMV therapy and viral breakthrough or non-response during ADV therapy were treated daily with TDF plus LMV for at least 6 months. The HBV DNA level, alanine aminotransferase (ALT), the Child,Pugh score and serum creatinine were monitored. Genotypic LMV- or ADV-resistant mutations were measured in stored samples. Results: In five of six patients, ADV-resistant mutations at rt181 or rt236 were detected during ADV therapy. At 6 months of starting TDF/LMV combination, HBV DNA levels became undetectable (detection limit, 400 copies/ml) in four of six patients. Within 12 months, HBV DNA levels became undetectable in all patients, and ALT levels were normalized in four of six patients. These responses persisted up to the end of the observation period (median duration 16.5 months, range 6,21 months). The Child,Pugh scores improved in two of three patients with hepatic decompensation. No significant changes in serum creatinine were observed. Conclusion: Our data demonstrated that TDF plus LMV safely and markedly suppressed HBV replication in patients with resistance to or non-response to ADV. This study suggests that this combination may be a promising rescue therapy for these patients, particularly those with liver cirrhosis or pre-existing LMV resistance. [source] Clinical reactivation after liver transplantation with an unusual minor strain of hepatitis B virus in an occult carrierLIVER TRANSPLANTATION, Issue 8 2006Bernhard Zöllner Hepatitis B virus (HBV) DNA is detectable in a number of liver transplant candidates who are negative for hepatitis B surface antigen (HBsAg). After liver transplantation (LT), such patients may have molecular and/or serologic evidence of HBV replication. However, clinical disease from reactivation of occult HBV infection after LT has not been described. We report a patient who underwent LT for cryptogenic cirrhosis and had to be retransplanted twice for hepatic artery thrombosis. The patient was negative for HBsAg and positive for anti,hepatitis B core (HBc) and anti-HBs before all LT procedures and developed acute hepatitis B shortly after receiving the third graft. The HBV strain isolated at that time exhibited an unusual in frame insertion of a CAG motif within the HBV polymerase (HBVINS+). HBVINS+ was detected retrospectively as a minor species in pretransplantation sera and the explanted native liver by insertion-specific polymerase chain reaction. This case in an occult HBV carrier shows that clinically apparent, endogenous reinfection of the graft may occur with minor HBV variants that are not detectable in pretransplantation samples by standard diagnostic procedures. This has implications for the analysis of sources of acute hepatitis B in patients after LT and possibly for consideration of antiviral prophylaxis in anti-HBc/anti-HBs/HBV DNA-positive patients. Liver Transpl 12:1283,1289, 2006. © 2006 AASLD. [source] Lamivudine after hepatitis B immune globulin is effective in preventing hepatitis B recurrence after liver transplantationLIVER TRANSPLANTATION, Issue 4 2000S. Forrest Dodson MD The prevention of recurrent hepatitis B virus (HBV) infection after orthotopic liver transplantation (OLT) with hepatitis B immunoglobulin (HBIG) is expensive and requires indefinite parenteral administration. Lamivudine is a nucleoside analogue capable of inhibiting HBV replication. The aim of this study is to determine the efficacy of lamivudine in the prevention of recurrent HBV infection after a course of HBIG in patients who were hepatitis B surface antigen (HBsAg) positive and hepatitis Be antigen (HBeAg) negative before OLT. Patients at high risk for recurrent HBV infection (HBeAg positive and HBV DNA positive) were excluded. Thirty HBsAg-positive, HBeAg-negative patients underwent OLT from January 1993 to June 1997. All 30 patients were administered HBIG after OLT and, after 2 years, were given the option of continuing with HBIG or switching to lamivudine. Five patients were excluded: 3 patients were lost to follow-up and 2 patients died of technical complications. Three patients terminated HBIG therapy at 8, 24, and 29 months after OLT, and reinfection with HBV occurred in 1 patient. Six patients elected to continue HBIG therapy for life; 1 patient died of melanoma and the remaining 5 patients are HBsAg negative, with an average follow-up of 73 months. Sixteen patients were converted to lamivudine after a course of HBIG, and all 16 patients are HBsAg negative, with an average follow-up of 51 months after OLT. Five patients have been on lamivudine monotherapy for more than 24 months. These results suggest that lamivudine administered after a posttransplantation course of HBIG can effectively prevent the recurrence of HBV infection in patients who are HBsAg positive and HBeAg negative before OLT. [source] Changes in hepatitis B virus serology in bone marrow transplanted childrenPEDIATRIC TRANSPLANTATION, Issue 5 2002Serhan Küpeli Abstract: Suppression of the immune system and reconstitution of the donor's immune system may affect the course of a chronic viral infection in the recipients. The aim of this study is to evaluate changes in hepatitis B virus (HBV) serology after bone marrow transplantation (BMT). HBV serology and hepatic function tests were examined in 45 children before and after BMT. Before BMT, 40 patients were HBsAg negative and 5 positive. There were no HBsAg positive donors. HBsAg disappeared in two patients and anti-HBs became positive in one. Donors of these patients were anti-HBs positive. In a third patient, acute HBV infection developed and lasted without complication. This patient also seroconverted to anti-HBs. Anti-HBs disappeared in 7 of 21 anti-HBs positive patients. Among 18 patients who were HBsAg and anti-HBs negative, 11 seroconverted to anti-HBs positivity. Our findings support the notion that having an anti-HBs positive donor is important for adoptive immunity transfer and for preventing HBV replication. [source] Anti-HBV effects of CpG oligodeoxynucleotide-activated peripheral blood mononuclear cells from patients with chronic hepatitis B,APMIS, Issue 10 2005NING LI Unmethylated CpG dinucleotides in bacterial DNA or synthetic oligodeoxynucleotides containing immunostimulatory CpG motifs (CpG ODN) are known as a potent Th1-like immune enhancer in vertebrates. Chronic hepatitis B is the immunocompromising condition. We therefore investigated the effects of CpG ODN on cultured cells from chronic hepatitis B patients and healthy controls. The inhibitory effects of CpG ODN on hepatitis B virus (HBV) were also studied. The secretion of IFN-, by CpG ODN-activated peripheral blood mononuclear cells (PBMCs) from chronic hepatitis B patients and healthy controls was significantly increased when compared with PBMCs alone or GpC ODN-stimulated PBMCs. After activation with CpG ODN, the IFN-, secretion by chronically HBV-infected patient PBMCs is less than that by healthy control PBMCs. Treatment of HepG2 2.2.15 cells with culture supernatants of PBMCs activated by CpG ODN can significantly suppress the secretion of HBsAg, HBeAg and HBV DNA as compared with that of PBMCs without CpG ODN activation under the same conditions. No inhibitory effect on the replication of HBV was found for CpG ODN treatment alone. Our results indicated that CpG ODN could efficiently enhance the immune response of chronic hepatitis B patients. Moreover, the CpG ODN-activated PBMCs from chronic hepatitis B patients were able to significantly inhibit HBV replication in vitro, suggesting that CpG ODN may be a potential immunoregulator against HBV infection in the future. [source] Cytidine deaminase APOBEC3B interacts with heterogeneous nuclear ribonucleoprotein K and suppresses hepatitis B virus expressionCELLULAR MICROBIOLOGY, Issue 1 2008Wei Zhang Summary The cytidine deaminase apolipoprotein B mRNA editing catalytic subunit-3 (APOBEC3) proteins have been identified as potent inhibitors of diverse retroviruses, retrotransposons and hepatitis B virus (HBV). The mechanism of APOBEC3 proteins in the control of HBV infection, however, is less clear. Here we report that APOBEC3B (A3B) displays dual inhibitory effects on both HBsAg and HBeAg expression as well as HBV core-associated DNA synthesis. Heterogeneous nuclear ribonucleoprotein K (hnRNP K), a positive regulator of HBV expression, has been identified as a major interaction partner of A3B protein. A3B protein inhibited the binding of hnRNP K to the enhancer II of HBV (Enh II), and S gene transcription of HBV. Moreover, A3B directly suppressed HBV S gene promoter activity. Individual variation in A3B expression was observed in both normal primary hepatocytes and liver tissues. Interestingly, A3B was able to inhibit CMV and SV40 promoter-mediated gene expression. In conclusion, A3B suppresses HBV replication in hepatocytes by inhibiting hnRNP K-mediated transcription and expression of HBV genes as well as HBV core DNA synthesis. In addition, A3B protein may be a broad antiviral host factor. Thus, regulated A3B expression may contribute to non-cytolytic HBV clearance in vivo. [source] | ||||||||||||||||||||||||||||