HBV Mutants (hbv + mutant)

Distribution by Scientific Domains


Selected Abstracts


Immunomodulatory therapy for chronic hepatitis B virus infection

FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2005
D. Sprengers
Abstract Hepatitis B virus (HBV) is one of the most prevalent viral pathogens of man with around 350 million chronically infected patients. It has been postulated that in persistently infected individuals the HBV-specific immune response is too weak to eliminate HBV from all infected hepatocytes, but sufficiently strong to continuously destroy HBV-infected hepatocytes and to induce chronic inflammatory liver disease. The primary aim in the treatment of chronic hepatitis B is to induce sustained disease remission and prevent serious complications like liver failure and/or hepatocellular carcinoma. The recent emergence of drug-resistant HBV mutants and post-treatment relapse as a consequence of nucleoside analogue monotherapy emphasizes that the principal goal should be to stimulate a successful immune response. In this paper we will focus on the immune response to HBV and we will review reported data on immunotherapeutic strategies like immunomodulatory drugs (cytokines and Thymic derivates) and vaccine therapies using currently available recombinant anti-HBV vaccines, lipopeptide-based T cell vaccine and newly developed genetic vaccines. [source]


Effect of the G1896A precore mutation on drug sensitivity and replication yield of lamivudine-resistant HBV in vitro

HEPATOLOGY, Issue 1 2003
Robert Y. M. Chen
Hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) is frequently caused by a mutation (G1896A) in the hepatitis B virus (HBV) precore (PC) reading frame that creates a stop codon, causing premature termination of the PC protein. During lamivudine treatment, drug resistance develops at a similar rate in HBeAg positive and HBeAg negative CHB. Lamivudine-resistant HBV mutants have been shown to replicate inefficiently in vitro in the absence of PC mutations, but it is unknown whether the presence of PC mutations affects replication efficiency or antiviral sensitivity. This study utilized the recombinant HBV baculovirus system to address these issues. HBV baculoviruses encoding the G1896A PC stop codon mutation were generated in wild-type (WT) and lamivudine-resistant (rtM204I and rtL180M + rtM204V) backgrounds, resulting in a panel of 6 related recombinant baculoviruses. In vitro assays were performed to compare the sensitivities of the PC mutant viruses with lamivudine and adefovir and to compare relative replication yields. The PC mutation did not significantly affect sensitivities to either adefovir or lamivudine. WT HBV and PC mutant HBV showed similar replication yields, whereas the replication yields of the lamivudine-resistant mutants were greatly reduced in HBeAg positive HBVs, confirming previous observations. However, the presence of the PC mutation was found to compensate for the replication deficiency in each of the lamivudine-resistant mutants, increasing the replication yields of each virus. In conclusion, the PC stop codon mutation appears to increase the replication efficacy of lamivudine-resistant virus but does not affect in vitro drug sensitivity. [source]


Preemptive lamivudine therapy based on HBV DNA level in HBsAg-positive kidney allograft recipients

HEPATOLOGY, Issue 5 2002
Tak Mao Chan
Hepatitis B surface antigen (HBsAg)-positive kidney transplant recipients have increased liver-related mortality. The impact of lamivudine treatment on patient survival, the optimal time to start treatment, and the feasibility of discontinuing treatment have not been determined. This study examined these issues with a novel management protocol. Serum hepatitis B virus (HBV) DNA levels were measured serially in HBsAg-positive kidney transplant recipients, and lamivudine was administered preemptively to patients with increasing HBV DNA levels with or without elevation of aminotransferase levels. Outcomes of patients who underwent transplantation before or after institution of this preemptive management strategy (in January 1996) were compared. Eleven de novo patients (91.7%) who underwent transplantation between 1996 and 2000 and 15 existing patients (39.5%) who underwent transplantation between 1983 and 1995 received preemptive lamivudine therapy for 32.6 ± 13.3 months. The treatment criteria were met by de novo patients at 8.4 ± 6.2 months (range, 1-18 months) after transplantation. Suppression of HBV DNA and normalization of aminotransferase levels were achieved in all treated patients, and 21.4% had hepatitis B e antigen (HBeAg) seroconversion. The survival of preemptively managed de novo transplant patients was similar to that of HBsAg-negative controls, whereas HBsAg-positive patients who underwent transplantation before January 1996 had inferior survival (relative risk of death, 9.7 [P < .001]; relative risk of liver-related mortality, 68.0 [P < .0001]). Eleven patients (40.7%) developed lamivudine resistance. Discontinuation of lamivudine was attempted in 12 low-risk patients after stabilization and was successful in 5 (41.7%). In conclusion, preemptive lamivudine therapy based on serial HBV DNA levels and clinical monitoring improved the survival of HBsAg-positive renal allograft recipients. Treatment can be discontinued safely in selected patients after stabilization to minimize the selection of drug-resistant HBV mutants. [source]


Complex HBV populations with mutations in core promoter, C gene, and pre-S region are associated with development of cirrhosis in long-term renal transplant recipients

HEPATOLOGY, Issue 2 2002
Petra Preikschat
Long-term immunosuppressed renal transplant recipients with chronic hepatitis B virus (HBV) infection often develop liver cirrhosis (LC) and end-stage liver disease (ESLD). This study investigated accumulation and persistence of specific HBV mutants in relation to the clinical course in these patients (n = 38; mean follow-up, 3.5 years). HBV was analyzed longitudinally via length polymorphism of polymerase chain reaction (PCR) fragments (median, 6.5 serum samples per patient) as well as by cloning and partial sequencing of 346 full-length HBV genomes. Fourteen patients (group 1) developed LC or died from ESLD, whereas 24 patients (group 2) showed no evidence of LC during follow-up. Development of LC and ESLD was associated with persistence of HBV mutant populations characterized by deletions/insertions in core promoter plus deletions in the C gene and/or deletions in the pre-S region (86% of group 1 vs. 17% of group 2; P < .0001). HBV without these mutations or with core promoter mutations alone were predominantly found in group 2 (14% of group 1 vs. 75% of group 2). In patients infected with core promoter mutants, the additional appearance and persistence of deletions in the C gene and/or the pre-S region were accompanied or followed by development of LC and ESLD. The mutations were distributed on individual genomes in various combinations, leading to a high complexity of the virus population. In conclusion, these data suggest that accumulation and persistence of specific HBV populations characterized by mutations in 3 subgenomic regions play a role in pathogenesis of LC and ESLD in long-term renal transplant recipients. [source]


Molecular, immunological and clinical properties of mutated hepatitis B viruses

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 1 2002
C. Kreutz
Abstract Hepatitis B virus (HBV) is at the origin of severe liver diseases like chronic active hepatitis, liver cirrhosis and hepatocellular carcinoma. There are some groups of patients with high risk of generation of HBV mutants: infected infants, immunosupressed individuals (including hemodialysis patients), patients treated with interferon and lamivudine for chronic HBV infection. These groups are the target for molecular investigations reviewed in this paper. The emergence of lamivudine- or other antiviral-resistant variants, rises concern regarding long term use of these drugs. Infection or immunization with one HBV subtype confers immunity to all subtypes. However, reinfection or reactivation of latent HBV infection with HBV mutants have been reported in patients undergoing transplant and those infected with HIV. Mutations of the viral genome which are not replicative incompetent can be selected in further course of infection or under prolonged antiviral treatment and might maintain the liver disease. Four open reading frames (ORF) which are called S-gene, C-gene, X-gene and P-gene were identified within the HBV genome. Mutations may affect each of the ORFs. Mutated S-genes were described to be responsible for HBV-infections in successfully vaccinated persons, mutated C-genes were found to provoke severe chronic liver diseases, mutated X-genes could cause serious medical problemes in blood donors by escaping the conventional test systems and mutated P-genes were considered to be the reason for chemotherapeutic drug resistance. This paper reviews molecular, immunological and clinical aspects of the HBV mutants. [source]


Hepatitis B virus BCP, precore/core, X gene mutations/genotypes and the risk of hepatocellular carcinoma in India

JOURNAL OF MEDICAL VIROLOGY, Issue 7 2010
Mohammad Asim
Abstract The study aims to characterize mutations of the HBV genome involving BCP, Precore/core and X regions and also defines HBV genotypes in patients of hepatocellular carcinoma (HCC). The study involved 150 HBV-related HCC cases and 136 HBV-related chronic liver disease patients without HCC as controls. HBV DNA was subjected to mutational analysis using SSCP technique, genotyping by RFLP, and direct nucleotide sequencing. HBV DNA was found in 58.7% (88/150) of the HCC cases and 74.3% (101/136) of controls. HBV mutants were observed in 44.3% of HCC cases and 43.2% of controls. HBV/D was prevalent amongst the patients and controls, followed by HBV/A. The prevalence of the TT1504 mutation in the X gene, the V1753 and T1762/A1764 mutations in the BCP region, and G1914 mutation in the core gene were significantly higher in the HCC group than in the non-HCC group. Multivariate analyses showed that the TT1504, V1753, A1762T/G1764A, and the G1914 mutations and the patient's age, sex, and HBeAg status increased the risk of HCC development significantly. Also, patients with HCC had lower levels of serum albumin, viral load, and platelet counts but higher values of alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, and Alpha feto-protein than those of controls (P,<,0.001 for all comparisons). HBV/D was the predominant genotype associated with HCC cases seen in India. The presence of different types of HBV mutations, age, sex, HBeAg status, and viral load was found to increase significantly the risk of HCC development in India. J. Med. Virol. 82: 1115,1125, 2010. © 2010 Wiley-Liss, Inc. [source]


Comparison of the technical and clinical performance of the Elecsys® HBsAg II assay with the Architect®, AxSym®, and Advia® Centaur HBsAg screening assays

JOURNAL OF MEDICAL VIROLOGY, Issue 5 2010
S. Louisirirotchanakul
Abstract South East Asia has some of the highest prevalence rates of hepatitis B virus (HBV) infection (,8%) in the world, and the emergence of hepatitis B surface antigen (HBsAg) mutant strains is a growing problem. Assays with the highest levels of sensitivity, including mutant detection, should be used for routine HBsAg screening. In this large multicenter study, the clinical and technical performance of the fully automated Elecsys HBsAg II assay was compared with the Architect, AxSYM, and Advia Centaur HBsAg assays for HBsAg screening. Nine laboratories (three each from Thailand, Korea, and Singapore) compared the Elecsys HBsAg II assay with their routine HBsAg screening assay against a range of stored and routine clinical samples, including recombinant mutants. The Elecsys HBsAg II assay demonstrated equivalent sensitivity and specificity to the Architect HBsAg assay. However, the Elecsys HBsAg II assay recognized a native mutant sample (L94S, L97V, L98V, T123A) that the Architect HBsAg assay failed to detect. The AxSYM and Advia Centaur HBsAg assays appeared less sensitive for the detection of early HBV infection and also failed to detect some of the recombinant mutant strains. There was almost complete agreement between the Elecsys HBsAg II assay and comparator assays with respect to routine serum samples. The results of this study demonstrate that the Elecsys HBsAg II assay is a highly sensitive and specific screening assay for HBsAg and detects reliably the most important and clinically relevant HBV mutants and genotypes. It is suitable for routine HBsAg screening in Asia. J. Med. Virol. 82: 755,762, 2010. © 2010 Wiley-Liss, Inc. [source]


Molecular characterization of a variant virus that caused de novo hepatitis B without elevation of hepatitis B surface antigen after chemotherapy with rituximab

JOURNAL OF MEDICAL VIROLOGY, Issue 12 2008
Masami Miyagawa
Abstract Hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)-negative patients following treatment with rituximab has been reported increasingly. The aim of this study was to investigate the molecular mechanisms underlying HBV reactivation in an HBsAg-negative patient. HBV was reactivated in a 75-year-old man following chemotherapy with rituximab, without elevation of HBsAg. The patient's full-length HBV genome was cloned and the entire sequence was determined. Transfection studies were performed in vitro using recombinant wild-type HBV (wild-type), the patient's HBV (patient), and two chimeric HBV constructs, in which the preS/S region of the patient and wild-type virus had been exchanged with one another. Secreted HBsAg and intra- and extra-cellular HBV DNA were measured. The number of amino acid substitutions in HBV from this patient was much higher than in previous reports of HBV mutants, such as occult HBV and vaccine escape HBV mutants. Levels of HBsAg and HBV DNA production in vitro were significantly lower in the patient compared to wild-type transfections. From analyses of the chimeric constructs, the altered preS/S region was responsible mainly for this impairment. These results show that highly mutated HBV can reactivate after chemotherapy with rituximab, despite an unusually large number of mutations, resulting in impaired viral replication in vitro. Severe immune suppression, probably caused by rituximab, may permit reactivation of highly mutated HBV. These findings have important clinical implications for the prevention and management of HBV reactivation and may explain partially the mechanism of recent, unusual cases of HBV reactivation. J. Med. Virol. 80:2069,2078, 2008. © 2008 Wiley-Liss, Inc. [source]


Fatal liver failure with the emergence of hepatitis B surface antigen variants with multiple stop mutations after discontinuation of lamivudine therapy

JOURNAL OF MEDICAL VIROLOGY, Issue 3 2006
Ji-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]