Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019163 (hepatitis B)
 38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Synthesis of the hepatitis B virus (HBV) DNA genome occurs within the viral nucleocapsid in a mechanistically ordered fashion. The nucleocapsid contains small pores that permit influx of nucleotide triphosphates and metabolites of nucleoside analogues such as lamivudine for DNA synthesis. Lamivudine is a potent inhibitor of HBV and human immunodeficiency virus (HIV) reverse transcriptases, but substitutions of isoleucine or valine for methionine within the tyrosine-methionine-aspartate-aspartate (YMDD) motif are associated with virologic and clinical resistance to lamivudine therapy. Under lamivudine selection pressure, the high viral production rate and the low fidelity viral polymerase contribute to frequent development of the YMDD mutants. However, the pattern and dynamics of emergence of the mutant viruses over the wild-type virus are determined by multiple factors including replication efficiency, host immune response, and availability of replication space. Structural modeling of HIV reverse transcriptase has permitted key insights into the molecular basis of lamivudine resistance of HBV based on evolutionary relatedness of HIV and HBV. The side groups of isoleucine and valine of the YMDD mutants sterically prevent lamivudine from appropriately configuring into the nucleotide binding site of the reverse transcriptase. Aminotransferase flares are associated with lamivudine therapy and may signify clinical resistance with emergence of YMDD mutants. They may also herald the recovery phase with seroconversion and viral clearance. Reconstitution of the endogenous anti-HBV immune response may be equally important in the control of viral replication by lamivudine and other nucleoside analogues.
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PMID:Molecular anatomy and pathophysiologic implications of drug resistance in hepatitis B virus infection. 1166 95

When human immunodeficiency virus type 1 (HIV-1) is selected for resistance to 3TC, the methionine normally present at position 184 is replaced by valine or isoleucine. Position 184 is the X of the conserved YXDD motif; positions 185 and 186 form part of the triad of aspartic acids at the polymerase active site. Structural and biochemical analysis of 3TC-resistant HIV-1 reverse transcriptase (RT) led to a model in which a beta-branched amino acid at position 184 would act as a steric gate. Normal deoxynucleoside triphosphates (dNTPs) could still be incorporated; the oxathiolane ring of 3TCTP would clash with the beta branch of the amino acid at position 184. This model can also explain 3TC resistance in feline immunodeficiency virus and human hepatitis B virus. However, it has been reported (14) that murine leukemia viruses (MLVs) with valine (the amino acid present in the wild type), isoleucine, alanine, serine, or methionine at the X position of the YXDD motif are all resistant to 3TC. We prepared purified wild-type MLV RT and mutant MLV RTs with methionine, isoleucine, and alanine at the X position. The behavior of these RTs was compared to those of wild-type HIV-1 RT and of HIV-1 RT with alanine at the X position. If alanine is present at the X position, both MLV RT and HIV-1 RT are relatively resistant to 3TCTP in vitro. However, the mutant enzymes were impaired relative to their wild-type counterparts; there appears to be steric hindrance for both 3TCTP and normal dNTPs.
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PMID:YADD mutants of human immunodeficiency virus type 1 and Moloney murine leukemia virus reverse transcriptase are resistant to lamivudine triphosphate (3TCTP) in vitro. 1141 98

Hepatitis B virus (HBV) genotyping and hepatitis B surface antigen (HBsAg) subtyping were carried out on sera from 196 HBsAg-positive patients, including 151 refugees entering the United States and 45 injection drug users in Seattle. HBsAg subtyping was performed by enzyme immunoassay (EIA) using a panel of monoclonal antibodies and the HBV genotype was determined by polymerase chain reaction (PCR) followed by detection of amplified HBV DNA by a reverse-phase hybridization line probe assay (LiPA) using genotype-specific probes. HBV DNA was detected by PCR in 155 (79%) of the 196 sera and all 155 were genotyped by LiPA. Samples from Southeast Asia were predominantly genotype B/subtype ayw1 and genotype C/adr; samples from the former Soviet Union and eastern Europe were mostly genotype D/ayw2 and genotype D/ayw3; samples from east Africa were mainly genotype A/adw2 and genotype D/ayw2; and samples from injection drug users were mostly genotype D/ayw3 and genotype A/adw2. Some strains of ayw3 gave atypical monoclonal antibody reactivity patterns in the subtyping assay due to a Val/Ala instead of a Thr at amino acid residue 118 and a Thr instead of a Met at residue 125. A strain of ayw2 also gave an atypical monoclonal antibody reactivity pattern due to an Ala instead of a Thr at amino acid residue 123. LiPA genotyping and monoclonal EIA subtyping can provide useful information for epidemiological studies.
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PMID:Hepatitis B virus genotypes and HBsAg subtypes in refugees and injection drug users in the United States determined by LiPA and monoclonal EIA. 1142 19

We present a case of infection with lamivudine-resistant mutant hepatitis B virus (HBV) that fatally exacerbated hepatitis following the emergence of HBV with mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) motif in an immunocompetent patient who was receiving long-term lamivudine therapy. Restriction fragment length polymorphism analysis showed that the YMDD-motif mutant was the predominant form of circulating HBV at the time of the fatal exacerbation, and a necropsy specimen of the liver revealed submassive hepatic necrosis without steatosis.
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PMID:Fatal submassive hepatic necrosis associated with tyrosine-methionine-aspartate-aspartate-motif mutation of hepatitis B virus after long-term lamivudine therapy. 1143 12

Both viral loads and genome variations have been implicated in the pathogenesis of acute exacerbation of chronic hepatitis B. Hepatitis B exacerbation in patients receiving lamivudine treatment represented a unique setting to clarify their importance. Three organ recipients with posttransplantation hepatitis B exacerbation and 3 patients with chronic hepatitis B were studied. All received lamivudine treatment and their alanine aminotransferase (ALT) levels and hepatitis B virus (HBV) loads were regularly followed. Full-length genomic sequences before and during lamivudine treatment were determined in patients who had breakthrough of serum HBV DNA or elevation of serum ALT. Breakthrough of serum HBV DNA occurred after 6 to 15 months of lamivudine treatment in all. A rapid increase of viral load accompanying the emergence of tyrosine-methionine-aspartate-aspartate (YMDD) variant was followed by hepatitis B exacerbation in each patient. The mean number of nucleotide and amino acid substitutions per genome pair was equivalent in immunosuppressed or immunocompetent patients (6.3 vs. 6.3 for nucleotide, P >.05; 6.0 vs. 6.7 for amino acid, P >.05). Changes of nucleotide and amino acid beyond the YMDD motif were distributed along the whole HBV genome but none occurred within the known B-cell epitopes and human leukocyte antigen class I- or II-restricted T-cell epitopes. Our results suggest that a resurgence of viral load rather than changes of the known immunogenic viral epitopes is more closely associated with the development of hepatitis B exacerbation after the emergence of YMDD variants in patients receiving lamivudine treatment.
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PMID:Hepatitis B virus variants in patients receiving lamivudine treatment with breakthrough hepatitis evaluated by serial viral loads and full-length viral sequences. 1152 46

Lamivudine is a nucleoside analogue with potent inhibitory effects on hepatitis B virus (HBV) replication. Prolonged therapy is required for sustained suppression. However, HBV species with mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) locus of the HBV RNA-dependent DNA polymerase conferring resistance to lamivudine may emerge after 9-10 months therapy with an incidence of 38 and 67% after 2 and 4 years of lamivudine therapy, respectively. During continued lamivudine therapy, patients with YMDD mutant HBV usually show serum alanine aminotransferase (ALT) and HBV DNA elevations at lower median levels than their baseline. Marked flare of serum ALT or acute exacerbation may occur as the result of CLT-mediated hepatocytolysis directed against YMDD mutants. Although viral clearance with or without emergence of distinct lamivudine-resistant mutants may occur after such exacerbations, 20% of the exacerbations are complicated with decompensation or even fatality. The exacerbations appear to be more severe than those that occur during the natural course of wild-type HBV chronic infection. In addition, some mutations may generate S gene truncation near 'transactivity-on-region'. Thus, the benefit of prolonged lamivudine therapy must be balanced against concern about YMDD mutants. Currently, the most cost-effective strategy is to select patients with stronger endogenous anti-HBV immunity, thereby increasing efficacy and shortening the duration of lamivudine therapy. New drugs and new strategies are needed to better achieve the goals of therapy and minimize the problem of YMDD mutants.
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PMID:Impact of YMDD mutations during lamivudine therapy in patients with chronic hepatitis B. 1159 91

To explore functional domains in the hepatitis B virus (HBV) polymerase, two naturally occurring HBV isolates (56 and 2-18) with 98.7% nucleic acid sequence homology but different replication efficiencies were studied. After transfection into HepG2 cells, HBV DNA isolated from intracellular virus core particles was much higher in 56-transfected cells than in cells transfected with 2-18. The structural basis for the difference in replication efficiency between these two isolates was studied by functional domain gene substitution. The complete polymerase (P) gene and its gene segments coding for the terminal protein (TP), spacer (SP), reverse transcriptase (RT), and RNase H in 2-18 were separately replaced with their counterparts from 56 to construct full-length chimeric genomes. Cell transfection analysis revealed that substitution of the complete P gene of 2-18 with the P gene from 56 slightly enhanced viral replication. The only chimeric genome that regained the high replication efficiency of the original 56 isolate was the one with substitution of the RT gene of 2-18 with that from 56. Within the RT region, amino acid differences between isolates 2-18 and 56 were located at positions 617 (methionine versus leucine), 652 (serine versus proline), and 682 (valine versus leucine). Point mutation identified amino acid 652 as being responsible for the difference in replication efficiency. Homologous modeling studies of the HBV RT domain suggest that the mutation of residue 652 from proline to serine might affect the conformation of HBV RT which interacts with the template-primer, leading to impaired polymerase activity.
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PMID:A single amino acid in the reverse transcriptase domain of hepatitis B virus affects virus replication efficiency. 1168 64

Lamivudine (Zeffix, Epivir, GlaxoSmithKline) is the most important recent advance in the treatment of chronic hepatitis B in both adults and children. It is the only available oral treatment and has an excellent safety profile, which makes it even more attractive. It increases the rate of hepatitis B e antigen (HBeAg) loss and seroconversion in compensated chronic HBeAg-positive carriers, with subsequent improvement of histology at a similar rate as IFN-alpha. Lamivudine is mostly active in patients with elevated transaminases and is not effective in compensated patients with quiescent disease. Long-term follow-up studies are still required to evaluate long-term benefits, including those on hepatitis B surface antigen (HBsAg) seroconversion rate and disease evolution control. In decompensated patients, the drug can stabilise and improve liver function, allowing the patient to wait safely for transplantation. Patients may improve to such an extent that transplantation can be postponed. Combined with hepatitis B immunoglobulin (HBIG), lamivudine considerably decreases the risk of graft re-infection after transplantation. It is also active in chronic HBeAg-negative hepatitis patients, for whom IFN is less efficient. The major drawback is the emergence of the tyrosine-methionine-aspartate-aspartate (YMDD) mutation, which prevents further efficacy of the drug and may lead to flares of hepatitis. Due to the questions the YMDD mutation raises and because hepatitis B is a complex disease, indications for treatment must be established with care and only by physicians with expert knowledge of the disease, the drug and YMDD mutation-related issues.
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PMID:Lamivudine for the treatment of chronic hepatitis B. 1186 82

Lamivudine therapy for chronic hepatitis and decompensated liver cirrhosis related to the hepatitis B virus (HBV) resulted in improvement of liver function and inhibition of viral replication. Despite emergence of the HBV mutant, e-antigen seroconversion and improvement of liver function may be achieved with continuation of lamivudine therapy. Although hepatic decompensation has been reported in a few cases after the emergence of lamivudine-resistant mutants, fatal cases of non-transplant patients have only rarely been reported in the literature. Here, we describe a patient with HBV-related liver cirrhosis who died after a breakthrough infection with a lamivudine-resistant mutant. Hepatic failure and mortality developed after flare-up of severe hepatitis after 13 months of lamivudine treatment. Emergence of the HBV mutant with substitution of isoleucine for leucine at residue 426 (L4261) in combination with isoleucine for methionine at residue 550 (M5501) was observed at 10 and 13 months of treatment.
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PMID:Fatal hepatic failure after emergence of the hepatitis B virus mutant during lamivudine therapy in a patient with liver cirrhosis. 1191 2

Therapy with interferon (IFN), an immunomodulant with anti-viral activities, is efficacious only in a minority of chronic hepatitis B (CHB); it is more efficacious in the hepatitis B e antigen (HBeAg)-positive variety sustained by the wild type hepatitis B virus (HBV) than in the HBeAg-negative variety sustained by mutant forms of the virus. Several other therapeutic approaches were attempted in recent years. The most promising is therapy with synthetic nucleosides as anti-virals capable of blocking the replicative activity of the HBV. Lamivudine (LAM) is the first of this class of compounds that has entered clinical use. It is well tolerated and highly effective in inhibiting HBV and abate HBV-related inflammation both in the HBeAg positive and negative variety of CHB. In the HBeAg positive variety it induces sero-conversion to anti-HBe at a rate that linearly increases over the years, reaching 40% at the third year. In the HBeAg-negative variety maintenance of viral repression requires continuative therapy. A major drawback of continued LAM therapy is the risk of the emergence of mutants in the tyrosine-methionine-aspartate-aspartate locus of the polymerase gene. These mutants are no longer responsive to LAM and may rekindle disease; wild type HBV and related disease often return after suspension of therapy. Other anti-viral drugs, the prototype of which is adefovir, are currently under clinical investigation in CHB as monotherapy or complementary therapy to LAM.
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PMID:Hepatitis B: therapeutic perspectives. 1194 59


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