Fulminant Hepatic Failure Resulting From Lamivudine-Resistant HBV in a Renal Transplant Recipient - Durable Response Post Olt on Adefovir Dipivoxil and Hepatitis B Immune Globulin.

Peters, Marvin; Singer, Gary; Howard, Todd K.; Xiong, X.; Murray, Alice M.

doi:10.1097/00007890-199904150-00863

Cited by 31 publications

(42 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Finally it is notable that single point mutations like Phe-501 to Leu or Leu-515 to Met [228] and the double point mutation Leu-528 to Met/Phe-514 to Leu [241] also were found in lamivudine-treated patients without changes in the YMDDmotif. While the replication of the Met-515-mutant was hardly reduced compared to the wildtype virus, the Leu-501-variant replicated at a very low level.…”

Section: The P-genementioning

confidence: 94%

Molecular, immunological and clinical properties of mutated hepatitis B viruses

Kreutz¹

2002

J Cellular Molecular Medi

View full text Add to dashboard Cite

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.

show abstract

Section: The P-genementioning

confidence: 94%

Molecular, immunological and clinical properties of mutated hepatitis B viruses

Kreutz¹

2002

J Cellular Molecular Medi

View full text Add to dashboard Cite

show abstract

“…FHB has been reported after nucleoside analogue therapy alone or in combination with HBIG therapy. [30][31][32] These HBV variants encoded the lamivudine-resistant changes in the reverse transcriptase region at rtM204I/V ϩ/Ϫ rtL180M (W196S/L, I195M in HBsAg) as well as other changes in the genome. Bock et al 30 reported on a series of HBV mutants with HBsAg changes in the "a" determinant at either P120T or G145R, which also contained lamivudineresistant mutations.…”

Section: Hbv Mutants Associated With Fulminant Hepatitismentioning

confidence: 99%

Hepatitis B Virus Mutants and Fulminant Hepatitis B: Fitness Plus Phenotype

Bartholomeusz

2001

Hepatology

View full text Add to dashboard Cite

The human hepatitis B virus (HBV) is the smallest known double-stranded DNA virus of man that replicates its genome through a novel mechanism of reverse transcription using the RNA-replicative intermediate and the viral pregenomic RNA. 1 Viral pregenomic RNA is synthesized from molecules of covalently closed circular (ccc) DNA, the major transcriptional template of the virus, functioning as a viral minichromosome within the nucleus of infected cells. 2 The reverse transcriptase of HBV lacks a conventional proofreading function, which is found in higher-order polymerases and, not surprisingly then, HBV exhibits a mutation rate more than 10-fold higher than other DNA viruses. The rates for nucleotide substitutions vary depending on the stage of disease. The natural evolutionary rate for the HBV genome in chronic hepatitis B is approximately 1.4 to 3.2 ϫ 10 Ϫ5 substitutions/site/year, 3 whereas in the liver transplantation setting, it is almost 100-fold higher. 4 Longitudinal studies have shown that these HBV mutations are not distributed evenly over the entire genome but rather tend to cluster into mutational patterns in particular parts of the viral DNA; in particular, the basal core promoter (BCP), the precore region and the "a" determinant of the viral envelope. 5 Importantly, the type and number of mutations that accumulate in the HBV genome over time have been shown to be a marker of the duration and/or severity of the liver disease, or the type and intensity of the immune response. 5 The outcome of HBV infection depends on the interplay between the virus, the hepatocyte, and the host's immune response. 6 Under normal circumstances, HBV is not cytopathic and liver damage is the result of the host's immune response targeting infected hepatocytes. However, during special or unusual circumstances, HBV appears to be directly cytopathic for hepatocytes often causing unique histopathologic conditions such as fibrosing cholestatic hepatitis, which, before the advent of specific antiviral therapy, 7 was invariably fatal. The molecular virologic and cellular basis for fulminant hepatitis B (FHB) has been the focus of intensive investigation, but to date the results have been controversial. In the report by Kalinina et al. in this issue of HEPATOLOGY, the investigators, have provided the first evidence, using in vitro functional studies that mutations in the S gene of the HBV isolated at the time of FHB had caused a severe defect in viral particle secretion. Earlier studies from this group had shown that the infectious clones from the same samples exhibited enhanced replication levels. 8 The enhanced replication and the severe defect in viral particle secretion most likely contributed to the fulminant clinical course of recurrent HBV infection posttransplantation. The patient was also hepatitis B e antigen (HBeAg) negative. REGULATION OF HEPADNAVIRAL cccDNA: ROLE OF THE VIRAL ENVELOPEVirus persistence in infected cells during chronic infection depends on the maintenance of the HBV cccDNA pool. 9 This pool of transcript...

show abstract

“…Treatment with lamivudine is well tolerated and effective in reducing HBV DNA in the sera of chronically infected patients (16,23,45). The major clinical limitation of lamivudine is the emergence of drug-resistant mutants (3,4,15,21,27,41). The incidence of lamivudine resistance is 14% to 32% after 1 year of treatment, 38% after 2 years, and 53% to 76% after 3 years (25).…”

mentioning

confidence: 99%

In Vitro Study of the Effects of Precore and Lamivudine-Resistant Mutations on Hepatitis B Virus Replication

Heipertz¹,

Miller²,

Kelley³

et al. 2007

J Virol

View full text Add to dashboard Cite

Understanding the consequences of mutation in the hepatitis B virus (HBV) genome on HBV replication is critical for treating chronic HBV infection. In this study, HBV replication in HepG2 cells initiated by transduction with precore (PC), rtM204I, and wild-type (wt) HBV recombinant baculoviruses was compared. The pattern and magnitude of HBV replication initiated by the PC HBV recombinant baculovirus were similar to those observed for wt HBV throughout the time course examined. In contrast, when the rtM204I mutation was introduced into wt HBV, by day 10 postinfection the levels of intra-and extracellular HBV DNA were markedly reduced compared to those for wt HBV. Although the rtM204I mutation reduced the production of HBV replicative intermediates, no effect on the level of covalently closed circular DNA or HBV transcripts was observed at late time points. Coinfection studies with different ratios of wt and rtM204I baculoviruses showed that the rtM204I variant did not produce a product that inhibited HBV replication. However, the combination of the wt and rtM204I baculoviruses yielded HBV DNA levels at late time points that were greater than those for the wt alone, suggesting that wt polymerase may function in trans to boost rtM204I replication. We concluded that the rtM204I mutation generates a polymerase that is not only resistant to lamivudine but also replicates nucleic acids to lower levels in vitro.

show abstract

Fulminant Hepatic Failure Resulting From Lamivudine-Resistant HBV in a Renal Transplant Recipient - Durable Response Post Olt on Adefovir Dipivoxil and Hepatitis B Immune Globulin.

Cited by 31 publications

References 0 publications

Molecular, immunological and clinical properties of mutated hepatitis B viruses

Molecular, immunological and clinical properties of mutated hepatitis B viruses

Hepatitis B Virus Mutants and Fulminant Hepatitis B: Fitness Plus Phenotype

In Vitro Study of the Effects of Precore and Lamivudine-Resistant Mutations on Hepatitis B Virus Replication

Contact Info

Product

Resources

About