Review article: success and failure of nucleoside and nucleotide analogues in chronic hepatitis B

Leemans, Wilhelmus F.; Borg, Martijn J. ter; Man, Robert A. de

doi:10.1111/j.1365-2036.2007.03481.x

Cited by 15 publications

(6 citation statements)

References 81 publications

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“…However, owing to the persistence of covalently closed circular DNA in hepatocytes, serum hepatitis B e antigen (HBeAg) remains positive in approximately 70% of patients even after 5 years of continuous therapy [8,9]. A high risk of relapse was observed upon withdrawal of oral antiviral agents, when patients were still in the HBeAg-positive stage [10]; therefore, maintained long-term viral suppression is now recommended as the major therapeutic strategy for chronic HBV infection. Unfortunately, long-term usage of oral antiviral agents lead to viral resistance [11].…”

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confidence: 99%

Development of HBV S gene mutants in chronic hepatitis B patients receiving nucleotide/nucleoside analogue therapy

Yeh¹

2010

Antivir Ther

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Structurally modified nucleotide/nucleoside analogues can exert potent inhibitory effect on HBV polymerase activities. Some of these agents have been approved for the treatment of chronic hepatitis B. Because of a high risk of reactivation upon drug withdrawal, continuous long-term therapy is recommended to maintain maximal viral suppression. Consequently, drug resistance has developed in a significant proportion of patients. During long-term therapy, mutations occur not only in the polymerase gene but also in the S gene, resulting in the emergence of surface protein mutants. Two types of surface protein mutants are recognized. The first type arises as a result of amino acid substitutions caused by primary and compensatory resistance mutations in the polymerase gene, which concomitantly generate S gene mutations owing to overlapping S and polymerase genes. The second type occurs because of prolonged viral suppression leading to seroclearance of HBV surface antigen, where vaccine-escape-like mutants might be selected. The second type of mutants does not possess primary resistance mutations in the polymerase gene. Some drug-related S gene mutations are nonsense mutations, leading to truncation of the surface proteins. Among them, the rtA181T/sW172* mutant has a dominant negative secretion effect as well as an increased oncogenic potential. The clinical consequences of infection by these S gene mutants demand further clarification. Judicious selection of the antiviral agents and vigilant monitoring of viral mutants during the course of therapy are advised.

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confidence: 99%

Development of HBV S gene mutants in chronic hepatitis B patients receiving nucleotide/nucleoside analogue therapy

Yeh¹

2010

Antivir Ther

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“…Analogues lacking a 3 0 -OH group on the sugar moiety result in immediate chain termination. Many of these compounds are unnatural L-enantiomers [35]. One of the significant impacts of these oral agents is their beneficial effects on end stage liver disease.…”

Section: Nucleoside and Nucleotide Analoguesmentioning

confidence: 99%

Clinical Profile, Genotype and Management Updates of Hepatitis B Virus

et al. 2011

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Hepatitis B virus (HBV) is a well known agent of acute and chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Around 400 million people worldwide carrier of HBV of which more than 250 million reside in Asia, and 1-2 million people have died from it. It has a partially double-stranded DNA, having 3.2-kb genome size and replicate via reverse transcription of RNA intermediate. In the natural history or during the antiviral therapy of chronic HBV infection, seroconversion from HBeAg to anti-HBeAg is usually accompanied by a decrease in viral replication and remission of liver disease. Based on genomic sequence data HBV is classified into eight genotypes A-H and four major serotypes ayw, ayr, adw and adr on the basis of complete genome and S gene sequence analysis. Genotypes and serotypes are useful tools in understanding the epidemiology of HBV infection. HBV genotypes have distinct geographical distributions. The HBV variants appear during HBeAg seroconversion and they bring mutations in the precore region (PC) that prevent HBeAg synthesis. Another common HBeAg variant is the basal core promoter mutant (BCP) characterized by point mutation in the promoter of both HBeAg mRNA and core protein mRNA. The most frequent core promoter mutation is the double A1762T and G1764A nucleotide exchange, which results in a substantial decrease in HBeAg expression but enhanced viral genome replication. The approved antiviral drugs such as Interferon, lamivudine, adefovir dipivoxil, entecavir and telbivudine for purpose of treating chronic HBV infection is to prevent or stop the progression of liver injury by suppressing viral replication or eliminating infection. Sustained losses of viral markers of active viral replication (HBeAg and HBV DNA) are the standard end point of the therapies.

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“…Lamivudine (LAM), adefovir dipivoxil (ADV), tenofovir (TDF), entecavir, and telbivudine have been approved for HBV treatment. However, these nucleos(t)ide analogs (NAs) are not effective in every patient [2]. One major reason for treatment failure is drug resistance [3].…”

Section: Introductionmentioning

confidence: 99%

Full-length hepatitis B virus sequences from naïve patients with fluctuation of viral load during ADV monotherapy

Zhu

Guo

et al. 2009

Virus Genes

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The reasons for adefovir dipivoxil (ADV) treatment failures appear diverse. Few studies have reported full-length hepatitis B virus (HBV) genome in patients with ADV treatment failures. The patients were from a phase III clinical trial that investigated the antiviral response to ADV in China. Seven patients had increase in HBV-DNA (>1 log(10) copies/ml above on-treatment nadir) at week 52. The serum HBV-DNA levels were above 10(4)copies/ml at week 92 in four of them. Sixteen full-length HBV genomes from the four patients at four time points were sequenced using cloning sequencing method. The frequency of substitutions at week 52 was higher than at weeks 28(16 wt) and 92(80). HBV-DNA reduction was correlated negatively with the frequency of substitutions at the three time points. No published ADV-resistant mutations were detected. The mutations, including substitutions in immunogenic epitopes and conserved sites of the polymerase gene, were frequent during ADV treatment. Amino acid deletions in X gene and basal core promoter/pre-core mutations appeared before or during ADV treatment. The substitutions in immunogenic epitopes (mainly of the surface gene) and conserved sites of the polymerase gene other than ADV-resistant mutations may have influenced antiviral efficacy in the study. More potent antiviral drugs may be important to rescue individual patients and for public health safety. It is needed to study how these substitutions influence HBV replication, disease progression, and antiviral treatment efficacy.

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Review article: success and failure of nucleoside and nucleotide analogues in chronic hepatitis B

Cited by 15 publications

References 81 publications

Development of HBV S gene mutants in chronic hepatitis B patients receiving nucleotide/nucleoside analogue therapy

Development of HBV S gene mutants in chronic hepatitis B patients receiving nucleotide/nucleoside analogue therapy

Clinical Profile, Genotype and Management Updates of Hepatitis B Virus

Full-length hepatitis B virus sequences from naïve patients with fluctuation of viral load during ADV monotherapy

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