Fatal Hepatic Failure After Emergence of the Hepatitis B Virus Mutant During Lamivudine Therapy in a Patient with Liver Cirrhosis

Wang, J H; Lu, Sheng–Nan; Lee, C M; Lee, J F; Chou, Yeh‐Pin

doi:10.1080/003655202317284309

Cited by 57 publications

(37 citation statements)

References 20 publications

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“…4,5 Viral breakthrough associated with selection of antiviral-resistant hepatitis B virus (HBV) mutants is usually followed by biochemical breakthrough and in some instances hepatitis flares and liver failure. [6][7][8][9][10] Therefore, treatment should be changed when viral breakthrough is detected. However, multi-drug resistant HBV has been reported in patients who received sequential treatment with NA monotherapies.…”

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confidence: 99%

Evolution of multi-drug resistant hepatitis B virus during sequential therapy

et al. 2006

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Multi-drug resistant hepatitis B virus (HBV) has been reported in hepatitis B patients who received sequential antiviral therapy. In vitro studies showed that HBV constructs with mutations resistant to lamivudine and adefovir have marked reduction in sensitivity to combination of lamivudine and adefovir, whereas constructs with mutations resistant to either drug remain sensitive to the other drug. We conducted this study to determine whether mutations conferring resistance to multiple antiviral agents co-locate on the same HBV genome in vivo and to describe the evolution of these mutations. Sera from six patients who had been found to have multi-drug resistant HBV mutations to lamivudine ؉ adefovir, lamivudine ؉ hepatitis B immunoglobulin (HBIG), or lamivudine ؉ entecavir on direct sequencing were cloned after nested polymerase chain reaction (PCR). Analysis of 215 clones from 11 samples with multi-drug resistant mutations on direct sequencing showed that 183 (85%) clones had mutations to both therapies on the same genome; 31 clones had lamivudine-resistant mutants only. Clonal analysis of serial samples from three patients showed progressive evolution from all clones with lamivudine-resistant HBV mutations only to mixtures of clones that have multi-drug resistant mutations and clones that have lamivudineresistant HBV mutations only, and ultimately all clones having multi-drug resistant HBV mutations. In conclusion, mutations conferring resistance to multiple antiviral agents colocate on the same viral genome, suggesting that combination therapy directed against mutants resistant to each treatment may not be adequate in suppressing multi-drug resistant HBV. De novo combination therapy may prevent the emergence of multi-drug resistant mutants. (HEPATOLOGY 2006;44:703-712.)

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confidence: 99%

Evolution of multi-drug resistant hepatitis B virus during sequential therapy

et al. 2006

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“…However, long-term therapy is associated with selection of HBV polymerase mutants and emergence of resistance (7,11,14,15,33). Resistance to antiviral treatment (including lamivudine) has Various methods have been used to detect YMDD mutant populations of viruses (among others, nested PCR, cloning, and sequence analysis).…”

Section: Discussionmentioning

confidence: 99%

Quantitative Detection of the M204V Hepatitis B Virus Minor Variants by Amplification Refractory Mutation System Real-Time PCR Combined with Molecular Beacon Technology

Ntziora¹,

Paraskevis²,

Haida³

et al. 2009

J Clin Microbiol

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Mutations in the highly conserved tyrosine-methionine-aspartate-aspartate (YMDD) motif are frequently associated with resistance to antivirals and represent a major concern in the treatment of hepatitis B virus (HBV) infection. Conventional methods fail to detect minority populations of drug-resistant viral quasispecies if they represent less than 25% of the total sample virus population. The amplification refractory mutation system real-time PCR (ARMS RT-PCR) was combined with molecular beacon technology using the LightCycler system. The samples from HBV patients selected for assay evaluation included (i) 57 samples from treatmentnaïve patients for biological discriminatory ability (cutoff) estimation, (ii) 12 samples from patients with treatment failure that were M204V positive by sequencing, and (iii) 13 samples from patients with treatment failure that were negative for mutation at codon 204 by sequencing. The discriminatory ability of the assay was 0.25% when tested with laboratory-synthesized DNA target sequences. The median mutant-to-wild-type ratio for samples from naive patients tested positive for the wild type and for mutant variants was 0.01% (5th and 95th percentiles ‫؍‬ 0.0001 and 0.04%, respectively). A value of 0.04% was selected as the biological cutoff of the assay of clinical samples. In all samples M204V positive by sequencing (12/12), the mutant variant was detected as the predominant population (range, 82.76 to 99.43%). Interestingly, in 5 (38%) of 13 samples negative by sequencing, the M204V variant was detected at a ratio above the biological cutoff (0.05 to 28%). The assay represents an efficient technique for the early detection and quantification of M204V variants before mutant strains emerge to dominate the population.Nucleoside analogs inhibit hepadnavirus replication by terminating viral DNA synthesis and have been used in the treatment of patients with hepatitis B virus (HBV) infection. Antiviral treatment has been shown to rapidly reduce serum HBV DNA to levels below the detection limit of standard commercial assays and to be well tolerated without major adverse events (23). However, as with other antivirals, resistance may occur at a rate mainly dependent on the nucleoside/nucleotide analogue used. Taking lamivudine as an example, resistance increases with longer durations of treatment, from 24% at year 1 to 65 to 70% of treated patients at year 5 (17).Resistance to lamivudine has been frequently associated with mutations that reside in the highly conserved tyrosinemethionine-aspartate-aspartate (YMDD) motif of the C domain (M204I, M204V) and secondarily with mutations residing outside the C domain but mainly in the B domain (V173L, L180M) of the HBV polymerase region (Pol/RT). The M204V mutation has also been associated with resistance to other antivirals such as entecavir and emtricitabine; selection of M204I/V mutants affects future treatment options (4,16). In vitro studies have demonstrated that mutant (Mut) viral variants exhibit a diminished replication capacity compared w...

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“…Our previous research has also indicated that in northern China, the YMDD mutation rate is approximate 56.3% after four years of lamivudine treatment [8] . YMDD mutations not only result in a reduction in the susceptibility to lamivudine, but also cause virological and biochemical breakthrough, which are represented as rebound of HBV DNA and ALT levels [19,20] . Moreover, acute exacerbation of hepatitis and hepatic failure may occur after the emergence of YMDD mutants.…”

Section: Discussionmentioning

confidence: 99%

Construction and expression of eukaryotic plasmids containing lamivudine-resistant or wild-type strains of Hepatitis B Virus genotype C

Fang²,

Li³

et al. 2008

WJG

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AIM:To construct eukaryotic expression plasmids of full-length Hepatitis B Virus (HBV) genotype C genome, which contain lamivudine-resistant mutants (YIDD, YVDD) or wild-type strain (YMDD), and to observe the expression of HBV DNA and antigens [hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg)] of the recombinant plasmids in HepG2 cells. METHODS: Three HBV full-length genomes were amplified from the plasmids pMD18T-HBV/YIDD, pMD18T-HBV/YVDD and pMD18T-HBV/YMDD, using PCR. Three recombinant plasmids were generated by inserting each of the PCR products into the eukaryotic expression vector pcDNA3.1 (+), between the Eco RI and Hin dⅢ sites. After being characterized by restriction endonuclease digestion, and DNA sequence analysis, the recombinant plasmids were transfected into HepG2 cells. At 48 and 72 h post-transfection, the levels of intracellular viral DNA replication were detected by real-time PCR, and the expression of HBsAg and HBeAg in the cell culture supernatant was determined by ELISA. RESULTS: Restriction endonuclease digestion and DNA sequence analysis confirmed that the three recombinant plasmids were correctly constructed. After transfecting the plasmids into HepG2 cells, high levels of intracellular viral DNA replication were observed, and HBsAg and HBeAg were secreted into the cell culture supernatant. CONCLUSION: Eukaryotic expression plasmids pcDNA3.1 (+)-HBV/YIDD, pcDNA3.1 (+)-HBV/YVDD or pcDNA3.1 (+)-HBV/YMDD, which contained HBV genotype C full-length genome, were successfully constructed. After transfection into HepG2 cells, the recombinant plasmids efficiently expressed HBV DNA, HBsAg and HBeAg. Our results provide an experimental basis for the further study of HBV lamivudine-resistant mutants.

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Fatal Hepatic Failure After Emergence of the Hepatitis B Virus Mutant During Lamivudine Therapy in a Patient with Liver Cirrhosis

Cited by 57 publications

References 20 publications

Evolution of multi-drug resistant hepatitis B virus during sequential therapy

Evolution of multi-drug resistant hepatitis B virus during sequential therapy

Quantitative Detection of the M204V Hepatitis B Virus Minor Variants by Amplification Refractory Mutation System Real-Time PCR Combined with Molecular Beacon Technology

Construction and expression of eukaryotic plasmids containing lamivudine-resistant or wild-type strains of Hepatitis B Virus genotype C

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