Detection of YMDD motif mutations in some lamivudine-untreated asymptomatic hepatitis B virus carriers

Kobayashi, Shohei; Ide, Tatsuya; Sata, Michio

doi:10.1016/s0168-8278(00)00023-4

Cited by 111 publications

(122 citation statements)

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“…It has been described that the overall prevalence of resistance-associated mutations in treatment-naïve, chronic HBV carriers ranges from 3.8% in Spain (6) to 28% in an Asian cohort (5). The results of our study clearly demonstrate that the impact of these naturally occurring HBV mutants on the outcome of antiviral treatment needs to be investigated in further clinical studies.…”

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confidence: 50%

Prevalence, Incidence, and Clinical Relevance of the Reverse Transcriptase V207I Mutation Outside the YMDD Motif of the Hepatitis B Virus Polymerase during Lamivudine Therapy

Zöllner¹,

Sterneck²,

Wursthorn

et al. 2005

J Clin Microbiol

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The reverse transcriptase V207I mutation within the hepatitis B virus (HBV) polymerase is associated with resistance to lamivudine in vitro. The prevalence of this mutation in treatment-naïve patients was 1% (1/96). A follow-up of the patient carrying this mutation prior to treatment revealed no loss of sensitivity of HBV to lamivudine in vivo.Treatment of chronic hepatitis B with lamivudine (3TC) leads to a substantial proportion of resistant hepatitis B virus (HBV) (3). Resistance-associated mutations outside the active site of the HBV polymerase (YMDD motif) include amino acid exchanges at the reverse transcriptase codon L180M (rtL180M) or the rtV207I codon (4, 7, 10). The 50% inhibitory concentration for HBV carrying the rtV207I mutation is 20 nM of 3TC, leading to a 3.6-fold resistance in vitro (4, 10). However, the relevance of this amino acid exchange to the resistance of HBV to 3TC in vivo is completely unknown.We investigated 96 consecutive, chronic HBV carriers. HBV polymerase sequences were analyzed at baseline (n ϭ 96), after 1 year (n ϭ 96), and after 2 years of 3TC treatment (n ϭ 92). Fifty patients carried HBV genotype A, and 46 were infected with HBV genotype D. The case patient was an immunocompetent male who was 19 years old at initiation of 3TC treatment. He carried HBV genotype A and was coinfected with hepatitis C virus (HCV) genotype 1a but tested negative for human immunodeficiency virus. The patient had received pegylated alpha interferon (pegIFN-␣; 80 g per week) and ribavirin (600 mg per day) 12 months prior to 3TC treatment due to his HCV infection without any effect on HBV DNA levels, concentration of serum hepatitis B surface antigen, or the status of hepatitis Be (HBe) antigen. He had never received 3TC or famciclovir before. At baseline of 3TC treatment (100 mg daily), his viral load was log 10 8.3 HBV DNA copies/ml, while the HCV RNA level was below the detection limit of the PCR assay (lower log 10 2 HCV RNA copies/ml). The HBe antigen test was positive, and the alanine aminotransferase (ALT) value at baseline was 20 U/ml (the normal value is below 22 U/ml).Serum hepatitis surface antigen and HBe antigen levels were determined by enzyme-linked immunosorbent assay (Abbott, Wiesbaden, Germany). HBV copy numbers were quantified by real-time PCR (LightCycler-DNA Master SYBR Green; Roche Diagnostics, Basel, Switzerland) as described previously (8). Genotypic HBV resistance was analyzed by sequencing the HBV polymerase from codons rt103 to rt244 (1). Viral population kinetics were investigated by cloning amplicons of the HBV polymerase into Escherichia coli (TOPO-TA cloning system; Invitrogen, Karlsruhe, Germany). Fifteen clones were sequenced from each sample as described previously (11).The prevalence of the rtV207I mutation in treatment-naïve patients was 1% (1/96). This patient was the case reported in this article. One additional patient carried wild-type HBV at baseline, but the rtV207I mutation emerged at month 24 of treatment in combination with the rtL180M and rtM204V exchange...

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confidence: 50%

Prevalence, Incidence, and Clinical Relevance of the Reverse Transcriptase V207I Mutation Outside the YMDD Motif of the Hepatitis B Virus Polymerase during Lamivudine Therapy

Zöllner¹,

Sterneck²,

Wursthorn

et al. 2005

J Clin Microbiol

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“…Second, a preexisting different viral strain was documented to emerge during lamivudine treatment in case F. Third, recent studies showed that evolution and reversion of HBV polymerase gene variations occurred commonly in patients receiving nucleoside analogue therapy. [8][9][10]38 Fourth, YMDD variants were detectable in a subset of HBsAg carriers not receiving lamivudine therapy in a recent study, 39 which implies that such variants can become the dominant strains under drug selection pressure.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B virus variants in patients receiving lamivudine treatment with breakthrough hepatitis evaluated by serial viral loads and full-length viral sequences

Liu¹,

Chen²,

Lai³

et al. 2001

Hepatology

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have all been implicated. 5-13 However, 2 problems are encountered in these studies. First, most studies focused on the analyses of subgenomic fragments of HBV DNA, which are limited by the following factors: (1) the changes of the viral sequences beyond the polymerase chain reaction (PCR)-amplified fragment(s) are not analyzed simultaneously 5,6,12,13 ; and (2) even when the entire viral sequences were obtained, these were usually assembled from overlapping subgenomic PCR products, which may be a combination from different viral strains (quasispecies) in the same host and therefore may not represent the true corresponding pathogen(s). 14,15 In addition, sequential analysis of viral strains, which helps to understand the immunopathogenesis of chronic hepatitis B, is not performed in most studies. 11,14-16 Full-length amplification and sequential analysis of HBV genome in the same patient may circumvent the 2 problems and help to examine the HBV variants during the acute exacerbations. To address part of this question, we applied a full-length sequencing approach in a special but clinically important group of patients with hepatitis B exacerbations during lamivudine treatment. Lamivudine can achieve a 3-to 4-log median reduction in serum virus levels in patients with chronic hepatitis B, 17-19 but drugresistant viruses (tyrosine-methionine-aspartic acid-aspartic acid variants, YMDD variants) appear in more than 50% of patients after a prolonged treatment of 4 years. [19][20][21][22] Interestingly, emergence of lamivudine-resistant mutants is followed by hepatitis flare-ups in more than 90% of those patients who continued to receive lamivudine treatment. 23 These patients are usually followed closely and serial blood samples are available. Thus, lamivudine treatment provides a unique and interesting occasion for studying the acute exacerbation of hepatitis B.Taking this situation and the advent of potent Taq polymerase(s) with a proofreading activity, we generated fulllength genomic data of HBV strains from patients with chronic hepatitis B receiving lamivudine treatment, as well as Abbreviations: HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; PCR, polymerase chain reaction; YMDD, tyrosine-methionine-aspartic acid-aspartic acid; ALT, alanine aminotransferase; rt, reverse transcriptase; HLA, human leukocyte antigen.From the

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“…Allen (8) classified YMDD mutations into two categories: rtM204V + rtL180M and rtM204I, and the study suggested that rtM204V and rtL180M do not occur alone. rtM204I + rtL180M was identified in a study by Lok et al (26) Kobayashi et al (27) detected YMDD mutations in HBV asymptomatic carriers who did not receive LAM therapy. Furthermore, the YMDD mutation was detected in patients with chronic hepatitis B that underwent pre-therapy with LAM (28,29), which differs from the previous conclusion that LAM therapy induced YMDD mutations (30).…”

Section: Discussionmentioning

confidence: 98%

Association between clinical features and YMDD mutations in patients with chronic hepatitis B following lamivudine therapy

Yuan

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. The aim of the present study was to investigate the correlation between feature and genotype with regard to the tyrosine-methionine-aspartate-aspartate (YMDD) mutation in chronic hepatitis B patients after lamivudine (LAM) therapy. A total of 30 patients with chronic hepatitis B were recruited, who underwent one year of LAM therapy. The patients' alanine aminotransferase (ALT) level and hepatitis B envelope antigen (HBeAg) seroconversion were evaluated, hepatitis B virus (HBV) DNA was genotyped using a new genotyping method and YMDD mutations were analyzed prior to treatment and at 6 and 12 months after LAM treatment. Furthermore, the secondary protein structure of the HBV DNA polymerase gene (P gene) was analyzed. Following treatment, the results suggested that LAM therapy improved ALT normalization. There was no correlation between clinical effects and ALT level before treatment. After 12 months treatment, the rate of HBeAg loss increased and the rate of HBeAg seroconversion decreased linearly with the rise of baseline ALT level. While ALT normalization and HBeAg seroconversion were highest in patients with HBV genotype B, HBeAg loss and HBVDNA loss were highest in those with genotype C. The effect was predominant in genotype D. No YMDD mutations were identified prior to 6 months of LAM therapy. The rate of YMDD mutations after 12 months LAM therapy was 12.12%. Two patients with rtM204V + rtL180M belonged to genotype C and another patient with rtL180M alone belonged to genotype D. The turn of secondary protein structure of P gene changed to β sheet when a rtM204V mutation occurred, and no change of secondary protein structure was associated with the rtL180M mutation. Thus, the present results indicate that one year of LAM therapy is able to improve ALT normalization. Long-term LAM therapy may induce YMDD mutation and drug resistance.

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Detection of YMDD motif mutations in some lamivudine-untreated asymptomatic hepatitis B virus carriers

Cited by 111 publications

References 6 publications

Prevalence, Incidence, and Clinical Relevance of the Reverse Transcriptase V207I Mutation Outside the YMDD Motif of the Hepatitis B Virus Polymerase during Lamivudine Therapy

Prevalence, Incidence, and Clinical Relevance of the Reverse Transcriptase V207I Mutation Outside the YMDD Motif of the Hepatitis B Virus Polymerase during Lamivudine Therapy

Hepatitis B virus variants in patients receiving lamivudine treatment with breakthrough hepatitis evaluated by serial viral loads and full-length viral sequences

Association between clinical features and YMDD mutations in patients with chronic hepatitis B following lamivudine therapy

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