Core promoter/pre-core mutations are associated with lamivudine-induced HBeAg loss in chronic hepatitis B with genotype C

Asahina, Yasuhiro; Izumi, Namiki; Uchihara, Masakatsu; Noguchi, Osamu; Nishimura, Yuki; Inoue, Kazunari; Ueda, Ken; Tsuchiya, Kaoru; Hamano, Kenzo; Itakura, Jun; Miyake, Shozo

doi:10.1016/s0168-8278(03)00467-7

Cited by 18 publications

(16 citation statements)

References 38 publications

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“…Particularly, at the end of follow-up, only one patient (Case II-3) had both precore and BCP mutations. Consistently, three recent studies demonstrated that in patients receiving lamivudine for chronic hepatitis B, the presence of precore and/or BCP mutation was associated with the loss of HBeAg and the lack of such mutations was frequently associated with the reversion of HBeAg [Asahina et al, 2003;Kuwahara et al, 2004;Lin et al, 2004]. Collectively, these facts support the hypothesis that the development of transient HBeAg seroconversion and seroreversion might be due to the lack of sustained precore nucleotide 1896 and BCP dinucleotide 1762/ 1764 mutations after HBeAg seroconversion.…”

Section: Discussionsupporting

confidence: 76%

Evolution of precore/core promoter mutations in hepatitis B carriers with hepatitis B e antigen seroreversion

Liu

Chen

Lai

et al. 2004

Journal of Medical Virology

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The evolution of precore stop codon mutation (A1896) and dinucleotide mutation (T1762/A1764) in the basic core promoter (BCP) of hepatitis B virus (HBV) genome during transient seroconversion and seroreversion of hepatitis B e antigen (HBeAg) remains unclarified. Five HBeAg-positive HBV carriers who experienced transient seroconversion followed by seroreversion of HBeAg (Group I, 3.3%) and 3 HBeAg-negative HBV carriers with documented reversion of HBeAg (Group II, 2.5%) in a prospective cohort of 272 patients with chronic hepatitis B were thus identified. The sequential changes at the precore nucleotide 1896 and BCP dinucleotide 1762/1764 were determined by polymerase chain reaction and direct sequencing. At enrollement, precore A1896 and BCP T1762/A1764 were noted in 4 (50%) and 1 (13%) of the eight patients. During a median follow-up period of 58 months (range: 31-76 months), 12 episodes of transient HBeAg seroconversion followed by seroreversion were encountered in Group I patients and 3 episodes of HBeAg seroreversion in Group II patients. Accompanying acute exacerbations were found in two-thirds of patients with either HBeAg seroconversion or seroreversion. Overall, precore nucleotide A1896 remained identical in 73% and 83% of the seroconversion and seroreversion events, respectively. BCP dinucleotide T1762/A1764 remained unchanged in 94% and 92% of the seroconversion and seroreversion events, respectively. At the end of follow-up, only one had both precore and BCP mutations. In conclusion, these data suggested that HBeAg seroreversion might be due to the lack of sustained precore and BCP mutations after HBeAg seroconversion. Although uncommon, HBeAg seroreversion can be associated with hepatitis exacerbation.

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Section: Discussionsupporting

confidence: 76%

Evolution of precore/core promoter mutations in hepatitis B carriers with hepatitis B e antigen seroreversion

Liu

Chen

Lai

et al. 2004

Journal of Medical Virology

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“…Previous clinical studies have shown that stop codon mutations were related to lower baseline viral load, replication rate, and breakthrough on LAM treatment. [13][14][15] The adverse impact of high baseline HBV DNA level was already known through studies in LAM-treated populations. [16][17][18] Likewise, high baseline DNA level (cut-off level of 10 5 -10 8 copies/mL) caused insufficient viral suppression, and even frequent emergence of resistance in ADV treatment for LAM-resistance CH-B patients.…”

Section: Discussionmentioning

confidence: 99%

A Low Viral Load Predicts a Higher Initial Virologic Response to Adefovir in Patients with Lamivudine-Resistant Chronic Hepatitis B

Shin¹,

Koh²,

Gwak³

et al. 2010

Gut Liver

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Background/Aims: Adefovir (ADV) is the preferred drug for treating lamivudine (LAM)-resistant hepatitis B. However, not all patients who face virologic breakthrough during LAM treatment respond to ADV. The aim of this study was to determine the factors associated with efficacy of ADV in LAM-resistant hepatitis B patients. Methods: The medical records of 231 patients who received ADV due to LAM-resistance were reviewed. Efficacy was assessed by the initial virologic response (IVR), defined as hepatitis B virus (HBV) DNA not being undetectable by real-time PCR at 6 months of ADV treatment. Results: Seventy patients (30%) achieved IVR. While 'add-on' modality, hepatitis B e antigen (HBeAg) negativity, and low baseline HBV DNA levels were associated with IVR in univariate analysis, multivariate analysis revealed HBeAg status and the DNA level to be the significant factors. The probability of IVR achievement increased sharply per each log10 copies/mL decrement in the baseline viral load, which was 133 times in patients who had HBV DNA ＜10 5 copies/mL compared with those who had ≥10 8 copies/mL. Conclusions: Factors associated with the IVR were HBeAg negativity and a low baseline viral load. Therefore, when virologic breakthrough with genotypic resistance emerges during LAM therapy, ADV treatment should be considered immediately before further increases in viral load. Additional long-term follow-up data are warranted.(Gut Liver 2010;4:530-536)

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“…Second, we have confirmed in the present study with a larger number of patients that core promoter and precore mutations are associated with a higher chance of achieving an ideal response to lamivudine (Table 1), a finding also observed in other studies. 25,26 Although the exact reasons for these phenomena have not been fully elucidated, both core promoter and precore mutant viruses may be more responsive to lamivudine treatment. This is indirectly supported by the finding from other studies that core promoter and precore mutants revert to the wild type with lamivudine treatment.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B virus DNA levels at week 4 of lamivudine treatment predict the 5-year ideal response

et al. 2007

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The best time and hepatitis B virus (HBV) DNA level during an early lamivudine treatment period for predicting the long-term outcome are unknown. We aimed to determine the optimal time and HBV DNA level during an early treatment period for the prediction of the response after a 5-year lamivudine treatment. The HBV DNA levels at the baseline, at weeks 2, 4, 8, 12, 16, 24, and 32, and at yearly intervals until year 5 were measured in 74 hepatitis B e antigen (HBeAg)-positive chronic HBV patients receiving lamivudine treatment. Seventeen patients achieved an ideal response [HBV DNA level < 2000 copies/mL (400 IU/ mL), HBeAg seroconversion, normal alanine aminotransferase levels, and absence of tyrosine-methionine-aspartate-aspartate (YMDD) mutations] at year 5. Receiver operating characteristic curves showed good predictions as early as week 4. The areas under the curve for weeks 4 and 16 were 0.89 and 0.94, respectively. Predictive indices revealed 4 and 3.6 log copies/mL (2000 and 800 IU/mL, respectively) to be the best cutoff HBV DNA levels for these 2 times, respectively. All patients with HBV DNA levels lower than these respective cutoff levels at the 2 times achieved an ideal response at year 5. Patients with HBV DNA levels above these cutoff values had 83.8% and 87.7% chances of not achieving an ideal response at year 5, respectively. Conclusion: The measurement of the HBV DNA levels at week 4 of lamivudine treatment should be performed in all patients to predict the long-term outcome. The treatment can be continued for those with HBV DNA levels of less than 4 log copies/mL (2000 IU/mL). The addition of or switch to alternative antiviral agents should be considered for patients who fail to achieve this early target. (HEPATOLOGY 2007;46:1695-1703 A pproximately 400 million people worldwide have chronic hepatitis B (CHB) infection, of whom 25%-40% will develop long-term sequelae of hepatocellular carcinoma (HCC) and/or cirrhotic complications. 1 The prevention of disease progression is the primary target for the treatment of CHB. Recent evidence shows that a high hepatitis B virus (HBV) DNA level is associated with a higher risk of development of HCC and cirrhosis. 2,3 Effective viral suppression by the nucleoside analogue, lamivudine, reduces the risk of complications in patients with or without advanced disease. 4,5 However, a prolonged lamivudine treatment is associated with increasing incidence of drug-resistant mutations [tyrosine-methionine-aspartate-aspartate (YMDD) mutants], which reaches more than 70% after 5 years of lamivudine treatment. 6 Despite this, lamivudine is still commonly used for several reasons. It has the longest surveillance for safety. Twenty to twenty-five percent of patients do not develop YMDD mutations and continue to have satisfactory viral suppression even after a prolonged treatment. 5 Moreover, it is the only nucleoside/nucleotide analogue proven in randomized controlled studies to reduce disease progression. 4 Therefore, identifying patients who are likely to achieve an ideal...

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Core promoter/pre-core mutations are associated with lamivudine-induced HBeAg loss in chronic hepatitis B with genotype C

Cited by 18 publications

References 38 publications

Evolution of precore/core promoter mutations in hepatitis B carriers with hepatitis B e antigen seroreversion

Evolution of precore/core promoter mutations in hepatitis B carriers with hepatitis B e antigen seroreversion

A Low Viral Load Predicts a Higher Initial Virologic Response to Adefovir in Patients with Lamivudine-Resistant Chronic Hepatitis B

Hepatitis B virus DNA levels at week 4 of lamivudine treatment predict the 5-year ideal response

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