Efficacy of Lamivudine Therapy and Factors Associated with Emergence of Resistance in Chronic Hepatitis B Virus Infection in Japan

Suzuki, Fumitaka; Tsubota, Akihito; Arase, Yasuji; Suzuki, Yoshiyuki; Akuta, Norio; Hosaka, Tetsuya; Someya, Takashi; Kobayashi, Mariko; Saitoh, Satoshi; Ikeda, Kenji; Matsuda, Masamichi; Satoh, Junko; Takagi, Kimiko; Kumada, Hiromitsu

doi:10.1159/000071460

Cited by 74 publications

(87 citation statements)

References 33 publications

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“…Previous studies suggested that the HBV genotype, 14 the ALT level, 9,15 the degree of the decline of the HBV DNA level during therapy. 16,17 the presence of HBeAg, 15,18 the presence of core promoter mutations, 19 and HBV core-related antigens 20 were factors that could predict the emergence of YMDD mutants.…”

Section: Discussionmentioning

confidence: 99%

Virologic Response at 12 Months of Treatment Predicts Sustained Antiviral Efficacy in Patients with Adefovir-Treated Lamivudine-Resistant Chronic Hepatitis B

Jung¹,

Yeon²,

Han³

et al. 2010

Gut Liver

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Background/Aims: The aim of our study was to define the potential role of virologic response at 12 months of treatment (VR12) in predicting subsequent virologic and clinical outcomes in adefovir (ADV)-treated lamivudine-resistant chronic hepatitis B. Methods: Two hundred and four patients with lamivudine-resistant chronic hepatitis B virus (HBV) treated with ADV monotherapy were included. Serum HBV DNA was quantified by real-time polymerase chain reactions. VR12 was defined as a HBV DNA level of less than 4 log10 copies/mL after 12 months of ADV treatment. Results: VR12 was observed in 110 of the 204 patients (54%). The mean HBV DNA reductions from baseline after 12 months of ADV treatment were 3.8 and 1.9 log10 copies/mL in patients with and without VR12, respectively (p＜0.001). The hepatitis B "e" antigen (HBeAg) seroconversion rates in patients with and without VR12 were 32% and 14% at 12 months treatment, respectively (p=0.018), and 40% and 27% at 24 months of treatment (p=0.032). The genotypic mutation rates to ADV in patients with and without VR12 were 0% and 6% at 12 months of treatment, respectively (p=0.033), and 21% and 42% at 24 months (p= 0.012). The rates of viral breakthrough in patients with and without VR12 were 0% and 7% at 12 months of treatment, respectively (p=0.072), and 9% and 25% at 24 months (p=0.006). Conclusions: Patients without VR12 may need to switch to or add on other potent antiviral drugs in their medical regimens. (Gut Liver 2010;4:212-218)

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Section: Discussionmentioning

confidence: 99%

Virologic Response at 12 Months of Treatment Predicts Sustained Antiviral Efficacy in Patients with Adefovir-Treated Lamivudine-Resistant Chronic Hepatitis B

Jung¹,

Yeon²,

Han³

et al. 2010

Gut Liver

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“…Using complex analysis, previous studies identified several factors predictive of emergence of YMDD mutants such as HBV genotype, 28 ALT level, 29,30 HBV DNA level before therapy, 28,[30][31][32] degree of decline of HBV DNA level during therapy, 33,34 presence of hepatitis B e antigen, 17,29,31,32,35 presence of core promoter mutations, 36 deletion of pre-S region, 37 and HBV core-related antigen. 38 We also showed that a slow decrease in HBV nucleic acid measured by the TMA-HPA is a marker of early emergence of mutants.…”

Section: Discussionmentioning

confidence: 99%

Serum HBV RNA is a predictor of early emergence of the YMDD mutant in patients treated with lamivudine

et al. 2007

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Lamivudine (LAM) is a nucleoside analogue widely used for the treatment of chronic hepatitis B virus (HBV) infection. Emergence of resistant strains with amino acid substitutions in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of reverse transcriptase is a serious problem in patients on LAM therapy. The amount of covalently closed circular DNA in the serum is reported to be higher in patients who develop YMDD mutants than in those without mutants. However, there is no useful serum marker that can predict early emergence of mutants during LAM therapy. Analysis of patients who were treated with entecavir (n ‫؍‬ 7) and LAM (n ‫؍‬ 36) showed some patients had high serum levels of HBV RNA. Median serum levels of HBV RNA were significantly higher in patients in whom the YMDD mutant had emerged within 1 year (n ‫؍‬ 6, 1.688 log copies/ml) than in those in whom the YMDD mutant emerged more than 1 year after treatment (n ‫؍‬ 12, 0.456 log copies/ml, P ‫؍‬ 0.0125) or in whom the YMDD mutant never emerged (n ‫؍‬ 18, 0.688 log copies/ml, P ‫؍‬ 0.039). Our results suggest that HBV RNA is a valuable predictor of early occurrence of viral mutation during LAM therapy. (HEPATOLOGY 2007;45:1179-1186 T he hepatitis B virus (HBV) is a member of the hepadnaviridae family. Worldwide, approximately 350 million people are estimated to be chronically infected with HBV. 1 Patients with chronic HBV infection develop chronic hepatitis, cirrhosis, and hepatocellular carcinoma, accounting for approximately 1 million deaths per year. 2 Recently, inhibitors of reverse transcriptase have been developed and widely used for patients with chronic HBV infection. Lamivudine (LAM), a cytosine nucleoside analogue, was first developed as an antiviral agent against HIV and later was used effectively against HBV because HBV also uses reverse transcriptase for replication. 3,4 Because LAM suppresses HBV replication, patients who are treated with LAM show a decreased level or disappearance of HBV DNA in serum and hepatitis B e antigen, normalization of serum alanine aminotransferase (ALT) level, and histological improvement. [5][6][7][8][9][10][11][12] However, discontinuation of therapy often leads to reactivation of HBV. 6,8,13,14 Therefore, long-term therapy is necessary for many patients with chronic HBV infection. During long-term LAM therapy, drug-resistant mutants with amino acid substitutions in the tyrosine-methionine-aspartate-aspartate (YMDD) motif emerge, resulting in expression of HBV DNA increasing again and in worsening of hepatitis. 6,10,[15][16][17][18] Moreover, some patients develop a severe flare-up of hepatitis that could lead to fatal hepatic failure. Therefore, prediction of the emergence of YMDD mutants is an important issue.In our hunt for useful serum markers to detect the early emergence of YMDD mutants, we noticed some patients who showed a discrepancy in the expression of HBV DNA measured by the transcription-mediated amplifica-

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“…It potently inhibits HBV replication by interfering with the reverse transcriptase activity of the viral polymerase, which results in a marked decrease of HBV DNA and ALT levels, seroconversion of HBeAg to anti-HBe, and histopathological improvement 11 . However, one major problem with long-term use of lamivudine is the potential development of viral resistance, associated with increases in HBV DNA and serum transaminases 12 . The incidence of drug-resistant hepatitis B virus during lamivudine treatment is 14-36% after one year of treatment and increases to 38%, 49% and 66% after two, three and four years of treatment, respectively 13 .…”

Section: Methodsmentioning

confidence: 99%

Hepatitis B virus genotyping among chronic hepatitis B patients with resistance to treatment with lamivudine in the City of Ribeirão Preto, State of São Paulo

Haddad¹,

Martinelli

Uyemura

et al. 2010

Rev. Soc. Bras. Med. Trop.

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Introduction: Lamivudine is a nucleoside analogue that is used clinically for treating chronic hepatitis B infection. However, the main problem with prolonged use of lamivudine is the development of viral resistance to the treatment. Mutations in the YMDD motif of the hepatitis B virus DNA polymerase gene have been associated with resistance to drug therapy. So far, there have not been many studies in Brazil reporting on genotype-dependent development of resistance to lamivudine. Thus, the aim of the present study was to determine the possible correlation between a certain genotype and increased development of resistance to lamivudine among chronic hepatitis B patients. Methods: HBV DNA in samples from 50 patients under lamivudine treatment was amplified by means of conventional PCR. Samples were collected at Hospital das Clínicas, FMRP-USP. The products were then sequenced and phylogenetic analysis was performed. Results: Phylogenetic analysis revealed that 29 (58%) patients were infected with genotype D, 20 (40%) with genotype A and one (2%) with genotype F. Mutations in the YMDD motif occurred in 20% of the patients with genotype A and 27.6% of the patients with genotype D. Conclusions: Despite the small number of samples, our results indicated that mutations in the YMDD motif were 1.38 times more frequent in genotype D than in genotype A.

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Efficacy of Lamivudine Therapy and Factors Associated with Emergence of Resistance in Chronic Hepatitis B Virus Infection in Japan

Cited by 74 publications

References 33 publications

Virologic Response at 12 Months of Treatment Predicts Sustained Antiviral Efficacy in Patients with Adefovir-Treated Lamivudine-Resistant Chronic Hepatitis B

Virologic Response at 12 Months of Treatment Predicts Sustained Antiviral Efficacy in Patients with Adefovir-Treated Lamivudine-Resistant Chronic Hepatitis B

Serum HBV RNA is a predictor of early emergence of the YMDD mutant in patients treated with lamivudine

Hepatitis B virus genotyping among chronic hepatitis B patients with resistance to treatment with lamivudine in the City of Ribeirão Preto, State of São Paulo

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