Viral features of lamivudine resistant hepatitis B genotypes A and D

Zöllner, Bernhard; Petersen, Jörg; Puchhammer‐Stöckl, Elisabeth; Kletzmayr, Josef; Sterneck, Martina; Fischer, Lutz; Schröter, Matthias; Laufs, Rainer; Feucht, Heinz‐Hubert

doi:10.1002/hep.20016

Cited by 99 publications

(94 citation statements)

References 37 publications

(43 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…12,13 However, in patients with a chronic HBV infection, an antiviral response as an indicator of future treatment outcomes has not yet been fully determined. 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: 98%

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

View full text Add to dashboard Cite

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)

show abstract

Section: Discussionmentioning

confidence: 98%

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

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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-

show abstract

“…Buti et al suggested that the emergence of lamivudine resistance were also comparable between genotypes A and D [122]. Nevertheless, studies from Germany and China indicated that there exist different YMDD mutational patterns among different lamivudine-resistant HBV genotypes [124,125]. For example, the frequency of rtM204I mutants is higher in genotypes C and D, whereas that of rtM204V is higher in genotypes B and A.…”

Section: Genotypesmentioning

confidence: 99%

Role of viral factors in the natural course and therapy of chronic hepatitis B

Kao

2007

Hepatol Int

View full text Add to dashboard Cite

Hepatitis B virus (HBV) infection is a global health problem that causes a wide spectrum of liver disease, including acute or fulminant hepatitis, inactive carrier state, chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The pathogenesis of hepatocyte damage associated with HBV is mainly through immune-mediated mechanisms. On the basis of the virus and host interactions, the natural history of HBV carriers who are infected in early life can be divided into four dynamic phases. The frequency, extent, and severity of hepatitis flares or acute exacerbation in the second immune clearance and/or fourth reactivation phase predict liver disease progression in HBV carriers. In the past decade, hepatitis B viral factors including serum HBV DNA level, genotype, and naturally occurring mutants predictive of clinical outcomes have been identified. The higher the serum HBV DNA level after the immune clearance phase, the higher the incidence of adverse outcomes over time. In addition, high viral load, genotype C, basal core promoter mutation, and pre-S deletion correlate with increased risk of cirrhosis and HCC development. As to the treatment of chronic hepatitis B, patients with high HBV DNA level and genotype C or D infection are shown to have a worse response to interferon therapy. In conclusion, serum HBV DNA level, genotype, and naturally occurring mutants are identified to influence liver disease progression and therapy of chronic hepatitis B. More investigations are needed to clarify the molecular mechanisms of the viral factors involved in the pathogenesis of each stage of liver disease and the response to antiviral treatments.

show abstract

Viral features of lamivudine resistant hepatitis B genotypes A and D

Cited by 99 publications

References 37 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

Role of viral factors in the natural course and therapy of chronic hepatitis B

Contact Info

Product

Resources

About