Characterization of hepatitis B virus reverse transcriptase sequences in Chinese treatment naive patients

Han, Yue; Huang, Li; Liu, Chuan Miao; Yang, Shu; Li, Juan; Lin, Zhiang; Kong, Xiao‐Fei; Yu, De Min; Zhang, Dong Hua; Jin, Gen Di; Lu, Zhongmin; Gong, Qi; Zhang, Xin Xin

doi:10.1111/j.1440-1746.2009.05864.x

Cited by 38 publications

(49 citation statements)

References 21 publications

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“…We recently demonstrated the usefulness of ultra-deep sequencing technology to unveil the massive genetic heterogeneity of hepatitis C virus (HCV) in association with treatment response to antiviral therapy [19]. On the other hand, there are a few published studies in which this technology was used to characterize genetic HBV sequence variations [20]–[22]. Margeridon-Thermet et al reported that the 454 Life Science GS20 sequencing platform provided higher sensitivity for detecting drug-resistant HBV mutations in the serum of patients treated with nucleoside and nucleotide reverse-transcriptase inhibitors [20].…”

Section: Introductionmentioning

confidence: 99%

Dynamics of Hepatitis B Virus Quasispecies in Association with Nucleos(t)ide Analogue Treatment Determined by Ultra-Deep Sequencing

et al. 2012

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Background and AimsAlthough the advent of ultra-deep sequencing technology allows for the analysis of heretofore-undetectable minor viral mutants, a limited amount of information is currently available regarding the clinical implications of hepatitis B virus (HBV) genomic heterogeneity.MethodsTo characterize the HBV genetic heterogeneity in association with anti-viral therapy, we performed ultra-deep sequencing of full-genome HBV in the liver and serum of 19 patients with chronic viral infection, including 14 therapy-naïve and 5 nucleos(t)ide analogue(NA)-treated cases.ResultsMost genomic changes observed in viral variants were single base substitutions and were widely distributed throughout the HBV genome. Four of eight (50%) chronic therapy-naïve HBeAg-negative patients showed a relatively low prevalence of the G1896A pre-core (pre-C) mutant in the liver tissues, suggesting that other mutations were involved in their HBeAg seroconversion. Interestingly, liver tissues in 4 of 5 (80%) of the chronic NA-treated anti-HBe-positive cases had extremely low levels of the G1896A pre-C mutant (0.0%, 0.0%, 0.1%, and 1.1%), suggesting the high sensitivity of the G1896A pre-C mutant to NA. Moreover, various abundances of clones resistant to NA were common in both the liver and serum of treatment-naïve patients, and the proportion of M204VI mutants resistant to lamivudine and entecavir expanded in response to entecavir treatment in the serum of 35.7% (5/14) of patients, suggesting the putative risk of developing drug resistance to NA.ConclusionOur findings illustrate the strong advantage of deep sequencing on viral genome as a tool for dissecting the pathophysiology of HBV infection.

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Section: Introductionmentioning

confidence: 99%

Dynamics of Hepatitis B Virus Quasispecies in Association with Nucleos(t)ide Analogue Treatment Determined by Ultra-Deep Sequencing

et al. 2012

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“…Meanwhile, the results also suggested that NA treatment is the major selecting factor of primary drug-resistant mutations and that NA treatment promotes putative NAr mutations (Li et al, 2012). Moreover, several previous studies showed that primary NAr mutations occur in patients with no history of NA treatment (Han et al, 2009;Kobashi et al, 2009;Pastor et al, 2009). Recently, another paper also reported that HBV resistance mutations were identified in 5 % of treatment-naïve patients by using INNO-LiPA (Fujirebio) line probe analysis (Mirandola et al, 2011).…”

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confidence: 99%

Nucleotide analogue-resistant mutations in hepatitis B viral genomes found in hepatitis B patients

Fan

Zhang

Xiong

et al. 2015

Journal of General Virology

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Chronic hepatitis B (CHB) is treated with nucleos(t)ide analogues (NAs). The reverse transcriptase (RT) region in the hepatitis B virus (HBV) genome mutates to resist NA treatment, yet the RT mutations have not been well characterized. Furthermore, the HBV genotype might influence RT sequence evolution, NA resistance (NAr) mutation patterns and drug resistance development. We examined 42 NAr mutation sites in 169 untreated and 131 NA-treated CHB patient samples. Patients were identified with HBV-B and HBV-C genotype infections, with a higher prevalence and mutation frequency of HBV-C than HBV-B. Seventeen reported NAr mutation sites and 13 novel mutations were detected. NAr-related mutation prevalence was significantly higher in NA-treated versus untreated patients. Primary antiviral-resistant mutants only existed in NA-treated patients. Sequencing data revealed seven HBV-C-specific mutations and three HBV-B-specific mutations. In conclusion, NA treatment and HBV genotype might constitute the selection basis and promote NA-resistant HBV strain evolution under antiviral therapy.Chronic hepatitis B (CHB), a life-threatening liver disease, is a global public health concern, caused by hepatitis B virus (HBV) (Chen et al., 2012;Franco et al., 2012;Zhao et al., 2010). IFN and nucleos(t)ide analogue (NAs) CHB treatments have been approved in China, including lamivudine (LAM), adefovir dipivoxil (ADV), entecavir and telbivudine (Pan et al., 2013;Shaw et al., 2006). NA treatment is more convenient than IFN-based therapy, has fewer side effects and more quickly reduces HBV DNA levels. NA therapy inhibits HBV DNA polymerase activity and DNA replication by targeting HBV-encoded reverse transcriptase (RT) (Leung et al., 2001;Locarnini & Mason, 2006;Locarnini et al., 2004). However, NA therapy is challenged by several conditions: viral persistence in infected hepatocytes, limited NA availability and antiviral NA resistance (NAr) mutations during long-term NA treatment (Fung et al., 2011;Liaw et al., 2004;Locarnini & Mason, 2006), which are the most important factors responsible for treatment failure (Locarnini, 2008; Lok et al., 2007b). Therefore, it is important to understand the mechanism underlying drug-resistant mutation evolution to prevent and control drug resistance (Khudyakov, 2010).A previous study analysed amino acid substitutions at 42 potential NAr mutation sites in the HBV full-length RT sequence (Baldick et al., 2008;Bartholomeusz et al., 2004;Ghany & Doo, 2009;Keeffe et al., 2008;Liu et al., 2010). NAr-associated mutations within the HBV RT region can be classified into five categories : primary drug-resistant mutations (category 1), compensatory mutations (category 2), putative NAr mutations (category 3), pre-treatment mutations (category 4) and new mutations (category 5) (Table S1, available in the online Supplementary Material).Recent studies demonstrated that the HBV genotype contributes to drug-resistant mutant evolution and selection . Moreover, HBV genotypes differ in LAM-resistant mutation patterns, as...

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“…Recent reports showing the existence of antiviral resistance strains in treatment-naïve hepatitis B individuals alert the need for baseline monitoring of antiviral resistance mutants [19][20][21] . Hence in the present study we attempted to identify and analyze the HBVrt amino acid substitutions capable of conferring resistance to antivirals in treatment-naïve HBV-infected individuals from the Indian subcontinent.…”

Section: Introductionmentioning

confidence: 99%

Antiviral Resistance Mutations and Genotype-Associated Amino Acid Substitutions in Treatment-Naïve Hepatitis B Virus-Infected Individuals from the Indian Subcontinent

Ismail¹,

Samuel

Eapen

et al. 2011

Intervirology

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Background/Aims: Antiviral resistance is a major challenge to the treatment currently available for hepatitis B virus (HBV). In this study, mutations that may affect the antiviral efficacy in treatment-naïve HBV-infected individuals were analyzed. Methods: Ninety-seven treatment-naïve HBV-infected individuals were included in this study. HBV reverse transcriptase (rt) domains were sequenced and nucleotide differences were compared to GenBank wild-type sequences. Furthermore, HBV genotypes, subgenotypes and subtypes were determined by analyzing surface gene sequences. Results: An adefovir-related rtI233V mutation was identified in 4 subjects. The rtS213T lamivudine and entecavir refractory mutant was presented in 3 individuals. Altogether, drug-related, atypical and novel HBVrt amino acid substitutions were seen in 73 positions. The HBV genotypes A, C, D and G were depicted in 15, 21, 60 and 1 individuals, respectively. There were 17 HBVrt amino acid substitutions that are associated with certain genotypes of HBV. Mutations in HBVrt corresponded to established surface gene mutations in 9 patients. Conclusion: This data shows that antiviral-resistant HBV strains do exist in treatment-naïve individuals in this region. Further studies are essential to characterize the role of HBVrt amino acid substitutions in response to anti-HBV therapy.

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Characterization of hepatitis B virus reverse transcriptase sequences in Chinese treatment naive patients

Cited by 38 publications

References 21 publications

Dynamics of Hepatitis B Virus Quasispecies in Association with Nucleos(t)ide Analogue Treatment Determined by Ultra-Deep Sequencing

Dynamics of Hepatitis B Virus Quasispecies in Association with Nucleos(t)ide Analogue Treatment Determined by Ultra-Deep Sequencing

Nucleotide analogue-resistant mutations in hepatitis B viral genomes found in hepatitis B patients

Antiviral Resistance Mutations and Genotype-Associated Amino Acid Substitutions in Treatment-Naïve Hepatitis B Virus-Infected Individuals from the Indian Subcontinent

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