Hepatitis B virus mutations potentially conferring adefovir/tenofovir resistance in treatment-naive patients

Pastor, Rebecca; Habersetzer, François; Fafi‐Kremer, Samira; Doffoël, Michel; Baumert, Thomas F.; Gut, Jean‐Pierre; Stoll‐Keller, Françoise; Schvoerer, Évelyne

doi:10.3748/wjg.15.753

Cited by 37 publications

(26 citation statements)

References 16 publications

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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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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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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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“…Nonetheless, antiviral therapy with these drugs is often ineffective because of the emergence of antiviral-drug resistance mutations, located in the HBV reverse transcriptase (RT) gene during long-term treatment (1). Therefore, antiviral-drug resistance mutations have even been reported in HBV isolated from treatment-naïve patients (2,3) HBV RT mutations are classified into 4 categories: primary drug resistance mutations, secondary, or compensatory mutations, putative NA resistance (NAr) mutations, and pretreatment mutations (4). Primary drug resistance mutations are directly responsible for NA resistance.…”

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Profile of Mutations in the Reverse Transcriptase and Overlapping Surface Genes of Hepatitis B Virus (HBV) in Treatment-Naïve Indonesian HBV Carriers

et al. 2017

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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.…”

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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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Hepatitis B virus mutations potentially conferring adefovir/tenofovir resistance in treatment-naive patients

Cited by 37 publications

References 16 publications

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

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

Profile of Mutations in the Reverse Transcriptase and Overlapping Surface Genes of Hepatitis B Virus (HBV) in Treatment-Naïve Indonesian HBV Carriers

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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