Genotype-specific mutations in the polymerase gene of hepatitis B virus potentially associated with resistance to oral antiviral therapy

Mirandola, Silvia; Sebastiani, Giada; Rossi, Cristina; Velo, Emanuela; Erne, Elke; Vario, Alessandro; Tempesta, Diego; Romualdi, Chiara; Campagnolo, Davide; Alberti, Alfredo

doi:10.1016/j.antiviral.2012.09.014

Cited by 26 publications

(25 citation statements)

References 34 publications

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“…The prevalence of genotypic resistance mutations was 41.72% (58/139), which is different from the prevalence reported in other countries [20][21][22][23], and is also different from studies in other regions of China [14,17,24]. The discrepancy might be due to race and genotype of HBV in different countries, because the predominant HBV genotypes in Europe are A and D. However, the dominating HBV genotype in Korea is C. In China, though genotypes B and C are major genotypes, reports of the distribution of the genotypes in different region are inconsistent [19], which may also affect the frequency of genotypic resistance mutations.…”

Section: Discussioncontrasting

confidence: 50%

Monitoring of genotypic resistance profile in chronic hepatitis B patients receiving nucleos(t)ide analogues in Huzhou, China

Qian

Qin

et al. 2016

J Infect Dev Ctries

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Introduction: Antiviral drug-resistance patterns of hepatitis B virus (HBV) mutants are complex and currently partly understood. The aim of this study was to monitor the genotypic resistance profile in patients with chronic hepatitis B (CHB) receiving nucleos(t)ide analogues (NAs) in Huzhou, eastern China. Methodology: Serum samples of 139 CHB patients undergoing NA treatment were obtained from Huzhou Central Hospital. The full-length HBV reverse transcriptase regions were amplified and sequenced. The NA resistance mutation positions, including rtL80, rtI169, rtV173, rtL180, rtA181, rtT184, rtA194, rtS202, rtM204, rtI233, rtN236, and rtM250 were analyzed. Results: Genotypic resistance mutations were detected in 41.72% (58/139) of patients with CHB. Drug resistance mutations were detected at positions rt80, rt173, rt180, rt181, rt194, rt202, rt204, rt236, and rt250, but were not observed at positions rt169, rt184, and rt233. The prevalence of mutations at rtM204 was 54.44% in 90 patients who were treated with lamivudine (LAM) or telbivudine (LDT). RtN236 mutations were detected in 7.14% (2/28) of the patients receiving adefovir (ADV) therapy. Additionally, rtA181 mutations were observed in 4 patients with LAM, ADV, and LDT-based therapy, but not in those patients treated with entecavir (ETV). Among patients who harbored rtM204 combination mutations, rtM204I and rtM204V were significantly associated with rtL80I/V and rtL180M, respectively. Conclusions: The mutation patterns of NA-resistant HBV are complicated in CHB patients in the current clinical setting. Thus, it is necessary to persistently monitor the resistance mutations of HBV for optimizing antiviral therapy strategy and for preventing an outbreak of clinical resistance.

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Section: Discussioncontrasting

confidence: 50%

Monitoring of genotypic resistance profile in chronic hepatitis B patients receiving nucleos(t)ide analogues in Huzhou, China

Qian

Qin

et al. 2016

J Infect Dev Ctries

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“…The mutation at position rtY221 was identified as a new mutation and may be relevant to the development and evolution of resistance to oral antiviral therapy. Its frequency is higher in HBV genotype A patients being treated with adefovir dipivoxil than in treatment-naïve patients (34). Nonetheless, the relation between these mutations in genotypes B or C and antiviral resistance are still unknown.…”

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confidence: 99%

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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“…Moreover, HBV genotypes differ in LAM-resistant mutation patterns, as HBV-A favours the rtM204V mutation, whilst HBV-B-D prefer rtM204I (Mirandola et al, 2012). In addition, the rtL180M mutation is significantly associated with the rtM204V mutation in HBV-A-C (Damerow et al, 2010).…”

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confidence: 93%

“…However, no significant difference was observed in this study. Notably, previous studies showed that HBV genotypes correlated with drug-resistant mutation patterns (Mirandola et al, 2012;Seifer et al, 2009;Svicher et al, 2009). Also, a recent study by Damerow et al (2010) demonstrated that HBV genotypes differed in their LAM-resistant mutation pattern.…”

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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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Genotype-specific mutations in the polymerase gene of hepatitis B virus potentially associated with resistance to oral antiviral therapy

Cited by 26 publications

References 34 publications

Monitoring of genotypic resistance profile in chronic hepatitis B patients receiving nucleos(t)ide analogues in Huzhou, China

Monitoring of genotypic resistance profile in chronic hepatitis B patients receiving nucleos(t)ide analogues in Huzhou, China

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

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

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