Early changes of hepatitis B virus quasispecies during lamivudine treatment and the correlation with antiviral efficacy

Chen, L.; Zhang, Qian; Yu, Demin; Wan, Mo-Bin; Zhang, Xinxin

doi:10.1016/j.jhep.2008.12.018

Cited by 65 publications

(61 citation statements)

References 35 publications

(41 reference statements)

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“…These results could be interpreted as the production of more variants in the quasispecies in the responders during the early therapeutic pressure compared with non-responders. The reasons why we obtained different patterns of quasispecies evolution from the previous studies (Chen et al, 2009;Liu et al, 2011) is possibly due to: (1) the method of calculation. In the previous studies, the quasispecies were detected by direct PCR sequencing and the variants in complexity were defined based on the whole length of the reads (Chen et al, 2009;Liu et al, 2011).…”

Section: Resistant Mutations and Hbv Quasispecies In Ldt Therapymentioning

confidence: 52%

“…The reasons why we obtained different patterns of quasispecies evolution from the previous studies (Chen et al, 2009;Liu et al, 2011) is possibly due to: (1) the method of calculation. In the previous studies, the quasispecies were detected by direct PCR sequencing and the variants in complexity were defined based on the whole length of the reads (Chen et al, 2009;Liu et al, 2011). However, in our study, the complexity was measured by the mean Shannon entropy (S n ) at each nt or aa position following the methods reported previously (Nishijima et al, 2012); (2) the time point of sampling.…”

Section: Resistant Mutations and Hbv Quasispecies In Ldt Therapymentioning

confidence: 52%

“…Studies of HBV quasispecies during treatment with either LAM or entecavir produced similar results indicating that quasispecies complexity was statistically lower in responders than in partial responders at week 4, although the complexity was comparable at baseline (Chen et al, 2009;Liu et al, 2011). In our study, quasispecies complexity at baseline was comparable for both groups at the nt level but was higher for the responder group at aa level, and at week 12, the complexity of the responder group was significantly higher than that of the non-responder group (Fig.…”

Section: Resistant Mutations and Hbv Quasispecies In Ldt Therapymentioning

confidence: 89%

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Resistant mutations and quasispecies complexity of hepatitis B virus during telbivudine treatment

Yin

Wei

et al. 2015

Journal of General Virology

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Ultra-deep pyrosequencing (UDPS) was used to analyse the dynamics of quasispecies and resistant mutations during telbivudine (LDT) treatment of hepatitis B patients. Twenty-six HBeAg-positive chronic hepatitis B patients were treated with LDT for a period of 104 weeks and were characterized as 16 responders, six partial responders and four viral breakthrough patients based on hepatitis B virus (HBV) DNA levels. The plasma samples were subjected to UDPS of the reverse transcriptase (RT) region of HBV. Mutations rtM204I, rtL80I and rtL80V were detected in at least three of the four viral breakthrough patients, indicating the significant roles of the mutations in resistance to LDT. The degree of complexity of viral quasispecies remained in a steady state in the absence of selection pressure, but increased after the LDT treatment. The complexity in the responder group at week 12 was significantly higher than that in the group comprising partial responders and viral breakthrough patients. In vitro replication efficiency analyses showed that the RT mutations had different impacts on HBV replication, with a tendency of rtM204I.rtL80V.rtL80I. Furthermore, double mutations rtL80I/M204I and rtL80V/M204V had replication efficiency similar to that of rtL80I and rtL80V, respectively. Consistent with previous studies, mutation rtM204I was found to be highly resistant to LDT. However, in contrast with their sensitivity to lamivudine, rtL80I and rtL80V were moderately resistant to LDT. Our results indicated that rtL80I and rtL80V may not only serve as replication complementary mutations to rtM204I, but also directly contribute to the LDT resistance.

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Section: Resistant Mutations and Hbv Quasispecies In Ldt Therapymentioning

confidence: 52%

Section: Resistant Mutations and Hbv Quasispecies In Ldt Therapymentioning

confidence: 52%

Section: Resistant Mutations and Hbv Quasispecies In Ldt Therapymentioning

confidence: 89%

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Resistant mutations and quasispecies complexity of hepatitis B virus during telbivudine treatment

Yin

Wei

et al. 2015

Journal of General Virology

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“…Our previous studies demonstrated the dynamic changes of HBV quasispecies within the RT region during early stages of antiviral therapy in patients who underwent NA treatment using clone-based sequencing (21,22). In the present study, HBV quasispecies within the RT region were analyzed with GS-FLX standard sequencing technology, which allows sequencing of DNA fragments exceeding 400 bp in length, including the fusion primers, from the same samples as in our previous studies.…”

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confidence: 79%

Comparison of Next-Generation Sequencing and Clone-Based Sequencing in Analysis of Hepatitis B Virus Reverse Transcriptase Quasispecies Heterogeneity

et al. 2013

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We previously reported that, based on clone-based sequencing (CBS), hepatitis B virus (HBV) heterogeneity within the reverse transcriptase (RT) region was a predictor of antiviral efficacy. Here, by comparing ultradeep pyrosequencing (UDPS), i.e., nextgeneration sequencing (NGS), with CBS in characterizing the genetic heterogeneity of HBV quasispecies within the RT region, we evaluated the performance of UDPS in the analysis of HBV viral populations. HBV genomic DNA was extracted from serum samples from 31 antiviral treatment-naive patients with chronic hepatitis B. The RT region quasispecies were analyzed in parallel using CBS and UDPS. Characterization of quasispecies heterogeneity was conducted using bioinformatics analysis. Quasispecies complexity values were calculated with the formula Sn ‫؍‬ ؊⌺ i (p i lnp i )/lnN. The number of qualified strains obtained by UDPS was much larger than that obtained by CBS (P < 0.001). Pearson analysis showed that there was a positive correlation of quasispecies complexity values at the nucleotide level for the two methods (P < 0.05), while the complexity value derived from UDPS data was higher than that derived from CBS data (P < 0.001). Study of the prevalences of variations within the RT region showed that CBS detected an average of 9.7 ؎ 1.1 amino acid substitutions/sample and UDPS detected an average of 16.2 ؎ 1.4 amino acid substitutions/sample. The phylogenetic analysis based on UDPS data showed more genetic entities than did that based on CBS data. Viral heterogeneity determination by the UDPS technique is more sensitive and efficient in terms of lowabundance variation detection and quasispecies simulation than that by the CBS method, although imperfect, and thus sheds light on the future clinical application of NGS in HBV quasispecies studies. Hepatitis B virus (HBV) is a noncytopathic DNA virus that infects approximately 350 million people worldwide and is a leading cause of liver cirrhosis and hepatocellular carcinoma. The evolutionary dynamics of HBV are characterized by high mutation rates (Ͼ10 Ϫ5 nucleotide substitutions/site/year) due to the error-prone reverse transcriptase (RT) (1) and rapid replication rates (Ͼ10 11 virions per day) (2, 3). Thus, a large number of viral variants are constantly generated, creating great genetic diversity on which natural selection operates. Heterogeneous populations of viruses are often referred to as viral quasispecies (4, 5). The massive heterogeneity present in HBV quasispecies has important biological consequences; it has been identified as an important factor in relation to the clinical features of the infection (transmission, persistence, and liver damage), and it may influence the outcomes of treatment and be important in the development of resistance to nucleoside/nucleotide analogue (NA) antiviral therapy (6).Cloning of PCR products and subsequent Sanger dideoxy sequencing have been widely used in analyses of the heterogeneity of viral quasispecies and determination of antiviral-associated drug resistance mutations, ...

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“…Viral QS heterogeneity was evaluated with complexity and diversity. QS complexity was measured using normalized Shannon entropy (Sn) as previously described (14,15). QS diversity was evaluated by three parameters: the mean genetic distance (d; also called Hamming distance), the number of synonymous substitutions per synonymous site (dS), and the number of nonsynonymous substitutions per nonsynonymous site (dN).…”

Section: Patientsmentioning

confidence: 99%

Clinical Implications of Evolutionary Patterns of Homologous, Full-Length Hepatitis B Virus Quasispecies in Different Hosts after Perinatal Infection

Liu

Huang

et al. 2014

J Clin Microbiol

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c Chronic hepatitis B virus (HBV) infection via perinatal transmission is common in the Asia-Pacific region, but related quasispecies (QS) characteristicsare not yet defined. To investigate the homologous, full-length HBV QS after perinatal infection and their clinical implications, five pairs of mother-daughter patients with chronic HBV infection (one patient with liver cirrhosis, one with immune tolerance, and eight with chronic hepatitis) were included. Full-length HBV were amplified by PCR from serum samples before antiviral treatment and cloned; an average of 17 clones per sample were sequenced, and the QS complexities, diversities, and evolution patterns were analyzed. Full-length HBV sequence similarities within mother-daughter pairs were 91.3 to 98.3%. The QS complexities of full-length HBV were similar between mothers and daughters (median of 0.9734 compared to 0.9688, P > 0.05), as were the diversities (median of 3.396 ؋ 10 ؊3 compared to 4.617 ؋ 10 ؊3 substitutions/site, P > 0.05). However, the distribution patterns of QS complexities and diversities within specific genes were different, and QS genetic distances of the mothers were higher than those of daughters, both more evident in pairs with different antiviral responses and different immune phases or stages. The nucleotide substitution rate of full-length HBV was 14.388 ؋ 10 ؊5 substitutions/site/year, whereas the preC/C gene rate was the highest. Mutations and indels were more common in clones from the mothers, which decreased the affinity of epitopes by 6-to 89-fold. The various genes from homologous HBV genomes evolved in different patterns despite numerically comparable full-length QS complexities and diversities. The different patterns may correlate with the immune stages of chronic HBV infection, which warrants further study. C hronic hepatitis B virus (HBV) infection is still a serious public health problem, with potential adverse sequelae, such as liver cirrhosis, liver failure, and hepatocellular carcinoma. More than 350 million people are chronically infected with HBV, and 75% reside in the Asia-Pacific region (1, 2), where the infection is usually acquired perinatally or in early childhood. In contrast to a very short immune-tolerant (IT) phase in adult-acquired chronic HBV infection, the perinatally or early-childhood-acquired chronic HBV infection has a long immune-tolerant phase, followed by an immune-reactive phase, inactive carrier state, HBeAg-negative chronic hepatitis B, and HBsAg-negative phase. The clinical and laboratory characteristics of each phase have been described in detail previously (3, 4).Due to absence of proofreading during reverse transcription and a high replication rate, the HBV population consists of genetically distinct but closely related variants known as quasispecies (QS). QS means a spectrum of mutants that possess different fitness levels in certain environments (5, 6). Mutants with higher fitness levels predominate by competitive replication, and the predominant mutant may differ in a changing environmen...

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Early changes of hepatitis B virus quasispecies during lamivudine treatment and the correlation with antiviral efficacy

Cited by 65 publications

References 35 publications

Resistant mutations and quasispecies complexity of hepatitis B virus during telbivudine treatment

Resistant mutations and quasispecies complexity of hepatitis B virus during telbivudine treatment

Comparison of Next-Generation Sequencing and Clone-Based Sequencing in Analysis of Hepatitis B Virus Reverse Transcriptase Quasispecies Heterogeneity

Clinical Implications of Evolutionary Patterns of Homologous, Full-Length Hepatitis B Virus Quasispecies in Different Hosts after Perinatal Infection

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