Long-term monitoring drug resistance by ultra-deep pyrosequencing in a chronic hepatitis B virus (HBV)-infected patient exposed to several unsuccessful therapy schemes

Sede, Mariano Miguel; Ojeda, Diego S.; Cassino, Lucila; Westergaard, Gastón; Vázquez, Martı́n; Benetti, Silvina; Fay, Fabián; Tanno, Hugo; Quarleri, Jorge

doi:10.1016/j.antiviral.2012.03.003

Cited by 11 publications

(8 citation statements)

References 24 publications

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“…The ADV group included patients for whom multidrug therapy had previously been unsuccessful. The frequency of mutations was higher under monotherapy compared with under multidrug therapy [14]. There are some studies on ADV-resistance mutations [11], but there are few studies about HBV RT region resistantance-assocaited mutations in multi-drugs combinations.…”

Section: Discussionmentioning

confidence: 99%

Pre-existing mutations related to tenofovir in chronic hepatitis B patients with long-term nucleos(t)ide analogue drugs treatment by ultra-deep pyrosequencing

Zhang

et al. 2016

Oncotarget

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AimsThe dynamics of resistance-associated mutations under combination therapy were explored.MethodsA total of 46 patients were classified into adefovir (n=14) and entecavir (n=32) groups. In the adefovir (ADV) group, six patients receiving combined therapy were DNA-positive after more than 3 years of therapy. Ultra-deep pyrosequencing was used to analyze the dynamics of multi-drugs resistance mutations.ResultsAt baseline, all 46 treatment-naïve patients harbored rtA181V/T substitutions (1.2%-4.6%) and rtN236T substitutions (1.6%-6.1%). In the ADV group, eight patients with long-term treatment were consecutively HBV DNA-positive for more than 3 years. During treatment, the rtA181T resistance-associated site appeared with increasing frequency in six of eight patients (NOs. 1-6), and two patients (NOs.4 and 8) carrying the rtA181T resistance mutations increasingly showed high levels of rtN236T. One patient (NO. 8) experienced virological breakthrough. Other known pre-existing mutations showed no dynamic fluctuations, including in rtA194T, rtP177G, rtF249A, and rtD263E. In addition to the common substitutions, some previously unknown amino acid substitutions, such as rtD134N, rtL145M/S, rtF151Y/L, rtR153Q, and rtS223A, should be further studied.ConclusionsHBV-resistance substitutions conferring to nucleoside analogs are present at baseline. The dynamics of the HBV RT-region quasispecies variation are heterogeneous and complex.

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Section: Discussionmentioning

confidence: 99%

Pre-existing mutations related to tenofovir in chronic hepatitis B patients with long-term nucleos(t)ide analogue drugs treatment by ultra-deep pyrosequencing

Zhang

et al. 2016

Oncotarget

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“…In the sequential analysis of the region encoded reverse transcriptase, NA-resistant HBV variants were present in combinations of amino acid substitutions that increased in complexity after viral breakthrough or unsuccessful therapy with NA, at which time the combined NA-resistant variants predominated and the pretreatment HBV variants did not show NA-resistant motifs. [41][42][43] In another study, primarily NA resistance-related mutant variants were found to exist with minor variants in treatment-naïve patients. 44…”

Section: Hepatitis B Virus (Hbv)mentioning

confidence: 99%

Application of deep sequence technology in hepatology

Ninomiya

Ueno

Shimosegawa

2013

Hepatology Research

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Deep sequencing technologies are currently cutting edge, and are opening fascinating opportunities in biomedicine, producing over 100-times more data compared to the conventional capillary sequencers based on the Sanger method. Next-generation sequencing (NGS) is now generally defined as the sequencing technology that, by employing parallel sequencing processes, producing thousands or millions of sequence reads simultaneously. Since the GS20 was released as the first NGS sequencer on the market by 454 Life Sciences, the competition in the development of the new sequencers has become intense. In this review, we describe the current deep sequencing systems and discuss the application of advanced technologies in the field of hepatology.

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“…47 More recently, these studies have become geared toward the longitudinal assessment of viral sequences in patient samples, with relevant clinical data allowing for a more detailed investigation of the HBV viral pool. 49,50 The spectrum of currently available data generated using ultradeep sequencing in studies of HBV is discussed in the context of three clinically relevant categories: viral discovery/ viral quasispecies analysis, disease pathogenesis, and response to therapy and immune pressure/antiviral resistance detection.…”

Section: Applications For Ultradeep Sequencing In Hbv Research: the Cmentioning

confidence: 99%

“…Most recently, Sede and colleagues used the 454-sequencing platform to demonstrate evidence of the lamivudine-resistant variant rtL180M 7 years prior to detection of lamivudine resistance via population-based sequencing. 49 Although data regarding the presence of rtL180M at baseline was not available, the presence of this variant at around 1% during the first 12 months of treatment suggests that lower levels may have been circulating within the patient prior to treatment initiation.…”

Section: Response To Therapy and Immune Pressure/antiviral Resistancementioning

confidence: 99%

“…50 This is in contrast to posttreatment samples in which common resistance variants including rtL180M, rtA181T, and rtM204V/I are present in the same viral sequence. 42,49,50 Ijaz and colleagues further suggest that the rtM204V substitution may be acquired prior to rtL180M in HBV patients on lamivudine monotherapy. 60 The same study also concluded that in some instances there may be a reversion to WT virus while on combination antiviral treatment, reflecting variation of effect due to replicative capacity.…”

Section: Response To Therapy and Immune Pressure/antiviral Resistancementioning

confidence: 99%

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Advances in the Molecular Diagnosis of Hepatitis B Infection: Providing Insight into the Next Generation of Disease

et al. 2013

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Hepatitis B virus (HBV) infection continues to represent a significant health threat, affecting over 400 million people worldwide. Historically, the diagnosis and treatment of chronic hepatitis B (CHB) relied in detection of the hepatitis B surface antigen (HBsAg) and more recently realtime polymerase chain reaction (PCR) analysis. The advent of novel technologies and equipment for the identification and staging of the different stages of HBV infection has resulted in dramatic changes to patient monitoring and management. Through the use of rapid, quantitative HBsAg immunoassays, it is now possible to predict the likelihood of patient response to treatment as well as the clinical course of disease. Ultradeep sequencing technologies (also known as next-generation sequencing) overcome many of the traditional limitations associated with population-based sequencing approaches, and have provided significant insight into the viral response to therapeutic intervention and the molecular pathogenesis of CHB. The authors discuss recent developments in the molecular diagnosis of HBV infection, as well as potential advantages and caveats resultant of this rapid progression of technology.

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Long-term monitoring drug resistance by ultra-deep pyrosequencing in a chronic hepatitis B virus (HBV)-infected patient exposed to several unsuccessful therapy schemes

Cited by 11 publications

References 24 publications

Pre-existing mutations related to tenofovir in chronic hepatitis B patients with long-term nucleos(t)ide analogue drugs treatment by ultra-deep pyrosequencing

Pre-existing mutations related to tenofovir in chronic hepatitis B patients with long-term nucleos(t)ide analogue drugs treatment by ultra-deep pyrosequencing

Application of deep sequence technology in hepatology

Advances in the Molecular Diagnosis of Hepatitis B Infection: Providing Insight into the Next Generation of Disease

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