Oncotarget

Research Papers:

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

Xiaxia Zhang _, Minran Li, Hongli Xi, Renwen Zhang, Jianhong Chen, Yu Zhang and Xiaoyuan Xu

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Oncotarget. 2016; 7:70264-70275. https://doi.org/10.18632/oncotarget.11840

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Abstract

Xiaxia Zhang1, Minran Li2, Hongli Xi1, Renwen Zhang1, Jianhong Chen1, Yu Zhang1, Xiaoyuan Xu1

1Department of Infectious Disease, Peking University First Hospital, Xicheng District, Beijing 100034, China

2Division of Liver Disease, The Fifth Hospital of Shijiazhuang, Hebei Medical University, Shijiazhuang 050023, China

Correspondence to:

Xiaoyuan Xu, email: xiaoyuanxu6@163.com

Keywords: hepatitis B virus, resistance, multi-drugs therapy, tenofovir, ultra-deep pyrosequencing

Received: June 29, 2016    Accepted: August 26, 2016    Published: September 02, 2016

ABSTRACT

Aims: The dynamics of resistance-associated mutations under combination therapy were explored.

Methods: A 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.

Results: At 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.

Conclusions: HBV-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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