Retrospective Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 21, 2020; 26(35): 5314-5327
Published online Sep 21, 2020. doi: 10.3748/wjg.v26.i35.5314
Investigation of immune escape-associated mutations of hepatitis B virus in patients harboring hepatitis B virus drug-resistance mutations
Bi-Xia Huang, Yan Liu, Zhen-Ping Fan, Lan-Lan Si, Rong-Juan Chen, Jun Wang, Dan Luo, Fu-Sheng Wang, Dong-Ping Xu, Xin-Guang Liu
Bi-Xia Huang, Xin-Guang Liu, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics/Institute of Biochemistry & Molecular Biology, Guangdong Medical University, Dongguan 523808, Guangdong Province, China
Yan Liu, Zhen-Ping Fan, Lan-Lan Si, Rong-Juan Chen, Jun Wang, Fu-Sheng Wang, Dong-Ping Xu, Institute of Infectious Diseases, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
Dan Luo, Department of Infectious Diseases, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
Author contributions: Huang BX was involved in the experiments, procedures, statistical analysis, writing of the original draft, and critical revision of manuscript; Liu Y performed the experiments and procedures; Fan ZP took part in the statistical analysis; Si LL was involved in the experiments and procedures; Chen RJ performed the experiments and procedures; Wang J took part in the statistical analysis; Luo D was involved in the study statistical analysis; Wang FS performed the study statistical analysis; Xu DP took part in the study conception, design, writing of the original draft, and critical revision of manuscript; Liu XG was involved in the study conception, design, writing of the original draft, and critical revision of manuscript; all authors have read and approved the final manuscript.
Supported by the National Natural Science Foundation of China, No. 81572010, No. 81671399, No. 81721002 and No. 81971329; the Capital Health Research and Development of Special Fund Program, No. 2016-2-5032; and the Beijing Natural Science Foundation No. 7172206.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee Approval Document of 302 Hospital, Institutional Review Board Approval No. 2012020D; The study was reviewed and approved by the Ethics Committee Approval Document of 302 Hospital, Institutional Review Board Approval No. 2013052D.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: We do not have any patents, whether planned, pending or issued, broadly relevant to the work.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Dong-Ping Xu, MD, PhD, Professor, Institute of Infectious Diseases, the Fifth Medical Center of Chinese PLA General Hospital, No. 100 Xisihuan Middle Road, Beijing 100039, China. xudongping302@sina.com
Received: April 23, 2020
Peer-review started: April 23, 2020
First decision: May 1, 2020
Revised: July 27, 2020
Accepted: August 12, 2020
Article in press: August 12, 2020
Published online: September 21, 2020
Processing time: 146 Days and 19.8 Hours
Abstract
BACKGROUND

It is unclear whether immune escape-associated mutations in the major hydrophilic region of hepatitis B virus surface antigen (HBsAg) are associated with nucleoside/nucleotide analog resistance.

AIM

To evaluate the association between immune escape-associated mutations and nucleoside/nucleotide analog resistance mutations.

METHODS

In total, 19440 patients with chronic hepatitis B virus infection, who underwent resistance testing at the Fifth Medical Center of Chinese PLA General Hospital between July 2007 and December 2017, were enrolled. As determined by sequence analysis, 6982 patients harbored a virus with resistance mutations and 12458 harbored a virus lacking resistance mutations. Phenotypic analyses were performed to evaluate HBsAg production, replication capacity, and drug-induced viral inhibition of patient-derived drug-resistant mutants with or without the coexistence of sA159V.

RESULTS

The rate of immune escape-associated mutation was significantly higher in 9 of the 39 analyzed mutation sites in patients with resistance mutations than in patients without resistance mutations. In particular, these mutations were sQ101H/K/R, sS114A/L/T, sT118A/K/M/R/S/V, sP120A/L/Q/S/T, sT/I126A/N/P/S, sM133I/L/T, sC137W/Y, sG145A/R, and sA159G/V. Among these, sA159V was detected in 1.95% (136/6982) of patients with resistance mutations and 1.08% (134/12,458) of patients lacking resistance mutations (P < 0.05). The coexistence of sA159V with lamivudine (LAM) and entecavir (ETV)-resistance mutations in the same viral genome was identified during follow-up in some patients with drug resistance. HBsAg production was significantly lower and the replication capacity was significantly higher, without a significant difference in LAM/ETV susceptibility, in sA159V-containing LAM/ETV-resistant mutants than in their sA159V-lacking counterparts.

CONCLUSION

In summary, we observed a close link between the increase in certain immune escape-associated mutations and the development of resistance mutations. sA159V might increase the fitness of LAM/ETV-resistant mutants under environmental pressure in some cases.

Keywords: Hepatitis B virus; Immune escape-associated mutation; Drug-resistance mutation; Nucleoside/nucleotide analogs; Hepatitis B surface antigen; Major hydrophilic region

Core Tip: A large number of patients were surveyed for immune escape-associated mutations, and the link between immune escape-associated and resistant mutations was identified. Contribution of sA159V to resistance was found in multiple followed up patients, in particular sA159V reduced hepatitis B surface antigen but raised the replication capacity of lamivudine/entecavir-resistant mutants.