Entecavir resistance mutations rtL180M/T184L/M204V combined with rtA200V lead to tenofovir resistance

被引：21
作者：
Jiang, Dong [1 ,2 ]
Wang, Jianghua [3 ,4 ]
Zhao, Xuesen [1 ,2 ]
Li, Yuxin [5 ]
Zhang, Qun [5 ]
Song, Chuan [1 ,2 ]
Zeng, Hui [1 ,2 ]
Wang, Xianbo [5 ]
机构：
[1] Capital Med Univ, Beijing Ditan Hosp, Inst Infect Dis, Beijing, Peoples R China
[2] Beijing Key Lab Emerging Infect Dis, Beijing, Peoples R China
[3] Peking Univ, Peoples Hosp, Hepatol Inst, Beijing, Peoples R China
[4] Peking Univ, Key Lab Hepatitis C & Immunotherapy Liver Dis, Beijing, Peoples R China
[5] Capital Med Univ, Beijing Ditan Hosp, Ctr Integrat Med, 8 Jingshundongjie, Beijing 100015, Peoples R China
来源：
LIVER INTERNATIONAL | 2020年 / 40卷 / 01期
基金：
中国国家自然科学基金;
关键词：
CHB; chronic hepatitis B; EC50; half maximal effective concentration; MDR; multidrug-resistant; NA; nucleoside and nucleotide analogues; tyrosine-methionine-aspartate-aspartate; YMDD; CHRONIC HEPATITIS-B; DISOPROXIL FUMARATE; COMBINATION THERAPY; VIRUS POLYMERASE; NAIVE PATIENTS; HBV; ADEFOVIR; LAMIVUDINE; EFFICACY; SUSCEPTIBILITY;
D O I：
10.1111/liv.14241
中图分类号：
R57 [消化系及腹部疾病];
学科分类号：
摘要：
Background Tenofovir disoproxil fumarate (TDF) imposes a high genetic barrier to drug resistance and potently inhibits replication of multidrug-resistant hepatitis B virus. Few clinical cases with confirmed TDF-resistance have been reported to date. Methods and Results Here, we report viral rebound in a patient with chronic hepatitis B who underwent TDF monotherapy and harboured a quadruple mutant consisting of classic entecavir (ETV)-resistance mutations (rtL180M/T184L/M204V) together with an rtA200V mutation in the reverse transcriptase gene. Sequencing analysis revealed that this quadruple mutant emerged as a major viral population. In vitro phenotyping demonstrated that the rtL180M/T184L/A200V/M204V mutant had moderate resistance to TDF treatment, with a 4.52-fold higher half maximal effective concentration than that of wild-type virus. Importantly, this patient with TDF resistance achieved virological suppression after TDF/ETV combination rescue therapy. Conclusion An rtL180M/T184L/A200V/M204V mutant with moderate resistance to TDF monotherapy was selected during sequential nucleoside analogue (NA) treatment in a stepwise manner. ETV/TDF combination therapy effectively suppressed replication of this TDF-resistant mutant. Our studies provide novel insights into the treatment of NA-naive patients as well as patients with TDF resistance.
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页码：83 / 91
页数：9
相关论文
共 37 条
[1]   Tenofovir disoproxil fumarate monotherapy for nucleos(t)ide-naive chronic hepatitis B patients in Korea: data from the clinical practice setting in a single-center cohort [J].
Ahn, Sung Soo ;
Chon, Young Eun ;
Kim, Beom Kyung ;
Kim, Seung Up ;
Kim, Do Young ;
Ahn, Sang Hoon ;
Han, Kwang-Hyub ;
Park, Jun Yong .
CLINICAL AND MOLECULAR HEPATOLOGY, 2014, 20 (03) :261-266
[2]   The rtA194T Polymerase Mutation Impacts Viral Replication and Susceptibility to Tenofovir in Hepatitis B e Antigen-Positive and Hepatitis B e Antigen-Negative Hepatitis B Virus Strains [J].
Amini-Bavil-Olyaee, Samad ;
Herbers, Ulf ;
Sheldon, Julie ;
Luedde, Tom ;
Trautwein, Christian ;
Tacke, Frank .
HEPATOLOGY, 2009, 49 (04) :1158-1165
[3]   Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase [J].
Angus, P ;
Vaughan, R ;
Xiong, S ;
Yang, HL ;
Delaney, W ;
Gibbs, C ;
Brosgart, C ;
Colledge, D ;
Edwards, R ;
Ayres, A ;
Bartholomeusz, A ;
Locarnini, S .
GASTROENTEROLOGY, 2003, 125 (02) :292-297
[4]   Susceptibility to antivirals of a human HBV strain with mutations conferring resistance to both lamivudine and adefovir [J].
Brunelle, MN ;
Jacquard, AC ;
Pichoud, C ;
Durantel, D ;
Carrouée-Durantel, S ;
Villeneuve, JP ;
Trépo, C ;
Zoulim, F .
HEPATOLOGY, 2005, 41 (06) :1391-1398
[5]   A dose-ranging study of the efficacy and tolerability of entecavir in lamivudine-refractory chronic hepatitis B patients [J].
Chang, TT ;
Gish, RG ;
Hadziyannis, SJ ;
Cianciara, J ;
Rizzetto, M ;
Schiff, ER ;
Pastore, G ;
Bacon, BR ;
Poynard, T ;
Joshi, S ;
Klesczewski, KS ;
Thiry, A ;
Rose, RE ;
Colonno, RJ ;
Hindes, RG .
GASTROENTEROLOGY, 2005, 129 (04) :1198-1209
[6]   No Resistance to Tenofovir Disoproxil Fumarate Through 96 Weeks of Treatment in Patients With Lamivudine-Resistant Chronic Hepatitis B [J].
Corsa, Amoreena C. ;
Liu, Yang ;
Flaherty, John F. ;
Ben Mitchell ;
Fung, Scott K. ;
Gane, Edward ;
Miller, Michael D. ;
Kitrinos, Kathryn M. .
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY, 2014, 12 (12) :2106-U393
[7]  
Gallego A, 2008, J VIRAL HEPATITIS, V15, P392, DOI [10.1111/j.1365-2893.2008.00966.x, 10.1111/j.1365-2893.2007.00966.x]
[8]   Clonal analysis of the quasispecies of antiviral-resistant HBV genomes in patients with entecavir resistance during rescue treatment and successful treatment of entecavir resistance with tenofovir [J].
Karatayli, Ersin ;
Idilman, Ramazan ;
Karatayli, Senem C. ;
Cevik, Emrah ;
Yakut, Mustafa ;
Seven, Gulseren ;
Kabacam, Gokhan ;
Bozdayi, A. Mithat ;
Yurdaydin, Cihan .
ANTIVIRAL THERAPY, 2013, 18 (01) :77-85
[9]   Efficacy of tenofovir in adefovir-experienced patients compared with treatment-naive patients with chronic hepatitis B [J].
Keskin, Onur ;
Ormeci, Asli C. ;
Baran, Bulent ;
Kabacam, Gokhan ;
Tuzun, Ali ;
Karatayli, Ersin ;
Akyuz, Filiz ;
Karatayli, Senem ;
Bozdayi, A. Mithat ;
Onel, Derya ;
Badur, Selim ;
Idilman, Ramazan ;
Kaymakoglu, Sabahattin ;
Yurdaydin, Cihan .
ANTIVIRAL THERAPY, 2014, 19 (06) :543-550
[10]   Switching from tenofovir and nucleoside analogue therapy to tenofovir monotherapy in virologically suppressed chronic hepatitis B patients with antiviral resistance [J].
Kim, Dong Yun ;
Lee, Hye Won ;
Song, Jeong Eun ;
Kim, Beom Kyung ;
Kim, Seung Up ;
Kim, Do Young ;
Ahn, Sang Hoon ;
Han, Kwang-Hyub ;
Park, Jun Yong .
JOURNAL OF MEDICAL VIROLOGY, 2018, 90 (03) :497-502
1234