大量慢性乙肝患者的核苷/核苷酸類似物治療研究乙型肝炎病

StephenW

Investigation of multidrug-resistance mutations of hepatitis B virus (HBV) in a large cohort of chronic HBV-infected patients with treatment of nucleoside/nucleotide analogs
Yan Liu  1 , Rongjuan Chen  1 , Wenhui Liu  2 , Lanlan Si  1 , Le Li  1 , Xiaodong Li  1 , ZengtaoYao  1 , Hao Liao  1 , Jun Wang  1 , Yuanhua Li  1 , Jun Zhao  3 , Dongping Xu  4
Affiliations
Affiliations

    1
    Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.
    2
    Department of Gastroenterology, The Second Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Geriatric Diseases, Beijing, 100853, China.
    3
    Department of Liver Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China. Electronic address: [email protected].
    4
    Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China. Electronic address: [email protected].

    PMID: 33711338 DOI: 10.1016/j.antiviral.2021.105058

Abstract

Multidrug-resistance hepatitis B virus (MDR HBV), defined as those with mutations resistant to both nucleoside analogs lamivudine/telbivudine/entecavir (LAM/LdT/ETV) and nucleotide analog adefovir (ADV), has potential to cause treatment difficulty. To clarify clinical prevalence and virological features of MDR HBV, we investigated serum samples from 28,236 chronic HBV-infected patients with treatment of nucleoside/nucleotide analogs. All patients underwent resistance testing in the Fifth Medical Center of Chinese PLA General Hospital between 2007 and 2019. MDR mutations were screened by direct sequencing; MDR strains (with mutations co-located on the same viral genome) were verified by clonal sequencing (≥20 clones/sample) and subjected to phenotypic analysis if necessary. MDR mutations were detected in 0.81% (229/28,236) patients. MDR strains were verified in 83.0% (190/229) of MDR mutation-positive patients. As ETV-resistance mutation (ETVr) had additional mutation(s) on LAMr conferring more resistance, MDR mutations fell into LAMr+ADVr and ETVr+ADVr subsets. Sixteen mutation patterns of MDR strains were verified, including eight with LAMr+ADVr and eight with ETVr+ADVr. Refractory to sequential therapies of LAM/LdT/ETV and ADV were closely linked with MDR HBV development. Ten representative MDR strains (five LAMr+ADVr and five ETVr+ADVr) tested all had decrease in replication capacity compared to wild-type strains and decrease extent was positively related with the number of primary resistance on viral genome. Compared to ADV+ETV, TDF/TDF+ETV showed higher inhibitory rates on MDR HBV, especially for the five ETVr+ADVr strains (74.5%-97.6% vs. 60.2%-79.5%, all P < 0.05). This study significantly extends the knowledge on MDR HBV and has clinical implications for resistance management.

Keywords: Hepatitis B virus; entecavir; inhibitory rates; multidrug-resistance; mutation.

Copyright © 2021 Elsevier B.V. All rights reserved.

StephenW

大量慢性乙肝患者的核苷/核苷酸類似物治療研究乙型肝炎病毒（HBV）的多藥耐藥性突變
劉彥1，陳榮娟1，劉文慧2，蘭蘭寺1，李黎1，李曉東1，增濤瑤1，廖浩1，王俊1，李元華1，趙俊3，徐東平4
隸屬關係
隸屬關係

    1個
    中國人民解放軍總醫院第五醫療中心傳染病科，北京100039
    2個
    中國人民解放軍總醫院第二醫學中心消化內科，國家老年病臨床研究中心，北京100853。
    3
    中國人民解放軍總醫院第五醫療中心肝病科，北京100039電子地址：[email protected]。
    4
    中國人民解放軍總醫院第五醫療中心傳染病科，北京100039電子地址：[email protected]。

    PMID：33711338 DOI：10.1016 / j.antiviral.2021.105058

抽象的

耐多藥性乙型肝炎病毒（MDR HBV）是指具有對核苷類似物拉米夫定/替比夫定/恩替卡韋（LAM / LdT / ETV）和核苷酸類似物阿德福韋（ADV）均具有抗性突變的病毒。為了闡明MDR HBV的臨床患病率和病毒學特徵，我們調查了28,236例慢性HBV感染患者的核苷/核苷酸類似物治療後的血清樣本。所有患者均於2007年至2019年間在中國人民解放軍總醫院第五醫療中心接受了抗藥性測試。通過克隆測序（≥20個克隆/樣品）驗證了MDR菌株（突變位於同一病毒基因組上），並在必要時進行表型分析。在0.81％（229 / 28,236）的患者中檢測到MDR突變。在83.0％（190/229）的MDR突變陽性患者中證實了MDR菌株。由於ETV抗性突變（ETVr）在LAMr上具有更多的突變，賦予了更多的抗性，因此MDR突變分為LAMr + ADVr和ETVr + ADVr子集。驗證了16種MDR菌株的突變模式，其中8種使用LAMr + ADVr，而8種使用ETVr + ADVr。 LAM / LdT / ETV和ADV的順序治療難治性與MDR HBV的發生密切相關。與野生型菌株相比，測試的十個代表性MDR菌株（五個LAMr + ADVr和五個ETVr + ADVr）的複制能力均下降，並且下降程度與病毒基因組的原代抗性數量呈正相關。與ADV + ETV相比，TDF / TDF + ETV對MDR HBV的抑制率更高，特別是對5株ETVr + ADVr菌株（74.5％-97.6％和60.2％-79.5％，所有P <0.05）。這項研究顯著擴展了關於MDR HBV的知識，並且對耐藥性管理具有臨床意義。

關鍵字：乙型肝炎病毒；恩替卡韋抑制率；多藥耐藥性突變。

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