在慢性乙型肝炎的“免疫耐受”阶段，HBV变异很常见

StephenW

J Viral Hepat. 2020 May 8. doi: 10.1111/jvh.13318. [Epub ahead of print]
HBV variants are common in the "immune-tolerant"phase of chronic hepatitis B.
Yuen L1, Revill PA1,2, Rosenberg G3, Wagner J1, Littlejohn M1, Bayliss J1, Jackson K1, Tan SK4, Gaggar A4, Kitrinos K4, Subramanian M4, Gane E5, Chan HL6, Li X1, Bowden S1, Locarnini S1, Thompson A7.
Author information

1
    Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the , Peter Doherty Institute for Infection and Immunity, Victoria, 3000, Australia.
2
    Department of Microbiology and Immunology, University of Melbourne, Parkville, 3000, Victoria, Australia.
3
    National Cancer Research Institute, London, England.
4
    Gilead Sciences, Inc, Foster City, CA, USA.
5
    New Zealand Transplant Unit, Auckland, New Zealand.
6
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong.
7
    St Vincent's Hospital, Melbourne, Australia.

Abstract

Nucleos(t)ide analouges (NUC) treatment prevents progression of liver fibrosis in subjects with chronic hepatitis B (CHB). However, risk for hepatocellular carcinoma (HCC) persists despite viral suppression. Specific HBV variants have been associated with adverse outcomes, including HCC, however the frequency of these variants during the seemingly benign immunotolerant (IT) phase is unknown. Next generation sequencing and detailed virological characterization on a cohort of treatment-naïve IT subjects was performed to determine the frequency of clinically relevant viral variants. Samples from 97 subjects (genotype B/C 55%/45%, median HBV-DNA 8.5 log10 IU/mL, median HBsAg 4.8 log10IU/mL, median HBeAg 3.6 log10 PEIU/mL) were analysed. Despite subjects being in the IT phase, clinically relevant HBV variants were common at baseline, particularly in the basal core promoter (BCP, overlaps the hepatitis B X (HBx) gene), precore, and PreS regions. BCP/HBx variants were independently associated with lower baseline HBeAg, HBsAg and HBV-DNA titres. Precore variants were independently associated with higher baseline ALT. Increased viral diversity was associated with increased age and lower HBV DNA, HBsAg and HBeAg levels. Low level (<5%) drug resistance associated amino acid substitutions in the HBV reverse transcriptase were detected in 9 (9%) subjects at pre-treatment but were not associated with reduced antiviral activity. Future studies should evaluate whether detection of HBV variant during IT CHB is predictive of progression to immune clearance and poor prognosis, and whether early initiation of antiviral therapy during IT CHB to prevent the selection of HBV variants is clinically beneficial.

This article is protected by copyright. All rights reserved.
KEYWORDS:

HBV variants; chronic hepatitis B; hepatitis B virus; immune tolerance; viral diversity

PMID:
    32384174
DOI:
    10.1111/jvh.13318

StephenW

J病毒性肝炎。 2020年5月8日。doi：10.1111 / jvh.13318。 [Epub提前发布]
在慢性乙型肝炎的“免疫耐受”阶段，HBV变异很常见。
元L1，Revill PA1，Rosenberg G3，Wagner J1，Littlejohn M1，Bayliss J1，Jackson K1，Tan SK4，Gaggar A4，Kitrinos K4，Subramanian M4，Gane E5，Chan HL6，Li X1，Bowden S1，Locarnini S1，汤普森A7。
作者信息

1个
    维多利亚皇家传染病参考实验室，皇家墨尔本医院，位于Peter Doherty感染与免疫研究所，澳大利亚维多利亚3000。
2
    墨尔本大学微生物学和免疫学系，澳大利亚维多利亚州帕克维尔，3000。
3
    英国伦敦国家癌症研究所。
4
    美国加利福尼亚州福斯特市的吉利德科学公司。
5
    新西兰移植单位，新西兰奥克兰。
6
    香港特别行政区香港中文大学医学与治疗学系。
7
    澳大利亚墨尔本圣文森特医院。

抽象

核仁类似物（NUC）治疗可预防慢性乙型肝炎（CHB）患者肝纤维化的进展。然而，尽管有病毒抑制，肝细胞癌（HCC）的风险仍然存在。特定的HBV变异已与包括HCC在内的不良结局相关，但是在看似良性的免疫耐受（IT）阶段，这些变异的发生频率尚不清楚。对一批未经治疗的IT受试者进行了下一代测序和详细的病毒学表征，以确定临床相关病毒变异的频率。分析了来自97名受试者的样本（基因型B / C 55％/ 45％，中位HBV-DNA 8.5 log10 IU / mL，中位HBsAg 4.8 log10IU / mL，中位HBeAg 3.6 log10 PEIU / mL）。尽管受试者处于IT阶段，但临床相关的HBV变异体在基线时很常见，尤其是在基础核心启动子（BCP，与B X（HBx）基因重叠），前核心区和PreS区。 BCP / HBx变异与较低的基线HBeAg，HBsAg和HBV-DNA滴度独立相关。前核变异与较高的基线ALT独立相关。病毒多样性增加与年龄增加和HBV DNA，HBsAg和HBeAg水平降低有关。在治疗前，在9名（9％）受试者中检测到HBV逆转录酶中低水平（<5％）的耐药性相关氨基酸取代，但与抗病毒活性降低无关。未来的研究应评估在IT CHB期间检测HBV变异是否预示着免疫清除进展和不良预后，以及在IT CHB期间尽早开始抗病毒治疗以防止选择HBV变异是否在临床上有益。

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关键字：

HBV变体；慢性乙型肝炎乙型肝炎病毒;免疫耐受病毒多样性

PMID：
    32384174
DOI：
    10.1111 / jvh.13318

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