在感染基因型 D 的儿童中，HBV 前核心突变体在 HBeAg/抗-HBe 血清转换期间被选择，并导致成年后 HBeAg 阴性慢性乙型肝炎。
HBV pre-core mutant in genotype-D infected children is selected during HBeAg/anti-HBe seroconversion and leads to HBeAg negative chronic hepatitis B in adulthood.
机构信息
Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Pisa, Italy.
Paediatric Gastroenterology Unit, Regina Margherita Children Hospital, Torino, Italy.
出版信息
J Med Virol. 2018 Jul;90(7):1232-1239. doi: 10.1002/jmv.25068. Epub 2018 Apr 23.
Selection of HBeAg defective HBV mutants (mt) during childhood might influence infection outcome in adults. Aim of this study was to correlate the dynamics of pre-core HBV mutant (pre-C mt) selection with virological/clinical outcomes in children followed-up until adulthood. Eighty subjects (50-M/30-F), 70 HBeAg-positive (87.5%), and 10 (12.5%) HBeAg-negative/anti-HBe-positive at the admission, mostly genotype D infected (91.2%), with median age of 6.5 (range: 0.2-17) years, were followed-up for 14.3 years (range: 1.1-24.5); 46 (57.5%) received IFN treatment. HBV-DNA and q-HBsAg were tested by commercial assays, Pre-Core 1896 mt by direct-sequence, oligo-hybridization-assay, and allele-specific-PCR (sensitivity: 30%, 10%, and 0.1% of total viremia). HBeAg/anti-HBe seroconversion (SC) occurred in 55/70 (78.6%) children. After SC, 8 (14.6%) developed HBeAg-negative chronic hepatitis (CHB), 41 (74.5%) remain with HBeAg-negative chronic infection, and 6 (10.9%) lost HBsAg. Baseline HBV-DNA and HBsAg were lower in SC than in no-SC children (median: 7.35 vs 8.95 Log IU/mL, P = 0.005, and 4.72 vs 5.04 Log IU/mL, P = 0.015). The prevalence of pre-C mt increased rapidly (10-40%) around SC. Eventually, pre-C mt was detected in 100% of CHB, in 33% of chronic infections without disease, and in 16% of subjects who cleared HBsAg (P < 0.001). HBV-DNA levels remained slightly higher in carriers of HBeAg negative infection with dominant/mixed pre-C mt populations, than in those with dominant pre-C wt (mean Log IU/mL: 3.83 and 3.42 vs 2.67, P = 0.007). In conclusion, pre-C-mt is selected during HBeAg/anti-HBe SC in children with poor control of HBV replication, leading to HBeAg-negative chronic-active-hepatitis during adulthood.
在儿童时期选择 HBeAg 缺陷型乙型肝炎病毒 (HBV) 突变体 (mt) 可能会影响成人感染的结果。本研究的目的是探讨前核心 HBV 突变体 (pre-C mt) 选择的动态与儿童期随访至成年期的病毒学/临床结果之间的相关性。80 名受试者（50 名男性/30 名女性），入院时 70 名 HBeAg 阳性（87.5%），10 名 HBeAg 阴性/抗-HBe 阳性（12.5%），主要感染基因型 D（91.2%），中位年龄为 6.5 岁（范围：0.2-17 岁），随访 14.3 年（范围：1.1-24.5 年）；46 名（57.5%）接受 IFN 治疗。采用商业检测方法检测 HBV-DNA 和 q-HBsAg，采用直接测序、寡核苷酸杂交检测和等位基因特异性-PCR 检测前核心 1896 mt（敏感性：总病毒血症的 30%、10%和 0.1%）。70 名 HBeAg 阳性儿童中有 55 名（78.6%）发生 HBeAg/抗-HBe 血清转换 (SC)。SC 后，8 名（14.6%）发生 HBeAg 阴性慢性乙型肝炎（CHB），41 名（74.5%）仍为 HBeAg 阴性慢性感染，6 名（10.9%）HBsAg 丢失。与未发生 SC 的儿童相比，发生 SC 后儿童的 HBV-DNA 和 HBsAg 基线水平较低（中位数：7.35 对数 IU/mL 与 8.95 对数 IU/mL，P = 0.005，4.72 对数 IU/mL 与 5.04 对数 IU/mL，P = 0.015）。在 SC 前后，前核心 mt 的检出率迅速增加（10-40%）。最终，CHB 患者 100%、无疾病慢性感染患者 33%、HBsAg 清除患者 16%（P < 0.001）检测到前核心 mt。与携带主导/混合前核心 wt 的 HBeAg 阴性感染者相比，HBV-DNA 水平在携带前核心 mt 主导人群中仍略高（平均 Log IU/mL：3.83 和 3.42 与 2.67，P = 0.007）。综上所述，在 HBeAg/抗-HBe SC 期间，HBV 复制控制不佳的儿童中会选择前核心 mt，导致成年后发生 HBeAg 阴性慢性活动性肝炎。
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