AASLD2016[1831] 前核心突变的比例决定HBV表型HBeAg血清转换后

StephenW

1831
Proportion of Pre-Core Mutation Determines HBV Phenotype
after HBeAg Seroconversion
Daniel F. Suarez1, Anthony Loria1, Michelle Ferreira1, Arati
Raziuddin2, Marc G. Ghany1; 1Liver Diseases Branch, National
Institutes of Health, Bethesda, MD; 2National Cancer Institute,
Bethesda, MD
Background: Following HBeAg seroconversion, most patients
enter a phase of low viral replication, termed inactive carrier
(IC). Some patients maintain high HBV DNA levels presumably
due to the development of viral immune escape mutations
in the pre-core (PC)-G1896A and basal core promoter
(BCP)- A1762T & G1764A, and are termed HBeAg Negative
Chronic Hepatitis B (eNegCHB). Moreover, some patients
reside between these two phenotypes and define an emerging
phenotype- indeterminant (ID). The cause of such phenotypic
variability after HBeAg seroconversion is unknown. We
hypothesized the amount of PC and BCP mutations, hereafter
referred to as PC and BCP, relative to wild type virus determines
a patient’s phenotype. Aims: To quantify the levels of
PC and BCP longitudinally in patients with IC, ID and eNeg-
CHB phenotypes and correlate with HBV DNA and ALT levels.
Methods: Patients representing the 3 HBeAg (-) phenotypes
were selected from a cohort based on sample availability: IC
was defined as HBV DNA <2,000 IU/ml and ALT <1.5 xULN,
eNegCHB as HBV DNA >20,000 IU/ml and ALT ≥1.5 xULN,
and ID as HBV DNA 2,000-20,000 IU/ml ±ALT elevation. HBV
DNA extracted from stored sera was PCR amplified. Proportion
of PC and BCP were quantified by pyrosequencing. Results:
29 untreated patients (10 IC, 10 ID and 9 eNegCHB), 62%
male with HBV genotypes (GT) A-E were studied. There was a
median of 5 samples/patient (3-7) over a mean follow-up of
3.9 years (0.3-10.5). BCP were detected at ≥10% of the viral
population in ≥1 sample in all patients, while PC was detected
in ≥1 sample in 25/29 patients. Among all samples (n=144),
the mean proportion of PC was higher than BCP, 48% vs 36%,
p<0.001. There was a significant stepwise increase in mean
proportion of PC from IC (27%) to ID (47%) to eNegCHB (74%),
p<0.0001. In contrast, the mean proportion of BCP did not differ
among the 3 phenotypes (23%, 38% and 37% respectively,
p=ns). PC and BCP were found in all GT, but PC was predominant
among GT B-E while BCP predominated among GT A and
C. The proportion of PC significantly correlated with HBV DNA
level. Patients with a >50% change in mutant proportion were
more likely to experience a parallel change in HBV DNA level
compared to those with stable viral populations. The proportion
of PC and BCP significantly correlated with ALT level. Patients
with a >50% increase in the PC/BCP were twice as likely to
experience an ALT flare compared to patients with a stable
viral population. Conclusion: These results suggest that HBV
phenotype after HBeAg seroconversion is closely related to the
proportion of PC but not BCP. An increase in PC or BCP mutant
population is associated with ALT flares.
Disclosures:
The following people have nothing to disclose: Daniel F. Suarez, Anthony Loria,
Michelle Ferreira, Arati Raziuddin, Marc G. Ghany

StephenW

AASLD2016 [1831]
前核心突变的比例决定HBV表型HBeAg血清转换后
前核心突变的比例决定HBV表型
后HBeAg血清转换
Daniel F. Suarez1，Anthony Loria1，Michelle Ferreira1，Arati
Raziuddin2，Marc G. Ghany1; 1肝病科
Institutes of Health，Bethesda，MD; 2国家癌症研究所，
Bethesda，MD
背景：HBeAg血清学转换后，大多数患者
进入低病毒复制阶段，称为无活性载体
（我知道了）。一些患者可能维持高的HBV DNA水平
由于病毒免疫逃逸突变的发展
在前核（PC）-G1896A和基础核心启动子
（BCP）-A1762T和G1764A，并且称为HBeAg阴性
慢性乙型肝炎（eNegCHB）。此外，一些病人
驻留在这两种表型之间并定义一种新兴的
表型 - 不确定因子（ID）。这种表型的原因
HBeAg血清学转换后的变异性未知。我们
假设PC和BCP突变的量，以下
称为PC和BCP，相对于野生型病毒确定
患者的表型。目的：量化的水平
PC和BCP纵向在IC，ID和eNeg-
CHB表型，并与HBV DNA和ALT水平相关。
方法：代表3 HBeAg（ - ）表型的患者
基于样品可用性：IC
定义为HBV DNA <2,000 IU / ml和ALT <1.5 xULN，
eNegCHB作为HBV DNA> 20,000IU / ml和ALT≥1.5xULN，
和ID作为HBV DNA 2,000-20,000IU / ml±ALT升高。 HBV
从存储的血清中提取的DNA进行PCR扩增。比例
的PC和BCP通过焦磷酸测序来定量。结果：
29名未治疗患者（10 IC，10 ID和9 eNegCHB），62％
男性与HBV基因型（GT）A-E。有一个
中位数5个样本/患者（3-7）在平均随访中
3.9年（0.3-10.5）。在≥10％的病毒中检测到BCP
所有患者的≥1个样本的人群，而检测到PC
在25/29例患者中≥1份样本。在所有样品（n = 144）中，
PC的平均比例高于BCP，48％比36％
p <0.001。平均值有显着的逐步增加
PC从IC（27％）到ID（47％）到eNegCHB（74％）的比例，
P <0.0001。相比之下，BCP的平均比例没有不同
在3种表型中（分别为23％，38％和37％
p = ns）。 PC和BCP在所有GT，但PC是主要
GT B-E中，BCP占优势
C. PC的比例与HBV DNA显着相关
水平。突变体比例改变> 50％的患者
更可能发生HBV DNA水平的平行变化
与那些具有稳定的病毒群体。比例
的PC和BCP与ALT水平显着相关。耐心
与PC / BCP的> 50％增加的可能性的两倍
与患有稳定的患者相比，经历ALT flare
病毒群体。结论：这些结果表明HBV
表型后HBeAg血清转换密切相关
PC而不是BCP的比例。 PC或BCP突变体的增加
人口与ALT火炬有关。
披露：
以下人士没有透露：丹尼尔·苏亚雷斯，安东尼·洛里亚，
Michelle Ferreira，Arati Raziuddin，Marc G. Ghany