Background and aim

Precore (PC) and basal core promoter (BCP) mutations are associated with responses to interferon-based treatment in HBeAg-positive chronic hepatitis B (CHB) patients. Here, we identify viral minority variants in these regions and assess association with response to peginterferon-alfa (Peg-IFN) and adefovir combination therapy.

Patients and methods

Ultra-deep pyrosequencing analysis of the BCP and PC region was performed for 89 CHB patients (42 HBeAg-positive; 47 HBeAg-negative), at baseline and during treatment. Specifically, associations of individual positions with the HBeAg-negative phenotype were studied, as well as the association of the most prevalent mutations with combined response in HBeAg-positive and –negative patients at week 72 (HBeAg negativity, HBV-DNA <2000 IU/mL and ALT normalization at 24 weeks of treatment-free follow-up).

Results

The mutations most strongly correlated with the HBeAg-negative phenotype were at positions 1762/1764 and 1896/1899 in the BCP and PC region, respectively. No major changes in nucleotide composition of these positions were observed during treatment. In HBeAg-negative patients, a combined presence of 1764A and 1896A was correlated with lower ALT levels (p = 0.004), whereas the presence of 1899A was correlated with higher age (p = 0.030), lower HBV-DNA level (p = 0.036), and previous IFN therapy (p = 0.032). The presence of 1764A/1896A or the absence of 1899A at baseline, was associated with lower response rates, after adjustment for HBV genotype (p = 0.031 and p = 0.017) and HBsAg level (p = 0.035 and p = 0.022).

Conclusion

We identified novel correlations between common BCP and PC variants with response to Peg-IFN and adefovir in HBeAg-negative patients. Ultimately, this may guide the selection of those patients most likely to benefit from Peg-IFN-based treatment.

中文翻译：

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通过深度测序鉴定的核心启动子和前核心区域中的病毒少数变异与HBeAg阴性慢性乙型肝炎患者对聚乙二醇干扰素和阿德福韦的应答有关

背景和目标

在HBeAg阳性慢性乙型肝炎（CHB）患者中，Precore（PC）和基础核心启动子（BCP）突变与基于干扰素的治疗反应有关。在这里，我们确定了这些区域的病毒少数变异，并评估了对聚乙二醇干扰素-阿尔法（Peg-IFN）和阿德福韦联合疗法的反应的相关性。

患者和方法

在基线和治疗期间，对89例CHB患者（42 HBeAg阳性； 47 HBeAg阴性）进行了BCP和PC区的超深焦磷酸测序分析。具体而言，研究了个体位置与HBeAg阴性表型的相关性，以及在72周时HBeAg阳性和阴性患者中最普遍的突变与合并反应的相关性（HBeAg阴性，HBV-DNA <2000 IU /无治疗随访24周时，mL和ALT正常化）。

结果

与HBeAg阴性表型最密切相关的突变分别位于BCP和PC区域的1762/1764和1896/1899位。在治疗过程中未观察到这些位置的核苷酸组成发生重大变化。在HBeAg阴性患者中，合并存在1764A和1896A与较低的ALT水平相关（p = 0.004），而存在1899A与较高的年龄（p = 0.030）和较低的HBV-DNA水平相关（p = 0.036） ）和先前的IFN治疗（p = 0.032）。在调整HBV基因型（p = 0.031和p = 0.017）和HBsAg水平（p = 0.035和p = 0.022）之后，基线时存在1764A / 1896A或不存在基线1899A与较低的缓解率相关。

结论

我们在HBeAg阴性患者中发现了常见的BCP和PC变异与对Peg-IFN和阿德福韦的应答之间的新型相关性。最终，这可以指导最有可能从基于Peg-IFN的治疗中受益的患者的选择。