Gastroenterology and Hepatology, Academic Medical Center (AMC), University of Amsterdam (UvA), Amsterdam, The Netherlands; Experimental Immunology, AMC, UvA, The Netherlands.
Medical Microbiology, AMC, UvA, The Netherlands.
Antiviral Res. 2017 Sep;145:87-95. doi: 10.1016/j.antiviral.2017.07.013. Epub 2017 Jul 25.
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.
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).
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).
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.
前核心 (PC) 和基本核心启动子 (BCP) 突变与 HBeAg 阳性慢性乙型肝炎 (CHB) 患者对干扰素治疗的反应有关。在此，我们鉴定了这些区域中的病毒少数变异体，并评估了其与聚乙二醇干扰素-α (Peg-IFN) 和阿德福韦联合治疗反应的相关性。
对 89 例 CHB 患者（42 例 HBeAg 阳性；47 例 HBeAg 阴性）进行 BCP 和 PC 区的超深度焦磷酸测序分析，分别在基线和治疗期间进行。具体来说，研究了各位置与 HBeAg 阴性表型的关联，以及最常见突变与 HBeAg 阳性和阴性患者第 72 周联合应答的关联（HBeAg 阴性，HBV-DNA <2000IU/mL 和 ALT 在治疗结束 24 周无治疗随访时正常）。
与 HBeAg 阴性表型相关性最强的突变分别位于 BCP 和 PC 区的 1762/1764 和 1896/1899 位。在治疗过程中，这些位置的核苷酸组成没有发生重大变化。在 HBeAg 阴性患者中，1764A 和 1896A 的共同存在与较低的 ALT 水平相关（p=0.004），而 1899A 的存在与较高的年龄相关（p=0.030），较低的 HBV-DNA 水平相关（p=0.036），以及之前的 IFN 治疗相关（p=0.032）。基线时存在 1764A/1896A 或不存在 1899A 与调整 HBV 基因型（p=0.031 和 p=0.017）和 HBsAg 水平（p=0.035 和 p=0.022）后的较低应答率相关。
我们发现了常见的 BCP 和 PC 变体与 HBeAg 阴性患者对 Peg-IFN 和阿德福韦反应之间的新关联。最终，这可能有助于指导选择最有可能从 Peg-IFN 治疗中获益的患者。
