Division of Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, Doherty Institute, Melbourne, Victoria, Australia.
Abbott Laboratories, Chicago, Illinois, USA.
Liver Int. 2019 Nov;39(11):2066-2076. doi: 10.1111/liv.14207. Epub 2019 Aug 21.
Functional cure is the major goal of chronic hepatitis B (CHB) therapy though few biomarkers predict this outcome. HBsAg epitope occupancy can be influenced by therapeutic and immune pressure. The aim of this study was to map the HBsAg epitope profiles during long-term nucleos(t)ide analogue therapy in patients with genotype A CHB, in the context of HBsAg loss (SL)/seroconversion.
We evaluated 25 genotype A CHB patients in the GS-US-174-0103 trial of HBeAg-positive CHB patients treated with tenofovir or adefovir for 4 years, 14 who achieved SL whilst 11 had no change. We epitope mapped the major domains of HBsAg to identify those patients with HBsAg clearance profile (CP) (loss of binding at both loops 1 and 2 epitopes of the 'a' determinant) vs non-clearance profile (no change in epitope recognition, or loss of epitope binding at one loop only), correlating this to on-treatment HBsAg responses. Complexed anti-HBs was also measured.
Analysis of the HBsAg epitope profiles of the 25 patients at baseline identified no predictive correlation with SL. In contrast, analysis at week 48 and end of study (week 192) or prior to SL identified significant predictive associations between development of HBsAg CPs and outcome of functional cure. The detection of a CP also correlated with the development of an alanine aminotransferase flare and detection of anti-HBs complexed with HBsAg.
The detection of HBsAg CPs by epitope mapping represents a novel viral biomarker, reflecting an emerging anti-HBs selection pressure prior to functional cure.
功能性治愈是慢性乙型肝炎（CHB）治疗的主要目标，但很少有生物标志物可以预测这一结果。HBsAg 表位占有率可受到治疗和免疫压力的影响。本研究的目的是在 HBeAg 阳性 CHB 患者接受核苷（酸）类似物治疗 4 年的 GS-US-174-0103 试验中，描绘基因型 A CHB 患者在 HBsAg 丢失（SL）/血清转换期间的 HBsAg 表位谱，分析 HBsAg 表位谱。
我们评估了 25 名在 GS-US-174-0103 试验中接受替诺福韦或阿德福韦酯治疗 4 年的 HBeAg 阳性 CHB 患者的基因型 A CHB 患者，其中 14 名患者实现了 SL，11 名患者没有变化。我们对 HBsAg 的主要结构域进行了表位作图，以确定具有 HBsAg 清除谱（CP）的患者（两个环 1 和 2 的“a”决定簇的表位结合丢失）与非清除谱（表位识别无变化，或仅一个环的表位结合丢失），并将其与治疗中的 HBsAg 反应相关联。同时也测量了复合抗-HBs。
对 25 名患者基线时的 HBsAg 表位谱分析未发现与 SL 有预测相关性。相比之下，在第 48 周和研究结束时（第 192 周）或在 SL 之前进行的分析表明，HBsAg CP 的发展与功能性治愈的结果之间存在显著的预测相关性。CP 的检测也与丙氨酸氨基转移酶（ALT）爆发的发展和 HBsAg 与抗-HBs 复合物的检测相关。
通过表位作图检测 HBsAg CP 代表了一种新的病毒学生物标志物，反映了功能性治愈前抗-HBs 选择压力的出现。
