Abstract：
Hepatitis B virus (HBV) integration exists throughout the clinical course of chronic hepatitis B (CHB). This study investigated the effects of long-term antiviral therapy on the level and profiles of transcriptionally active HBV integration. Serial liver biopsies and paired blood samples were obtained from 16, 16, and 22 patients with CHB at baseline, 78, and 260 weeks of entecavir monotherapy or combined with pegylated interferon alfa, respectively. Serum HBV biomarkers were longitudinally assessed. RNA-seq and HIVID2 program was used to identify HBV-host chimeric RNAs transcribed from integrated DNA. The counts of HBV integration reads were positively related to both serum HBV DNA levels (r = 0.695, p = 0.004) and HBeAg titers (r = 0.724, p = 0.021) at baseline, but the positive correlation exited only to the serum HBsAg levels after 260 weeks of antiviral therapy (r = 0.662, p = 0.001). After 78 weeks of antiviral therapy, the levels of HBV integration expression decreased by 12.25 folds from baseline. The viral junction points were enriched at the S and HBx genes after the long-term antiviral therapy. HBs-FN1 became one of the main transcripts, with the mean proportion of HBs-FN1 in all integrated expression increased from 2.79% at baseline to 10.54% at Week 260 of antiviral treatment. Antiviral therapy may reduce but not eliminate the HBV integration events and integration expression. Certain integration events, such as HBs-FN1 can persist in long-term antiviral treatment.
摘要：
乙型肝炎病毒（HBV）整合存在于整个慢性乙型肝炎（CHB）的临床过程。这项研究调查了长期抗病毒治疗对转录活性HBV整合水平和概况的影响。连续的肝活检和配对的血液样本从16，16和22例CHB患者在基线获得，78和260周恩替卡韦单药治疗或联合聚乙二醇干扰素α，分别。纵向评估血清HBV生物标志物。RNA-seq和HIVID2程序用于鉴定从整合的DNA转录的HBV宿主嵌合RNA。HBV整合读数的计数与基线时血清HBVDNA水平（r=0.695，p=0.004）和HBeAg滴度（r=0.724，p=0.021）呈正相关，但阳性相关性仅存在于260周抗病毒治疗后的血清HBsAg水平（r=0.662，p=0.001）。经过78周的抗病毒治疗，HBV整合表达水平较基线下降12.25倍.长期抗病毒治疗后，病毒连接点富集在S和HBx基因。HBs-FN1成为主要转录物之一,HBs-FN1在所有整合表达中的平均比例从基线时的2.79％增加到抗病毒治疗260周时的10.54％。抗病毒治疗可以减少但不能消除HBV整合事件和整合表达。某些集成事件，如HBs-FN1在长期抗病毒治疗中可以持续存在。
