Wooddell Christine I, Mak Lung Yi, Seto Wai-Kay, Given Bruce D, Yuen Man-Fung
Arrowhead Pharmaceuticals Inc., 502 S. Rosa Road, Madison, WI 53719, USA.
Department of Medicine, State Key Laboratory of Liver Research, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China.
Microorganisms. 2025 Jul 31;13(8):1787. doi: 10.3390/microorganisms13081787.
In a previous study, eight chronically HBV-infected nucleos (t)ide analog (NA)-naïve patients began receiving entecavir (ETV) concomitant with a single ARC-520 HBV siRNA injection. This single dose of ARC-520 (SD) was followed by 6-8 months of ETV alone before the patients received 4-9 monthly doses of ARC-520, the multi-dose (MD) period, while continuing ETV. Quantities of HBV DNA, RNA, and antigens were measured from serum and a liver biopsy collected ~30 months after the last MD from five patients. All full-length HBV transcripts from the livers were characterized. Viral parameters and HBV transcripts from patients were compared to these measurements collected at multiple points in ARC-520 + ETV-treated chronically HBV-infected chimpanzees. Multiple forms of HBx mRNA were observed, and these differed between chimpanzees and patients. Products of cccDNA were greatly decreased in patients who were previously highly viremic and HBeAg+, although a biopsied patient had similar amounts of cccDNA to the highly viremic HBeAg+ chimpanzees. The comparison of all HBV transcripts and cccDNA levels between patients and chimpanzees demonstrate the transcriptional silencing of cccDNA following the siRNA treatment of patients but not the chimpanzees that received a different treatment regimen. Results from this small study suggest that continued NA treatment during and between periods of HBV antigen re-expression post-siRNA treatment enhanced viral parameter reductions.
在之前的一项研究中，8名慢性乙肝病毒（HBV）感染且未接受过核苷（酸）类似物（NA）治疗的患者开始接受恩替卡韦（ETV）治疗，并同时注射一剂ARC-520 HBV小干扰RNA（siRNA）。在这剂ARC-520单剂量（SD）注射后，患者先单独接受6 - 8个月的ETV治疗，然后在继续使用ETV的同时，接受4 - 9个月每月一次的ARC-520注射，即多剂量（MD）阶段。在最后一次MD治疗约30个月后，从5名患者的血清和肝活检样本中检测HBV DNA、RNA和抗原的量。对肝脏中所有全长HBV转录本进行了特征分析。将患者的病毒参数和HBV转录本与在接受ARC-520 + ETV治疗的慢性HBV感染黑猩猩的多个时间点采集的测量值进行比较。观察到多种形式的HBx mRNA，且黑猩猩和患者之间存在差异。在之前病毒载量高且HBeAg阳性的患者中，cccDNA产物大幅减少，尽管一名接受活检的患者的cccDNA量与病毒载量高的HBeAg阳性黑猩猩相似。患者与黑猩猩之间所有HBV转录本和cccDNA水平的比较表明，患者接受siRNA治疗后cccDNA发生转录沉默，而接受不同治疗方案的黑猩猩则未出现这种情况。这项小型研究的结果表明，在siRNA治疗后HBV抗原重新表达期间及之间持续进行NA治疗可增强病毒参数的降低。
