Background and aims RNA interference has been extensively explored in patients with chronic hepatitis B (CHB) infection. We aimed to characterise the long-term efficacy of small interfering RNA (siRNA) on hepatitis B surface antigen (HBsAg) suppression. Methods We prospectively followed up participants with CHB who received siRNA, either ARC-520 or JNJ-73763989 (JNJ-3989), in combination with nucleoside analogue (NUC) in our centre. Participants enrolled included 15 receiving 4 monthly injections of ARC-520, 38 receiving 3 injections of JNJ-3989 at 1, 2 or 4 weekly intervals and 5 receiving placebo in previous clinical trials. Serial blood sampling was performed according to the original protocols and on completion every 24 weeks until last follow-up (LFU) with mean duration of 52.5 months. Results Among the 53 NUC+siRNA-treated participants (mean age 46.8, baseline HBsAg 3.08 log, 83% previously on NUC, 34% hepatitis B e antigen+), the proportion of patients achieving HBsAg seroclearance or <100 IU/mL at LFU was 1.9% and 32.1%, respectively, compared with 0% and 0% for placebo. Among siRNA-recipients, 48.5% and 5.0% of those with HBsAg <100 IU/mL and >100 IU/mL at nadir or ≤24 weeks from last dose could maintain or achieve HBsAg <100 IU/mL at LFU, respectively. Compared with placebo recipients, siRNA-recipients demonstrated faster overall annual decline of HBsAg (0.08 vs 0.21 log IU/mL/year) contributed predominantly by changes in the first year. Age was negatively correlated with HBsAg reduction at LFU (r=−0.427, p=0.001). Conclusion Short-duration siRNA treatment suppressed HBsAg expression with a prolonged effect for up to 6 years in some participants. All data relevant to the study are included in the article or uploaded as online supplemental information.

中文翻译：

---

ARC-520 或 JNJ-3989 有限治疗后的长期乙型肝炎表面抗原反应


背景和目的 RNA 干扰已在慢性乙型肝炎 (CHB) 感染患者中得到广泛研究。我们的目的是表征小干扰 RNA (siRNA) 对乙型肝炎表面抗原 (HBsAg) 抑制的长期功效。方法 我们对在我们中心接受 siRNA（ARC-520 或 JNJ-73763989 (JNJ-3989)）联合核苷类似物 (NUC) 的慢性乙型肝炎参与者进行前瞻性随访。入组的参与者包括 15 名患者，每月注射 4 次 ARC-520，38 名患者，每隔 1、2 或 4 周注射 3 次 JNJ-3989，5 名患者在之前的临床试验中接受安慰剂。根据最初的方案进行连续血液采样，每 24 周完成一次，直到最后一次随访 (LFU)，平均持续时间为 52.5 个月。结果 在 53 名接受 NUC+siRNA 治疗的参与者中（平均年龄 46.8 岁，基线 HBsAg 3.08 log，83% 之前接受过 NUC，34% 乙型肝炎 e 抗原+），LFU 时实现 HBsAg 血清清除或 <100 IU/mL 的患者比例为分别为 1.9% 和 32.1%，而安慰剂为 0% 和 0%。在 siRNA 接受者中，在最低点或距离最后一次给药后 24 周内 HBsAg <100 IU/mL 和 >100 IU/mL 的患者中，分别有 48.5% 和 5.0% 可以在 LFU 时维持或达到 HBsAg <100 IU/mL。与安慰剂接受者相比，siRNA 接受者表现出 HBsAg 总体年度下降更快（0.08 vs 0.21 log IU/mL/年），这主要是由第一年的变化所致。年龄与 LFU 时 HBsAg 减少呈负相关（r=-0.427，p=0.001）。结论 短期 siRNA 治疗可抑制 HBsAg 表达，在一些参与者中效果可长达 6 年。与研究相关的所有数据都包含在文章中或作为在线补充信息上传。