Mak Lung Yi, Wooddell Christine I, Lenz Oliver, Schluep Thomas, Hamilton James, Davis Heather L, Mao Xianhua, Seto Wai-Kay, Biermer Michael, Yuen Man-Fung
Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong.
Arrowhead Madison, Arrowhead Pharmaceuticals Inc Madison Office, Madison, Wisconsin, USA.
Gut. 2025 Feb 6;74(3):440-450. doi: 10.1136/gutjnl-2024-333026.
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.
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.
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).
Short-duration siRNA treatment suppressed HBsAg expression with a prolonged effect for up to 6 years in some participants.
RNA干扰已在慢性乙型肝炎（CHB）感染患者中得到广泛研究。我们旨在确定小干扰RNA（siRNA）对乙肝表面抗原（HBsAg）抑制的长期疗效。
我们对在本中心接受siRNA（ARC-520或JNJ-73763989，即JNJ-3989）联合核苷类似物（NUC）治疗的CHB参与者进行了前瞻性随访。纳入的参与者包括15名接受每月一次共4次ARC-520注射的患者、38名接受每1、2或4周一次共3次JNJ-3989注射的患者，以及5名在先前临床试验中接受安慰剂治疗的患者。根据原始方案进行系列血液采样，并在每次完成后每24周进行一次，直至最后一次随访（LFU），平均随访时间为52.5个月。
在53名接受NUC+siRNA治疗的参与者中（平均年龄46.8岁，基线HBsAg为3.08 log，83%既往接受过NUC治疗, 34%乙肝e抗原阳性），在LFU时实现HBsAg血清学清除或HBsAg<100 IU/mL的患者比例分别为1.9%和32.1%，而安慰剂组分别为0%和0%。在接受siRNA治疗的患者中，在最低点或末次给药后≤24周时HBsAg<100 IU/mL和>100 IU/mL的患者中，分别有48.5%和5.0%在LFU时可维持或实现HBsAg<100 IU/mL。与接受安慰剂的患者相比，接受siRNA治疗的患者HBsAg总体年下降速度更快（0.08 vs 0.21 log IU/mL/年），主要是第一年的变化所致。年龄与LFU时HBsAg下降呈负相关（r=-0.427，p=0.001）。
短期siRNA治疗可抑制HBsAg表达，部分参与者的这种效果可持续长达6年。
