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Abstract
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.
- HEPATITIS B
- LIVER
Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information.
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Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information.
Footnotes
Contributors The authors declare they have participated in the preparation of the manuscript and have seen and approved the final version. LYM was involved in acquisition of data, analysis and interpretation of data and drafting of manuscript. CIW, TS and JH were involved in the literature review data acquisition and data interpretation. OL and HLD were involved in data collection, data analysis and critical revision of manuscript. XM was involved in data analysis and statistical support. W-KS and MB were involved in study concept and design, analysis and interpretation of data, critical revision of manuscript. M-FY was involved in study conceptualisation, critical revision of manuscript and overall study supervision. MFY is the guarantor of the study.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests LYM served as an advisor for Gilead Sciences and Roche Diagnostics. OL, HLD and MB are employees of Janssen Pharmaceutica and stockholders of Johnson & Johnson. W-KS received speaker’s fees from AstraZeneca, is an advisory board member and received speaker’s fees of Abbott, received research funding from Alexion Pharmaceuticals, Boehringer Ingelheim, Pfizer and Ribo Life Science and is an advisory board member, received speaker’s fees and researching funding from Gilead Sciences. M-FY serves as advisor/consultant for AbbVie, Assembly Biosciences, Aligos Therapeutics, Arbutus Biopharma, Bristol Myer Squibb, Clear B Therapeutics, Dicerna Pharmaceuticals, Finch Therapeutics, GlaxoSmithKline, Gilead Sciences, Immunocore, Janssen, Merck Sharp and Dohme, Hoffmann-La Roche and Springbank Pharmaceuticals, Vir Biotechnology and receives grant/research support from Assembly Biosciences, Aligos Therapeutics, Arrowhead Pharmaceuticals, Bristol Myer Squibb, Fujirebio Incorporation, Gilead Sciences, Immunocore, Merck Sharp and Dohme, Hoffmann-La Roche, Springbank Pharmaceuticals and Sysmex Corporation. The remaining authors have no conflict of interests.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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