A Double-Blind Randomized Controlled Trial of Intradermal Hepatitis B Vaccination with Topical Imiquimod in Subjects with Occult Hepatitis B Infection

Abstract

Background: Patients with occult hepatitis B infection (OBI) remain at risk of hepatitis B virus reactivation when undergoing high-risk immunosuppressive therapy. Imiquimod, a synthetic Toll-like receptor 7 agonist, has been shown to significantly improve hepatitis B vaccine immunogenicity in patients on renal replacement therapy. We therefore performed a prospective double-blind randomized controlled trial is to evaluate the effect and safety of topical treatment with imiquimod before intradermal hepatitis B vaccination (HBVv) in OBI patients. Methods: We enrolled adult patients followed up in the hepatitis specialty outpatient clinic in the Queen Mary Hospital, Hong Kong in 2017. All recruited patients had documented loss of HBsAg and negative anti-HBs. The HBVv used in this study is Sci-B-Vac™. Enrolled patients were randomized into 3 groups. All patients received 3 doses HBVv regime at 0, 1 and 6 months. Group 1 received 10μg intradermal HBVv with topical imiquimod ointment pretreatment before vaccination. Group 2 received 10μg intradermal HBVv with topical placebo aqueous cream pretreatment before vaccination; Group 3 received 10μg intramuscular HBVv with topical placebo aqueous cream pretreatment. Anti-HBs titre was measured at baseline and at 1, 6 and 12 months after the first HBVv. The primary outcome was the seroprotection rate at 12-month defined by the percentage of recruited subjects with anti-HBs antibody titre ≥10 IU/L. The secondary outcome include seroprotection rate at 1 and 6 months and the geometric mean titre (GMT) at 1, 6 and 12 months after first HBVv. Results: 75 patients were recruited and the median age was 54 years. 25, 23 and 27 patients were randomized to group 1, 2 and 3 respectively. The seroprotection rate was significantly higher in Group 1 at 12-month (Group 1 vs. Group 2 vs. Group 3 = 100% vs. 87% vs. 77.8%; P=0.047). There was no difference in the seroprotection rate among the three groups at 1 and 6-month. However, the GMT anti-HBs was significantly higher in Group 1 at 6 and 12-month, (6-month: Group 1 vs. Group 2 vs. Group 3 = 373.3 IU/L, 95% CI 177.8-783.4 IU/L vs. 169.8 IU/L, 95% CI 62.5-462.4 IU/L; vs. 76 IU/L, 95% CI 33.3-174.2 IU/L; P=0.026; (12-month: Group 1 vs. Group 2 vs. Group 3 = 3191.5 IU/L, 95% CI 1207.8-8433.3 IU/L vs. 818.5 IU/L, 95% CI 225.9-2964.8 IU/L; vs. 58.5 IU/L, 95% CI 28.7-118.9 IU/L; P<0.0001). Overall side effects were few and self-limiting with no difference among the three groups. Conclusion: Topical imiquimod before intradermal HBVv was highly effective in OBI patients, with significantly higher seroprotection rate and GMT at 12 months after vaccination. This vaccination strategy could effectively prevent hepatitis B virus reactivation in OBI patients.