Treatment of chronic hepatitis B naïve patients with a therapeutic vaccine containing HBs and HBc antigens (a randomized, open and treatment controlled phase III clinical trial)

Context
Current drugs for chronic hepatitis B therapy have a poor efficacy in terms of post-treatment sustained viral suppression and generate important side effects during and after therapy. Therapeutic vaccination with HBV antigens is an attractive alternative to test.
Objective
Evaluating the efficacy of a therapeutic vaccine candidate (designated NASVAC) containing both hepatitis B surface antigen (HBsAg) and core antigen (HBcAg) versus pegylated interferon (Peg-IFN) in naïve chronic hepatitis B patients.
Design, setting, participants
An open phase III, randomised and treatment controlled clinical trial was conducted in a total of 160 CHB patients, allocated into two groups of 80 patients each to receive NASVAC or Peg-IFN. The vaccine formulation comprised 100 μg of each HBsAg and HBcAg, and was administered in 2 cycles of 5 doses. The control group received 48 subcutaneous injections of Peg-IFN alfa 2b, 180 μg per dose, every week, for 48 consecutive weeks.
Main outcome measure
The primary outcome measure was in relation with the proportion of patients showing reduction of the viral load under the limit of detection (250 copies/mL) after 24 weeks of treatment completion.
Results
Sustained control of HBV DNA was significantly more common in NASVAC group (p<0.05) at 24 weeks of follow up. NASVAC-induced increases of alanine aminotransferases (ALT) were detected in 85% patients after 5 nasal vaccinations, although seen in only 30% of patients receiving Peg-IFN. At the end of treatment (EOT) antiviral effect was comparable in both NASVAC and Peg-IFN groups. Clearance of Hepatitis B e antigen (HBeAg) was also more frequent in NASVAC group compared to Peg-IFN recipients. A lower progression to cirrhosis was found in NASVAC group compared to Peg-IFN group.
Conclusion
Nasvac induced a superior reduction of the viral load under the limit of detection compared to Peg-IFN treatment. It is a safe and efficacious finite alternative of antiviral treatment for CHB patients.
Trial registration
ClinicalTrials.gov NCT 01374308.

研究背景
当前用于慢性乙型肝炎（chronic hepatitis B, CHB）治疗的药物，在停药后持续病毒抑制方面疗效欠佳，且在治疗期间及治疗后会产生显著不良反应。采用乙型肝炎病毒（hepatitis B virus, HBV）抗原进行治疗性疫苗接种，是颇具研究价值的替代治疗方案。

研究目的
本研究旨在评估同时含乙型肝炎表面抗原（hepatitis B surface antigen, HBsAg）与乙型肝炎核心抗原（core antigen, HBcAg）的候选治疗性疫苗NASVAC，与聚乙二醇化干扰素（pegylated interferon, Peg-IFN）在初治慢性乙型肝炎患者中的疗效差异。

试验设计、研究场景与研究对象
本研究为开放标签、随机对照Ⅲ期临床试验，共纳入160例慢性乙型肝炎患者，按1:1比例分为两组，每组80例，分别接受NASVAC或Peg-IFN治疗。疫苗制剂每剂含HBsAg与HBcAg各100μg，采用2个疗程给药，每个疗程含5剂。对照组则接受聚乙二醇干扰素α-2b皮下注射，每周1次，每次180μg，连续给药48周，共计48剂。

主要结局指标
主要结局指标为治疗结束后随访24周时，病毒载量降至检测下限（250 copies/mL）以下的患者比例。

试验结果
随访24周时，NASVAC组患者的HBV DNA持续抑制率显著更高（p<0.05）。在完成5剂鼻腔接种后，85%的NASVAC组患者出现丙氨酸氨基转移酶（alanine aminotransferase, ALT）升高，而Peg-IFN组仅30%的患者出现该反应。治疗结束（end of treatment, EOT）时，两组的抗病毒效果相当。NASVAC组的乙型肝炎e抗原（hepatitis B e antigen, HBeAg）血清清除率也显著高于Peg-IFN组。与Peg-IFN组相比，NASVAC组患者的肝硬化进展率更低。

研究结论
与Peg-IFN治疗相比，NASVAC可使更多患者的病毒载量降至检测下限以下，是一种安全有效、疗程有限的慢性乙型肝炎抗病毒治疗替代方案。

临床试验注册
ClinicalTrials.gov NCT 01374308。