替诺福韦地索普西富马酸盐加治疗慢性HBV感染的疫苗

StephenW

SUMMARY AND COMMENT | GASTROENTEROLOGY

April 12, 2019

Tenofovir Disoproxil Fumarate plus a Therapeutic Vaccine for Chronic HBV Infection

Atif Zaman, MD, MPH reviewing Boni C et al. Gastroenterology 2019 Mar 28

Adding investigational vaccine GS-4775 activated immune response but did not reduce hepatitis B surface antigen levels.

Current treatment modalities cannot cure hepatitis B virus (HBV) infection. There has been some hope that adding adjunctive therapies to available direct-acting antiviral agents could stimulate HBV-specific T-cell responses that could ultimately lead to cure.

In an industry-funded, phase II, open-label study, researchers evaluated the safety and efficacy of adding GS-4774, a yeast-based therapeutic vaccine that expresses HBV antigens, to tenofovir disoproxil fumarate (TDF) in treatment-naive HBV-infected patients. Patients with HBV DNA ≥2000 IU/mL were randomized in a 1:2:2:2 fashion to receive daily TDF 300 mg alone (n=27) or in combination with 2, 10, or 40 GS-4774 yeast units, given subcutaneously every 4 weeks until week 20 (n=168).

The primary efficacy endpoint, reduction in hepatitis B surface antigen (HBsAg) levels from baseline to week 24, was not greater with addition of GS-4774. Although patients receiving the highest GS-4774 dose had the greatest HBsAg decline, it was not significantly different compared with the TDF-only group. Only a small proportion of patients receiving GS-4774 demonstrated a ≥0.5 log10 IU/mL decline in HBsAg level. In a small subgroup analysis of HBeAg-negative patients, those that received GS-4774 had increased production of tumor necrosis factor, interleukin 2, and interferon gamma by CD8+ T cells exposed to antigenic peptides but did not have increased CD4+ T cell production.
Comment

Although the use of a therapeutic vaccine with a direct-acting antiviral agent induced an immune response in these HBV-infected patients, it did not reduce HBsAg levels. This is likely due to the lack of CD4+ T cell induction. I expect to see continued research on therapeutic vaccines as part of an anti-HBV treatment regimen that ultimately may be curative.

StephenW

摘要和评论|胃肠病

2019年4月12日

替诺福韦地索普西富马酸盐加治疗慢性HBV感染的疫苗

Atif Zaman，MD，MPH审查Boni C等人。消化内科2019年3月28日

添加研究性疫苗GS-4775激活免疫反应，但未降低乙型肝炎表面抗原水平。

目前的治疗方式无法治愈乙型肝炎病毒（HBV）感染。有一些希望，为现有的直接作用抗病毒药物添加辅助疗法可以刺激HBV特异性T细胞反应，最终导致治愈。

在一项由行业资助的第二阶段开放标签研究中，研究人员评估了在治疗初期HBV中添加表达HBV抗原的基于酵母的治疗性疫苗GS-4774的安全性和有效性，以及替诺福韦地索普西富马酸盐（TDF）感染病人。 HBVDNA≥2000IU/ mL的患者以1：2：2：2的方式随机分组，每日接受TDF 300 mg（n = 27）或与2,10或40个GS-4774酵母单位联合使用每4周皮下注射一次，直到第20周（n = 168）。

从基线到第24周，乙肝表面抗原（HBsAg）水平降低的主要疗效终点并未随着GS-4774的添加而增加。虽然接受最高GS-4774剂量的患者HBsAg下降最多，但与仅TDF组相比没有显着差异。只有一小部分接受GS-4774治疗的患者HBsAg水平下降≥0.5log10IU / mL。在HBeAg阴性患者的小亚组分析中，接受GS-4774的患者通过暴露于抗原肽的CD8 + T细胞增加了肿瘤坏死因子，白细胞介素2和干扰素γ的产生，但没有增加CD4 + T细胞产生。
评论

尽管使用具有直接作用抗病毒剂的治疗性疫苗在这些HBV感染的患者中诱导免疫应答，但它并未降低HBsAg水平。这可能是由于缺乏CD4 + T细胞诱导。我希望看到继续研究治疗性疫苗作为抗HBV治疗方案的一部分，最终可能是治愈性的。