替诺福韦地索普西富马酸盐加治疗慢性HBV感染的疫苗

StephenW

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.

Note to readers: At the time we reviewed this paper, its publisher noted that it was not in final form and that subsequent changes might be made.
EDITOR DISCLOSURES AT TIME OF PUBLICATION
Disclosures for Atif Zaman, MD, MPH at time of publication
Grant/Research Support        Merck
Citation(s):

Boni C et al. Combined GS-4774 and tenofovir therapy can improve HBV-specific T-cell responses in patients with chronic hepatitis. Gastroenterology 2019 Mar 28; [e-pub]. (https://doi.org/10.1053/j.gastro.2019.03.044)

StephenW

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性研究中，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。 HBVDNA≥2000IU/ mL的患者以1：2：2：2的方式随机分组，每日接受单独的TDF 300 mg（n = 27）或与2,10或40个GS-4774酵母单位组合使用每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，但并不显着只有一小部分接受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。

读者注意：在我们审阅本文时，其出版商指出，它不是最终形式，可能会进行后续处理。
编辑在出版时披露
Atif Zaman，MD，MPH在出版时的披露
格兰克/研究支持默克
引用（S）：

Boni C等。联合GS-4774和替诺福韦治疗可以改善慢性肝炎患者的HBV特异性T细胞反应。消化内科2019年3月28日; [E-PUB]。 （https://doi.org/10.1053/j .gastro.2019.03.044）