Randomized phase II study of GS-4774 as a therapeutic vaccine in virally suppressed patients with chronic hepatitis B

详细信息    查看全文

• 作者：Anna S. Lok¹ ; ^{aslok@med.umich.edu" class="auth_mail" title="E-mail the corresponding author} ; Calvin Q. Pan² ; Steven-Huy B. Han³ ; Huy N. Trinh⁴ ; W. Jeffrey Fessel⁵ ; Timothy Rodell⁶ ; Benedetta Massetto⁷ ; Lanjia Lin⁷ ; Anuj Gaggar⁷ ; G. Mani Subramanian⁷ ; John G. McHutchison⁷ ; Carlo Ferrari⁸ ; Hannah Lee⁹ ; Stuart C. Gordon¹⁰ ; Edward J. Gane¹¹
• 关键词：AE ; adverse event ; ALT ; alanine aminotransferase ; Anti-HBs ; hepatitis B surface antibody ; AST ; aspartate aminotransferase ; CI ; confidence interval ; HBeAg ; hepatitis B e antigen ; HBsAg ; hepatitis B surface antigen ; HBV ; hepatitis B virus ; HBx ; hepatitis B X ; LLOQ ; lower limit of quantification ; OAV ; oral antiviral ; PBMC ; peripheral blood mononuclear cell ; SD ; standard deviation ; Tarmogen ; Targeted Molecular Immunogen ; ULN ; upper limit of normal ; YU ; yeast unit
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：65
• 期：3
• 页码：509-516
• 全文大小：789 K

文摘

GS-4774 is a heat-inactivated, yeast-based, T-cell vaccine designed to elicit hepatitis B virus (HBV)-specific T-cell responses. We evaluated the safety, tolerability and efficacy of GS-4774 in patients with chronic HBV infection.

Methods

In this phase II study, 178 patients with chronic HBV infection and no cirrhosis who were virally suppressed on an oral antiviral (OAV) for ⩾1 year were randomized (1:2:2:2) to continue OAV alone or receive OAV plus GS-4774 2, 10, or 40 yeast units (YU) subcutaneously every 4 weeks until week 20. OAV was continued for the remainder of the study. Efficacy was measured by decline in serum hepatitis B surface antigen (HBsAg) from baseline to week 24.

Results

Baseline characteristics were similar across groups (mean age, 45–50 years; male, 62–74%; Asian, 68–80%; hepatitis B e antigen (HBeAg)-positive, 24–26%; mean HBsAg, 2.5–3.1 log₁₀ IU/ml). There were no significant differences between groups in mean HBsAg declines from baseline to week 24 or 48. Five HBeAg-positive patients receiving GS-4774 experienced HBeAg loss vs. none in the control group. Three GS-4774 40 YU–treated patients had HBsAg declines ⩾0.5 log₁₀ IU/ml, but no patient experienced loss of serum HBsAg. No virologic breakthrough occurred. Injection site reactions were the most frequent adverse event (AE), and there were no treatment discontinuations.

Conclusions

GS-4774 was well tolerated, but did not provide significant reductions in serum HBsAg in virally suppressed patients with chronic hepatitis B. Efficacy of GS-4774 in treatment-naïve patients remains to be determined.

Lay summary

GS-4774 is a therapeutic vaccine designed to improve the immune response against hepatitis B virus (HBV) in patients who already have chronic infection with HBV. In this study, GS-4774 was safe and well tolerated in patients with chronic HBV infection receiving oral antiviral therapy, but did not result in a clinical benefit. Combination approaches with other agents, and evaluation in other populations of patients with HBV are ongoing to determine if GS-4774 might have a therapeutic benefit.

Clinical trial registration number: NCT01943799.