Sulkowski Mark S, Agarwal Kosh, Ma Xiaoli, Nguyen Tuan T, Schiff Eugene R, Hann Hie-Won L, Dieterich Douglas T, Nahass Ronald G, Park James S, Chan Sing, Han Steven-Huy B, Gane Edward J, Bennett Michael, Alves Katia, Evanchik Marc, Yan Ran, Huang Qi, Lopatin Uri, Colonno Richard, Ma Julie, Knox Steven J, Stamm Luisa M, Bonacini Maurizio, Jacobson Ira M, Ayoub Walid S, Weilert Frank, Ravendhran Natarajan, Ramji Alnoor, Kwo Paul Yien, Elkhashab Magdy, Hassanein Tarek, Bae Ho S, Lalezari Jacob P, Fung Scott K, Yuen Man-Fung
Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Institute of Liver Studies, King's College Hospital, London, UK.
J Hepatol. 2022 Nov;77(5):1265-1275. doi: 10.1016/j.jhep.2022.05.027. Epub 2022 Jun 11.
BACKGROUND & AIMS: Nucleos(t)ide reverse transcriptase inhibitors do not completely suppress HBV DNA in chronic HBV infection (cHBV). Vebicorvir (VBR) is an investigational core inhibitor that interferes with multiple aspects of HBV replication. This phase II trial evaluated the safety and efficacy of VBR in combination with entecavir (ETV) in treatment-naïve patients with cHBV.
HBeAg-positive, treatment-naïve patients without cirrhosis were randomised 1:1 in a double-blind manner to once-daily VBR 300 mg+ETV 0.5 mg or placebo (PBO)+ETV 0.5 mg for 24 weeks. The primary endpoint was change in mean log HBV DNA from Baseline to Week 12 and 24.
All patients in both treatment groups (PBO+ETV: 12/12; VBR+ETV: 13/13) completed the study. At Week 12, VBR+ETV led to a greater mean (SD) reduction from Baseline in log IU/ml HBV DNA (-4.45 [1.03]) vs. PBO+ETV (-3.30 [1.18]; p = 0.0077). At Week 24, VBR+ETV led to a greater reduction from Baseline in log IU/ml HBV DNA (-5.33 [1.59]) vs. PBO+ETV (-4.20 [0.98]; p = 0.0084). Greater mean reductions in pregenomic RNA were observed at Week 12 and 24 in patients receiving VBR+ETV vs. PBO+ETV (p <0.0001 and p <0.0001). Changes in viral antigens were similar in both groups. No drug interaction between VBR and ETV was observed. Two patients experienced HBV DNA rebound during treatment, with no resistance breakthrough detected. The safety of VBR+ETV was similar to PBO+ETV. All treatment-emergent adverse events and laboratory abnormalities were Grade 1/2. There were no deaths, serious adverse events, or evidence of drug-induced liver injury.
In this 24-week study, VBR+ETV provided additive antiviral activity over PBO+ETV in treatment-naïve patients with cHBV, with a favourable safety and tolerability profile.
NCT03577171 LAY SUMMARY: Hepatitis B is a long-lasting viral infection of the liver. Current treatments can suppress hepatitis B virus but do not offer the opportunity of cure, hence, new treatment approaches are required. Herein, we show that the combination of the novel core inhibitor vebicorvir with an existing antiviral (entecavir) in treatment-naïve patients chronically infected with hepatitis B virus demonstrated greater antiviral activity than entecavir alone. Additionally, vebicorvir was safe and well tolerated. Thus, further studies evaluating its potential role in the treatment of chronic hepatitis B are warranted.
核苷（酸）逆转录酶抑制剂不能完全抑制慢性乙型肝炎病毒（HBV）感染（cHBV）中的HBV DNA。维比科韦（VBR）是一种正在研究的核心抑制剂，可干扰HBV复制的多个方面。本II期试验评估了VBR联合恩替卡韦（ETV）治疗初治cHBV患者的安全性和疗效。
HBeAg阳性、无肝硬化的初治患者以1:1的比例随机双盲接受每日一次的VBR 300mg+ETV 0.5mg或安慰剂（PBO）+ETV 0.5mg治疗24周。主要终点是从基线到第12周和第24周时平均log HBV DNA的变化。
两个治疗组的所有患者（PBO+ETV组：12/12；VBR+ETV组：13/13）均完成了研究。在第12周时，VBR+ETV组相较于PBO+ETV组，log IU/ml HBV DNA从基线的平均（标准差）下降幅度更大（-4.45 [1.03] 对比 -3.30 [1.18]；p = 0.0077）。在第24周时，VBR+ETV组相较于PBO+ETV组，log IU/ml HBV DNA从基线的下降幅度更大（-5.33 [1.59] 对比 -4.20 [0.98]；p = 0.0084）。在第12周和第24周时，接受VBR+ETV治疗的患者相较于PBO+ETV治疗的患者，前基因组RNA的平均下降幅度更大（p <0.0001和p <0.0001）。两组病毒抗原的变化相似。未观察到VBR与ETV之间存在药物相互作用。两名患者在治疗期间出现HBV DNA反弹，未检测到耐药突破。VBR+ETV的安全性与PBO+ETV相似。所有治疗期间出现的不良事件和实验室异常均为1/2级。无死亡病例、严重不良事件或药物性肝损伤的证据。
在这项为期24周的研究中，VBR+ETV在初治cHBV患者中比PBO+ETV具有更强的抗病毒活性，且安全性和耐受性良好。
NCT03577171 通俗总结：乙型肝炎是一种肝脏的持续性病毒感染。目前的治疗方法可以抑制乙型肝炎病毒，但无法实现治愈，因此需要新的治疗方法。在此，我们表明，新型核心抑制剂维比科韦与现有的抗病毒药物（恩替卡韦）联合使用，在初治的慢性乙型肝炎病毒感染患者中显示出比单独使用恩替卡韦更强的抗病毒活性。此外，维比科韦安全且耐受性良好。因此，有必要进一步研究评估其在慢性乙型肝炎治疗中的潜在作用。
