Bakacs Tibor, Safadi Rifaat, Puskás László G, Fehér Liliána Z, Kovesdi Imre
Department of Probability, Alfred Renyi Institute of Mathematics, The Eotvos Lorand Research Network (ELKH), Budapest, HUN.
The Liver Unit, Hadassah Medical Organization, Hadassah Hebrew University Medical Center, Jerusalem, ISR.
Cureus. 2022 Mar 1;14(3):e22750. doi: 10.7759/cureus.22750. eCollection 2022 Mar.
Based on the recommendation of the International Coalition to Eliminate hepatitis B virus (ICE-HBV), we intend to mimic the spontaneous resolution of HBV infection to achieve a functional cure of chronic hepatitis B virus (HBV) infection. To this end, we propose sequential targeting of the innate and adaptive host immune responses. Long-term suppression of HBV replication and hepatitis B surface antigen (HbsAg) production will be achieved first by inducing a strong innate immune response. The clinically validated viral superinfection therapy (SIT) will be administered, which employs an attenuated, non-lytic, double-stranded RNA (dsRNA) infectious bursal disease virus (IBDV) that provides an exceptionally strong interferon (IFN) response. Then, the exhausted HBV-specific T cell function will be restored by blocking the cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) receptors with immune checkpoint inhibitors (ICIs). In order to minimize any risk of toxicity, off-label low doses of nivolumab (0.5 mg/kg) plus ipilimumab (0.3 mg/kg) will be administered, the safety and efficacy of which has already been demonstrated in 131 unselected stage IV cancer patients. We predict that this combination therapy will provide sustained off-treatment virological and clinical responses during a relatively short treatment period.
基于国际消除乙肝病毒联盟（ICE-HBV）的建议，我们打算模拟乙肝病毒感染的自然清除过程，以实现慢性乙肝病毒（HBV）感染的功能性治愈。为此，我们建议依次靶向宿主的固有免疫反应和适应性免疫反应。首先，通过诱导强烈的固有免疫反应，实现对HBV复制和乙肝表面抗原（HbsAg）产生的长期抑制。将采用经临床验证的病毒重叠感染疗法（SIT），该疗法使用一种减毒、非裂解性的双链RNA（dsRNA）传染性法氏囊病病毒（IBDV），可引发异常强烈的干扰素（IFN）反应。然后，通过使用免疫检查点抑制剂（ICIs）阻断细胞毒性T淋巴细胞相关抗原4（CTLA-4）和程序性细胞死亡蛋白1（PD-1）受体，恢复耗竭的HBV特异性T细胞功能。为了将毒性风险降至最低，将使用未按药品说明书用药的低剂量纳武单抗（0.5 mg/kg）加伊匹单抗（0.3 mg/kg），其安全性和有效性已在131例未经选择的IV期癌症患者中得到证实。我们预测，这种联合疗法将在相对较短的治疗期内提供持续的停药后病毒学和临床反应。
