Department of Infectious Diseases, Nanjing Zhong-Da Hospital, Southeast University School of Medicine, Nanjing 210009, Jiangsu Province, China.
Department of Infectious Diseases, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
World J Gastroenterol. 2021 Feb 28;27(8):666-676. doi: 10.3748/wjg.v27.i8.666.
Chronic hepatitis B virus (HBV) infection (CHB) is a public health concern worldwide. Current therapies utilizing nucleos(t)ide analogs (NA) have not resulted in a complete cure for CHB. Furthermore, patients on long-term NA treatment often develop low-level viremia (LLV). Persistent LLV, in addition to causing the progression of liver disease or hepatocellular carcinoma, may shed light on the current plight of NA therapy. Here, we review the literature on LLV, NA treatment, and various doses of entecavir to find a strategy for improving the efficacy of this antiviral agent. For LLV patients, three therapeutic options are available, switching to another antiviral monotherapy, interferon-α switching therapy, and continuing monotherapy. In real-world clinical practice, entecavir overdose has been used in antiviral therapy for CHB patients with NA refractory and persistent LLV, which encouraged us to conduct further in-depth literature survey on dosage and duration related entecavir studies. The studies of pharmacodynamics and pharmacokinetics show that entecavir has the maximal selected index for safety, and has great potential in inhibiting HBV replication, in all of the NAs. In the particular section of the drug approval package published by the United States Food and Drug Administration, entecavir doses 2.5-20 mg/d do not increase adverse events, and entecavir doses higher than 1.0 mg/d might improve the antiviral efficacy. The literature survey led us to two suggestions: (1) Increasing entecavir dose to 1.0 mg/d for the treatment of NA naïve patients with HBV DNA >2 × 10 IU/mL is feasible and would provide better prognosis; and (2) Further research is needed to assess the long-term toxic effects of higher entecavir doses (2.5 and 5.0 mg/d), which may prove beneficial in treating patients with prior NA treatment, partial virological response, or LLV state.
慢性乙型肝炎病毒（HBV）感染（CHB）是全球范围内的公共卫生关注点。目前利用核苷（酸）类似物（NA）的治疗方法并未实现 CHB 的完全治愈。此外，长期接受 NA 治疗的患者常常会出现低水平病毒血症（LLV）。持续性 LLV 除了导致肝病或肝细胞癌的进展外，还可能揭示了当前 NA 治疗的困境。在这里，我们回顾了关于 LLV、NA 治疗和各种剂量恩替卡韦的文献，以寻找改善这种抗病毒药物疗效的策略。对于 LLV 患者，有三种治疗选择，分别是转换为另一种抗病毒单药治疗、干扰素-α转换治疗和继续单药治疗。在实际临床实践中，NA 耐药和持续性 LLV 的 CHB 患者在抗病毒治疗中使用了恩替卡韦过量，这促使我们对与恩替卡韦剂量和持续时间相关的研究进行了进一步深入的文献调查。药代动力学和药效学研究表明，恩替卡韦在所有 NA 中具有最大的安全性选择指数，在抑制 HBV 复制方面具有很大的潜力。在美国食品和药物管理局发布的药物批准包的特定部分中，恩替卡韦剂量为 2.5-20 mg/d 不会增加不良反应，而恩替卡韦剂量高于 1.0 mg/d 可能会提高抗病毒疗效。文献调查使我们得出了两个建议：（1）对于 HBV DNA >2×10 IU/mL 的初治 NA 患者，增加恩替卡韦剂量至 1.0 mg/d 是可行的，并且会提供更好的预后；（2）需要进一步研究评估更高恩替卡韦剂量（2.5 和 5.0 mg/d）的长期毒性作用，这可能对治疗有既往 NA 治疗、部分病毒学应答或 LLV 状态的患者有益。
