The standard treatment of chronic hepatitis B virus (HBV) infection, nucleos(t)ide analogues (NUC), is usually long-term, as HBsAg loss is rarely achieved, which signifies functional cure. Recent evidence suggests that selected HBeAg-negative individuals with prolonged viral suppression and no advanced liver fibrosis can discontinue NUC therapy before HBsAg loss [1]. Studies, including a prospective randomised trial, show a higher chance of HBsAg loss after discontinuing NUC therapy [2, 3]. However, HBsAg loss rates vary by patient origin and HBsAg levels. Caucasians have higher HBsAg loss rates (up to 41%) when levels are < 1000 IU/mL, while Asian patients achieve significant HBsAg loss when levels are < 100 IU/mL [4]. Immunological events, marked by transient ALT increases after NUC discontinuation, may trigger HBsAg loss, though the exact mechanisms are unclear [5, 6]. The appropriate time to restart NUC therapy remains debated. Premature re-treatment may inhibit beneficial flares, whereas delayed re-treatment could lead to immune exhaustion, or possibly severe hepatic flares. Studies show conflicting results regarding ALT flares and HBsAg loss [6, 7], highlighting the complexity.

Against this background, the ‘Nuc-Stop Study’ from Norway, Sweden, Denmark and Ethiopia aimed to assess two strategies for restarting NUC therapy [8]. This prospective trial involved 127 HBeAg-negative, non-cirrhotic patients with at least 24 months of viral suppression. Participants discontinued antiviral therapy and were randomly assigned to either a low-threshold or high-threshold group for restarting therapy, based on HBV DNA and ALT values (Figure 1). The primary endpoint was HBsAg loss within 36 months post-therapy. The study showed no statistically significant difference in HBsAg loss between the low-threshold (4.7%) and high-threshold (12.7%) groups. However, the study was underpowered due to the sample size calculation, which assumed HBsAg loss would occur in 20% of the high-threshold group and only 1% of the low-threshold group. The overall HBsAg loss rate was 8.7%, lower than in earlier studies [9]. Importantly, all cases of HBsAg loss occurred in patients with HBsAg < 1000 IU/mL, among whom the HBsAg loss rate was indeed higher in the high-threshold group (53.3%) than in the low-threshold group (11.5%), indicating a possible strategic benefit.

While the optimal timing for restarting NUC therapy remains elusive, the study confirmed increased HBsAg loss rates post-NUC discontinuation in patients with HBsAg levels < 1000 IU/mL. Future research should focus on these patients and include immunologic testing to understand functional cure mechanisms. The study also found very low HBsAg loss rates in patients with genotypes B and C, more common in Asia, confirming a higher barrier for HBsAg loss after NUC discontinuation in these populations [4].

In conclusion, the concept of ‘Stop-NUC’ shows promise, especially in patients with low HBsAg levels, but many questions remain about the immunologic mechanisms involved in achieving a functional cure. However, regardless of immunologic considerations, we would recommend restarting treatment at the latest when HBV DNA levels exceed 100,000 IU/mL or consistently rise above 2000 IU/mL. Delaying restarting treatment can be dangerous, and, if incautious, can lead to severe flares, or hepatic decompensation (as was documented in a patient from London [10]), affecting the safety and efficacy of this strategy.

慢性乙型肝炎病毒 （HBV） 感染的标准治疗，即核苷（酸）类似物 （NUC），通常是长期的，因为 HBsAg 很少消失，这意味着功能性治愈。最近的证据表明，选定的 HBeAg 阴性个体具有长期病毒抑制且无晚期肝纤维化，可以在 HBsAg 消失之前停止 NUC 治疗 [1]。包括一项前瞻性随机试验在内的研究表明，停止 NUC 治疗后 HBsAg 丢失的几率更高 [2， 3]。然而，HBsAg 丢失率因患者来源和 HBsAg 水平而异。当 HBsAg 水平为 < 1000 IU/mL 时，高加索人的 HBsAg 丢失率较高（高达 41%），而亚洲患者当 < 100 IU/mL 时，HBsAg 丢失率较高 [4]。免疫事件（以 NUC 停药后短暂 ALT 升高为特征）可能触发 HBsAg 丢失，但确切机制尚不清楚 [5， 6]。重新开始 NUC 治疗的合适时间仍存在争议。过早再治疗可能会抑制有益的发作，而延迟再治疗可能导致免疫衰竭，或可能导致严重的肝脏发作。研究表明，关于 ALT 发作和 HBsAg 丢失的结果相互矛盾 [6， 7]，突出了复杂性。

在此背景下，来自挪威、瑞典、丹麦和埃塞俄比亚的“Nuc-Stop 研究”旨在评估重新启动 NUC 治疗的两种策略 [8]。这项前瞻性试验涉及 127 名 HBeAg 阴性的非肝硬化患者，这些患者接受了至少 24 个月的病毒抑制。参与者停止抗病毒治疗，并根据 HBV DNA 和 ALT 值被随机分配到低阈值或高阈值组以重新开始治疗（图 1）。主要终点是治疗后 36 个月内 HBsAg 消失。该研究显示，低阈值 （4.7%） 和高阈值 （12.7%） 组之间的 HBsAg 损失没有统计学意义差异。然而，由于样本量计算，该研究的把握度不足，该计算假设 HBsAg 损失将发生在高阈值组的 20% 和低阈值组的 1% 中。总体 HBsAg 丢失率为 8.7%，低于早期研究 [9]。重要的是，所有 HBsAg 丢失病例都发生在 HBsAg < 1000 IU/mL 患者中，其中高阈值组 （53.3%） 的 HBsAg 丢失率确实高于低阈值组 （11.5%），表明可能存在战略益处。

虽然重新开始 NUC 治疗的最佳时机仍然难以捉摸，但该研究证实，在 HBsAg 水平 < 1000 IU/mL 的患者中，停用 NUC 后 HBsAg 丢失率增加。未来的研究应侧重于这些患者，并包括免疫学测试以了解功能性治愈机制。该研究还发现，基因型 B 和 C 患者的 HBsAg 丢失率非常低，这在亚洲更常见，这证实了这些人群停用 NUC 后 HBsAg 丢失的障碍更高 [4]。

总之，“Stop-NUC”的概念显示出前景，尤其是在 HBsAg 水平低的患者中，但关于实现功能性治愈所涉及的免疫机制仍然存在许多问题。然而，无论免疫学考虑如何，我们建议最迟在 HBV DNA 水平超过 100,000 IU/mL 或持续高于 2000 IU/mL 时重新开始治疗。延迟重新开始治疗可能很危险，如果不小心，可能导致严重的发作或肝脏失代偿（如伦敦的一名患者所记录的[10]），从而影响该策略的安全性和有效性。