治疗结束时的 HBcrAg 和 HBsAb 水平可确定 CHB 患者在基于 Peg-IFN

StephenW

治疗结束时的 HBcrAg 和 HBsAb 水平可确定 CHB 患者在基于 Peg-IFN 的治疗后的持久功能性治愈

    大黄†
    吴迪†
    王鹏
    罗小平
    严伟明
    秦宁
   

开放存取发布时间：2022 年 2 月 8 日DOI：https://doi.org/10.1016/j.jhep.2022.01.021


强调

    •
    HBsAb 出现是一个替代终点，可以补充 HBsAg 的丧失，以反映乙型肝炎的功能性治愈。
    •
    治疗中的 HBsAg 或 HBcrAg 水平与基于 Peg-IFN 的治疗的 HBsAg 消失或 HBsAb 出现相关。
    •
    治疗中的 HBsAg 或 HBsAb 水平与基于 Peg-IFN 的治疗后的持久功能性治愈相关。
    •
    EOT HBcrAg <4 log10U/ml 和 HBsAb >2 log10IU/L 可以识别可能实现持久功能性治愈的反应者。
    •
    HBcrAg 和 HBsAb 水平部分反映了宿主治疗后的抗 HBV 免疫反应。

背景与目标
部分慢性乙型肝炎 (CHB) 患者在以聚乙二醇干扰素 α (Peg-IFN-ɑ) 为基础的治疗后失去乙型肝炎表面抗原 (HBsAg) 可以维持功能性治愈。在这项研究中，我们旨在确定与持久功能性治愈相关的生物标志物，并剖析潜在的免疫机制。
方法
在 ANCHOR 研究中的 257 名核苷（酸）类似物抑制的 CHB 患者中，80 名患者被随机分配到基于 Peg-IFN-α 的 96 周治疗和 24 周的停药随访中。 .动态检查病毒学和免疫学生物标志物。反应定义为治疗结束 (EOT) 时 HBsAg 消失或出现乙型肝炎表面抗体 (HBsAb)。持续缓解 (SR) 或持久功能性治愈定义为在随访结束 (EOF) 时出现或不出现 HBsAb 的持续 HBsAg 消失。
结果
80 名患者中有 36 名 (45.0%) 在 EOT 时达到了反应； 58.3% (21/36) 的响应者在 EOF 维持 SR。 EOT 时的定量乙型肝炎核心相关抗原 (qHBcrAg) 和 HBsAb 与 SR 相关，AUROC 分别为 0.697 (0.512-0.882, p = 0.047) 和 0.744 (0.573-0.915, p = 0.013)。 EOT 时 HBcrAg <4 log10U/ml 和 HBsAb >2 log10IU/L 对 SR 的阳性预测值为 100%，AUROC 为 0.822（0.684-0.961，p = 0.001）。这些患者的 HBV 包膜特异性 CD8+T 和 B 细胞比例保持不变，Peg-IFN-ɑ 停药后 T 滤泡辅助细胞比例显着增加，HBV 聚合酶特异性 CD8+T 和 CD86+CD19 比例显着增加EOF 处的 +B 细胞。
结论
EOT 时较低的 HBcrAg 和较高的 HBsAb 水平与持续的细胞和体液免疫反应相关。它们可用于识别可能在基于 Peg-IFN 的治疗后实现持久功能性治愈的患者。
ClinicalTrials.gov 标识符
NCT02327416
总结
部分慢性乙型肝炎患者在以聚乙二醇干扰素 α 为基础的治疗后可以维持功能性治愈。然而，预测谁将实现持久的功能性治愈仍然具有挑战性。在此，我们表明，治疗结束时乙型肝炎核心相关抗原水平较低和乙型肝炎表面抗体水平较高与免疫反应有关，并且与持久的功能性治愈有关。

StephenW

End-of-treatment HBcrAg and HBsAb levels identify durable functional cure after Peg-IFN-based therapy in patients with CHB

    Da Huang †
    Di Wu †
    Peng Wang
    Xiaoping Luo
    Weiming Yan
    Qin Ning
   

Open AccessPublished:February 08, 2022DOI:https://doi.org/10.1016/j.jhep.2022.01.021


Highlights

    •
    HBsAb appearance is a surrogate endpoint that may complement HBsAg loss in reflecting functional cure of hepatitis B.
    •
    On-treatment HBsAg or HBcrAg levels correlated with HBsAg loss or HBsAb appearance with Peg-IFN-based treatment.
    •
    On-treatment HBsAg or HBsAb levels correlated with durable functional cure post Peg-IFN-based therapy.
    •
    EOT HBcrAg <4 log10U/ml and HBsAb >2 log10IU/L can identify responders likely to achieve durable functional cure.
    •
    HBcrAg and HBsAb levels partially reflect post-therapy anti-HBV immune responses in the host.

Background & Aims
Functional cure can be sustained in a proportion of patients with chronic hepatitis B (CHB) who lose hepatitis B surface antigen (HBsAg) after pegylated interferon alpha (Peg-IFN-ɑ)-based treatment. In this study, we aimed to identify biomarkers associated with a durable functional cure and to dissect potential immunological mechanisms.
Methods
Of 257 nucleos(t)ide analogue-suppressed patients with CHB in the ANCHOR study, 80 patients randomly assigned to 96-week Peg-IFN-α-based therapy with 24-week off-treatment follow-up were included in this parallel study. Virologic and immunological biomarkers were examined dynamically. A response was defined as HBsAg loss or hepatitis B surface antibody (HBsAb) appearance at the end of treatment (EOT). Sustained response (SR) or durable functional cure was defined as sustained HBsAg loss with or without the appearance of HBsAb at the end of follow-up (EOF).
Results
Thirty-six (45.0%) out of 80 patients achieved a response at EOT; 58.3% (21/36) of responders maintained SR at EOF. Quantitative hepatitis B core-related antigen (qHBcrAg) and HBsAb at EOT were associated with SR, with AUROCs of 0.697 (0.512-0.882, p = 0.047) and 0.744 (0.573-0.915, p = 0.013), respectively. A combination of HBcrAg <4 log10U/ml and HBsAb >2 log10IU/L at EOT had a positive predictive value of 100% for SR with an AUROC of 0.822 (0.684-0.961, p = 0.001). These patients showed maintained proportions of HBV envelope-specific CD8+T and B cells, a markedly increased proportion of T follicular helper cells after Peg-IFN-ɑ discontinuation, and significantly higher proportions of HBV polymerase-specific CD8+T and CD86+CD19+B cells at EOF.
Conclusions
Lower HBcrAg and higher HBsAb levels at EOT were associated with sustained cellular and humoral immune responses. They can be used to identify patients likely to achieve durable functional cure post Peg-IFN-based therapy.
ClinicalTrials.gov identifier
NCT02327416
Lay summary
Functional cure can be sustained in a proportion of patients with chronic hepatitis B after pegylated interferon alpha-based treatment. However, predicting who will achieve durable functional cure remains challenging. Herein, we show that low levels of hepatitis B core-related antigen and higher levels of hepatitis B surface antibodies at the end of treatment are linked to immunological responses and are associated with durable functional cure.

StephenW

http://www.journal-of-hepatology.eu/article/S0168827822000666/pdf