BACKGROUND & AIMS Clearance of hepatitis B surface antigen (HBsAg) from serum is the most desirable end point and a proposed definition of functional cure for hepatitis B virus (HBV) infection. However, little is known about the long-term durability of HBsAg loss, and there is controversy over whether the development of antibodies against HBsAg (anti-HBs) is required for maintenance. We aimed to assess the durability of spontaneous or treatment-related (interferon or nucleos(t)ide analogue [NA]) loss of HBsAg. METHODS We performed a retrospective study of patients with chronic HBV infection followed up at the National Institutes of Health from February 1980 through November 2017. We identified those with HBsAg loss, confirmed on 2 visits at least 24 weeks apart. Patients with hepatitis C virus, hepatitis D virus, human immunodeficiency virus, or human T lymphocyte virus co-infection or HBsAg loss after liver transplantation were excluded. Patients were assigned to the following groups: spontaneous clearance (cleared HBsAg without ever receiving treatment or those who received treatment with a NA or interferon and discontinued therapy >5 years before HBsAg loss), interferon-treated (cleared HBsAg either during treatment or ≤5 years after stopping interferon), and NA-treated (cleared HBsAg either during treatment or ≤5 years after stopping NA). RESULTS Among the 787 HBsAg-positive patients, 89 achieved HBsAg loss; 65 of 89 had confirmed HBsAg loss, which was spontaneous in 19 of the patients (29%), after interferon in 22 (34%), and after NA in 24 (37%). Of the 65 patients with confirmed loss of HBsAg, 62 patients (95%) remained HBsAg negative after a mean time of 9.6 years from the first negative HBsAg test result. HBsAg seroreversion occurred in 3 of the 46 treated patients (7%) (1 interferon and 2 NA), 1 of whom was positive for anti-HBs. At the time of HBsAg loss, 33 of 65 (51%) were anti-HBs positive. At the last follow-up evaluation, anti-HBs was detectable in 50 of the 62 patients (81%) assessed. The rate of development of anti-HBs was proportionally higher among interferon-treated patients (19 of 21; 90%) than NA-treated patients (17 of 22; 77%) or patients with spontaneous loss of HBsAg (14 of 19; 74%). CONCLUSIONS In a retrospective study of 787 HBsAg-positive patients, loss of HBsAg (either spontaneous or after treatment) was confirmed in 8% and was durable. Seroconversion to anti-HBs increased over time and appeared to be more frequent after interferon treatment. HBsAg loss is therefore a robust end point for functional cure.

中文翻译：

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乙型肝炎抗原自发和治疗相关损失的持久性。

背景和目的 从血清中清除乙型肝炎表面抗原 (HBsAg) 是最理想的终点，也是乙型肝炎病毒 (HBV) 感染的功能性治愈的建议定义。然而，人们对 HBsAg 消失的长期持久性知之甚少，对于维持是否需要产生抗 HBsAg 抗体（抗 HBs）存在争议。我们旨在评估 HBsAg 自发或治疗相关（干扰素或核苷（酸）类似物 [NA]）丢失的持久性。方法 我们对 1980 年 2 月至 2017 年 11 月在美国国立卫生研究院随访的慢性 HBV 感染患者进行了一项回顾性研究。我们确定了 HBsAg 消失的患者，并在至少相隔 24 周的 2 次就诊中得到证实。丙型肝炎病毒、丁型肝炎病毒、人类免疫缺陷病毒、排除人T淋巴细胞病毒合并感染或肝移植后HBsAg消失。患者被分为以下几组：自发清除（HBsAg 清除但未接受治疗，或接受 NA 或干扰素治疗并在 HBsAg 消失前 5 年停止治疗的患者）、干扰素治疗组（治疗期间或≤5 年清除 HBsAg停止干扰素后数年），和 NA 治疗（治疗期间或停止 NA 后 ≤ 5 年清除 HBsAg）。结果 787例HBsAg阳性患者中，89例HBsAg消失；89 人中有 65 人已确认 HBsAg 消失，其中 19 名患者 (29%) 自发消失，干扰素后 22 名 (34%) 和 24 名 (37%) NA 后自发消失。在确认 HBsAg 消失的 65 名患者中，62 名患者 (95%) 在平均时间为 9 后仍保持 HBsAg 阴性。从第一次 HBsAg 检测结果呈阴性起 6 年。46 名接受治疗的患者中有 3 名 (7%)（1 名干扰素和 2 名 NA）出现 HBsAg 血清学逆转，其中 1 名抗 HBs 呈阳性。在 HBsAg 消失时，65 人中有 33 人 (51%) 是抗 HBs 阳性的。在最后一次随访评估中，在评估的 62 名患者中有 50 名 (81%) 可检测到抗 HBs。干扰素治疗患者中抗 HBs 的发生率（21 人中的 19 人；90%）高于 NA 治疗患者（22 人中的 17 人；77%）或 HBsAg 自发消失的患者（19 人中的 14 人；74 %）。结论 在一项对 787 名 HBsAg 阳性患者的回顾性研究中，8% 的 HBsAg 消失（自发性或治疗后）被确认并且是持久的。随着时间的推移，抗 HBs 的血清转换增加，并且在干扰素治疗后似乎更频繁。