Hôpital Saint Joseph, Marseille, France.
Sorbonne Universités, University Pierre and Marie Curie Univ Paris 06, Institut National de la santé et de la Recherche Médicale, Institut Pierre Louis d'épidémiologie et de Santé Publique, Paris, France.
Lancet Gastroenterol Hepatol. 2017 Mar;2(3):177-188. doi: 10.1016/S2468-1253(16)30189-3. Epub 2017 Jan 20.
Findings from uncontrolled studies suggest that addition of pegylated interferon in patients with HBe antigen (HBeAg)-negative chronic hepatitis B receiving nucleos(t)ide analogues with undetectable plasma hepatitis B virus (HBV) DNA might increase HBs antigen (HBsAg) clearance. We aimed to assess this strategy.
In this randomised, controlled, open-label trial, we enrolled patients aged 18-75 years with HBeAg-negative chronic hepatitis B and documented negative HBV DNA while on stable nucleos(t)ide analogue regimens for at least 1 year from 30 hepatology tertiary care wards in France. Patients had to have an alanine aminotransferase concentration of less than or equal to five times the upper normal range, no hepatocellular carcinoma, and a serum α fetoprotein concentration of less than 50 ng/mL, normal dilated fundus oculi examination, and a negative pregnancy test in women. Patients with contraindications to pegylated interferon were not eligible. A centralised randomisation used computer-generated lists of random permuted blocks of four with stratification by HBsAg titres (< or ≥2·25 log IU/mL) to allocate patients (1:1) to receive a 48 week course of subcutaneous injections of 180 μg per week of pegylated interferon alfa-2a in addition to the nucleos(t)ide analogue regimen or to continue to receive nucleos(t)ide analogues only. The primary endpoint was HBsAg loss at week 96 by intention-to-treat analysis. This trial is closed and registered with ClinicalTrials.gov, number NCT01172392.
Between Jan 20, 2011, and July 18, 2012, we randomly allocated 185 patients (92 [50%] to pegylated interferon and nucleos(t)ide analogues and 93 [50%] to nucleos(t)ide analogues alone). We excluded two patients from the pegylated interferon plus nucleos(t)ide analogues group from analyses because of withdrawal of consent (one patient) or violation of inclusion criteria (one patient). At week 96, loss of HBsAg was reported in seven (7·8%) of 90 patients in the pegylated interferon plus nucleos(t)ide analogues group versus three (3·2%) of 93 in the nucleos(t)ide analogues-alone group (difference 4·6% [95% CI -2·6 to 12·5]; p=0·15). 85 (94%) of 90 patients started pegylated interferon, three (4%) of whom had a dose reduction and 17 (20%) had an early discontinuation of pegylated interferon (seven [41%] for serious adverse events). Grade 3 and 4 adverse events were more frequent in the pegylated interferon plus nucleos(t)ide analogues group (26 [29%] grade 3 adverse events; 19 [21%] grade 4 adverse events) than in the nucleos(t)ide analogues-alone group (three [3%] grade 3; six [6%] grade 4).
Addition of a 48 week course of pegylated interferon to nucleos(t)ide analogue therapy in patients with HBeAg-negative chronic hepatitis B with undetectable HBV DNA for a least 1 year was poorly tolerated and did not result in a significant increase of HBsAg clearance.
Institut national de la santé et de la recherche médicale-Agence nationale de recherches sur le sida et les hépatites virales (France Recherche Nord&sud Sida-vih Hepatites).
来自非对照研究的结果表明，对于 HBe 抗原（HBeAg）阴性、慢性乙型肝炎患者，在接受核苷（酸）类似物治疗且血液中乙型肝炎病毒（HBV）DNA 不可检测至少 1 年的基础上，加用聚乙二醇干扰素可能会增加 HBs 抗原（HBsAg）清除率。我们旨在评估这种策略。
在这项随机、对照、开放性试验中，我们纳入了来自法国 30 个三级肝病护理病房的年龄在 18-75 岁之间的患者，这些患者患有 HBeAg 阴性慢性乙型肝炎，并且在接受稳定的核苷（酸）类似物治疗方案至少 1 年后血液中 HBV DNA 不可检测。患者的丙氨酸氨基转移酶浓度必须低于或等于正常值上限的 5 倍，无肝细胞癌，血清α胎蛋白浓度低于 50ng/ml，眼底检查正常，女性患者妊娠试验阴性。有聚乙二醇干扰素禁忌证的患者不符合入组条件。采用中央随机化方法，使用计算机生成的随机化排列块列表（4 个随机排列块），按 HBsAg 滴度（<或≥2.25 log IU/ml）分层，将患者（1:1）随机分配接受每周 180μg 皮下注射聚乙二醇干扰素 alfa-2a 48 周，联合核苷（酸）类似物治疗方案，或继续单独接受核苷（酸）类似物治疗。主要终点是通过意向治疗分析在第 96 周时 HBsAg 丢失。本试验已完成并在 ClinicalTrials.gov 注册，编号为 NCT01172392。
在 2011 年 1 月 20 日至 2012 年 7 月 18 日期间，我们随机分配了 185 名患者（92[50%]名接受聚乙二醇干扰素和核苷[酸]类似物联合治疗，93[50%]名接受核苷[酸]类似物单独治疗）。我们排除了聚乙二醇干扰素联合核苷[酸]类似物组中的 2 名患者（1 名患者因撤回同意，1 名患者因违反纳入标准），不参与分析。在第 96 周时，聚乙二醇干扰素联合核苷[酸]类似物组有 7（7.8%）名患者 HBsAg 丢失，核苷[酸]类似物组有 3（3.2%）名患者 HBsAg 丢失（差异 4.6%[95%CI-2.6 至 12.5]；p=0.15）。90 名患者中有 85 名（94%）开始使用聚乙二醇干扰素，其中 3 名（4%）患者剂量减少，17 名（20%）患者提前停用聚乙二醇干扰素（7 名[41%]因严重不良事件）。聚乙二醇干扰素联合核苷[酸]类似物组（26 名[29%]3 级不良事件；19 名[21%]4 级不良事件）比核苷[酸]类似物组（3 名[3%]3 级不良事件；6 名[6%]4 级不良事件）更频繁出现 3 级和 4 级不良事件。
对于 HBeAg 阴性、慢性乙型肝炎患者，在接受核苷（酸）类似物治疗且血液中 HBV DNA 不可检测至少 1 年的基础上，加用 48 周的聚乙二醇干扰素治疗，耐受性差，且未能显著增加 HBsAg 清除率。
法国国家卫生与医学研究所-国家艾滋病和病毒性肝炎研究署（法国研究 Nord&sud Sida-vih Hepatites）。
