Chokshi Shilpa, Cooksley Helen, Riva Antonio, Phillips Sandra, Williams Roger, Gaggar Anuj, Naoumov Nikolai V
1 Institute of Hepatology , Foundation for Liver Research, London, United Kingdom .
Viral Immunol. 2014 Jun;27(5):235-44. doi: 10.1089/vim.2014.0022. Epub 2014 May 5.
The major shortcoming of nucleos(t)ide analogue therapy for chronic hepatitis B (CHB) is the frequent requirement for indefinite therapy. Withdrawal of treatment can result in viral rebound with an alanine aminotransferase (ALT) flare leading to hepatic decompensation, while in others this can lead to hepatitis B e antigen (HBeAg) seroconversion. The aim of the study was to identify host immune profiles associated with these different outcomes. Eighteen HBeAg(+) patients, enrolled on a phase III trial with the nucleoside analogue adefovir dipivoxil, were followed for up to 128 weeks. For the first 48 weeks, all patients received continuous therapy. Subsequently, patients experienced cycles of treatment interruptions due to random drug/placebo misallocations. Host immune profiles were characterized by measuring a panel of serum cytokines before, during, and after each cycle of treatment withdrawal. Virus-specific T-cell responses were also determined at these time points in a subset of patients to elucidate the mechanisms utilized to control hepatitis B virus (HBV) replication post-treatment. Significantly, elevated levels of IFN-γ, IP-10, and IL-2 on-treatment were associated with HBeAg seroconversion after treatment withdrawal. In these patients, treatment interruption induced further increases in serum IFN-γ levels and marked increases in virus-specific T-cells producing IFN-γ, but minimal alterations in viremia and ALT. In HBeAg(+) patients with low on-treatment levels of serum IFN-γ, the interruption of therapy induced significant elevations in HBV-DNA, ALT, IP-10, and increases in virus-specific T-cells producing IL-10. Evaluating on-treatment serum cytokines in concert with virologic and clinical parameters may help to identify CHB patients who can successfully discontinue nucleos(t)ide analogue therapy.
核苷（酸）类似物治疗慢性乙型肝炎（CHB）的主要缺点是常常需要进行长期治疗。停药可能导致病毒反弹，伴有丙氨酸氨基转移酶（ALT）升高，进而引起肝功能失代偿，而在其他患者中，这可能导致乙肝e抗原（HBeAg）血清学转换。本研究的目的是确定与这些不同结果相关的宿主免疫特征。18例HBeAg阳性患者参加了一项使用核苷类似物阿德福韦酯的III期试验，随访长达128周。在最初的48周，所有患者接受持续治疗。随后，由于随机药物/安慰剂分配错误，患者经历了治疗中断周期。通过在每个治疗停药周期之前、期间和之后测量一组血清细胞因子来表征宿主免疫特征。在一部分患者的这些时间点还测定了病毒特异性T细胞反应，以阐明治疗后控制乙型肝炎病毒（HBV）复制所利用的机制。值得注意的是，治疗期间IFN-γ、IP-10和IL-2水平升高与停药后HBeAg血清学转换相关。在这些患者中，治疗中断导致血清IFN-γ水平进一步升高，以及产生IFN-γ的病毒特异性T细胞显著增加，但病毒血症和ALT变化极小。在治疗期间血清IFN-γ水平较低的HBeAg阳性患者中，治疗中断导致HBV-DNA、ALT、IP-10显著升高，以及产生IL-10的病毒特异性T细胞增加。结合病毒学和临床参数评估治疗期间的血清细胞因子可能有助于识别能够成功停用核苷（酸）类似物治疗的CHB患者。
