Sprengers D, van der Molen R G, Binda R, Kusters J G, de Man R A, Niesters H G M, Schalm S W, Janssen H L A
Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
J Viral Hepat. 2007 Oct;14(10):743-9. doi: 10.1111/j.1365-2893.2007.00841.x.
Only in a minority of patients with chronic hepatitis B (CHB) will treatment with interferon (IFN)-alpha or nucleoside analogues lead to sustained virological response. In vivo immunization (IVI) following virus suppression aims to optimize conditions for an effective immune response: following rapid and profound virus suppression by interferon-lamivudine combination therapy, lamivudine is withdrawn intermittently during continued interferon therapy. It is thought that withdrawal of lamivudine will lead to increased viral replication and increased antigen expression with subsequent immune stimulation. The aim of this prospective pilot study was to evaluate IVI as a therapeutic approach for CHB. Fourteen HBeAg-positive CHB patients were treated for 42 weeks with a combination of pegylated interferon-alpha 2b and lamivudine. After 12 weeks of combination therapy lamivudine was withdrawn intermittently for three consecutive periods of 4 weeks until it was permanently stopped on week 36. At the end of follow-up (week 52) all patients had remained HBeAg positive and the median viral load was similar to baseline. During the initial 12 weeks of treatment, there was a reduction of both the hepatitis B virus (HBV)-specific proliferation capacity of Th-cells and the frequencies of IFNgamma-producing cells. During the lamivudine interruption-cycle there was an inverse relation between the increase of HBV-DNA, and the decrease in proliferation capacity and frequency of IFN-gamma-producing cells. The intrahepatic fraction of CD8(+) T-cells increased during lamivudine withdrawal. In conclusion, IVI was able to transiently stimulate the HBV-specific immune responsiveness of T-cells, but the magnitude of the response was insufficient to cause a beneficial virological effect.
只有少数慢性乙型肝炎（CHB）患者使用α干扰素（IFN）或核苷类似物治疗会产生持续病毒学应答。病毒抑制后的体内免疫（IVI）旨在优化有效免疫应答的条件：在干扰素-拉米夫定联合治疗快速且显著抑制病毒后，在持续干扰素治疗期间间歇性停用拉米夫定。据认为，停用拉米夫定将导致病毒复制增加和抗原表达增加，随后产生免疫刺激。这项前瞻性初步研究的目的是评估IVI作为CHB的一种治疗方法。14例HBeAg阳性的CHB患者接受聚乙二醇化α-2b干扰素和拉米夫定联合治疗42周。联合治疗12周后，拉米夫定间歇性停用3个连续的4周疗程，直至在第36周永久停药。随访结束时（第52周），所有患者仍为HBeAg阳性，病毒载量中位数与基线相似。在治疗的最初12周内，Th细胞的乙肝病毒（HBV）特异性增殖能力和产生IFNγ的细胞频率均降低。在拉米夫定中断周期中，HBV-DNA的增加与增殖能力的降低以及产生IFN-γ的细胞频率之间呈负相关。拉米夫定停药期间，肝内CD8(+) T细胞比例增加。总之，IVI能够短暂刺激T细胞的HBV特异性免疫反应性，但反应程度不足以产生有益的病毒学效应。
