Klein Marina B, Campeol Nadia, Lalonde Richard G, Brenner Bluma, Wainberg Mark A
Immunodeficiency Service, Montreal Chest Institute, Department of Medicine, McGill University Health Centre, Montreal, Quebec Canada.
AIDS. 2003 May 2;17(7):1001-8. doi: 10.1097/01.aids.0000060357.78202.25.
To evaluate the antiviral triple combination didanosine (ddI), interferon-alfa (IFN-alpha), and ribavirin for potential synergy in inhibition of HIV-1 replication in vitro.
Phytohaemagglutinin-stimulated cord blood mononuclear cells were infected with HIV-1(IIIB) or the HXB2D molecular clone of HIV-1 then cultured with interleukin-2 with ddI, ribavirin or IFN-alpha, alone and in combination. Reverse transcriptase activity was measured after 7 days to determine the inhibitory concentration of 50% (IC(50)) for the various drugs in replicate assays. Analysis of combined effects was performed using both the median effect principle (CalcuSyn, Biosoft) and three-dimensional modelling (MacSynergy II).
The triple combination was highly synergistic against HIV-1 in vitro with combination indices < 1. The mean IC(50) was reduced from 6.85 to 0.90 micromol/l (P < 0.001) for ddI and from 6.58 to 1.00 micromol/l (P < 0.001) for IFN-alpha. No increased cytotoxicity was observed. Results were similar with both viral strains and using both analyses. In the triple combination, increasing concentrations of IFN-alpha resulted only a slight enhancement of synergy: synergy volumes were 134 [95% confidence limit (CL), 77-191] with 5 U IFN-alpha and 214.92 (95% CL, 116-314) with 10 U. This supporting the observation that the majority of the synergistic activity was derived from the combination of ddI and ribavirin, with IFN-alpha providing additional additive suppression.
This novel triple combination has the potential to provide simultaneous activity against both HIV and hepatitis C and deserves further study to determine if can be safely administered in the clinical setting.
评估抗病毒三联组合药物去羟肌苷（ddI）、α干扰素（IFN-α）和利巴韦林在体外抑制HIV-1复制方面的潜在协同作用。
用植物血凝素刺激的脐血单个核细胞感染HIV-1（IIIB）或HIV-1的HXB2D分子克隆，然后与白细胞介素-2一起培养，分别单独使用ddI、利巴韦林或IFN-α以及联合使用这些药物。7天后测量逆转录酶活性，以确定重复试验中各种药物的50%抑制浓度（IC50）。使用中位效应原理（CalcuSyn，Biosoft）和三维建模（MacSynergy II）对联合效应进行分析。
三联组合在体外对HIV-1具有高度协同作用，联合指数<1。ddI的平均IC50从6.85微摩尔/升降至0.90微摩尔/升（P<0.001），IFN-α的平均IC50从6.58微摩尔/升降至1.00微摩尔/升（P<0.001）。未观察到细胞毒性增加。两种病毒株以及使用两种分析方法得到的结果相似。在三联组合中，IFN-α浓度增加仅导致协同作用略有增强：5单位IFN-α时协同体积为134[95%置信限（CL），77-191]，10单位IFN-α时协同体积为214.92（95%CL，116-314）。这支持了以下观察结果，即大部分协同活性来自ddI和利巴韦林的组合，IFN-α提供额外的相加性抑制作用。
这种新型三联组合有可能同时对HIV和丙型肝炎发挥作用，值得进一步研究以确定其在临床环境中能否安全给药。
