Stein D S, Drusano G L
Department of Medicine, Albany Medical College, New York 12208, USA.
Antimicrob Agents Chemother. 1997 Feb;41(2):449-53. doi: 10.1128/AAC.41.2.449.
We investigated the relationships between changes in CD4 lymphocytes counts over 24 weeks after the initiation of therapy with indinavir at dosages of > or = 2.4 g/day (n = 15) in human immunodeficiency virus-positive patients and compared them to the baseline values. Starting CD4 count were linked to the time-weighted average CD4 cell count (return) through a nonlinear effect model. The diminution of destruction of CD4 cells after the initiation of indinavir therapy was estimated by fitting simultaneous differential equations to the data by using a linked lymph node (LN)-blood (BL) (two-compartment) system in which there is a constant rate of generation (R), first-order transfer rate constants (KLN-BL and KBL-LN) of compartment exchange, and first-order rate constants of CD4 destruction in the absence and presence of indinavir (KLN-OUT1 and KLN-OUT2). The half-life of CD4 lymphocytes was calculated from the rate constants by standard two-compartment methods. The CD4 lymphocyte counts at the start and return were linked in a sigmoid-Emax model were the maximal effect (Emax) was at 574.6 cells/microliters and 50% of the effect occurred at 157.1 cells/microliters (r2 = 0.94; P < 0.001). The mean +/- standard deviation (median) KLN-OUT2 was 0.574 +/- 0.202 (0.589), indicating that indinavir decrease the destruction of CD4 cells by circa 41 to 42%. The mean (median) CD4 half-life was 11.5 +/- 5.72 day (10.3 days). In multivariate analysis, KLN-OUT2 was significantly correlated with starting the CD4 cells count and the change in the CD4 cell count on therapy. The relationship between CD4 lymphocyte half-life and the starting CD4 lymphocyte count was hyperbolic, with a rapid increase in half-life as the CD4 count decreased. On the basis of the calculated half-life, the average production (destruction) of CD4 lymphocytes was approximately 3 x 10(9) cells/day, with an individual variation of 44-fold. These findings suggest that (i) the CD4 lymphocyte cell count at the start is significantly correlated to both the decrease in the destruction rate of CD4 cells and the degree of change in the CD4 lymphocytes on therapy, (ii) the lower the initial CD4 lymphocyte count, the higher the amount of CD4 lymphocyte turnover and the lower the ability of the immune system to increase absolute CD4 lymphocyte levels after viral suppression, consistent with a decreased regenerative capacity with progression of disease; and (iii) the increase in CD4 lymphocytes is likely secondary to the expansion of proliferating pool of cells since our determinations are based on 24 weeks of effect.
我们研究了人类免疫缺陷病毒阳性患者接受剂量≥2.4克/天的茚地那韦治疗24周后CD4淋巴细胞计数的变化，并将这些变化与基线值进行比较。起始CD4计数通过非线性效应模型与时间加权平均CD4细胞计数（恢复值）相关联。通过使用连接淋巴结（LN）-血液（BL）（双室）系统对数据拟合联立微分方程，估计茚地那韦治疗开始后CD4细胞破坏的减少情况，该系统中存在恒定生成率（R）、室交换的一级转移速率常数（KLN-BL和KBL-LN）以及在不存在和存在茚地那韦时CD4破坏的一级速率常数（KLN-OUT1和KLN-OUT2）。CD4淋巴细胞的半衰期通过标准双室方法根据速率常数计算得出。起始和恢复时的CD4淋巴细胞计数通过S形Emax模型相关联，其中最大效应（Emax）为574.6个细胞/微升，50%的效应发生在157.1个细胞/微升（r2 = 0.94；P < 0.001）。KLN-OUT2的平均值±标准差（中位数）为0.574±0.202（0.589），表明茚地那韦使CD4细胞的破坏减少约41%至42%。平均（中位数）CD4半衰期为11.5±5.72天（10.3天）。在多变量分析中，KLN-OUT2与起始CD4细胞计数以及治疗期间CD4细胞计数的变化显著相关。CD4淋巴细胞半衰期与起始CD4淋巴细胞计数之间的关系呈双曲线，随着CD4计数降低，半衰期迅速增加。根据计算出的半衰期，CD4淋巴细胞的平均产生（破坏）量约为3×10⁹个细胞/天，个体差异为44倍。这些发现表明：（i）起始时的CD4淋巴细胞计数与CD4细胞破坏率的降低以及治疗期间CD4淋巴细胞变化程度均显著相关；（ii）初始CD4淋巴细胞计数越低，CD4淋巴细胞周转率越高，病毒抑制后免疫系统增加绝对CD4淋巴细胞水平的能力越低，这与疾病进展导致再生能力下降一致；（iii）CD4淋巴细胞的增加可能继发于增殖细胞池的扩大，因为我们的测定基于24周的效应。
