Hughes M D, Daniels M J, Fischl M A, Kim S, Schooley R T
Department of Biostatistics, and Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
AIDS. 1998 Oct 1;12(14):1823-32. doi: 10.1097/00002030-199814000-00014.
To evaluate initial changes in CD4 cell count as a surrogate endpoint for clinical outcome in HIV-infected patients.
Meta-analysis of all relevant Phase II and III randomized clinical trials undertaken by the Adult AIDS Clinical Trials Group.
Individual patient data were obtained from each clinical trial, and the difference between a pair of treatments in their effect on clinical outcome (AIDS or death, or death alone) during 2 years of follow-up was evaluated. The proportion of treatment effect explained (PTE) was the proportion of this difference explained by the change in CD4 cell count 6 months after starting treatment, evaluated using proportional hazards models. A weighted average PTE across treatment comparisons was obtained. The association between the difference between treatments in clinical outcome, expressed as hazard ratio, and the difference in mean change in CD4 cell count was evaluated using regression analysis.
There were 15 clinical trials involving 24 treatment comparisons. The weighted average PTE for both progression to AIDS or death was 0.16 [95% confidence interval (Cl), 0.07-0.26] and for death was 0.10 (95% Cl, 0.00-0.20). There were significant associations between treatment differences in effect on AIDS or death, and on death alone, and the difference in mean change in CD4 cell count. A difference in mean change in CD4 cell count of 30 or 40 x 10(6)/l or more in favor of the test treatment indicated with high probability that there was a corresponding difference in progression to AIDS or death.
The small PTE suggest that other mechanisms of drug action not captured by initial change in CD4 cells are important. CD4 cell count is a weak surrogate endpoint, but has some value as an aid for screening treatments for drug development or preliminary regulatory approval.
评估CD4细胞计数的初始变化作为HIV感染患者临床结局替代终点的情况。
对成人艾滋病临床试验组进行的所有相关II期和III期随机临床试验进行荟萃分析。
从每项临床试验中获取个体患者数据，并评估两种治疗在2年随访期间对临床结局（艾滋病或死亡，或仅死亡）的影响差异。治疗效果解释比例（PTE）是开始治疗6个月后CD4细胞计数变化所解释的该差异的比例，使用比例风险模型进行评估。获得各治疗比较的加权平均PTE。使用回归分析评估以风险比表示的临床结局治疗差异与CD4细胞计数平均变化差异之间的关联。
有15项临床试验，涉及24种治疗比较。进展为艾滋病或死亡的加权平均PTE为0.16[95%置信区间（Cl），0.07 - 0.26]，死亡的加权平均PTE为0.10（95%Cl，0.00 - 0.20）。治疗对艾滋病或死亡以及仅对死亡的影响差异与CD4细胞计数平均变化差异之间存在显著关联。CD4细胞计数平均变化差异为30或40×10⁶/L或更高且有利于试验治疗，高度表明在进展为艾滋病或死亡方面存在相应差异。
较小的PTE表明CD4细胞初始变化未涵盖的其他药物作用机制很重要。CD4细胞计数是一个较弱的替代终点，但作为药物开发或初步监管批准的治疗筛选辅助手段有一定价值。
