Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD; and.
Fred Hutchinson Cancer Research Center, Seattle, WA.
J Acquir Immune Defic Syndr. 2020 May 1;84(1):37-44. doi: 10.1097/QAI.0000000000002306.
Vaccines and biologics containing CD4 molecules or HIV-1 gp120 might induce antibodies targeting CD4. We evaluated temporal variability of CD4 levels in healthy volunteers to quantify declines that could indicate true adverse events.
Prospective observational cohort study of 100 healthy adults without HIV-1 infection from the Baltimore region.
Participants enrolled and consented to blood draws for immunologic laboratory panels performed once every 8 weeks for 48 weeks. The primary CD4 measurements were CD4 absolute count (cells/mm) and CD4 percentage (CD4%, total CD4 cells/total lymphocyte cells). CD4 changes over time were modeled using fold changes for CD4 absolute counts and differences for CD4 percentages.
Variation of average CD4 cell counts and percentages were highly participant-specific (P < 0.001 for both). However, changes in both CD4 measurements over time were stable in the population. We proposed thresholds to flag unusual drops using 1.5 SD estimates, calculated as 1.5-fold declines for CD4 count and 6.4% declines for CD4 percentage. In this healthy cohort, flagging simultaneous declines in both measurements corresponded to a low false-positive rate (5.26%).
Normal biological variation in large lymphocytes should be taken into account to establish thresholds for adverse changes in clinical trials. The inherent subject-specific variability in CD4 levels makes establishing absolute cutoffs difficult. However, this study proposes that thresholds for declines using 1.5 SDs from these data (50% in absolute count and 6.4% for CD4 percentage) allow a small false-positive rate (∼5%) that could maintain sensitivity for true adverse events in a clinical trial.
含有 CD4 分子或 HIV-1 gp120 的疫苗和生物制剂可能会诱导针对 CD4 的抗体。我们评估了健康志愿者中 CD4 水平的时间变异性，以量化可能表明真实不良事件的下降。
来自巴尔的摩地区的 100 名未感染 HIV-1 的健康成年人的前瞻性观察队列研究。
参与者入组并同意在 48 周内每 8 周进行一次免疫实验室小组的血液采集。主要的 CD4 测量是 CD4 绝对计数（细胞/mm）和 CD4 百分比（CD4%，总 CD4 细胞/总淋巴细胞细胞）。使用 CD4 绝对计数的倍数变化和 CD4 百分比的差异来模拟 CD4 随时间的变化。
平均 CD4 细胞计数和百分比的变化高度具有个体特异性（两者均 P < 0.001）。然而，在人群中，两种 CD4 测量值随时间的变化是稳定的。我们提出了使用 1.5 SD 估计值标记异常下降的阈值，这是通过 CD4 计数下降 1.5 倍和 CD4 百分比下降 6.4%来计算的。在这个健康队列中，同时标记两种测量值的下降对应于低假阳性率（5.26%）。
应该考虑大淋巴细胞的正常生物学变异性，以确定临床试验中不良变化的阈值。CD4 水平固有的个体特异性变异性使得确定绝对截止值变得困难。然而，本研究提出，使用这些数据的 1.5 SD 来确定下降的阈值（绝对计数的 50%和 CD4 百分比的 6.4%）可以将小的假阳性率（约 5%）保持在临床试验中对真实不良事件的敏感性。
