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Variability of CD4+ cell counts in HIV-1 uninfected volunteers who are eligible for a Phase I HIV vaccine study.

OBJECTIVE
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.


DESIGN
Prospective observational cohort study of 100 healthy adults without HIV-1 infection from the Baltimore region.


METHODS
Participants enrolled and consented to blood draws for immunologic lab panels performed once every eight 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.


RESULTS
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 standard deviation estimates, calculated as 1.5-fold declines for CD4+ count 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%).


CONCLUSIONS
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 make establishing absolute cutoffs difficult. However, this study proposes that thresholds for declines using 1.5 standard deviations 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.