CD4 T CELL ASSESSMENTS IN EVALUATION OF HIV THERAPEUTICS - Flow Cytometry in Drug Discovery and Development - page 169

testing the efficacy and safety of the drug. Therewas mounting criticism that the drugs
had been approved too quickly without sufficient testing of the toxicity of the drug.
In 1990, the NIH-NIAID AIDS Clinical Trials Group conducted a large, multi-
institutional trial to test the efficacy of AZT in asymptomatic adults with CD4 counts
below 500 cells/mm 3 [18]. The primary criteria for response were clinical end points,
including survival and the development of AIDS or AIDS-related complex defined as
two successive CD4 counts

200 cells/mm 3 and the presence of at least two
symptoms indicative of AIDS-related complex. The secondary criteria for response
included an increase in CD4 cell counts or a reduced rate of decline, a decrease in
serum HIV p24 antigen levels, or both. Of the study participants, 428 subjects
received placebo, 453 received 500 mg of zidovudine, and 457 received 1500 mg of
ziduvudine; however, the placebo arm was terminated by the independent board
monitoring data and safety because treatment of AZTat a lower dosage was shown to
delay the onset of AIDS. Patients receiving the 500mg of AZT saw a median annual
increase of 39 CD4 cells/mm 3 , while the group receiving 1500mg saw a median
annual increase of 26 CD4 cells/mm 3 . AZT had the greatest effect on patients with
200-499 CD4 cells/mm 3 . This finding suggested that initiating therapy at earlier
stages of HIV infection would have a greater impact than during the late stage of the
disease.
Although the first AZT trial indicated that the drug was effective at increasing CD4
counts and preventing opportunistic infections, further trials were needed to assess
whether the duration of treatment impacted CD4 counts and whether drug resistance
could be detected. Another trial testing the safety and efficacy of AZT during the early
stage of infection investigated the relationship between stage of infection and the
effect on CD4 counts [19]. Based on the finding that AZT generated a larger increase
in CD4 T cells in patients in early-stage disease as seen with asymptomatic HIV
infection and counts less than 500 cells/mm 3 , this trial tested the safety and efficacy in
patients with mildly symptomatic HIV infection to see if patients would experience
sustained increases in CD4 T cells and less toxicity. This hypothesis was based on the
understanding that a more robust immune system would not be as susceptible to
potential drug toxicity.
In this large, multi-institutional trial of 711 subjects with mildly symptomatic
HIV infection, patients were enrolled with CD4 T cell counts ranging from
200-800 cells/mm 3 . Criteria for response were clinical end points, including the
prevention of or delay to AIDS or advanced AIDS-related complex, and immuno-
logical end points such as a sustained increase in the absolute number of CD4
T cells. Patients were stratified into two groups - one group with CD4 T cell counts
ranging 200-500 cells/mm 3 and the other groupwith 500-799 cells/mm 3 .Again,the
treatment group with baseline CD4 counts of 200-500 CD4 cells/mm 3 saw the
greatest increase in CD4 T cell counts by the end of the study. It was determined that
patients with CD4 T cell counts above 500 cells/mm 3 might not benefit from AZT
because the risk of toxicity is too great and there were not enough data to support a
positive immunological response. Recommendations from this study included the
monitoring of CD4 T cell count in patients with relatively normal counts as a method
of anticipating potential progression to AIDS.

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