Incomplete reconstitution of T cell subsets on combination antiretroviral therapy in the AIDS Clinical Trials Group protocol 384

Abstract

Background: Initiation of combination antiretroviral therapy (ART) results in higher total CD4 cell counts, a surrogate for immune reconstitution. Whether the baseline CD4 cell count affects reconstitution of immune cell subsets has not been well characterized.

Methods: Using data from 978 patients (621 with comprehensive immunological assessments) from the AIDS [Acquired Immunodeficiency Syndrome] Clinical Trials Group protocol 384, a randomized trial of initial ART, we compared reconstitution of CD4(+), CD4(+) naive and memory, CD4(+) activation, CD8(+), CD8(+) activation, B, and natural killer cells among patients in different baseline CD4(+) strata. Reference ranges for T cell populations in control patients negative for human immunodeficiency virus (HIV) infection were calculated using data from AIDS Clinical Trials Group protocol A5113.

Results: Patients in the lower baseline CD4(+) strata did not achieve total CD4(+) cell counts similar to those of patients in the higher strata during 144 weeks of ART, although CD4(+) cell count increases were similar. Ratios of CD4(+) naive-memory cell counts and CD4(+):CD8(+) cell counts remained significantly reduced in patients with lower baseline CD4(+) cell counts (<or=350 cells/mm(3)). These immune imbalances were most notable for those initiating ART with a baseline CD4(+) cell count <or=200 cells/mm(3), even after adjustment for baseline plasma HIV RNA levels.

Conclusions: After nearly 3 years of ART, T cell subsets in patients with baseline CD4(+) cell counts >350 cells/mm(3) achieved or approached the reference range those of control individuals without HIV infection. In contrast, patients who began ART with <or=350 CD4(+) cells/mm(3) generally did not regain normal CD4(+) naive-memory cell ratios. These results support current guidelines to start ART at a threshold of 350 cells/mm(3) and suggest that there may be immunological benefits associated with initiating therapy at even higher CD4(+) cell counts.

Figure 1

Median (interquartile range) CD4⁺ cell counts (A), CD4⁺ naive cell counts (B), and CD4⁺ memory cell counts (C) by baseline CD4⁺ stratum and study week for patients who underwent comprehensive immunological assessments by advanced flow cytometry. The shaded band reflects the lowest and highest interquartiles of the 2 age groups of HIV-negative control subjects (from AIDS Clinical Trials Group protocol A5113) [33].

Figure 2

Median (interquartile range) activated CD4⁺ cell counts (CD4⁺/CD38⁺/HLA-DR⁺) for patients who underwent comprehensive immunological assessments by advanced flow cytometry. Percentages (A) and absolute counts (B) by baseline CD4⁺ stratum over time are shown. The shaded area reflects the lowest and highest interquartiles of the 2 age groups of HIV-negative control subjects (from AIDS Clinical Trials Group protocol A5113) [33].

Figure 3

Median (interquartile range) CD8⁺ cell counts by baseline CD4⁺ stratum over time for patients who underwent comprehensive immunological assessments by advanced flow cytometry. The shaded area reflects the lowest and highest interquartiles of the 2 age groups of HIV-negative control subjects (from AIDS Clinical Trials Group protocol A5113) [33].

Figure 4

Median (interquartile range) activated CD8⁺ cell counts (CD8⁺/CD38⁺/HLA-DR⁺) percentages (A) and absolute counts (B) by baseline CD4⁺ stratum over time for patients who underwent comprehensive immunological assessments by advanced flow cytometry. The shaded area reflects the lowest and highest interquartiles of the 2 age groups of HIV-negative control subjects (from AIDS Clinical Trials Group protocol A5113) [33].

Figure 5

Median (interquartile range) for natural killer cell (CD3⁻/CD56⁺ and CD16⁺) counts (A) and B cell (CD3⁻/CD19⁺) counts (B) by baseline CD4⁺ stratum over time for patients who underwent comprehensive immunological assessments by advanced flow cytometry. The shaded area reflects the lowest and highest interquartiles of the 2 age groups of HIV-negative control subjects (from AIDS Clinical Trials Group protocol A5113) [33].

Figure 6

Median (interquartile range) CD4⁺ naive-memory cell ratios by baseline CD4⁺ stratum and study week for patients who underwent comprehensive immunological assessments by advanced flow cytometry and HIV-negative control subjects (from AIDS Clinical Trials Group [ACTG] protocol A5113) [33]. The y-axis reflects the absolute count for both CD4⁺ naive and memory cells. CD4⁺ naive-memory cell ratios are shown above the bars at each time point, and the interquartile ranges are shown above, in parentheses. Results for HIV-negative control subjects from ACTG protocol A5113 are shown to the right of the week 144 bars, for comparison. After controlling for baseline HIV RNA level, the CD4⁺ naive-memory cell ratio for stratum 1 was significantly different from stratum 3 (weeks 0 and 24), stratum 4 (weeks 0, 24, 48, and 96), and stratum 5 (weeks 0, 24, and 48), and the stratum 2 CD4⁺ naive-memory ratio was significantly different from stratum 4 (weeks 24 and 96) and stratum 5 (weeks 0, 24, and 48).

Figure 7

Median (interquartile range) CD4⁺:CD8⁺ cell ratios by baseline CD4⁺ stratum over time for patients who underwent comprehensive immunological assessments by advanced flow cytometry and for HIV-negative control subjects (from AIDS Clinical Trials Group [ACTG] protocol A5113) [33]. The y-axis reflects the absolute count for both CD4⁺ and CD8⁺ cells. Median CD4⁺:CD8⁺ cell ratios are shown above the box plot at each time point, and interquartile ranges are above in parentheses. Results for HIV-negative control subjects from ACTG protocol A5113 are shown to the right of the week 144 bars, for comparison.

Figure 8

Change in CD4⁺ cell count from baseline in percentiles (10th, 25th, 50th, 75th, and 90th) for all AIDS Clinical Trials Group (ACTG) protocol 384 patients (n =978). This plot is based on HIV-positive antiretroviral therapy–naive patients after initiating HAART in ACTG protocol 384 with a median (interquartile range) baseline CD4⁺ cell count of 279 (98–444) cells/mm³. *At weeks 16 and 24, the ΔCD4⁺ cell count was positively associated with the baseline CD4⁺ cell count. The median ΔCD4⁺ cell count was ~47 and 39 cells greater for patients with a baseline CD4⁺ cell count of >500 cells/mm³ versus ≤50 cells/mm³ at weeks 16 and 24, respectively. **There might be a lack of precision after week 96 because of dropouts and limited follow-up in ACTG protocol 384.