A randomized, controlled trial of raltegravir intensification in antiretroviral-treated, HIV-infected patients with a suboptimal CD4+ T cell response

Abstract

Background: Some human immunodeficiency virus (HIV)-infected individuals are not able to achieve a normal CD4(+) T cell count despite prolonged, treatment-mediated viral suppression. We conducted an intensification study to assess whether residual viral replication contributes to replenishment of the latent reservoir and whether mucosal HIV-specific T cell responses limit the reservoir size.

Methods: Thirty treated subjects with CD4(+) T cell counts of <350 cells/mm(3) despite viral suppression for ≥ 1 year were randomized to add raltegravir (400 mg twice daily) or matching placebo for 24 weeks. The primary end points were the proportion of subjects with undetectable plasma viremia (determined using an ultrasensitive assay with a lower limit of detection of <.3 copy/mL) and a change in the percentage of CD38(+)HLA-DR(+)CD8(+) T cells in peripheral blood mononuclear cells (PBMCs).

Results: The proportion of subjects with undetectable plasma viremia did not differ between the 2 groups (P = .42). Raltegravir intensification did not have a significant effect on immune activation or HIV-specific responses in PBMCs or gut-associated lymphoid tissue.

Conclusions: Low-level viremia is not likely to be a significant cause of suboptimal CD4(+) T cell gains during HIV treatment.

Clinical trials registration: NCT00631449.

Figures

Figure 1.

Plasma human immunodeficiency virus (HIV) RNA (as determined by ultrasensitive assay with a lower limit of detection of <.3 copy both raltegravir>red) and placebo (PBO) (blue) groups had significant decreases in plasma RNA at week 12 (raltegravir, −1.6 copies/mL [P < .05]; placebo, −2.5 copies/mL [P < .01]). However, raltegravir intensification did not decrease plasma RNA more than placebo (P = .39). Thin lines represent raw data for each subject; thick lines, estimated mean values over time from generalized estimating equations for each group. Eight time points at which the internal standard for the assay failed were excluded from analyses and from the figure. “Undetectable” outcomes were assigned the lower limit of the assay (.3 copy/mL).

Figure 2.

Percentages of CD38+HLA-DR+CD8+ and CD38+HLA-DR+CD4+ T cells in peripheral blood mononuclear cells (PBMCs). RGV, raltegravir (red); PBO, placebo (blue). Thin lines represent raw data for each subject; thick lines, estimated mean values over time from generalized estimating equations for each group. A, Raltegravir intensification had no effect on CD8+ T cell activation in PBMCs (P = .33). B, Both groups had significant decreases in CD4+ T cell activation in PBMCs (raltegravir, −1.1%, [P = .02]; placebo, −.9% [P = .02]), but raltegravir intensification did not decrease CD4+ T cell activation in PBMCs more than placebo (P = .67).

Figure 3.

Percentages of CD38+HLA-DR+CD8+ and CD38+HLA-DR+CD4+ T cells in gut-associated lymphoid tissue (GALT). RGV, raltegravir (red); PBO, placebo (blue). Thin lines represent raw data for each subject; thick lines, estimated mean value over time from generalized estimating equation for each group. Raltegravir intensification had no effect on CD8+ (A) (P = .53) or CD4+ (B) (P = .14) T cell activation in GALT.

Figure 4.

Percentages of Gag-specific CD8+ and CD4+ T cells expressing interferon (IFN) γ and interleukin (IL) 2 in peripheral blood mononuclear cells (PBMCs). RGV, raltegravir (red); PBO, placebo (blue). Thin lines represent raw data for each subject; thick lines, estimated mean values over time from generalized estimating equations for each group. Raltegravir intensification had no effect on Gag-specific IFN-γ+IL2+CD8+ (A) (P = .19) or IFN-γ+IL2+CD4+ (B) (P = .80) T cell responses in PBMCs.

Figure 5.

Percentages of Gag-specific interferon (IFN) γ, interleukin (IL) 2, tumor necrosis factor (TNF) α, or CD107a CD8+ and CD4+ T cell responses in gut-associated lymphoid tissue (GALT). RGV, raltegravir (red); PBO, placebo (blue). Thin lines represent raw data for each subject; thick lines, estimated mean values over time from generalized estimating equations for each group. Raltegravir intensification had no effect on Gag-specific IFN-γ, IL-2, TNF-α, or CD107a CD8+ (A) (P = .91) or CD4+ (B) (P = .30) T cell responses in GALT.

Figure 6.

Possible associations between baseline human immunodeficiency virus (HIV)–specific responses in gut-associated lymphoid tissue (GALT) and baseline measures of viral persistence. A, Higher percentages of Gag-specific interferon (IFN) γ, interleukin (IL) 2, tumor necrosis factor (TNF) α, or CD107a CD8+ T cells in GALT were associated with lower levels of proviral DNA in peripheral blood mononuclear cells (PBMCs) (Spearman's ρ = −.50; P = .03). Gag-specific IFN-γ, IL-2, TNF-α, or CD107a CD8+ T cell responses and proviral DNA levels were measured at baseline (figure includes subjects in both raltegravir and placebo groups). B, There appeared to be a possible association between Gag-specific IFN-γ, IL-2, TNF-α, or CD107a CD4+ T cell responses in GALT and proviral DNA in PBMCs, but this association did not reach statistical significance (Spearman's ρ = −.42; P = .07). Gag-specific IFN-γ, IL-2, TNF-α, or CD107a CD4+ T cell responses and proviral DNA levels were measured at baseline (figure includes subjects in both raltegravir and placebo groups).