The effect of leflunomide on cycling and activation of T-cells in HIV-1-infected participants

Abstract

Background: The pathogenesis of immunodeficiency due to human immunodeficiency virus (HIV)-1 is incompletely understood, but immune activation is believed to play a central role. Immunomodulatory agents that decrease immune activation may be useful in the treatment of HIV-1 infection.

Methodology: A randomized, double blind, placebo-controlled pilot study of leflunomide for 28 days was performed in participants with HIV-1 infection who were not receiving antiretroviral therapy. Participants randomized to leflunomide were subsequently treated with cholestyramine until leflunomide levels were below detection limit.

Findings: Treatment with leflunomide was well tolerated with mostly low-grade adverse events. Leflunomide administration reduced cycling of CD4 T cells (by ex vivo bromodeoxyuridine uptake and Ki67 expression) and decreased expression of activation markers (HLA-DR/CD38 co-expression) on CD8 T cells in peripheral blood. In addition, decreased expression of HIV-1 co-receptors was observed in both CD4 and CD8 T cells in the leflunomide group. There were no significant changes in naïve and memory T cell subsets, apoptosis of T cells or markers of microbial translocation.

Conclusions: Leflunomide was effective in reducing immune activation in the setting of chronic HIV-1 infection suggesting that targeting immune activation with immunomodulatory agents may be a feasible strategy.

Trial registration: ClinicalTrials.gov NCT00101374.

Figure 1. Flow chart of clinical study.

Figure 2. Changes in T cell counts and HIV viral load.

A) Changes from baseline in CD4 T cell counts, and B) CD8 T cell counts throughout the study duration; median values and interquartile ranges; C) Change from baseline in HIV plasma viral load; median values and interquartile ranges. There was a significant decrease in HIV-1 RNA at Day 15 in the leflunomide group (*p-value<0.05).

Figure 3. Changes in markers of CD4 T cell cycling and CD8 T cell activation.

A) Change from baseline in percent Ki67 expression in CD4 T cells; median values and interquartile ranges. There was a significant decrease in Ki67 expression by CD4 T cells at Day 29 in the leflunomide group (*p-value<0.05). B) Change from baseline in percent BrdU incorporation by CD4 T cells; median values and interquartile ranges. There was a significantly greater change in BrdU incorporation by CD4 T cells in the leflunomide group compared to the placebo group at Day 15 and Day 29 (**p-value<0.05). C) Change from baseline in percent of activated CD8 T cells (%CD8CD38+HLADR+), median values and interquartile ranges. There was a significant decrease in activated CD8 T cells at Day 29 in the leflunomide group (*p-value<0.05). D) Change from baseline in percent of CD4 T cells co-expressing CD38 and HLA-DR, median values and interquartile ranges.

Figure 4. Changes in HIV coreceptor expression.

A) Change from baseline in percent of CD4 T cells, and B) CD8 T cells expressing CCR5, median values and interquartile ranges. In the leflunomide group, there were significant decreases in CCR5 expression by CD4 and CD8 T cells at Day 15 and Day 29 (*p-value<0.05). C) Change from baseline in percent of CD4 and D) CD8 T cells expressing CXCR4; median values and interquartile ranges. In the leflunomide group, there were significant decreases in CXCR4 expression by CD4 and CD8 T cells at Day 15 and Day 29 (*p-value<0.05).