Impact of CD8+ T Cell Activation on CD4+ T Cell Recovery and Mortality in HIV-infected Ugandans Initiating Antiretroviral Therapy

Abstract

Objectives—To assess whether T cell activation independently predicts the extent of CD4+ T cell recovery and mortality in HIV-infected Ugandans initiating antiretroviral therapy (ART). Design—Prospective cohort study Methods—HIV-infected adults starting ART and achieving a plasma HIV RNA level (VL) <400 copies/ml by month 6 were sampled from the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort in Mbarara, Uganda. CD4 count, VL, and the % activated (CD38+HLA-DR+) T cells were measured every 3 months. Results—Of 451 HIV-infected Ugandans starting ART, most were women (70%) with median pre-ART values: age, 34 years; CD4 count, 135 cells/mm3; and VL, 5.1 log10 copies/ml. Of these, 93% achieved a VL<400 c/ml by month 6 and were followed for a median of 24 months, with 8% lost to follow up at 3 years. Higher pre-ART CD8+ T cell activation was associated with diminished CD4 recovery after year 1, after adjustment for pre-ART CD4 count, VL, and gender (P=0.017). Thirty-four participants died, 15 after month 6. Each 10 percentage-point increase in activated CD8+ T cells at month 6 of suppressive ART was associated with a 1.6-fold increased hazard of subsequent death after adjusting for pre-therapy CD4 count (P=0.048). Conclusions—Higher pre-ART CD8+ T cell activation independently predicts slower CD4+ T cell recovery and higher persistent CD8+ T cell activation during ART-mediated viral suppression independently predicts increased mortality among HIV-infected Ugandans. Novel therapeutic strategies aimed at preventing or reversing immune activation during ART are needed in this setting.