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) less than 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 percentage-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/μl; and VL, 5.1 log(10) copies/ml. Of these, 93% achieved a VL less than 400 copies/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 sex (P = 0.017). Thirty-four participants died, 15 after month 6. Each 10% 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 pretherapy 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.

Figure 1. Independent Predictors of CD4+ T Cell Recovery in HIV-infected Ugandans Maintaining Treatment-mediated Viral Suppression

Pre-therapy predictors of the rate of CD4+ T cell recovery were assessed in HIV-infected Ugandans with multivariable linear mixed models. CD4+ T cell recovery was modeled as a linear spline, allowing the rate of recovery to vary across three segments: baseline to month 3, month 3 to month 12, and month 12 onward. The plots depict the estimated mean CD4+ T cell changes for the 15^th and 85^th percentile values of each predictor in the multivariable model when setting all other significant predictors to median values. P values test whether the slope of CD4+ T cell recovery varies according to the predictor of interest within each spline segment and the mean adjusted difference in CD4+ T cell count at month 36 is reported for each predictor. For the prototypic female participant with a pre-therapy plasma HIV RNA level of 5.1 log₁₀ copies/ml and a CD4+ T cell count of 135 cells/mm³, higher pre-therapy CD8+ T cell activation was associated with decreased rates of CD4+ T cell recovery after month 3 (A). Higher pre-treatment plasma HIV RNA levels predicted a more rapid rate of CD4+ T cell recovery in the first 3 months when adjusting for gender, pre-treatment CD4+ T cell count, and CD8+ T cell activation (B). Lower pre-treatment CD4+ T cell counts were associated with more rapid CD4+ T cell recovery in the first 12 months of antiretroviral therapy, but slower CD4+ T cell recovery thereafter, after adjustment for gender, pre-treatment plasma HIV RNA level, and CD8+ T cell activation (C). Women experienced a greater rate of CD4 recovery than men both during the first 3 months and after 12 months of antiretroviral therapy after adjusting for pre-treatment CD4+ T cell count, plasma HIV RNA level, and CD8+ T cell activation level (D).

Figure 2. Changes in CD8+ T cell activation during ART-mediated viral suppression in HIV-infected Ugandans

Changes in the frequency of activated (CD38+ HLA-DR+) CD8+ T cells was assessed over time with a linear mixed model among HIV-infected Ugandans achieving a plasma HIV RNA level <400 copies/ml by month 6 of ART, censoring observations for subsequent plasma HIV RNA levels >1000 copies/ml. Changes were modeled as a linear spline with a change point at month 6. Predicted changes in T cell activation from the linear mixed model are displayed when setting pre-therapy CD8+ T cell activation to 15^th (51%), 50^th (68%), and 85^th (81%) percentile values, P values representing whether the average rate of decline was significantly different than zero (A). While the mean rate of decline in CD8+ T cell activation after month 6 (−1.0%/month, P<0.001) was similar regardless of pre-therapy CD8+ T cell activation level (P for interaction = 0.68), the rate of decline in the first 6 months was more rapid for participants with higher pre-therapy CD8+ T cell activation levels (−4.7%/mo for a participant with the 85^th percentile value and −2.5%/month for a participant with the 15^th percentile value, P for interaction=0.001) in the first 6 months of ART (P<0.001). Despite early differences in the rate of decline in CD8+ T cell activation, those with higher pre-therapy CD8+ T cell activation levels continued to have higher CD8+ T cell activation levels at month 12 (rho: 0.43, P<0.001, B).

Figure 3. Predictors of mortality during antiretroviral therapy among HIV-infected Ugandans

Predictors of mortality were assessed using Kaplan-Meier methods among all HIV-infected Ugandans initiating ART as well as the subset achieving a plasma HIV RNA level <400 copies/ml by month 6 of ART. Predictors were assessed in tertiles. Lower pre-therapy CD4+ T cell counts predicted earlier death among all participants, largely driven by deaths occurring in the first 6 months of ART (P for trend=0.027, A). Among participants with plasma HIV RNA levels<400 copies/ml at month 6 of ART, higher CD8+ T cell activation predicted earlier subsequent mortality (P for trend=0.031, B). However, there was no evidence for a relationship between month 6 CD4+ T cell count and subsequent mortality among participants with plasma HIV RNA levels<400 copies/ml (P for trend=0.80, C).