Objectives.  To examine trajectories of CD8⁺ T-cell counts before and after combination antiretroviral therapy (cART) in human immunodeficiency virus (HIV)-infected individuals and associations with mortality.

Methods.  CD8⁺ T-cell counts were measured in 3882 HIV-infected individuals who received care in Copenhagen during 1995–2012. Reference values were obtained from 1230 persons from the background population. Mortality rate ratios were estimated by Poisson regression.

Results.  CD8⁺ T-cell counts were elevated during untreated HIV infection and remained elevated through 10 years of cART. A slight drop of 130 cells/µL (interquartile range, −160 to 410 cells/μL) in the median CD8⁺ T-cell count was observed after cART initiation. CD8⁺ T-cell counts stabilized at approximately 900 cells/µL (95th percentile of the background population, 835 cells/µL). Markedly elevated CD8⁺ T-cell counts at cART initiation were associated with a poor increase in the CD4⁺ T-cell count (relative risk, 2.22; 95% confidence interval [CI], 1.42–3.48). Individuals with a CD8⁺ T-cell count of <500 cells/µL 1 year after cART initiation had an increased mortality rate (mortality rate ratio, 1.73; 95% CI, 1.29–2.32) and a higher proportion of deaths attributable to AIDS-related conditions, compared with individuals with CD8⁺ T-cell counts of ≥500 cells/µL. After receiving cART for 10 years, a CD8⁺ T-cell count of >1500 cells/µL was associated with increased non–AIDS-related mortality (mortality rate ratio, 1.82; 95% CI, 1.09–3.22), compared with a CD4⁺ T-cell count of 500–1500 cells/µL.

Conclusions.  CD8⁺ T-cell counts are elevated during HIV infection and do not normalize despite long-term cART. Low CD8⁺ T-cell counts are associated with increased AIDS-related mortality. Marked elevations in CD8⁺ T-cell counts after long-term cART are associated with increased non–AIDS-related mortality.