Delay in cART Initiation Results in Persistent Immune Dysregulation and Poor Recovery of T-Cell Phenotype Despite a Decade of Successful HIV Suppression

Background: Successful combination antiretroviral therapy (cART) increases levels of CD4+ T-cells, however this increase may not accurately reflect long-term immune recovery since T-cell dysregulation and loss of T-cell homeostasis often persist. We therefore assessed the impact of a decade of effective cART on immune regulation, T-cell homeostasis, and overall T-cell phenotype. Methods: We conducted a retrospective study of 288 HIV+ cART-naive patients initiating therapy. We identified 86 individuals who received cART for at least a decade, of which 44 consistently maintained undetectable plasma HIV-RNA levels throughout therapy. At baseline, participants were classified into three groups according to pre-treatment CD4+ T-cell counts: Group I (CD4 < 200 cells/mm(3)); Group II (CD4: 200-350 cells/mm(3)); Group III (CD4 > 350 cells/mm(3)). Outcomes of interest were: (1) CD4+ T-cell count restoration (CD4 > 532 cells/mm(3)); (2) normalization of CD4: CD8 T-cell ratio (1.2-3.3); (3) maintenance of CD3+ T-cell homeostasis (CD3: 65%-85% of peripheral lymphocytes); (4) normalization of the complete T Cell phenotype (TCP). Results: Despite a decade of sustained successful cART, complete T-cell phenotype normalization only occurred in 16% of patients, most of whom had initiated therapy at high CD4+ T-cell counts (> 350 cells/mm(3)). The TCP parameter that was the least restored among patients was the CD4: CD8 T-cell ratio. Conclusions: Failure to normalize the complete T-cell phenotype was most apparent in patients who initiated cART with a CD4+ T-cell count < 200 cells/mm(3). The impact of this impaired T-cell phenotype on life-long immune function and potential comorbidities remains to be elucidated.