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-naïve 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/mm3); Group II (CD4: 200-350 cells/mm3); Group III (CD4>350 cells/mm3). Outcomes of interest were: (1) CD4+ T-cell count restoration (CD4>532 cells/mm3); (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/mm3). 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/mm3. The impact of this impaired T-cell phenotype on life-long immune function and potential comorbidities remains to be elucidated.