Discordant Immune-Virologic Responses During Antiretroviral Therapy: Immune Dysregulation Patterns, CD4/CD8 Ratio...

(1) Background: Despite the success of combination antiretroviral therapy (cART), immune recovery in treated HIV infection remains heterogeneous, and discordant immune-virologic responses persist in a substantial proportion of people living with HIV (PLWH). These patterns may reflect ongoing immune dysregulation despite effective viral suppression. This study aimed to characterize discordant treatment classifications, evaluate immune imbalance using the CD4/CD8 ratio, identify associated clinical predictors, and assess opportunistic infection burden in a Romanian cohort of people living with HIV receiving long-term cART. (2) Methods: A retrospective cross-sectional study was conducted in 462 adults with HIV-1 infection receiving cART at the "Prof. Dr. Matei Balș" National Institute of Infectious Diseases, Bucharest (2018-2021). PLWH were classified as concordant responders (CR), immunological discordant responders (ID), or virological discordant responders (VD) based on plasma HIV-1 RNA and CD4+ T-cell count thresholds. Immune dysregulation was assessed using the CD4/CD8 ratio. Multinomial logistic, logistic, and negative binomial regression models were used to identify predictors of discordant responses, severe CD4/CD8 ratio inversion, and opportunistic infection burden. (3) Results: Discordant responses were observed in 30.7% of PLWH (14.5% ID, 16.2% VD). CD4/CD8 ratio inversion occurred in 71.2% and severe inversion in 40.0%. Significant differences across clinical classification groups were found for CD4+T-cell counts (H = 153.62, p < 0.001, ε² = 0.33) and CD4/CD8 ratio (H = 115.10, p < 0.001, ε² = 0.25), while CD8+ counts were similar (p = 0.571). Male sex was associated with both ID and VD, and severe CD4/CD8 inversion was strongly associated with ID. Opportunistic infection burden was associated with duration of HIV infection and CDC stage. (4) Conclusions: Discordant immune-virologic responses remain frequent during long-term cART and are characterized by persistent immune imbalance reflected by CD4/CD8 ratio inversion. The CD4/CD8 ratio may provide clinically relevant information on immune recovery beyond CD4+ T-cell counts.