HIV-1-specific T-cell responses and exhaustion profiles in people with HIV after switching to dual therapy vs. maintaining triple therapy based on integrase inhibitors

Abstract

Background: Dual therapy (DT) has shown comparable results to triple therapy (TT) in efficacy and other immunological aspects. However, there are still some concerns about DT, including several immunological features. Therefore, we evaluated whether HIV-1-specific memory T-cell responses and exhaustion phenotypes are adversely influenced after simplification to DT.

Methods: HIV-1-specific CD4⁺ and CD8⁺ T-cell responses were assessed by intracellular cytokine and degranulation marker staining, and polyfunctionality indexes after stimulation with a Gag peptide pool. Exhaustion phenotypes were evaluated by PD-1, TIM-3, and LAG-3 expression in CD4⁺ and CD8⁺ T cells.

Results: Forty participants in the TRIDUAL trial (ClinicalTrials.gov: NCT03447873) who were randomized to continue integrase inhibitor-based TT (n = 20) or to switch to DT (dolutegravir or darunavir/cobicistat plus lamivudine) (n = 20). After 96 weeks, the magnitude of CD4⁺ and CD8⁺ T-cell responses was similar in both treatment arms (p = 0.221 and p = 0.602, respectively). The CD4⁺ polyfunctionality index decreased in the TT arm (p = 0.013) and remained stable in the DT arm, while the polyfunctionality of CD8⁺ T cells was unchanged in both arms. There was a significant decrease in the expression of PD-1, TIM-3, and the co-expression of PD-1⁺TIM-3⁺LAG-3⁺, and PD-1 +TIM-3 + in both CD4⁺ and CD8⁺ T cells. However, the decrease in the expression of exhaustion markers did not improve HIV-1-specific T-cell responses.

Conclusions: Our results suggest that simplification to DT does not negatively influence the HIV-1-specific T-cell response or the exhaustion phenotype after 96 weeks of follow-up.

Keywords: Dual therapy; HIV treatment; HIV-specific T-cell response; T-cell exhaustion; Treatment simplification; Triple therapy.