Prospective Immune Dynamics during the First 24 Weeks of Efavirenz Based-Antiretroviral Therapy in HIV-1-Infected Subjects, According to CD4(+) T-Cell Counts at Presentation: The IMMUNEF Clinical Trial

BACKGROUND: Longitudinal characterization of immune recovery in the first-phase of antiretroviral therapy (ART) is poorly described. We compared immune kinetics in individuals who were diagnosed early or late with HIV-1 infection, (thus commencing ART with different CD4(+) T-cell counts), in order to investigate possible mechanisms involved in subsequent poor immune recovery. METHODS: Immunophenotyping, immune activation, proliferation, apoptosis, regulatory T-cells and intracellular cytokine production were compared at baseline and during 24-week follow-up in two groups of HIV-1-infected patients initiating the same ART (tenofovir/emtricitabine/efavirenz) and divided according to baseline CD4(+) T-cell counts (late: ≤200/μL; early: >200/μL). Wilcoxon-rank sum test and analysis for repeated measures were used to evaluate differences between groups over time. RESULTS: Twenty-four out of 30 enrolled subjects were evaluable for the analysis, 13 late and 11 early presenters. Significantly lower CD4(+) naïve and memory T-cells, and higher plasma viral load, as well as augmented percentages of activated (CD4(+)/CD25(+) cells), apoptotic (CD4(+)/AnnexinV(+)/7AAD(−), CD4(+)/caspase 8(+) and CD4(+)/caspase 9(+)), and proliferating (CD8(+)/Ki67(+) cells) lymphocytes were present at baseline in late presenters; ART resulted in a reduction of apoptotic and proliferating lymphocytes within the follow-up period. CONCLUSIONS: A skewing towards memory/activated/apoptotic phenotype is seen in HIV-1-infected subjects starting ART at low CD4(+) T-cell counts; ART results in early (24 weeks) trend towards normalization of these parameters. Antiretroviral therapy may play a role in rapidly limiting aberrant immune exhaustion even in late presenters, while requiring more time for re-population of highly depleted naïve T-cells. TRIAL REGISTRATION: EU Clinical Trial Register EUDRACT number 2008-006188-35 https://www.clinicaltrialsregister.eu/ctr-search/trial/2008-006188-35/IT