Influence of the Antiretroviral Regimen on the Early Changes in Plasma HIV RNA and Immune Activation at Initiation of Antiretroviral Therapy in Naïve HIV-1–Infected Patients

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To the Editors: Combined antiretroviral (ARV) therapy significantly improves life expectancy of people living with the HIV, but remains insufficient to correct abnormal immune activation, despite suppression plasma viral replication.1,2 Levels of T-cell activation, assessed by CD38 and Human Leukocyte Antigen-DR (HLA-DR) markers expression have been shown to be good predictors of disease progression in untreated HIV-infected individuals,3–5 and better correlate with CD4 T-cell depletion than plasma HIV RNA.6,7 It has been proposed that increasing the potency and celerity of ARV action using integrase inhibitors may result in a more rapid and complete reduction in immune activation and immune restoration. Testing this hypothesis requires highly sensitive and reliable methods to monitor immune activation. Although percentages of cells expressing HLA-DR and/or CD38 are generally used, quantifying the density of expression of membrane-bound molecules at the single cell level may be more informative. This can be estimated by flow cytometry methods analyzing the CD38 mean fluorescence intensities (MFI).8 The use of calibrated beads conjugated to known amounts of the same fluorochrome used in the anti-CD38 antibodies9 to directly quantify the number of CD38 molecules on CD8 cells, may provide a more sensitive and standardized measure of immune activation. In addition T-cell activation has also a complex relationship with the expression of CCR5, the HIV co-receptor, as increased CCR5 expression leads to T-cell activation,10,11 whereas T-cell activation can upregulate the expression of the CCR5,12 which affects HIV acquisition, disease progression rates, viral load, and immune recovery under ART.13–17 The aim of the present study was to evaluate the impact of treatment intensification at time of initiation using either ritonavir-boosted darunavir + raltegravir (DRV/r+RAL) or tenofovir-disoproxil-fumarate/emtricitabine (DRV/r+TDF/FTC) on the early and long-time alterations in cellular immune activation and T-cell subsets in relationship with viral dynamics. We performed a multicentric flow-cytometry analysis to test whether rapid virologic responses observed with combined antiretroviral therapy initiation had a differential impact on cellular immune activation, assessed notably on numbers of CD38 molecules per CD8 cell in patients from the Viral and Immunologic dynamics and Inflammation (VIDI) substudy of the NEAT 001/ANRS 143 international randomized, open-label noninferiority clinical trial, which had showed noninferiority over 96 weeks of DRV/r+RAL versus DRV/r+TDF/FTC in 805 antiretroviral-naïve HIV-infected adults with CD4 cell counts higher than 200 cells per μL.18 The VIDI substudy prospectively enrolled 48 patients from 4 countries (France: n = 21; Spain: n = 14; Germany: n = 10; United Kingdom: n = 3), who were randomized as in the whole study,18 with 26 participants in the DRV/r+RAL and 22 in the DRV/r+TDF/FTC arms. Baseline characteristics of the VIDI participants were similar to the whole study participants group18 (see Table, Supplemental Digital Content, https://links.lww.com/QAI/B587). Median and (interquartile range) plasma HIV RNA were 4.9 (4.2–5.2) log10 cop/mL and 5.0 (4.2–5.3) and CD4 counts were 381 (263–420) and 328 (216–434) cells/mm,3 in the DRV/r+RAL and the DRV/r+TDF/FTC arms, respectively. A flow cytometry T-cell analysis was performed on cryopreserved peripheral blood mononuclear cells in the 4 country laboratories standardized for instrument set‐up, reagents, sample preparation, and analysis. All time points from each patient were tested in batch analysis. Cells were stained with the following antibodies CD3-APCCy7, CD4-Percp, CD8-BV421, CD45RA-FITC, CCR7-PeCy7, CD27-BV605, CCR5-PE-CF594, anti-HLADR-APC, CD38-PE, and the PE-conjugated Quantibrite beads (all from BD Biosciences, San Jose, CA)9 to directly quantify the number of CD38 molecules on CD8 cells. During the whole 96-week study treatment period, we observed similar findings in the 2 treatment arms. Viral loads significantly declined over time without differences between arms (P = 0.33) (Fig. 1A), whereas median CD4 counts significantly increased in both arms without significant differences up to 564 and 490 cells/mm3 (IQR = 478–637 and 430–603) at W96 in the DRV/r+RAL and the DRV/r+TDF/FTC arms, respectively. The median CD8 counts also significantly decreased in both arms without differences with 636 and 691 cells/mm3 (IQR = 515–844 and 458–912) at W96 in the DRV/r+RAL and the DRV/r+TDF/FTC arms, respectively. We also observed in both arms, the expected significant increases in percentages of naïve (TN: CD45RA+CCR7+CD27+) CD4 (P = 0.01) and CD8 (P < 0.01) T cells and of CD8 central-memory cells (TCM: CD45RA−CCR7+CD27+) (P < 0.01), whereas percentages of both CD4 and CD8 transitional-memory (TTM: CD45RA−CCR7−CD27+), effector-memory (TEM: CD45RA−CCR7−CD27−), and effector (TE: CD45RA+CCR7−CD27−) T cells significantly decreased (P < 0.01). Proportions of activated HLA-DR+ in both CD4 and CD8 T cells and in all subsets also decreased in both arms (P < 0.01), with a parallel significant decrease in the intensity of CD38 expression assessed by both CD38 MFI values and number of CD38 PE molecules per CD8 T cell. Finally, the CCR5 expression on total and all CD4 T cells and CD8 T cells subsets also decreased (P < 0.01). The dynamic of changes over time did not significantly differ between the 2 arms, except for a significantly faster decline in the percentages of CD38+CD8 TN cells in the DRV/r+TDF/FTC arm (P = 0.03 after false discovery rate adjustment).FIGURE 1.: A, Changes from baseline over the study period for HIV viral load, in DRV/r+RAL and DRV/r + TDF/FTC arms. Numbers of patients per arm are indicated for each time-point (B) change of value of MFI of CD38 and number of CD38 PE molecules in CD8 subtypes cells in function of HIV viral load change between W0 and W4, for markers significantly correlated with HIV viral load decline.We then focused our analysis on the early period. At month 1, the decrease in HIV RNA was more pronounced in the DRV/r+RAL arm [median: 1.72 log10 (IQR: 1.60–2.21)] compared with the DRV/r+TDF/FTC arm [median: 2.66 log10 copies/mL (IQR: 2.35–3.18)], (P < 0.01) (Fig. 1A). Meanwhile, median CD4 counts increased in both arms [426 and 408 cells/mm3 (IQR = 352–510 and 299–484) in the DRV/r+RAL and the DRV/r+TDF/FTC arms, respectively, without significant difference between treatment arms nor significant association between HIV-RNA decline and changes in CD4 T cell subpopulations or activation or co-receptor expression. In contrast, the early HIV-RNA decline was significantly and positively correlated (Spearman correlation), with the declines in CD8 T-cell activation as assessed by CD38 MFI values and numbers of CD38 PE molecules on total CD8 T cells (r = 0.61, P < 0.01 and r = 0.51, P < 0.01, respectively) and on effector CD8 T cells (r = 0.58, P < 0.01 and r = 0.53, P < 0.01, respectively) (Fig. 1B). Declines of CD38 MFI and CD38 molecules values on total CD8 T cells were significantly deeper in the DRV/r+RAL compared with the DRV/r+TDF/FTC arm (median −830 versus −379, respectively, P = 0.02, and −711.4 versus −339.1, P = 0.04, respectively) although tempered after false discovery rate adjustment (P = 0.05 and P = 0.1). Finally, for each immune marker showing significantly different dynamics profiles between the 2 treatment arms, we estimated their individual slopes by nonlinear mixed models and we analyzed the correlation with HIV RNA declines between W0 and W4. The individual HIV RNA changes were positively correlated with the estimated slope of the CD8 lymphocytes percentages (r = 0.51, P < 0.01), but negatively correlated with the slope of the percentage of CM CD8 cells (r = −0.36, P = 0.01). DISCUSSION Altogether our results show that using ritonavir-boosted darunavir + raltegravir versus tenofovir disoproxil fumarate/emtricitabine in antiretrovira

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