Immune Reconstitution but Persistent Activation After 48 Weeks of Antiretroviral Therapy in Youth With Pre-Therapy CD4 >350 in ATN 061

Abstract

Measures of immune outcomes in youth who initiate combination antiretroviral therapy (cART) early in HIV infection are limited. Design Adolescent Trials Network 061 examined changes over 48 weeks of cART in T cell subsets and markers of T cell and macrophage activation in subjects with pre-therapy CD4>350. All subjects had optimal viral suppression from weeks 24 through 48. Methods Subjects (n=48) initiated cART with tenofovir/emtricitabine plus ritonavir-boosted atazanavir. Data were collected at baseline and weeks 12, 24, and 48. Trends were compared to uninfected controls. Results Significant increases over 48 weeks were noted in all CD4 populations including total, naïve, central memory (CM), and effector memory RO (EM RO) and effector memory RA (EM RA) while numbers of CM and EMRO CD8 cells declined significantly. By week 48, CD4 naïve cells were similar to controls while CM CD4 cells remained significantly lower and EM RO and EM RA subsets were significantly higher. CD38 and HLA DR expression, both individually and when co-expressed, decreased over 48 weeks of cART on CD8 cells but remained significantly higher than controls at week 48. In contrast, markers of macrophage activation measured by sCD14 and sCD163 in plasma did not change with cART and were significantly higher than controls. Conclusion In youth initiating early cART, CD4 cell reconstitution is robust with decreases in CD8 cells. However CD8 T cell and macrophage activation persists at higher levels than uninfected controls.

Effect of Antiretroviral Therapy on the Memory and Activation Profiles of B Cells in HIV-Infected African Women

“…Interestingly, whilst there was a relative normalization of B cells post-ART, plasma sCD14 concentration did not decrease overall upon treatment. This phenomenon has been observed in several studies, where sCD14 levels remain elevated even after several years on ART (61–63), and unreversed damage to the gastrointestinal tract has been proposed to account for this. These data confirm that in African women, inflammation persists after ART even while there is a substantial decrease in cellular activation.…”

Soluble CD14, CD163, and CD27 biomarkers distinguish ART-suppressed youth living with HIV from healthy controls

“…The results indicate that early use of ART and prolonged viral suppression can reverse many but not all of the inflammatory pathways impacted by HIV in other cohorts. Previous studies show that control of viral replication by ART has no impact on sCD14 levels, a biomarker of macrophage activation primarily mediated by microbial translocation [11, 14]. This inflammatory pathway remained unchanged even after years of viral suppression and confirms the persistence of macrophage activation due to gastrointestinal microbial translocation and LPS binding to TLR4/CD14 [18].…”

“…9,10 YLWH who initiate ART prior to CD4 T cell decline have a high capacity to reconstitute functional T cell immunity, 11 although macrophage and T cell activation, osteopenia, and biomarkers of vascular injury persist, even when viral replication is optimally controlled and CD4 T cell counts are normal. [11][12][13] For example, effective ART lowers plasma levels of biomarkers for lymphocyte activation, soluble CD27 (sCD27), and macrophage activation, soluble CD163 (sCD163), compared with untreated individuals, 14,15 even though biomarker levels among virally suppressed individuals remain elevated compared with HIV-uninfected youth. 11 A comprehensive, integrated assessment of biomarkers associated with lymphocyte, macrophage, vascular, and bone metabolism in YLWH compared with uninfected youth is lacking.…”

“…[11][12][13] For example, effective ART lowers plasma levels of biomarkers for lymphocyte activation, soluble CD27 (sCD27), and macrophage activation, soluble CD163 (sCD163), compared with untreated individuals, 14,15 even though biomarker levels among virally suppressed individuals remain elevated compared with HIV-uninfected youth. 11 A comprehensive, integrated assessment of biomarkers associated with lymphocyte, macrophage, vascular, and bone metabolism in YLWH compared with uninfected youth is lacking. The goal of the current study was to examine multiple biomarkers associated with distinct inflammatory pathways altered by HIV infection in YLWH using novel biostatistical modeling to identify inflammatory profiles among YLWH.…”

Inflammation, Immune Activation, and Antiretroviral Therapy in HIV

“…In a 2-year observational study, IL-6, interferon γ-inducible protein-10 (IP-10), and monokine induced by interferon γ (MIG) decreased significantly, essentially to normal levels, whereas sCD14 did not change in treatment-naïve participants initiating ABC/3TC or TDF/FTC with EFV, LPV/r, or ATV/r [45]. Last, in the Adolescent Trials Network (ATN) study 061, among young adults achieving HIV-1 RNA <100 cps/mL by week 24 after initiating TDF/FTC and ATV/r, levels of CD8+ T cell activation, measured by CD38 and HLA DR expression, decreased over 48 weeks but remained higher than levels in the comparison group of uninfected young adults not on ART [46••]. Levels of sCD14 and sCD163 did not decrease following ART initiation in this study.…”