The Immunomodulatory Effects of Intensification among ART-suppressed Patients with Incomplete CD4 Recovery Peter W. Hunt, Nancy Shulman, Tim Hayes, Viktor Dahl, Ma Somsouk, Nick Funderburg, Alan L. Landay, Oluwatoyin Adeyemi, Robert Shafer, Brian Clagett, Benigno Rodriguez, Jeffrey N. Martin, Barbara Shacklett, Sarah Palmer, Michael M. Lederman, Steven G. Deeks Inclusion/Exclusion Criteria Incomplete CD4 Recovery During Suppressive ART: Stable ART regimen > 1 year All plasma HIV RNA levels <48 c/ml in last year Detectable VL blips < c/ml in last yr OK if flanked by VLs <48 c/ml All CD4 counts <35 cells/mm 3 in last year CD4 count gain < cells/mm 3 in last year >9% self-reported ARV adherence Excluded for: Anticipating in ARV of HBV/HCV Rx in next 6 months Immunomodulatory/suppressive Rx in last 4 months Serious illness past 3 months ANC<1., plts <5, HgB<8, CrCl<4, AST/ALT>2.5x ULN Pregnancy/Breastfeeding Concurrent ddi+tdf use in ART regimen
Intensification Trial Schematic Randomize (N=42) Add BID x 24 weeks Add BID x 24 weeks ART alone x 12 weeks ART alone x 12 weeks Study Visits at Weeks: -2 1 2 4 6 8 12 16 2 22 24 28 36 T Cell Activation, biomarkers, Low-level Viremia (SCA) Clinical monitoring, CD4 count Flexible Sigmoidoscopy, Rectosigmoid Biopsy (UCSF only) VL by Single Copy Assay Declines in Both Arms But no Difference between Groups Plasma HIV RNA Level by SCA (Copies/ml) 2. 1.5 1..5. P=.97 P=.33 P=.75 P values are for comparison of change from baseline between groups
Similar CD4 Count Increase in Both Arms CD4+ T Cell Count in Cells/mm 3 + 38 cells/mm 3 per year P=.8 CD4+ T Cell Count in Cells/mm 3 + 37 cells/mm 3 per year P=.4 No evidence for difference in the rate of CD4+ T cell recovery between arms, P=.97 CD8+ T Cells (PB) 25 2 15 1 5 Increases CD8 Activation Compared to P=.1 P=.1 P values represent difference between groups in the change from baseline at each time point. P=.12
CD4+ T Cells (PB) 12.5 1. 7.5 5. 2.5. Prevents the Decline in CD4 Activation Compared to P=.24 P=.26 P values represent difference between groups in the change from baseline at each time point. P=.76 CD4+ CD8+ 75 5 25 4 3 2 1 But Intensification Results in a Nearly 2-fold Increase in Rectal T Cell Activation P=.21 P=.72 75 5 25 3 2 1 Mean 2.3-fold increase over 22 weeks P=.17 Mean 1.9-fold increase over 22 weeks P=.3 P=.23 for difference between arms
Plasma LPS Declines Significantly During Intensification Serum LPS Level 15 5 Wk -4 P=.55 P for Trend =.22 Wk -24 P=.25 P=.36 Serum LPS Level 15 5 Wk -4 P=.44 P for Trend =.41 Wk -24 P=.42 P=.99 Difference between arms is not statistically significant, however >2-fold Increase in CCR5 Expression (MFI) on Rectal CD4+ T cells During MVC Intensification P <.1.41 CCR5 MFI on Rectal CCR5+ CD4+ T Cells P=.9 for Trend CCR5 MFI on Rectal CCR5+ CD4+ T Cells P=.8 Similar trends observed on Rectal CD8+ T cells and B cells
>2-fold Increase in Plasma MIP-1β (CCR5 Ligand) Levels During Intensification Plasma MIP-1β Level Wk -4 P=.44 P for Trend =.7 Wk -24 P=..38 P=.26 Plasma MIP-1β Level Wk -4 P<.1 P for Trend <.1 Wk -24 P<.1 P<.1 Conclusions intensification in HIV+ subjects with incomplete ART-mediated CD4 recovery: Causes a nearly 2-fold increase in T cell activation in GALT, and more modest increases in peripheral blood Appears to redistribute CD8+ T cells from lymphoid tissues into blood while having little effect on CD4 counts May decrease plasma LPS levels while increasing scd14, compatible with enhanced macrophage-mediated clearance CCR5 ligand signaling through other chemokine receptors should be explored as a possible causal mechanism The clinical implications of these findings are unclear CADIRIS, ANRS studies with clinical endpoints ongoing