 |
|
|
| |
Turnover Following Viral Control Correlates with Markers of Microbial Translocation in Treatment-Naïve Patients Receiving Raltegravir (RAL)- based Antiretroviral Therapy (ART): Preliminary Results from ACTG A5248
|
| |
| |
Reported by Jules Levin CROI 2011 Boston Feb 27-March 2
Nicholas Funderburg1, A Andrade2, E Chan3, D Lu3, S Rosenkranz3, J Jacobson4, J Mellors5, E Daar6, D Kuritzkes7, and M Lederman1
1Case Western Reserve Univ, Cleveland, OH, US; 2Johns Hopkins Univ, Baltimore, MD, US; 3Harvard Sch of Publ Hlth, Boston, MA, US; 4Drexel Univ, Philadelphia, PA, US; 5Univ of Pittsburgh Med Ctr, PA, US; 6Harbor-UCLA Med Ctr, Los Angeles, CA, US; and 7Brigham and Women`s Hosp, Harvard Med Sch, Boston, MA, US
Background: Potential drivers of immune activation in HIV disease include viral replication and translocated microbial products. Their dynamics and relationships to indices of immune activation following ART initiation are not well characterized.
Conclusions:
· Activation markers on CD4 and CD8 T cells, and sCD14 levels decreased after initiation of RAL- based ART, but high level CD4 T cell cycling persisted for 8 weeks, and was never lowered to levels seen in controls.
· Changes in sCD14 levels correlated with changes in CD4 and central memory CD4 T cell cycling, suggesting microbial translocation may play a role in turnover of central memory CD4 cells in HIV infection.
Study Design
· A5248: prospective, open-label, multicenter, single-arm, 72-week pilot study.
· Population: HIV-1 infected, ARV-drug naive, ≥18 yrs, HIV-1 RNA between 10,000 and 300,000 c/mL.
· Regimen: RAL 400mg PO twice daily and FTC/TDF 200/300 mg PO once daily
· Immunology assays were performed at pre-entry, entry; days (D) 2, 7and 14; and weeks (W) 4, 8, 24, and 48.
Statistical Methods
· N=37 subjects with immunology results; results from virologic failure (VF), analytic rebound (AR) or clinical rebound (CR) were excluded1
· All tests were two-sided, 5% level, and not adjusted for multiple testing.
· Wilcoxon signed rank tests were used to evaluate the significance of the changes from baseline.
· Wilcoxon rank sum tests were used to evaluate the differences from normal controls.
· Spearman correlations were used to evaluate the associations between responses
Results:
· Immunology data were available for 37 of 39 subjects enrolled (median CD4 count 259 cells/mm3; VL 38565 c/mL). (Table 1)
· VL was significantly reduced within 2 days after initiating ART and by week 48, VL in all 31 subjects eligible fell to <50 c/mL. (Figure 1)
· Plasma sCD14 fell below BL at D2 (p<0.001) but plasma LPS did not decrease significantly until W8 (p=0.028). (Figure 1)
· The %CD8+ and %CD4+ T cells that expressed both CD38 and HLADR decreased significantly by D7 (p=0.015) and D2 (p=0.050), respectively (Figure 3), yet the %CD8+ and %CD4+ T cells that were Ki67+ did not fall significantly until D7 (p=0.028) and W8 (p<0.001) (Figure 4) and none of these indices reached levels seen in controls (p<0.001).
· TNFr1 fell significantly by W4 (p=0.038) but IL-6 levels did not fall consistently (Figure 2).
· Greater sCD14 decline at D7 predicted greater W48 declines in cycling (Ki-67+) CD4 cells (r=0.45, p=0.029) and Ki-67+ central memory CD4 T cells (r=0.48, p=0.019). (Table 2)
· Changes from BL VL at D7 and W48 (ranks equivalent to BL) did not associate with any indices.
ABSTRACT
Delayed Reduction in CD4 T Cell Turnover following Viral Control Correlates with Markers of Microbial Translocation in Treatment-naïve Patients Receiving RAL-based ART: Preliminary Results from ACTG A5248
Nicholas Funderburg1, A Andrade2, E Chan3, D Lu3, S Rosenkranz3, J Jacobson4, J Mellors5, E Daar6, D Kuritzkes7, and M Lederman1
1Case Western Reserve Univ, Cleveland, OH, US; 2Johns Hopkins Univ, Baltimore, MD, US; 3Harvard Sch of Publ Hlth, Boston, MA, US; 4Drexel Univ, Philadelphia, PA, US; 5Univ of Pittsburgh Med Ctr, PA, US; 6Harbor-UCLA Med Ctr, Los Angeles, CA, US; and 7Brigham and Women`s Hosp, Harvard Med Sch, Boston, MA, US
Background: Potential drivers of immune activation in HIV disease include viral replication and translocated microbial products. Their dynamics and relationships to indices of immune activation following ART initiation are not well characterized.
Methods: A5248 is a single-arm, 72-week pilot study. ART-naïve subjects with plasma HIV RNA viral load 10 to 300K c/mL initiated raltegravir (RAL), emtricitabine/tenofovir. Markers of T cell activation (CD38, HLA-DR) and cycling (Ki67), measured by flow cytometry, viral load (Roche Ultrasensitive), LPS (limulus lysate assay) and its soluble receptor (sCD14), IL-6 and TNFr1 (ELISA) were measured at baseline (BL), days 2 and 7, and weeks 2, 4, 8, 24, and 48. Markers collected after virologic failure/rebound were excluded from analysis. Wilcoxon signed rank and rank sum tests were used to evaluate the time at which values of each marker changed from BL and differed from healthy control values, respectively, with nominal significance level p <0.05. Associations between variables were assessed via Spearman correlations. All analyses were exploratory (not adjusted for multiple testing).
Results: Thirty-nine subjects (median CD4 count 259 cells/mm3; viral load 37,490 copies/mL) enrolled. Viral load was significantly reduced within 2 days after initiating ART and by week 48, viral load in all 31 subjects eligible fell to <50 c/mL. Plasma sCD14 fell below BL at day 2 (p <0.001) but plasma LPS did not decrease significantly until week 8 (p = 0.028). The percent CD8+ and percent CD4+ T cells that expressed both CD38 and HLA-DR decreased significantly by day 7 (p = 0.015) and day 2 (p = 0.050), respectively, yet the percent CD8+ and percent CD4+ T cells that were Ki67+ did not fall significantly until day 7 (p = 0.028) and week 8 (p <0.001) and none of these indices reached levels seen in controls (p <0.001). TNFr1 fell significantly by week 4 (p = 0.038) but IL-6 levels did not fall consistently. Greater sCD14 decline at day 7 predicted greater week 48 declines in cycling (Ki-67+) CD4 cells (r = 0.45, p = 0.029), and Ki-67+ central memory CD4 T cells (r = 0.48, p = 0.019). Changes from BL viral load at day 7 and week 48 (ranks equivalent to BL) did not associate with any indices.
Conclusions: Activation markers on CD4 and CD8 T cells, and sCD14 levels decreased after initiation of RAL-based ART, but high-level CD4 T cell cycling persisted for 8 weeks, and was never lowered to levels seen in controls. Changes in sCD14 levels correlated with changes in CD4 and central memory CD4 T cell cycling, suggesting microbial translocation may play a role in turnover of central memory CD4 cells in HIV infection.
Conclusions:
·Activation markers on CD4 and CD8 T cells, and sCD14 levels decreased after initiation of RAL- based ART, but high level CD4 T cell cycling persisted for 8 weeks, and was never lowered to levels seen in controls.
·Changes in sCD14 levels correlated with changes in CD4 and central memory CD4 T cell cycling, suggesting microbial translocation may play a role in turnover of central memory CD4 cells in HIV infection.
|
| |
|
|
|
|
|
