Baseline natural killer and T cell populations correlation with virologic outcome after regimen simplification to atazanavir/ritonavir alone (ACTG 5201).

OBJECTIVES: Simplified maintenance therapy with ritonavir-boosted atazanavir (ATV/r) provides an alternative treatment option for HIV-1 infection that spares nucleoside analogs (NRTI) for future use and decreased toxicity. We hypothesized that the level of immune activation (IA) and recovery of lymphocyte populations could influence virologic outcomes after regimen simplification. METHODS: Thirty-four participants with virologic suppression ≥ 48 weeks on antiretroviral therapy (2 NRTI plus protease inhibitor) were switched to ATV/r alone in the context of the ACTG 5201 clinical trial. Flow cytometric analyses were performed on PBMC isolated from 25 patients with available samples, of which 24 had lymphocyte recovery sufficient for this study. Assessments included enumeration of T-cells (CD4/CD8), natural killer (NK) (CD3+CD56+CD16+) cells and cell-associated markers (HLA-DR, CD\u27s 38/69/94/95/158/279). RESULTS: Eight of the 24 patients had at least one plasma HIV-1 RNA level (VL) \u3e50 copies/mL during the study. NK cell levels below the group median of 7.1% at study entry were associated with development of VL \u3e50 copies/mL following simplification by regression and survival analyses (p = 0.043 and 0.023), with an odds ratio of 10.3 (95% CI: 1.92-55.3). Simplification was associated with transient increases in naïve and CD25+ CD4+ T-cells, and had no impact on IA levels. CONCLUSIONS: Lower NK cell levels prior to regimen simplification were predictive of virologic rebound after discontinuation of nucleoside analogs. Regimen simplification did not have a sustained impact on markers of IA or T lymphocyte populations in 48 weeks of clinical monitoring. TRIAL REGISTRATION: ClinicalTrials.gov NCT00084019

Baseline natural killer and T cell populations correlation with virologic outcome after regimen simplification to atazanavir/ritonavir alone (ACTG 5201)

Objectives: Simplified maintenance therapy with ritonavir-boosted atazanavir (ATV/r) provides an alternative treatment option for HIV-1 infection that spares nucleoside analogs (NRTI) for future use and decreased toxicity. We hypothesized that the level of immune activation (IA) and recovery of lymphocyte populations could influence virologic outcomes after regimen simplification. Methods: Thirty-four participants with virologic suppression ≥48 weeks on antiretroviral therapy (2 NRTI plus protease inhibitor) were switched to ATV/r alone in the context of the ACTG 5201 clinical trial. Flow cytometric analyses were performed on PBMC isolated from 25 patients with available samples, of which 24 had lymphocyte recovery sufficient for this study. Assessments included enumeration of T-cells (CD4/CD8), natural killer (NK) (CD3+CD56 +CD16+) cells and cell-associated markers (HLA-DR, CD's 38/69/94/95/158/279). Results: Eight of the 24 patients had at least one plasma HIV-1 RNA level (VL) <50 copies/mL during the study. NK cell levels below the group median of 7.1% at study entry were associated with development of VL <50 copies/mL following simplification by regression and survival analyses (p = 0.043 and 0.023), with an odds ratio of 10.3 (95% CI: 1.92-55.3). Simplification was associated with transient increases in naïve and CD25+ CD4+ T-cells, and had no impact on IA levels. Conclusions: Lower NK cell levels prior to regimen simplification were predictive of virologic rebound after discontinuation of nucleoside analogs. Regimen simplification did not have a sustained impact on markers of IA or T lymphocyte populations in 48 weeks of clinical monitoring. Trial Registration: ClinicalTrials.gov NCT00084019

Univariate analysis of Baseline T and NK Cell Populations and Immune Activation Markers with in Participants with and without detectable HIV-1 RNA after Regimen Simplification.

<p>The significant p-values for univariate comparisons are in bold.</p

Proportions with HIV-1 RNA < 50 copies/ml after regimen simplification by baseline NK cell levels.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0095524#pone-0095524-g002" target="_blank">Figure 2</a> shows a Kaplan-Meier plot for the survival with HIV-1 RNA level above 50 copies/mL during the A5201 study based on the participant's NK cell level at study entry. The p-value is 0.023 by Kaplan-Meier analyses for the difference at 54 weeks between the groups above and below the median NK cell level.</p

Baseline NK Cell percentages by HIV-1 RNA Outcome following Regimen Simplification.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0095524#pone-0095524-g001" target="_blank">Figure 1</a> compares the baseline NK cell levels, defined by CD3-CD56+CD16+ cells, and virologic outcome (HIV-1 RNA below or above 50 copies/mL, throughout the study). The circles represent each study participant with either sustained HIV-1 RNA suppression during the trial and those participants who developed detectable viremia following treatment simplification. The difference in the median NK cell levels between the groups with detectable and suppressed viremia was statistically significant with a p-value of 0.002. The median level is noted by the line in the scatterplot for each group.</p

Comparison of NK cells and T cell populations based on HIV-1 viremia below and above 50 copies/mL.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0095524#pone-0095524-g003" target="_blank">Figure 3</a> demonstrates that the population percentage of CD3-CD56+CD16+ cells (panel 1) and CD4-CD45RO+CCR7+CD27- cells (panel 2) were decreased in samples with HIV-1 RNA levels of 50–99 copies/mL as compared to samples obtained with HIV-1 RNA below 50 copies/mL with p-values of 0.036 and 0.018, respectively. The median level for each cell population is indicated by the line in the scatterplot for each group.</p

Univariate and Multivariate Regression Analysis of Baseline T and NK Cell Populations and Immune Activation Markers and the Risk of Detectable Plasma HIV-1 RNA.

<p>Cox regression analyses included all variables with p-values ≤0.1 in the univariate analyses, and age, race and CD4 nadir prior to starting ART. Odds ratio above 1.0 are associated with increased risk of virologic failure.</p