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Inflammation/Activation Markers Drop With ATV, DRV, RAL, But Not Completely - ACTG Study
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20th International AIDS Conference, July 20-25, 2014, Melbourne
Mark Mascolini
Markers of inflammation and immune activation generally dropped through 96 weeks of treatment with atazanavir/ritonavir (ATV/r), darunavir/ritonavir (DRV/r), and raltegravir (RAL), with only a few differences between antiretroviral regimens, in an AIDS Clinical Trials Group (ACTG) study [1]. But results at week 96 indicated incomplete control of inflammation and immune activation with these standard regimens.
Prior research found that inflammation and immune activation persist in people who achieve and maintain an undetectable viral load with combination antiretroviral therapy. The ACTG team noted that research has linked interleukin (IL)-6, high-sensitivity C-reactive protein (hsCRP), and soluble (s)CD14 with all-cause mortality in people with HIV.
To measure inflammation and immune activation more precisely among antiretroviral-naive people starting a standard regimen, ACTG investigators analysed 24-, 48-, and 96-week changes in an array of biomarkers in study A5260s [2]. This trial randomized participants to standard doses of raltegravir, atazanavir/ritonavir, or darunavir/ritonavir, all with tenofovir/emtricitabine. Based on research to date, the ACTG hypothesized that raltegravir therapy would lead to greater drops in inflammation and immune activation than protease inhibitor-based therapy, and that atazanavir/ritonavir would lower inflammation and activation markers more than darunavir/ritonavir.
The investigators measured biomarker changes as the ratio of the follow-up value to the baseline value (figured as average fold change) after 24 and 96 weeks for cellular biomarkers and after 48 and 96 weeks for plasma biomarkers. All changes reported below are week-96 changes. A 1.0 ratio indicates no change; a ratio below 1.0 indicates falling marker levels.
-- Inflammation and coagulation: hsCRP, IL-6, D-dimer
-- Macrophage activation: sCD14, sCD163, percent CD14+CD16+ of monocytes
-- T-cell activation: sIL-2r, percent CD38+DR+ of CD8 cells
The analysis involved 234 trial participants, 68 taking atazanavir/ritonavir, 82 raltegravir, and 84 darunavir/ritonavir. About 10% were women, 48% were white, 29% black, and 19% Hispanic. Age averaged 38 years. Pretreatment median CD4 counts were 294 in the atazanavir arm, 347 in the raltegravir arm, and 337 in the darunavir arm. Overall pretreatment median viral load stood around 40,000 copies. All study participants had reached a viral load below 50 copies by treatment week 24.
hsCRP dropped by one third at week 96 with atazanavir and raltegravir but did not change substantially with darunavir (see the list below for specific ratios). IL-6, an inflammation marker, did not drop consistently with any of the three antiretrovirals. Levels of the coagulation marker D-dimer fell with atazanavir (fold change 0.48) and darunavir (fold change 0.65) but not with raltegravir.
sCD163, a signal of macrophage activation, declined at similar rates (fold change 0.50 to 0.58) across the three antiretroviral groups. Percent CD14+CD16+ of monocytes, another marker of macrophage activation, fell more with atazanavir (fold change 0.58) and darunavir (fold change 0.71) than with raltegravir (fold change 0.85). But sCD14, a third signal of macrophage activation, did not decline with any regimen. The two T-cell activation markers dropped at similar rates with the three antiretrovirals.
Week-96 marker changes with ATV/r, RAL, and DRV/r
-- hsCRP (baseline 1.48 ug/mL): ATV/r 0.64, RAL 0.66, DRV/r 1.21
-- IL-6 (baseline 0.28 pg/mL): ATV/r 0.87, RAL 0.76, DRV/r 0.97
-- D-dimer (baseline 0.26 ug/mL): ATV/r 0.48, RAL 0.82, DRV/r 0.65
-- sCD14 (baseline 1688 ng/mL): ATV/r 0.96, RAL 0.89, DRV/r 0.96
-- sCD163 (baseline 1090 ng/mL): ATV/r 0.50, RAL 0.55, DRV/r 0.58
-- sIL-2r (baseline 1790 pg/mL): ATV/r 0.65, RAL 0.61, DRV/r 0.65
-- Percent CD38+DR+ of CD8 cells (baseline 42.9%): ATV/r 0.33, RAL 0.36, DRV/r 0.34
-- Percent CD14+CD16+ of monocytes (baseline 8.2%): ATV/r 0.58, RAL 0.85, DRV/r 0.71
The ACTG investigators concluded that, through 96 weeks, raltegravir did not differ from protease inhibitors in its impact on systemic inflammation or immune activation. They believe their findings "suggest incomplete reversal of immune defects [with cART] that may drive residual inflammation and immune activation and/or persisting viral replication reservoirs in the setting of effective treatment with these different therapeutic agents." The investigators suggested that longer follow-up may better define differences between regimens and potential correlations with long-term complications.
References
1. Kelesidis T, Tran TTT, McComsey GA, et al. Comparison of effects of atazanavir, raltegravir, or darunavir with FTC/tenofovir on biomarkers of systemic inflammation, macrophage and T cell activation: ACTG A5260s. AIDS 2014. 20th International AIDS Conference. July 20-25, 2014. Melbourne. Abstract WEAB0106LB.
2. ClinicalTrials.gov. Impact of antiretroviral therapy on metabolic, skeletal, and cardiovascular parameters. http://clinicaltrials.gov/ct2/show/NCT00851799
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