Effects of Antiretroviral Therapy on Immune Function and Arterial Inflammation in Treatment-Naive Patients With Human Immunodeficiency Virus Infection

Abstract

Importance HIV-infected individuals with suppressed viremia on combined antiretroviral therapy (ART) have an increased risk of myocardial infarction (MI) versus uninfected control subjects. Effects of ART on arterial inflammation among treatment-naïve individuals with HIV are unknown. Objective To determine the effects of newly initiated ART on arterial inflammation and other immune/inflammatory indices in ART-naïve HIV-infected patients. Design, Setting, Participants 12 treatment-naïve HIV-infected subjects underwent 18fluorine-2-deoxy-D-glucose positron emission tomography (18F-FDG-PET) scanning for assessment of arterial inflammation, coronary CT angiography (CCTA) for assessment of subclinical atherosclerosis, and systemic immune/metabolic phenotyping prior to and 6 months after the initiation of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF). Systemic immune / metabolic parameters were also assessed in 12 prospectively recruited, non-HIV control subjects. The study began in July 2012 and was completed in May 2015. Intervention E/C/F/TDF in the HIV-infected cohort Results In addition to suppressing viral load (P<0.0001) and increasing CD4 count (P=0.0005), E/C/F/TDF markedly reduced the percentages of circulating activated CD4+ T cells (HLA-DR+CD38+CD4+) (P=0.008) and CD8+ T cells (HLA-DR+CD38+CD8+) (P=0.008), increased the percentage of circulating classical CD14+CD16− monocytes (P=0.04), and reduced levels of CXCL10 (P=0.03). With E/C/F/TDF, uptake of 18F-FDG in the axillary lymph nodes, as measured by target-to-background ratio (TBR), decreased from 3.7 (1.3, 7.0) at baseline to 1.4 (0.9, 1.9) [median (IQR) (P=0.01)] at study end. In contrast, no decrease was seen in aortic TBR in response to E/C/F/TDF (1.9±0.2 [2.0 (1.8, 2.1)] at baseline to 2.2±0.4 [2.1 (1.9, 2.6)] at study end, P=0.04 by two-way test; P=0.98 for test of decrease by one-way test). Changes in aortic TBR during E/C/F/TDF were significantly associated with changes in lipoprotein-associated phospholipase A2 (Lp-PLA2) (r=0.67, P=0.03). Coronary plaque increased among those HIV-infected participants with baseline plaque (n=3) and developed de novo in one participant during treatment with E/C/F/TDF. Conclusions and Relevance Newly initiated E/C/F/TDF in treatment-naïve HIV-infected subjects had discordant effects to restore immune homeostasis and dampen systemic immune activation without reducing arterial inflammation over the duration of treatment in this study. Complementary strategies to reduce arterial inflammation among ART-treated HIV-infected individuals may be needed. Clinical Trial Registration Number NCT01766726.

Interferon-γ-Inducible Protein 10 (IP-10) Kinetics after Antiretroviral Treatment Initiation in Ethiopian Adults with HIV

“…The marked initial IP-10 decline after starting ART corroborates findings from previous studies ( 23 , 24 ). With our study design we could show that this decline mainly occurs during the initial month after ART initiation.…”

Interferon-γ-Inducible Protein 10 (IP-10) Kinetics after Antiretroviral Treatment Initiation in Ethiopian Adults with HIV

“…The marked initial IP-10 decline after starting ART corroborates findings from previous studies ( 23 , 24 ). With our study design we could show that this decline mainly occurs during the initial month after ART initiation.…”

Effects of atorvastatin on biomarkers of immune activation, inflammation, and lipids in virologically suppressed, human immunodeficiency virus-1–infected individuals with low-density lipoprotein cholesterol <130 mg/dL (AIDS Clinical Trials Group Study A5275)

“…In another randomized, placebo-controlled study in 40 HIV-infected participants (85% virologically suppressed) atorvastatin 40mg/day was associated with a reduction in non-calcified coronary plaque progression that correlated with reductions in oxLDL and Lp-PLA 2 (−18%) but not sCD14 or sCD163, which, as in the present study, were unaffected [37]. These and other recent studies [21,38] suggests that biomarkers that more closely reflect events within the vascular intima such as oxLDL and Lp-PLA 2 may prove more useful in predicting CVD clinical outcomes with statin therapy and related strategies than more systemic biomarkers of immune activation and inflammation.…”

Inflammation and Arterial Injury in Individuals With Human Immunodeficiency Virus Infection

“…1 With the exception of CXCL10, a chemokine that increases with viral infections and decreases with their treatment, there were no significant differences in any of the inflammatory biomarkers that the authors measured after ART, including several associated with ASCVD risk, which is consistent with the absence of changes in aortic [ 18 F]-FDG PET that they observed. 1 …”

Interferon-γ-Inducible Protein 10 (IP-10) Kinetics after Antiretroviral Treatment Initiation in Ethiopian Adults with HIV

“…The marked initial IP-10 decline after starting ART corroborates findings from previous studies ( 23 , 24 ). With our study design we could show that this decline mainly occurs during the initial month after ART initiation.…”

Effects of atorvastatin on biomarkers of immune activation, inflammation, and lipids in virologically suppressed, human immunodeficiency virus-1–infected individuals with low-density lipoprotein cholesterol <130 mg/dL (AIDS Clinical Trials Group Study A5275)

“…In another randomized, placebo-controlled study in 40 HIV-infected participants (85% virologically suppressed) atorvastatin 40mg/day was associated with a reduction in non-calcified coronary plaque progression that correlated with reductions in oxLDL and Lp-PLA 2 (−18%) but not sCD14 or sCD163, which, as in the present study, were unaffected [37]. These and other recent studies [21,38] suggests that biomarkers that more closely reflect events within the vascular intima such as oxLDL and Lp-PLA 2 may prove more useful in predicting CVD clinical outcomes with statin therapy and related strategies than more systemic biomarkers of immune activation and inflammation.…”

Inflammation and Arterial Injury in Individuals With Human Immunodeficiency Virus Infection

“…1 With the exception of CXCL10, a chemokine that increases with viral infections and decreases with their treatment, there were no significant differences in any of the inflammatory biomarkers that the authors measured after ART, including several associated with ASCVD risk, which is consistent with the absence of changes in aortic [ 18 F]-FDG PET that they observed. 1 …”

Interferon-γ-Inducible Protein 10 (IP-10) Kinetics after Antiretroviral Treatment Initiation in Ethiopian Adults with HIV

“…The marked initial IP-10 decline after starting ART corroborates findings from previous studies ( 23 , 24 ). With our study design we could show that this decline mainly occurs during the initial month after ART initiation.…”

Effects of atorvastatin on biomarkers of immune activation, inflammation, and lipids in virologically suppressed, human immunodeficiency virus-1–infected individuals with low-density lipoprotein cholesterol <130 mg/dL (AIDS Clinical Trials Group Study A5275)

“…In another randomized, placebo-controlled study in 40 HIV-infected participants (85% virologically suppressed) atorvastatin 40mg/day was associated with a reduction in non-calcified coronary plaque progression that correlated with reductions in oxLDL and Lp-PLA 2 (−18%) but not sCD14 or sCD163, which, as in the present study, were unaffected [37]. These and other recent studies [21,38] suggests that biomarkers that more closely reflect events within the vascular intima such as oxLDL and Lp-PLA 2 may prove more useful in predicting CVD clinical outcomes with statin therapy and related strategies than more systemic biomarkers of immune activation and inflammation.…”

Inflammation and Arterial Injury in Individuals With Human Immunodeficiency Virus Infection

“…1 With the exception of CXCL10, a chemokine that increases with viral infections and decreases with their treatment, there were no significant differences in any of the inflammatory biomarkers that the authors measured after ART, including several associated with ASCVD risk, which is consistent with the absence of changes in aortic [ 18 F]-FDG PET that they observed. 1 …”