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
Keywords: HIV, inflammation
INTRODUCTION
Myocardial infarction rates are increased 50% in HIV-infected vs. uninfected patients, controlling for traditional cardiovascular disease (CVD) risk factors1,2. Mechanisms for increased MI risk in HIV remain unclear, but may relate in part to effects of the virus itself and the body’s immune response3,4. Effects of ART on MI risk in HIV are not fully understood5,6.
We explored effects of newly initiated integrase-inhibitor based ART on arterial inflammation by 18F-FDG-PET among treatment-naïve HIV-infected subjects without known CVD. Arterial inflammation is a marker of CVD risk in the general population7 and is increased among ART-treated HIV-infected patients8. We hypothesized that initiation of ART in treatment-naïve subjects would reduce arterial inflammation together with systemic immune activation/inflammation.
METHODS
Study Design
This study evaluated effects of initiation of ART with E/C/F/TDF (Stribild) on arterial inflammation by cardiac 18F-FDG-PET scanning among ART-naïve HIV-infected subjects. ART-effects on coronary plaque by coronary CT angiography and systemic immune and metabolic parameters were simultaneously assessed. The study began in July 2012 and was completed in May 2015. All participants provided informed consent. This study was approved by the MGH Institutional Review Board and registered on clinicaltrials.gov (NCT01766726).
Twelve ART-naïve HIV-infected subjects initiating E/C/F/TDF once a day by their treating clinician were recruited from infectious disease clinics in Boston. All 12 subjects (males) qualified and enrolled at the General Clinical Research Center at MGH. In addition, 12 confirmed HIV-negative subjects were recruited for contextualization of data on immune/inflammatory indices in the HIV-infected group. Uninfected control subjects underwent blood testing at baseline only. Control subjects did not initiate E/C/F/TDF or undergo 18F-FDG-PET/CCTA. HIV-infected and uninfected subjects were enrolled based on similar criteria, including age >18 years, no history of current or prior coronary artery disease or significant autoimmune/inflammatory disease, and eGFR ≥70ml/min/1.73m2. For HIV-infected participants, assessments were performed at baseline and after 6 months of E/C/F/TDF therapy. Assessments were delayed beyond 6 months in 3 of 12 participants, one of whom did not have end-of-study 18F-FDG-PET. The median time of follow-up, including these subjects, was 7 months.
Study Procedures
HIV-infected subjects underwent 18F-FDG-PET scanning8 which imaged the aorta, heart, axillary lymph nodes, spleen, and bone marrow. These subjects also underwent coronary CT angiography9 (e-Methods). Lipid levels and creatinine were determined using standard techniques. CD4+ and CD8+ T cells counts were determined using flow cytometry. HIV viral load was determined using an ultrasensitive RT PCR (Cobas Ampliprep; lower limit of detection, 20 copies/mL). Flow cytometric analysis of lymphocytes and monocytes were performed and levels of immune/inflammatory biomarkers were assessed (e-Methods).
Statistical Analysis
The pre-specified primary endpoint was change in aortic TBR on 18F-FDG-PET with E/C/F/TDF treatment in the HIV-infected group. The study was powered at 80% to detect a decrease in aortic TBR of 0.3 (one-way testing), based on an assumed SD of 0.428. The study size was chosen a priori to enable detection of a decrease in aortic TBR of 0.3, representing the difference between (ART-treated) HIV-infected and uninfected groups in our prior work8. The selected six-month study duration was long enough to allow for ART effects on arterial and systemic inflammation. Indeed, other anti-inflammatory strategies have reduced aortic TBR in comparable time-frames10. Two-way tests for change within the HIV group are reported for all variables. A one-way test for change is also reported for aortic TBR, the primary endpoint, consistent with the primary study hypothesis. Statistical analyses were performed using SAS JMP software (version 11.0; SAS Institute).
RESULTS
Baseline Immune and Cardiometabolic Parameters
HIV-infected subjects were ART-naïve, with a median time since diagnosis of 0.9 years (0.2, 1.7 [median (IQR)]), CD4+ count of 483±166 cells/mm3 and viral load of 4.3±0.6 log copies. The HIV-infected and uninfected groups had very low and similar traditional CVD risk scores [10-year ASCVD risk score 2.1% vs. 1.8% (HIV vs. control) (P = 0.91)] (e-Table 1). No subjects were receiving statin therapy. At baseline, prior to ART, HIV-infected subjects demonstrated a higher percentage of activated CD4+ and CD8+ T cells and higher levels of the chemokine CXCL10 compared to controls (Table 1).
Table 1.
Effects of Newly Initiated E/C/F/TDF Therapy on Traditional Risk, HIV-Specific, Immune, Flow Cytometry, and 18F-FDG-PET Parameters
| HIV+ at Baseline Mean ± SD Median (IQR) |
HIV+ After Treatment Mean ± SD Median (IQR) |
P-Value Change Over Time |
Controls Mean ± SD Median (IQR) |
P-Value HIV+ at Baseline vs. Control |
P-Value HIV+ After Treatment vs. Control |
|
|---|---|---|---|---|---|---|
| TRADITIONAL RISK PARAMETERS | ||||||
| Total Cholesterol (mg/dL) | 159 (136, 172) 155 ± 29 (n=12) |
163 (147, 194) 173 ± 35 (n=12) |
0.01 (n=12) |
173 (153, 186) 175 ± 32 (n=12) |
0.09 | 0.73 |
| LDL (mg/dL) | 99 (68, 101) 93 ± 26 (n=12) |
94 (74, 123) 101 ± 32 (n=12) |
0.15 (n=12) |
108 (76, 114) 102 ± 24 (n=12) |
0.18 | 0.58 |
| HDL (mg/dL) | 40 (36, 47) 45 ± 14 (n=12) |
45 (41, 56) 49 ± 10 (n=12) |
0.06 (n=12) |
52 (45, 64) 55 ± 16 (n=12) |
0.06 | 0.27 |
| Total Cholesterol to HDL Ratio | 3.5 (3.0, 4.4) 3.7 ± 0.9 (n=12) |
3.6 (3.3, 4.1) 3.7 ± 0.8 (n=12) |
0.79 (n=12) |
3.3 (2.6, 4.0) 3.3 ± 0.7 (n=12) |
0.40 | 0.44 |
| Triglycerides (mg/dL) | 90 (60, 116) 89 ± 29 (n=12) |
92 (80, 163) 119 ± 69 (n=12) |
0.12 (n=12) |
96 (58, 113) 89 ± 34 (n=12) |
0.93 | 0.58 |
| Systolic Blood Pressure (mmHg) | 115 (112, 121) 116 ± 7 (n=12) |
118 (111, 120) 118 ± 8 (n=12) |
0.33 (n=12) |
119 (112, 139) 123 ± 14 (n=12) |
0.22 | 0.43 |
| BMI (kg/m2) | 25.8 (22.6, 28.1) 25.7 ± 3.6 (n=12) |
25.9 (23.4, 27.1) 26.0 ± 3.4 (n=12) |
0.30 (n=12) |
25.3 (24.3, 28.9) 26.2 ± 2.9 (n=12) |
0.84 | 0.80 |
| WHR (Iliac waist) | 0.9 (0.8, 0.9) 0.9 ± 0.1 (n=12) |
0.9 (0.9, 1.0) 0.9 ± 0.1 (n=12) |
0.02 (n=12) |
1.0 (0.9, 1.0) 0.9 ± 0.1 (n=12) |
0.18 | 0.35 |
| 10-year ASCVD Risk Score* (%) | 2.1 (0.7, 3.6) 2.5 ± 1.8 (n=12) |
2.1 (0.8, 4.9) 2.7 ± 2.0 (n=12) |
0.28 (n=12) |
1.8 (0.7, 5.3) 4.2 ± 6.6 (n=12) |
0.91 | 1.00 |
| Creatinine (mg/dL) | 0.90 (0.76, 0.99) 0.89 ± 0.16 (n=12) |
0.96 (0.82, 1.08) 0.96 ± 0.17 (n=12) |
0.02 (n=12) |
-- | -- | -- |
| HIV SPECIFIC PARAMETERS | ||||||
| CD4+ T Cell Count (cells/mm3) | 461 (332, 663) 483 ± 166 (n=12) |
687 (533, 882) 698 ± 197 (n=12) |
0.0005 (n=12) |
-- | -- | -- |
| CD8+ T Cell Count (cells/mm3) | 767 (594, 1009) 933 ± 576 (n=12) |
723 (602, 1321) 922 ± 435 (n=12) |
1.00 (n=12) |
-- | -- | -- |
| CD4/CD8 Ratio | 0.60 (0.42, 0.80) 0.63 ± 0.28 (n=12) |
0.87 (0.54, 1.25) 0.89 ± 0.40 (n=12) |
0.0005 (n=12) |
-- | -- | -- |
| Log VL (copies/mL) | 4.5 (3.9, 4.8) 4.3 ± 0.6 (n=12) |
1.3 (1.3, 1.3) 1.3 ± 0.0 (n=12) |
<0.0001 (n=12) |
-- | -- | -- |
| IMMUNE ACTIVATION AND INFLAMMATION PARAMETERS | ||||||
| Log sCD163 sCD163 (ng/mL) |
3.1 ± 0.2 1253 (910, 1779) (n=12) |
3.2 ± 0.2 1521 (1088, 2318) (n=12) |
0.58 (n=12) |
3.0± 0.2 956 (608, 1281) (n=12) |
0.12 | 0.06 |
| Log sCD14 sCD14 (ng/mL) |
3.4 ± 0.1 2819 (2209, 3012) (n=12) |
3.2 ± 0.4 2447 (582, 2764) (n=12) |
0.08 (n=12) |
3.3 ± 0.3 2082 (1697, 2832) (n=12) |
0.10 | 0.53 |
| Log CXCL10 CXCL10 (pg/mL) |
2.4 ± 0.4 234 (132, 599) (n=12) |
2.2 ± 0.4 144 (93, 293) (n=12) |
0.03 (n=12) |
1.9 ± 0.2 78 (59, 112) (n=12) |
0.001 | 0.03 |
| Log Lp-PLA2 Lp-PLA2 (ng/mL) |
2.2 ± 0.1 158 (142, 219) (n=12) |
2.3 ± 0.1 192 (156, 234) (n=12) |
0.07 (n=12) |
2.3 ± 0.1 203 (198, 216) (n=12) |
0.03 | 0.60 |
| Log MCP-1 MCP-1 (pg/mL) |
2.2 ± 0.1 162.5 (126.4, 192.8) (n=12) |
2.2 ± 0.1 143.7 (131.3, 188.7) (n=12) |
0.93 (n=12) |
2.2 ± 0.1 153.9 (131.1, 198.8) (n=12) |
0.72 | 0.79 |
| Log hsIL-6 hsIL-6 (pg/mL) |
0.2 ± 0.2 1.5 (0.9, 2.2) (n=12) |
0.2 ± 0.4 1.3 (0.9, 1.5) (n=12) |
0.82 (n=12) |
0.2 ± 0.2 1.3 (0.9, 2.1) (n=12) |
0.99 | 0.84 |
| Log CRP CRP (ng/mL) |
2.2 ± 0.7 83 (43, 365) (n=12) |
2.1 ± 0.4 132 (69, 265) (n=12) |
0.63 (n=12) |
2.2 ± 0.6 147 (86, 369) (n=12) |
0.73 | 0.45 |
| FLOW CYTOMETRY PARAMETERS | ||||||
| % CD4+ T Cells (as % of lymphocytes) | 30.1 (15.3, 32.3) 24.3 ± 13.7 (n=10) |
32.2 (4.2, 38.5) 26.4 ± 17.8 (n=10) |
0.15 (n=8) |
45.7 (39.3, 50.5) 42.6 ± 13.8 (n=12) |
0.002 | 0.009 |
| % HLA-DR+CD38+CD4+ T Cells (as % of CD4+ T Cells) | 3.7 (1.8, 5.0) 4.7 ± 5.0 (n=10) |
1.3 (0.3, 2.0) 1.4 ± 1.2 (n=10) |
0.008 (n=8) |
0.3 (0.1, 0.4) 0.3 ± 0.2 (n=12) |
<0.0001 | 0.02 |
| % CD8+ T Cells (as % of lymphocytes) | 40.7 (35.5, 53.6) 44.6 ± 10.7 (n=10) |
38.4 (32.8, 49.8) 40.1 ± 9.0 (n=10) |
0.02 (n=8) |
24.6 (18.0, 28.8) 24.4 ± 8.7 (n=12) |
0.0004 | 0.001 |
| % HLA-DR+CD38+CD8+ T Cells (as % of CD8+ T Cells) | 18.3 (8.1, 27.0) 17.4 ± 9.9 (n=10) |
4.0 (1.5, 7.8) 5.5 ± 5.1 (n=10) |
0.008 (n=8) |
1.3 (0.6, 3.1) 1.8 ± 1.6 (n=12) |
0.0001 | 0.02 |
| % CD14-CD16+ (as % of monocytes) | 4.7 (2.8, 7.2) 5.2 ± 3.2 (n=10) |
3.1 (2.1, 5.1) 3.7 ± 1.8 (n=11) |
0.20 (n=9) |
3.2 (2.6, 3.7) 3.5 ± 1.2 (n=12) |
0.14 | 0.93 |
| % CD14+CD16+ (as % of monocytes) | 8.0 (3.7, 11.6) 10.2 ± 9.6 (n=10) |
4.4 (3.0, 7.4) 5.2 ± 2.5 (n=11) |
0.07 (n=9) |
8.7 (6.7, 12.2) 9.8 ± 5.3 (n=12) |
0.60 | 0.01 |
| % CD14+CD16− (as % of monocytes) | 85.8 (83.7, 90.8) 83.8 ± 12.2 (n=10) |
91.8 (87.5, 93.2) 90.8 ± 2.9 (n=11) |
0.04 (n=9) |
88.0 (85.2, 89.7) 85.8 ± 6.4 (n=12) |
0.72 | 0.03 |
| 18F-FDG-PET PARAMETERS | ||||||
| Aortic TBR | 2.0 (1.8, 2.1) 1.9 ± 0.2 (n=11) |
2.1 (1.9, 2.6) 2.2 ± 0.4 (n=10) |
0.04 (n=10) |
-- | -- | -- |
| Splenic TBR | 3.4 (2.8, 3.7) 3.3 ± 0.8 (n=12) |
2.8 (2.5, 3.3) 2.9 ± 0.7 (n=11) |
0.15 (n=11) |
-- | -- | -- |
| Bone Marrow TBR | 3.2 (3.0, 3.5) 3.2 ± 0.5 (n=12) |
3.0 (2.7, 3.7) 3.2 ± 0.6 (n=11) |
0.58 (n=11) |
-- | -- | -- |
| Bilateral Axillary Lymph Node TBR | 3.7 (1.3, 7.0) 4.5 ± 4.1 (n=12) |
1.4 (0.9, 1.9) 1.5 ± 1.0 (n=11) |
0.01 (n=11) |
-- | -- | -- |
All data are presented as median (IQR) and mean ± standard deviation. Matched pairs testing was used to assess change in parameters in response to E/C/F/TDF among ART- naïve HIV-infected subjects; student’s t-test were used for log-transformed data, and otherwise Wilcoxon signed rank tests were used. Between group comparisons of data for HIV-infected subjects versus non-infected subjects were made using the student’s t-test for log-transformed data, and otherwise using the Wilcoxon rank sum test as appropriate, for continuous data and using the Chi-square (χ2) test for categorical data. P<0.05 indicates statistical significance. Abbreviations: LDL, low-density lipoprotein; HDL, high-density lipoprotein; BMI, body mass index; WHR, waist-hip ratio; ASCVD, atherosclerotic cardiovascular disease; VL, viral load; PET, positron emission tomography; TBR, target-to-background ratio.
For participants outside the 40–79 age range, an imputed age was used to calculate the 10-year ASCVD Risk Score.
Effects of E/C/F/TDF
Arterial Inflammation and Coronary Plaque
In response to E/C/F/TDF, aortic TBR increased from a baseline of 1.9±0.2 [2.0 (1.8, 2.1) median (IQR)] to 2.2±0.4 [2.1 (1.9, 2.6) median (IQR)] (P=0.04, using two-way test; P=0.98 using one-way test for decrease) (Figures 1 and 2, Table 1). A strong relationship was observed between the increase in aortic TBR and increase in Lp-PLA2 (r=0.67, P=0.03). At baseline, 3 of 12 (25%) HIV-infected subjects demonstrated subclinical coronary plaque. Additionally, one HIV-infected subject without baseline plaque developed de novo plaque over the study period. Total, noncalcified, and calcified plaque volumes were higher after therapy among those HIV-infected subjects with any plaque at baseline (eTable 2).
Figure 1. Representative 18F-FDG-PET/CT Imaging of the Aorta and Axillary Lymph Nodes in a Treatment-Naïve HIV-infected Subject Before and After E/C/F/TDF Therapy.
Arrows depict right and left axillary lymph nodes. Ao = aorta. LN = lymph node.
Figure 2. Effects of E/C/F/TDF Therapy on 18F-FDG-PET/CT Outcomes Among ART-Naïve HIV-infected Subjects.
Top row represents data as median (IQR). Bottom row displays individual data points before and after ART. Bilateral axillary lymph node TBR decreased significantly (P=0.01) and aortic TBR increased significantly (P=0.04 by two-way Wilcoxon signed rank test; P=0.98 for one-way test of decrease by Wilcoxon signed rank test). Ten of the 11 subjects’ lymph node TBR decreased while 8 of the 10 subjects’ aortic TBR increased after ART. Aortic TBR data on one participant could not be utilized as significant activity in the thymus caused spillover of activity into the aorta.
Inflammation in the Axillary Lymph Nodes, Spleen, and Bone Marrow
Among HIV-infected subjects, there was visible high-level FDG uptake in the bilateral axillary lymph nodes, spleen, and bone marrow. In response to E/C/F/TDF, bilateral axillary lymph node TBR was reduced significantly (Figures 1 and 2, Table 1). There was also a trend towards a reduction in TBR in the spleen but not in the bone marrow (Table 1).
Immune Function and Systemic Markers of Immune Activation
Treatment with E/C/F/TDF increased the CD4+ count and CD4/CD8 ratio and reduced viral load (P<0.0001), as anticipated (Table 1, eFigure 2). Viral load, assessed by an ultrasensitive assay, was suppressed to undetectable (<20 copies/mL) in 11/12 subjects and to 25 copies/mL in one subject. E/C/F/TDF also reduced the percent of circulating activated CD4+ and CD8+ T cells, and levels of the chemokine CXCL10, albeit not down to the levels observed in control subjects (Table 1, eFigure 3). Finally, E/C/F/TDF increased the circulating percentage of classical CD14+CD16− monocytes with a trend toward a concomitant decrease in the percentage of CD14+CD16+ monocytes (Table 1, eFigure 3).
Metabolic and Renal Parameters
With E/C/F/TDF, HDL tended to increase and total cholesterol increased modestly, but the ratio of total cholesterol to HDL cholesterol did not change. Creatinine increased slightly. There was no relationship between change in metabolic and renal parameters and change in aortic TBR. Overall, 10-year ASCVD risk score did not change significantly (Table 1).
Adverse Events
E/C/F/TDF was well tolerated without related adverse events.
DISCUSSION
Arterial inflammation, reflected in the aortic TBR, did not decrease after treatment with E/C/F/TDF. In contrast, TBR of the axillary lymph nodes consistently decreased with ART. For context, the increase in aortic TBR among subjects initiating ART in the current study resulted in a final level of aortic TBR roughly equivalent to that seen among more chronically treated HIV-infected patients in our prior study8. We observed a significant correlation between ART-induced changes in two separate measures of arterial inflammation – aortic TBR on 18F-FDG-PET and plasma levels of Lp-PLA2, a marker that relates to incident CVD events in the general population11. While our study was not primarily powered to detect changes in coronary plaque, our CCTA assessments revealed progression of atherosclerotic plaque volume coinciding with ART treatment among those HIV-infected subjects with baseline plaque. Changes in coronary plaque volume occurred over a short time period among young HIV-infected subjects with a low 10-year ASCVD risk score.
Notably, ART-induced changes in arterial inflammation and coronary atherosclerosis occurred in the context of improved immune homeostasis. In addition to potently suppressing viremia, E/C/F/TDF increased the CD4+ T cell count and reduced axillary lymph node TBR on 18F-FDG-PET. E/C/F/TDF also reduced CD4+ and CD8+ T cell activation and levels of the chemoxine CXCL10, although not down to the levels seen in controls. Moreover, with therapy, subpopulations of circulating monocytes shifted, favoring a relative increase in the percentage of classical CD14+CD16− monocytes and a decrease in the intermediate/inflammatory CD14+CD16+ population. For context, previous studies have demonstrated effects of select ART regimens, including those incorporating the integrase inhibitor raltegravir, to reduce CD4+ and CD8+ T cell activation12. Of note, in previous studies involving other regimens, newly-initiated ART did not change the proportions of monocyte subsets but did change patterns of monocyte cell surface expression13.
Several possible explanations exist for why arterial inflammation was not reduced in the context of favorable E/C/F/TDF effects on immune parameters. First, E/C/F/TDF only partially dampened select indices of immune activation. For example, although E/C/F/TDF reduced T cell activation, the percent of circulating activated T cells remained elevated relative to those seen in controls. In addition, select monocyte activation markers linked to arterial inflammation8 were not reduced by E/C/F/TDF therapy. Second, effects of integrase-inhibitor based therapy to alter monocyte cell surface receptor expression (such as expression of CX3CR1, not tested in this study), could influence honing of monocytes to the vascular endothelium14. Third, small, anticipated E/C/F/TDF-mediated effects to increase creatinine15 might be expected to influence arterial inflammation, but in our study, change in creatinine did not relate to change in aortic TBR. Finally, it is possible that different results would be observed among patients with longer duration HIV, longer duration ART, or higher baseline traditional CVD risk.
Our findings reinforce the overall benefits of immediate ART 16, including favorable effects of ART to suppress viremia, partially restore immune homeostasis, and partially dampen select immune activation indices. However, our longitudinal study provides novel data derived from 18F-FDG-PET and CCTA to suggest for the first time that these effects may be insufficient to forestall the progression of HIV-associated CVD, at least over the short-term. Complementary strategies to further improve immune activation indices and arterial inflammation - including statins and other immuno-modulatory strategies - may be needed, in addition to ART. Strengths of our study include the novel application of 18F-FDG-PET and CCTA in concert with detailed immune and metabolic phenotyping before and after new initiation of a contemporary ART regimen. Limitations include the relatively small sample size and the absence of women in the cohort. Furthermore, we utilized stand-alone 18F-FDG-PET imaging with manual co-registration to CCTA imaging. Moreover, the full clinical impact of arterial inflammation as measured by 18F-FDG-PET in the HIV population remains unknown. Future studies are needed to examine longer-term, comparative effects of different ART regimens on arterial inflammation and to elucidate the relationship between arterial inflammation, atherogenesis, and MI in HIV.
Supplementary Material
Acknowledgments
Funding/Support: This work was supported by an investigator-initiated grant from Gilead Sciences to S.K.G., as well as by NIH M01-RR-01066 and 1 UL1 RR025758-01, Harvard Clinical and Translational Science Center, from the National Center for Research Resources, and P30 DK040561, Nutrition Obesity Research Center at Harvard. M.V.Z.’s effort was supported by a Medical Research Investigator Training (MeRIT) award from the Harvard Catalyst / The Harvard Clinical and Translational Sciences Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award 8KL2TR000168–05). Dr. Lu was supported by the American Roentgen Ray Society Scholarship. Funding sources had no role in the design of the study, data analysis or the writing of the manuscript.
Footnotes
Role of the Sponsors: The study funders had no role in the design or conduct of the study; collection, management, analysis, and interpretation of the data; preparation of the manuscript; or decision to submit the manuscript for publication. Gilead Sciences reviewed the manuscript prior to submission, but submission was not contingent upon approval by Gilead Sciences.
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or Gilead Sciences.
Previous Presentations: These data have not been previously presented.
Additional Contributions: The investigators would like to thank the nursing staff on the MGH Clinical Research Center as well as the volunteers who participated in this study.
Author Contribution: Dr. Grinspoon had full access to the data in the study and he takes full responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Zanni, Grinspoon
Acquisition analysis and interpretation of the data: All authors
Drafting of the manuscript: Zanni, Toribio, Martin, Grinspoon
Critical revision of the manuscript for important intellectual content: All authors
Statistical analyses: Zanni, Toribio, Martin, Lee, Grinspoon
Obtained funding: Zanni, Grinspoon
Administrative, technical or material support: Martin, Robbins, Lu, Ishai, Hoffmann, Tawakol, Burdo, Williams
Study supervision: Grinspoon
Conflict of Interest Disclosures: Dr. Zanni reported participating in a scientific advisory board meeting for Roche Diagnostics and reported receiving grant support from Gilead Sciences, both unrelated to the manuscript. Dr. Melbourne is employed by Gilead Sciences. Dr. Hoffman reported receipt of grants from HeartFlow Inc, Siemens Healthcare, Genzyme, and the American College of Radiology Imaging Network and personal fees from the American Heart Association, all unrelated to this manuscript. Dr. Williams reported serving on the scientific advisory board of Macrophage Therapeutics LLC, unrelated to the manuscript. Dr. Tawakol reported serving as a consultant for Actelion, Amgen, AstraZeneca, Carenis, and Takeda and receiving grant support from Actelion, Genentech and Takeda, all unrelated to the manuscript. Dr. Grinspoon received research funding for this investigator-initiated research project from Gilead Sciences. In addition, Dr. Grinspoon reported serving as a consultant to Gilead Sciences, Theratechnologies, BMS, NovoNordisk, Merck, Navidea, Aileron, and Astra Zeneca and reported receiving grant support from Amgen, BMS, Gilead Sciences, KOWA Pharmaceuticals and Theratechnologies, all unrelated to the manuscript. No other authors reported any disclosures.
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