Table 1. Cardiovascular disease.
| Author, year | Study design | Age | % male | HIV Virological Control | NCD Examined | Main findings | |
|---|---|---|---|---|---|---|---|
| 1 | Kelesidis 2012, USA | Longitudinal analysis of cohort study (A5078), 1. PWH (n = 55) and 2. HIV negative (n = 36) | Years (median, IQR): 41 (38–45), HIV- 40 (36–45) |
1. 96%, 2. 89% |
84% undetectable/ supressed viral load | CIMT | Serum sCD14 and LPS were associated with the progression of subclinical atherosclerosis. |
| 2 | Blodget 2012, USA | Sub-study of RCT (A5152s) (n = 75) 1. Baseline and 2. Week 24, and cross-sectional analysis of Indiana University Cohort study (n = 85). 3. On ART, 4. Not on ART |
Years (mean, SD) 1. 35±8 2. 35±8 3. 40±8 3. 38±11 |
1. 92% 2. 94% 3. 63% 4. 79% |
1. 0%, 2. 92%, 3. 84%, 4. 11% undetectable/ suppressed viral load |
Endothelial function, assessed by ultrasonic measurement of brachial artery FMD 60 seconds after lower forearm cuff release expressed as a % change | No significant correlation between brachial FMD and either sCD14 or LPS across groups in A5152s study. Negative correlation between LPS and brachial FMD, with a progressive step-wise decrease in median % FMD across increasing tertiles of LPS levels om Indiana cohort study. |
| 3 | Manner 2013 Norway | Cohort study, PWH (n = 42) and HIV negative (n = 15) | Years (median, IQR) PWH 42 (32–46), HIV- 40 (36–45) |
80% | 44000 (3550–165000) copies/mL (median, IQR) | BP at two visits | Plasma levels of LPS correlated with sCD14 in PWH. LPS and sCD14 were strongly correlated in patients with HTN with a stepwise increase in BP across the tertiles of LPS and sCD14. |
| 4 | Qi 2018 Australia | Cohort study, 1. PWH (n = 520) and 2. HIV negative (n = 217) at two time points, median follow up 7 years | Years (median, IQR) 1. 44 (40.5, 42), 2. 44.5 (41.5–50.5) | 1.44%, 2.50% |
women- 160 (80–4700), Men 40 (40–1280) copies/mL, (median, IQR) |
CAP measurement by carotid ultrasound; sCD14, sCD163, galectin-3, Gal-3 binding protein, CRP, IL-6 | Tryptophan, kynurenic acid, and KTR were higher in PWH and correlated with serum sCD14, Gal-3. Higher plasma tryptophan was significantly associated with a lower risk of CAP while higher plasma kynurenic acid and KTR were significantly associated with an increased risk of CAP. |
| 5 | Sinha 2015 USA | Case control study, PWH (n = 82) and HIV- (n = 20) | Years (mean, SD) PWH 50.6 +- 9.6, HIV- 48.9 +- 12.4 | 94% | 75.9% undetectable/ suppressed viral load | CIMT | PWH had similar TMAO levels as uninfected individuals with CAD. With increasing TMAO and carnitine, there was a mild association with increased mean CIMT. |
| 6 | Srinivasa 2015 USA & France | Cross sectional study, 1.PWH (n = 155) and2. HIV–(n = 67) | Years (mean, SD) PWH 47 ± 7, HIV- 46 ¬± 7 |
1.61%, 2.58% |
86% undetectable/ suppressed viral load | CTA imaging for assessment of CAP; VAT and SAT by CT scan; Dietary intake collected through a 4-day food record. | PWH had a significantly higher prevalence of CAP and number of total CAP segments. In PWH, serum TMA was significantly and positively associated with calcium score, number of total CAP, number of calcified CAP, calcium plaque volume and calcium plaque mass. TMA levels inversely correlated with HDL and were positively correlated with LPS. |
| 7 | Haissman 2016, Norway | Cross sectional study, 1. PWH without CHD (n = 105), 2. HIV- without CHD (n = 105), And Case-control study 3. PWH with first-time MI (n = 55), 4. HIV- controls (n = 182) |
Years (mean, SD) PWH 46 +- 8, HIV—47 +-9 |
1. 89%, 2. 89%; 3. 91% 4. 92% |
90% undetectable/ suppressed viral load | Myocardial perfusion scintigraphy, CACS, CIMT; The Framingham risk score; Measurement of Cholesterol, triglycerides, and glucose | No difference in plasma TMAO or choline between groups with first-time MI, but betaine was lower in HIV-infected person;. 18% of PWH had MPD vs. 0% among HIV- and MPD was associated with elevated TMA. |
| 8 | Elliott-Miller 2016, USA | Case control study of MACS cohort (n = 102), Cases = CAP > 50% in 1 or more coronary segments, (n = 51). Controls = No CAP on CCTA, (n = 51) | Years (median, IQR) cases 55 (51–58), controls 54 (51–59) | 100% | 80% undetectable/ suppressed viral load | Non-contrast cardiac CT and CCTA to define presence/ absence of atherosclerosis. | TMAO levels showed an inverted U shaped association with coronary artery stenosis in PWH, not controls. |
| 9 | Knudsen 2016, Denmark & Norway | Cross sectional study- SHADE, PWH (n = 94) | Years (mean, SD) 49.6 +-1.0 | 53% | 100% undetectable/ suppressed viral load | MBF reserve determined by 82Rb PET/CT at rest and during adenosine-induced stress; Framingham risk score | No association between TMAO and myocardial perfusion, left ventricular ejection fraction, age or CAC score as assessed by 82Rb PET/CT. |
| 10 | Haissman 2017, Norway | Cross sectional study, PWH on cART n = 50, PWH not on cART n = 50 |
Years (median, IQR) on ART 43 (36–48), not an ART 41 (33–46) | 88% | 1. Untreated PWH 23,026 (5517–90,321), 2. Treated PWH 19 (19–20), copies/mL (median, IQR) | Platelet function was determined by whole-blood multiple electrode impedance aggregometry. | Elevated ratios of TMAO/betaine and TMAO/carnitine found in PWH on ART. |
| 11 | Shan 2018, USA | Cohort study (WIHS and MACS cohorts),1. PWH n = 520, 2.HIV- n = 217 | Years (median, IQR) PWH women 42 (38–46), men 46 (43–50), HIV- women 42 (38–47), men 47 (45–54) |
1.44%, 2. 50% |
1. women- 160 (80–4700), 2. Men 40 (40–1280) copies/mL, (median, IQR) |
CAP measurement by carotid ultrasound; Serum measurement of sCD14, sCD163, galectin-3, galectin-3 binding protein, CRP, and IL-6. Plasma measurement of TMAO and KP | Higher plasma TMAO was significantly associated with an increased risk of CAP in PWH; TMAO was significantly positively correlated with plasma KTR and sCD14; |
| 12 | Kehrmann 2019, Germany | Cross sectional study of PWH with CHD (n = 30) and without CHD (n = 30) | Years (mean, SD) CHD + 54.1± 11.2, CHD—51.6 ¬± 10.7 | 93% | 96% undetectable/ suppressed viral load | CHD+ defined by: (1) diagnosis of CHD by positive heart catheter examination; (2) history of MI; and (3) history of CHD+ | Lower α-diversity in CHD+ compared to CHD-. CHD- co-occurrence network defined by abundant genera Bacteroides and Prevotella; CHD+ co-occurrence network defined by a Prevotella and a Ruminococcaceae abundance. The Prevotella-rich cluster was largely composed of MSM (97%), whereas the Bacteroides-rich cluster comprised both MSM (45%) and heterosexual individuals (55%). Higher TMAO was associated with a higher relative abundance of 4 OTUs, belonging to the genera Phascolarctobacterium, Desulfovibrio, Sutterella, and Faecalibacterium. |
| 13 | Sinha 2019, USA | A cross sectional analysis of 1. the SCOPE cohort (n = 162) and a case-control analysis of the CNICS cohort- 2. PWH (n = 36 cases (MI), 3. n = 69 controls (no MI)) |
Years (median, IQR) 1.49 (42–55), 2. 50 (47–58), 3. 49(46–57) |
1.91%, 2.78%, 3.77% | 75 (50–982) copies/mL (median, IQR) | 1. total cholesterol, HDL, lLDL, triglycerides, Il-6, hs-CRP and d-dimer measurements; 2 & 3: CIMT measurements at baseline and at the end of the study (median time 3.1 yrs) | In the SCOPE cohort- carnitine was strongly associated with baseline CAP but both betaine and carnitine were significantly associated with progression of CIMT. IL-6 and D-dimer were associated with atherosclerosis but not with carnitine or betaine. In the CNICS cohort- higher carnitine levels carried increased risk of MI. |
| 14 | Montrucchio 2020, Italy | Cross sectional analysis of cohort study of PWH and HIV–(n = 175) and a probiotic intervention pilot study (n = 25) | Years (median, IQR) 50 (44–55) | 79.40% | 90.7% undetectable/ suppressed viral load | CIMT; Framingham; D:A:;, ASCVD/AHA/ACC and CUORE scores; | Higher TMAO levels associated with higher CIMT; |
| 15 | El-Far 2021, USA | Cross sectional study, PWH (n = 79) and HIV- (n = 49) | Years (mean, SD) PWH Plaque—52.48 +- 6.27, PWH Plaque + 55.55 +-6.54, HIV- Plaque + 55.81 +-7.47, HIV- Plaque- 53.05 +- 6.39 |
100% | 99.9% undetectable/ suppressed viral load | Non-contrast cardiac CT and CTA to define presence/ absence of atherosclerosis; Inflammatory markers measured included six IL-32 isoforms (α, β, γ, D, ϵ and θ), IL-18, IL-β, IL-10, TNF-α and IL-6 |
All IL-32 isoforms were higher in PWH; IL-32D and IL-32θ isoforms were further upregulated in HIV+ CAD+ compared to HIV+ CAD-; Plasma LBP in PWH correlated with expression of IL-32D, IL-32α, β, and ϵ, IL-18, TNF- α-and IL-6; Increased expression of IL-32 isoforms in PWH with CAP was associated with increased abundance of Rothia and Eggerthella species) and lower abundance of the SCFA caproic acid, |
| 16 | Colaco 2021, USA | Cross sectional study of PWH 1. with DD (n = 94), 2. NDD (n = 101) | Years (mean, SD) 1. 58.0±8.1 2. 52.5±5.7 |
71% | 20 (20–40) copies/mL, (median, IQR) | ECHO; cardiac MRI, plasma measurement of Choline metabolites | TMAO and choline were higher in the DD+ group and TMAO was associated with ECHO DD indexes; TMAO and betaine were associated with measures of myocardial fibrosis and TMAO was correlated with NT‐proBNP, troponin‐I, galectin‐3, GDF‐15, IL‐6 and sCD14. |
| 17 | Wang 2022, USA | A cross-sectional study of the WIHS Cohort of PWH and HIV-, n = 361 (264 plaque- and 97 plaque+), and a longitudinal observational analysis of the same cohort (n = 112) |
Years (median, IQR) plaque—52 (46–57) plaque + 57 (52–62) |
0% | 74.7% undetectable/ suppressed viral load | Carotid artery ultrasound; Plasma metabolomic/ lipidomic profiling |
Fusobacterium was associated with CAP, diastolic BP, plasma lipids and the metabolites lysophosphatidylcholines, lysophosphatidylethanolamines and diglycerides; Proteus was also associated with CAP; Odoribacter was inversely associated with CAP and systolic BP; Adlercreutzia had a moderate inverse correlation with HbA1c. Baseline plasma gut microbiota-related lipid profiles were significantly associated with incident CAP over 7 years. |
| 18 | Wang 2023, USA | A cross-sectional study of the WIHS Cohort of 1. CAP+ (n = 84) and 2. CAP- (n = 236) | Years (median, IQR) 1. 57 (53–62) 2. 51(46–56) |
0% | 74.6% undetectable/ suppressed viral load | Carotid artery ultrasound; Plasma metabolomic/ lipidomic profiling |
CAP was associated with enriched Fusobacterium nucleatum and depleted Roseburia hominis, Roseburia inulinivorans, Odoribacter splanchnicus, Clostridium saccharolyticum, and Johnsonella ignava Fusobacterium nucleatum was alo associated serum proteomic markers–eg CXCL9 CAP-associated species were correlated with several plasma metabolites, including the microbial metabolite imidazole-propionate (ImP) |
| 19 | Luo 2023, USA | A cross-sectional study of the WIHS Cohort of (n = 361) women with CAP | 0% | 1. Without plaque 71.0 (36.5, 1,912.5), 2. With plaque 43.0 (33.50, 224.0) copies/mL, (median, IQR) |
Carotid artery ultrasound; KP metabolites measured by high performance liquid chromatography. |
KYNA and KYNA/TRP were positively associated with plaque, indole-3-propionate (IPA) and IPA/KYNA were inversely associated with plaque. Five gut bacterial genera were positively associated with IPA including Roseburia spp., Eubacterium spp., Lachnospira spp., and Coprobacter spp.; An IPA-associated-bacteria score was inversely associated with plaque |
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| 20 | Peters 2023, USA | A cross-sectional study of the WIHS Cohort of (n = 197) post-menopausal women with CAP | Years (median, IQR) 58 (54, 61) | 0% | 1.00 (1.00, 20.00), copies/mL, (median, IQR) | Carotid artery ultrasound; Sex steroid hormones and sex hormone binding globulin (SHBG |
Higher α-diversity was associated with DHEA-S:DHEA ratio, E2, E1, free E2, E1-S, the E1:4-dione ratio, and the E2:testosterone ratio. Estrogens were positively associated with Alistipes, Collinsella, Erysipelotrichia, and Clostridia spp; Androgens were positively associated with Actinomyces, Erysipelotrichia, and Clostridia spp; Adrenal precursors were positively associated with Prevotella, Gammaproteobacteria, Actinomyces, and Megasphaera spp |
Abbreviations: ART, antiretroviral therapy; ASCVD, Atherosclerotic Cardiovascular Disease; BMI, body mass index; BNP, brain natriuretic peptide, BP, Blood Pressure; CAC, coronary artery calcium; CAP, Carotid artery plaque; CIMT, Carotid intima media thickness; CHD, coronary heart disease; CCTA, Cardiac CT angiography; CT, computed tomography; CVD, cardiovascular disease; CVS, cardiovascular system; DD, Diastolic dysfunction; ECHO, Echocardiography; FMD, flow-mediated dilation; FRS, Framingham Risk Score; HDL, high‐density lipoprotein; hsCRP, high‐sensitivity C‐reactive protein; IL-6, interleukin‐6; KTR, Kynurenine to Tryptophan Ratio; MBF, Myocardial blood flow; MI, myocardial infarction; MLWH, men living with HIV; MPD, myocardial perfusion defects; MRI, magnetic resonance imaging; MSM, men who have sex with men; NDD, No diastolic dysfunction; sCD14, soluble CD14; SAT, subcutaneous adipose tissue; SCFA, short-chain fatty acid; VAT, visceral abdominal tissue; WLWH, women living with HIV; PI, protease inhibitors; PWH, people living with HIV; RR, risk ratio; WIHS, Women’s Interagency HIV Study.