Objective To determine the associations of markers of immune activation with atherosclerosis and mortality, in participants with treated and suppressed HIV infection. Design Observational study of 149 HIV-infected participants with virologic suppression on antiretroviral therapy. Methods Cryopreserved mononuclear cells and plasma were used to evaluate markers of T cell and monocyte activation, inflammation and coagulopathy. Carotid artery intima-media thickness (CIMT) was measured by high-resolution ultrasound at the common, bifurcation and internal carotid regions. Associations of immunologic markers with CIMT and all-cause mortality were assessed using multivariable linear regression and Cox proportional hazards regression. Results The majority of participants were male (93%) and white (67%), median age of 48.5 years and median CD4+ T cell count of 522 cells/μL. The median baseline IMT was 1.0 mm. Over a median of 8.3 years of follow-up, 12 deaths occurred. In multivariate analysis, adjusted for traditional cardiovascular risk factors, higher monocyte CCR5 expression (5.4%, 95%CI [2.4–8.4], p=0.001) was associated with greater common carotid IMT. Higher plasma IL-6 was associated with greater bifurcation (8.0%, 95%CI [2.3–13.7], p=0.007) and overall mean IMT (5.2%, 95%CI [0.7–9.7], p=0.026). Finally, higher plasma IL-6 (HR 1.9, 95%CI [1.0–3.7], p=0.030), internal carotid (HR 4.1, 95%CI [1.2–13.7], p=0.022) and mean IMT (HR 5.2, 95%CI [1.2–22.1], p=0.026) were individually associated with all-cause mortality. Conclusions Higher monocyte CCR5 expression and plasma IL-6 were associated with atherosclerosis, independent of traditional cardiovascular risk factors. IL-6 and CIMT were individually associated with all-cause mortality. The impact of therapies targeting immune activation in CVD in treated HIV infection merits additional investigation.

BackgroundProprotein convertase subtilisin kexin 9 (PCSK9) inhibitors reduce low‐density lipoprotein cholesterol (LDL‐C) and improve outcomes in the general population. HIV‐infected individuals are at increased risk for cardiovascular events and have high rates of dyslipidemia and hepatitis C virus (HCV) coinfection, making PCSK9 inhibition a potentially attractive therapy.Methods and ResultsWe studied 567 participants from a clinic‐based cohort to compare PCSK9 levels in patients with HIV/HCV coinfection (n=110) with those with HIV infection alone (n=385) and with uninfected controls (n=72). The mean age was 49 years, and the median LDL‐C level was 100 mg/dL (IQR 77–124 mg/dL); 21% were taking statins. The 3 groups had similar rates of traditional risk factors. Total cholesterol, LDL‐C, and high‐density lipoprotein cholesterol levels were lower in coinfected patients compared with controls (P<0.001). PCSK9 was 21% higher in HIV/HCV‐coinfected patients versus controls (95% CI 9–34%, P<0.001) and 11% higher in coinfected individuals versus those with HIV infection alone (95% CI 3–20%, P=0.008). After adjustment for cardiovascular risk factors, HIV/HCV coinfection remained significantly associated with 20% higher PCSK9 levels versus controls (95% CI 8–33%, P=0.001). Interleukin‐6 levels increased in a stepwise fashion from controls (lowest) to HIV‐infected to HIV/HCV‐coinfected individuals (highest) and correlated with PCSK9 (r=0.11, P=0.018).ConclusionsDespite having lower LDL‐C, circulating PCSK9 levels were increased in patients coinfected with HIV and HCV in parallel with elevations in the inflammatory, proatherogenic cytokine interleukin‐6. Clinical trials should be conducted to determine the efficacy of targeted PCSK9 inhibition in the setting of HIV/HCV coinfection.

Background HIV infection is associated with a high risk of cardiovascular diseases (CVD) and increased arterial inflammation. In HIV, inflammation is also increased within lymph nodes (LN), tissues known to harbor the virus even among treated and suppressed individuals. We tested the hypothesis that arterial inflammation is linked to HIV disease activity and to inflammation within HIV-infected tissues (LN). Methods Seventy-four individuals were studied: 45 HIV-infected individuals and 29 uninfected controls. Arterial and LN inflammation were measured using 18F-fluorodeoxyglucose positron emission tomography, (FDG-PET). Detailed immunophenotyping was performed, along with measurement of viral activity/persistence, and circulating inflammatory biomarkers. Results Median age was 53 years, 100% male. Lymph node inflammation was higher in HIV-infected individuals and correlated with markers of viral disease activity (viral load, CD8+ T cells, CD4/CD8 ratio) and CD4+ T cell activation. Arterial inflammation was modestly increased in HIV-infected individuals and was positively correlated with circulating inflammatory biomarkers (hsCRP, IL-6) and activated monocytes (CD14dimCD16+; non-classical) but not to markers of HIV. While LN and arterial inflammation were increased in HIV, inflammatory activity in these tissues was not related (r=0.09, p=0.56). Conclusion While LN and to a lesser degree, the arterial wall are inflamed in HIV, inflammation in these tissues is not closely linked. Namely, measures of HIV disease activity strongly associate with LN inflammation but not arterial inflammation. These data suggest that LN and arterial inflammation do not share underlying pathways of immune activation and suggests therapeutic interventions that reduce viral disease activity may not predictably reduce arterial inflammation in HIV or its down-stream consequence (CVD).

BackgroundCompared to uninfected adults, HIV‐infected adults on antiretroviral therapy are at increased risk of cardiovascular disease. Given the increase in T‐cell dysfunction, inflammation, and coagulation in HIV infection, microvascular dysfunction is thought to contribute to this excess cardiovascular risk. However, the relationships between these variables remain undefined.Methods and ResultsThis was a cross‐sectional study of 358 HIV‐infected adults from the SCOPE cohort. Macrovascular endothelial function was assessed using flow‐mediated dilation of the brachial artery and microvascular function by reactive hyperemia. T‐cell phenotype was determined by flow cytometry. Plasma markers of inflammation (tumor necrosis factor‐α, interleukin‐6, high‐sensitivity C‐reactive protein, sCD14) and coagulation (fibrinogen, D‐dimer) were also measured. In all HIV+ subjects, markers of inflammation (tumor necrosis factor‐α, high‐sensitivity C‐reactive protein), coagulation (D‐dimer) and T‐cell activation (CD8+PD1+, CD4+interferon+cytomegalovirus‐specific) were associated with worse reactive hyperemia after adjusting for traditional cardiovascular risk factors and co‐infections. In treated and suppressed subjects, tumor necrosis factor‐α and CD8+PD1+ cells remained associated with worse reactive hyperemia after adjustment. Compared to the untreated subjects, CD8+PD1+ cells were increased in the virally suppressed group. Reactive hyperemia was predictive of flow‐mediated dilation.Conclusions CD8+PD1+ cells and tumor necrosis factor‐α were associated with microvascular dysfunction in all HIV+ subjects and the treated and suppressed group. Additionally, D‐dimer, high‐sensitivity C‐reactive protein, sCD‐14, and interleukin‐6 were associated with microvascular dysfunction in all HIV+ subjects. Although T‐cell dysfunction, inflammation, and microvascular dysfunction are thought to play a role in cardiovascular disease in HIV, this study is the first to look at which T‐cell and inflammatory markers are associated with microvascular dysfunction in HIV‐infected individuals.

Objective To examine the relationship between asymmetric dimethylarginine (ADMA) and HIV-associated pulmonary arterial hypertension (PAH). Design HIV infection is an independent risk factor for PAH, but the underlying pathogenesis remains unclear. Chronic inflammation resulting in nitric oxide-mediated endothelial dysfunction is a key mechanism underlying other types of PAH. ADMA is an endogenous inhibitor of endothelial nitric oxide synthase. Among uninfected individuals, ADMA is associated with PAH and predicts disease-related mortality. Methods We measured ADMA, high sensitivity C-reactive protein, interleukin-6 (IL-6), D-dimer, and pulmonary artery systolic pressure (PASP) using echocardiography in HIV-infected individuals. Right heart catheterization (RHC) was performed in individuals with a PASP at least 30 mmHg. We performed multivariable analysis to identify factors associated with high PASP by echocardiogram and PAH by RHC. Results Among 214 HIV-infected individuals, the median age was 50 years, 82% were men, 71% were on antiretroviral therapy, and 4.2% carried a prior diagnosis of PAH. ADMA and IL-6 were associated with increased values of PASP following multivariable adjustment (7.2% per 0.1 μmol/l, P =0.0049 and 3.9% per doubling, P =0.027, respectively). In adjusted analysis among the 85 participants who underwent RHC, ADMA and IL-6 were associated with higher values of mean PAP (14.2% per 0.1 μmol/l, P =0.0014 and 5.8% per doubling, P =0.038, respectively). However, only ADMA was associated with PAH (prevalence ratio =1.74, P =0.029). Conclusion Elevated levels of ADMA are independently associated with PAH among HIV-infected individuals. Our findings suggest that chronic HIV-associated inflammation leading to an accumulation of ADMA and subsequent nitric oxide-mediated endothelial dysfunction may represent a novel mechanism for HIV-associated PAH.

Background—Although HIV is associated with increased atherosclerotic cardiovascular disease (CVD) risk, it is unknown whether guidelines can identify HIV-infected adults who may benefit from statins. We compared the 2013 American College of Cardiology/American Heart Association and 2004 Adult Treatment Panel III recommendations in HIV-infected adults and evaluated associations with carotid artery intima-media thickness and plaque.Methods and Results—Carotid artery intima-media thickness was measured at baseline and 3 years later in 352 HIV-infected adults without clinical atherosclerotic CVD and not on statins. Plaque was defined as IMT >1.5 mm in any segment. At baseline, the median age was 43 (interquartile range, 39–49), 85% were men, 74% were on antiretroviral medication, and 50% had plaque. The American College of Cardiology/American Heart Association guidelines were more likely to recommend statins compared with the Adult Treatment Panel III guidelines, both overall (26% versus 14%; P<0.001), in those with plaque (32% versus 17%; P=0.0002), and in those without plaque (16% versus 7%; P=0.025). In multivariable analysis, older age, higher low-density lipoprotein cholesterol, pack per year of smoking, and history of opportunistic infection were associated with baseline plaque. Baseline IMT (hazard ratio, 1.18 per 10% increment; 95% confidence interval, 1.05–1.33; P=0.005) and plaque (hazard ratio, 2.06; 95% confidence interval, 1.02–4.08; P=0.037) were each associated with all-cause mortality, independent of traditional CVD risk factors.Conclusions—Although the American College of Cardiology/American Heart Association guidelines recommended statins to a greater number of HIV-infected adults compared with the Adult Treatment Panel III guidelines, both failed to recommend therapy in the majority of HIV-affected adults with carotid plaque. Baseline carotid atherosclerosis but not atherosclerotic CVD risk scores was an independent predictor of mortality. HIV-specific guidelines that include detection of subclinical atherosclerosis may help to identify HIV-infected adults who are at increased atherosclerotic CVD risk and may be considered for statins.

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