HIV persists in late coronary atheroma and is associated with increased local inflammation and disease progression.

Chronic inflammation contributes to the prevalence of cardiovascular disease in people living with HIV (PLWH). The immune mechanisms driving atherosclerosis progression in PLWH remain unclear. This study conducted comprehensive assessments of medium-sized coronary arteries and aorta from deceased PLWH and controls without HIV using DNA/RNA assays, spatial transcriptomics, and high-resolution mass spectrometry. Findings revealed more significant inflammation correlated with higher HIV copy numbers in late atheroma of PLWH. Enhanced CXCL12 and decreased ABCA1/ABCG1 expression in CD163+ macrophages were co-localized in coronaries of PLWH, suggesting a reduction in plasma lipoprotein clearance compared to controls. Spatial analyses identified potential therapeutic targets by revealing inflammatory changes in medium-sized arteries and the aorta. We examined the relationship between atherosclerotic phenotypes and inflammatory gene expression in Vanderbilts Biobank to study these findings in a larger clinical cohort. This established a significant association between ABCA1 and CXCL12 gene expressions with atherosclerosis, partly influenced by HIV.

Cytokine and chemokine receptor profiles in adipose tissue vasculature unravel endothelial cell responses in HIV.

Chronic systemic inflammation significantly increases myocardial infarction risk in people living with HIV (PLWH). Endothelial cell dysfunction disrupts vascular homeostasis regulation, increasing the risk of vasoconstriction, inflammation, and thrombosis, contributing to cardiovascular disease. We aimed to characterize endothelial cell (EC) chemokines, cytokine, and chemokine receptors of PLWH, hypothesizing that in our cohort, glucose intolerance contributes to their differential expression implicated in endothelial dysfunction. Using single-cell transcriptomic analysis, we phenotyped chemokine and cytokine receptor expression on arterial ECs, capillary ECs, venous ECs, and vascular smooth muscle cells (VSMCs) in subcutaneous adipose tissue of 59 PLWH with and without glucose intolerance. Our results show that arterial and capillary ECs express significantly higher interferon and tumor necrosis factor (TNF) receptors than venous ECs and VSMCs. Venous ECs exhibited more interleukin (IL)1R1 and ACKR1 receptors, and VSMCs showed significant IL6R expression than arterial and capillary ECs. When stratified by group, arterial ECs from PLWH with glucose intolerance expressed significantly higher IL1R1, IL6R, CXCL12, CCL14, and ICAM2 transcripts than arterial ECs from PLWH without diabetes. Of the different vascular cell types studied, arterial ECs as a proportion of all ECs in adipose tissue were positively correlated with plasma fasting blood glucose. In contrast, venous ECs and VSMCs were positively correlated with plasma IL6. To directly assess the effect of plasma from PLWH on endothelial function, we cultured human arterial ECs (HAECs) in plasma-conditioned media from PLWH and performed bulk RNA sequencing. Plasma from PLWH stimulated ECs with the upregulation of genes that enrich for the oxidative phosphorylation and the TNF-α via NFK-ß pathways. In conclusion, ECs in PLWH show heterogeneous cytokine and chemokine receptor expression, and arterial ECs were the most influenced by glucose intolerance. Further research must explicate cytokine and chemokine roles in EC dysfunction and identify biomarkers for disease progression and therapeutic response.

Inflammation in HIV and Its Impact on Atherosclerotic Cardiovascular Disease.

People living with HIV have a 1.5- to 2-fold increased risk of developing cardiovascular disease. Despite treatment with highly effective antiretroviral therapy, people living with HIV have chronic inflammation that makes them susceptible to multiple comorbidities. Several factors, including the HIV reservoir, coinfections, clonal hematopoiesis of indeterminate potential (CHIP), microbial translocation, and antiretroviral therapy, may contribute to the chronic state of inflammation. Within the innate immune system, macrophages harbor latent HIV and are among the prominent immune cells present in atheroma during the progression of atherosclerosis. They secrete inflammatory cytokines such as IL (interleukin)-6 and tumor necrosis-α that stimulate the expression of adhesion molecules on the endothelium. This leads to the recruitment of other immune cells, including cluster of differentiation (CD)8+ and CD4+ T cells, also present in early and late atheroma. As such, cells of the innate and adaptive immune systems contribute to both systemic inflammation and vascular inflammation. On a molecular level, HIV-1 primes the NLRP3 (NLR family pyrin domain containing 3) inflammasome, leading to an increased expression of IL-1ß, which is important for cardiovascular outcomes. Moreover, activation of TLRs (toll-like receptors) by HIV, gut microbes, and substance abuse further activates the NLRP3 inflammasome pathway. Finally, HIV proteins such as Nef (negative regulatory factor) can inhibit cholesterol efflux in monocytes and macrophages through direct action on the cholesterol transporter ABCA1 (ATP-binding cassette transporter A1), which promotes the formation of foam cells and the progression of atherosclerotic plaque. Here, we summarize the stages of atherosclerosis in the context of HIV, highlighting the effects of HIV, coinfections, and antiretroviral therapy on cells of the innate and adaptive immune system and describe current and future interventions to reduce residual inflammation and improve cardiovascular outcomes among people living with HIV.

Cytokine and Chemokine Receptor Profiles in Adipose Tissue Vasculature Unravel Endothelial Cell Responses in HIV.

Chronic systemic inflammation contributes to a substantially elevated risk of myocardial infarction in people living with HIV (PLWH). Endothelial cell dysfunction disrupts vascular homeostasis regulation, increasing the risk of vasoconstriction, inflammation, and thrombosis that contribute to cardiovascular disease. Our objective was to study the effects of plasma from PLWH on endothelial cell (EC) function, with the hypothesis that cytokines and chemokines are major drivers of EC activation. We first broadly phenotyped chemokine and cytokine receptor expression on arterial ECs, capillary ECs, venous ECs, and vascular smooth muscle cells (VSMCs) in adipose tissue in the subcutaneous adipose tissue of 59 PLWH using single cell transcriptomic analysis. We used CellChat to predict cell-cell interactions between ECs and other cells in the adipose tissue and Spearman correlation to measure the association between ECs and plasma cytokines. Finally, we cultured human arterial ECs (HAECs) in plasma-conditioned media from PLWH and performed bulk sequencing to study the direct effects ex-vivo. We observed that arterial and capillary ECs expressed higher interferon and tumor necrosis factor (TNF) receptors. Venous ECs had more interleukin (IL)-1R1 and ACKR1 receptors, and VSMCs had high significant IL-6R expression. CellChat predicted ligand-receptor interactions between adipose tissue immune cells as senders and capillary ECs as recipients in TNF-TNFRSF1A/B interactions. Chemokines expressed largely by capillary ECs were predicted to bind ACKR1 receptors on venous ECs. Beyond the adipose tissue, the proportion of venous ECs and VSMCs were positively plasma IL-6. In ex-vivo experiments, HAECs cultured with plasma-conditioned media from PLWH expressed transcripts that enriched for the TNF-α and reactive oxidative phosphorylation pathways. In conclusion, ECs demonstrate heterogeneity in cytokine and chemokine receptor expression. Further research is needed to fully elucidate the role of cytokines and chemokines in EC dysfunction and to develop effective therapeutic strategies.

HIV assisted partner services (aPS) to support integrated HIV and hypertension screening in Kenya: a pre-post intervention study.

BACKGROUND: People living with HIV (PLWH) have a higher risk of developing hypertension compared to HIV uninfected individuals. HIV assisted partner services (aPS), where PLWH are assisted by a healthcare provider to disclose their status to sexual and / or drug injecting partner(s), offers an opportunity for integrated HIV and hypertension screening. We evaluated the feasibility of the aPS model in supporting integrated HIV and hypertension screening at the Kenyatta National Hospital, Kenya. METHODS: Between August 2019 and December 2020, we conducted a pre-post intervention study. We enrolled women receiving HIV testing services (HTS) with confirmed hypertension (female index clients) and traced their male relatives for HIV and hypertension screening and reviewed management at 3-months. Hypertension was defined as systolic blood pressure (SBP) ≥ 140 mmHg, diastolic blood pressure (DBP) ≥ 90 mmHg, and/or use of antihypertensive medication. RESULTS: One hundred female index clients (median age: 55 years; interquartile range (IQR): 47-65) mentioned 165 male relatives (median: 49 years; IQR: 40-59) of whom 35% (n = 58/165) were enrolled. Of the male relatives, 29% had hypertension (n = 17/58), 34% had pre-hypertension (n = 20/58), and none were HIV-positive (n = 0/58). Among the female index clients, there was a statistically significant decline in SBP (pre: 156 mmHg, post: 133 mmHg, p-value: < 0.0001) and DBP (pre: 97 mmHg, post: 80 mmHg, p-value: < 0.0001), and increase in antihypertensive medication uptake (pre: 91%, n = 84/92; post: 98%, n = 90/92; X2: 4.3931, p-value: 0.036) relative to baseline. Among the male relatives, there was a statistically significant increase in antihypertensive medication uptake among those with hypertension (pre: 13%, n = 6/46; post: 17%, n = 8/46; X2: 32.7750, p-value: < 0.0001) relative to baseline. CONCLUSION: HIV aPS holds promise for integrated HIV and hypertension screening among at-risk clients and their families. Twenty-nine percent of the male relatives had hypertension, higher than the national prevalence (24%), while one-third had pre-hypertension. We observed relatively high participant retention, reductions in blood pressure, and increase in antihypertensive medication uptake among those with confirmed hypertension. Future research expanding the aPS model to other non-communicable diseases through larger studies with longer follow-ups is required to better assess causal relationships and optimize integrated service delivery.

Circulating plasma NT-proBNP predicts subclinical coronary atherosclerosis on CT angiography among older adults in Uganda.

OBJECTIVE: Phenotypes and mechanisms of cardiovascular disease (CVD) may differ across global populations. In sub-Saharan Africa (SSA), distinct environmental determinants may influence development and progression of atherosclerotic coronary artery disease (CAD). METHODS: We investigated associations between 6 established markers of myocardial stress and subsequent subclinical CAD (sCAD), defined as presence of any atherosclerosis on coronary CT angiography (CCTA) in a 2-year prospective cohort of Ugandan adults enriched for cardiometabolic risk factors (RFs) and HIV. Six plasma biomarkers were measured baseline among 200 participants (50% with HIV) aged ≥ 45 years with ≥ 1 cardiovascular RF. At 2-year follow-up, 132 participants (52% with HIV) who returned underwent coronary CCTA. RESULTS: In logistic regression models adjusted for cardiovascular RFs (age, diabetes, hypertension, hyperlipidemia, smoking, obesity) and non-traditional RFs (HIV, chronic kidney disease), only NT-proBNP predicted subsequent subclinical CAD (p < 0.008, Bonferroni correction for multiple testing). In sensitivity analyses adjusted for ASCVD risk category (instead of individual RFs) in the baseline cohort with multiple imputation applied to missing year 2 CCTA data (n = 200), NT-proBNP remained significantly associated with subsequent CAD (p < 0.008). CONCLUSIONS: NT-proBNP consistently predicted subclinical CAD in Uganda in the absence of such an association among other markers of myocardial stress, suggesting a role for NT-proBNP in atherosclerosis independently of coronary microvascular dysfunction.

Distinct CD3 + CD14 + T Cell-Monocytes are dynamic complexes that harbor HIV and are increased with glucose intolerance.

Persistent systemic inflammation in persons with HIV (PWH) is accompanied by an increased risk of metabolic disease. Yet, changes in the innate and adaptive immune system in PWH who develop metabolic disease remain poorly defined. Using unbiased approaches, we show that PWH with prediabetes/diabetes have a significantly higher proportion of circulating CD14 + monocytes complexed to T cells. The complexed CD3 + T cells and CD14 + monocytes demonstrate functional immune synapses, increased expression of proinflammatory cytokines, and greater glucose utilization. Furthermore, these complexes harbor more latent HIV DNA compared to CD14 + monocytes or CD4 + T cells. Our results demonstrate that circulating CD3 + CD14 + T cell-monocyte pairs represent functional dynamic cellular interactions that likely contribute to inflammation and, in light of their increased proportion, may have a role in metabolic disease pathogenesis. These findings provide an incentive for future studies to investigate T cell-monocyte immune complexes as mechanistic in HIV cure and diseases of aging. Highlights: Persons with HIV and diabetes have increased circulating CD3 + CD14 + T cell-monocyte complexes. CD3 + CD14 + T cell-monocytes are a heterogenous group of functional and dynamic complexes. We can detect HIV in T cell-monocyte complexes. The proportion of CD3 + CD14 + T cell-monocyte complexes is positively associated with blood glucose levels and negatively with plasma IL-10 and CD4 + T regulatory cells.

CD4+ T cells expressing CX3CR1, GPR56, with variable CD57 are associated with cardiometabolic diseases in persons with HIV.

Persons with HIV (PWH) on long-term antiretroviral therapy (ART) have a higher incidence and prevalence of cardiometabolic diseases attributed, in part, to persistent inflammation despite viral suppression. In addition to traditional risk factors, immune responses to co-infections such as cytomegalovirus (CMV) may play an unappreciated role in cardiometabolic comorbidities and offer new potential therapeutic targets in a subgroup of individuals. We assessed the relationship of CX3CR1+, GPR56+, and CD57+/- T cells (termed CGC+) with comorbid conditions in a cohort of 134 PWH co-infected with CMV on long-term ART. We found that PWH with cardiometabolic diseases (non-alcoholic fatty liver disease, calcified coronary arteries, or diabetes) had higher circulating CGC+CD4+ T cells compared to metabolically healthy PWH. The traditional risk factor most correlated with CGC+CD4+ T cell frequency was fasting blood glucose, as well as starch/sucrose metabolites. While unstimulated CGC+CD4+ T cells, like other memory T cells, depend on oxidative phosphorylation for energy, they exhibited higher expression of carnitine palmitoyl transferase 1A compared to other CD4+ T cell subsets, suggesting a potentially greater capacity for fatty acid ß-oxidation. Lastly, we show that CMV-specific T cells against multiple viral epitopes are predominantly CGC+. Together, this study suggests that among PWH, CGC+ CD4+ T cells are frequently CMV-specific and are associated with diabetes, coronary arterial calcium, and non-alcoholic fatty liver disease. Future studies should assess whether anti-CMV therapies could reduce cardiometabolic disease risk in some individuals.

Latent tuberculosis is associated with heightened levels of pro-and anti-inflammatory cytokines among Kenyan men and women living with HIV on long-term antiretroviral therapy.

BACKGROUND: Persons with HIV (PWH) on antiretroviral therapy (ART) have persistent immune activation associated with increased risk for non-AIDS related diseases. Latent tuberculosis infection (LTBI), endemic in Africa, may contribute to this immune dysregulation. We evaluated the impact of HIV and TB co-infection on plasma pro- and anti-inflammatory cytokines among Kenyan adults. METHODS: We compared data from 221 PWH on long-term ART and 177 HIV-negative adults examining biomarkers of pro-[sCD14, interleukin (IL)-2, IL-6, interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), IL-12p70, IL-17A] and anti(IL-4, IL-5, IL-13) inflammatory cytokines, by HIV/LTBI status (HIV+LTBI+, HIV+LTBI-, HIV-LTBI+, HIV-LTBI-). LTBI was diagnosed based on a positive QuantiFERON TB Gold-Plus test in the absence of active TB symptoms. Linear regression was used to evaluate the associations of HIV, LTBI, and HIV/LTBI status with biomarkers adjusting for clinical factors including HIV-specific factors. RESULTS: Half of the participants were women and 52% had LTBI. HIV was independently associated with higher sCD14, IL-15, IL-6, IL-4, IL-5. LTBI was independently associated with higher TNF-α, IL-12p70, IL-17A, IL-4, IL-13 in adjusted models ( P  < 0.05). LTBI status was associated with higher IL-4 and IL-12p70 only among PWH, but not HIV-negative participants ( P  < 0.05 for interactions). In multivariate analysis, only HIV+LTBI+ demonstrated elevated levels of TNF-α, IL-6, IL-12p70, IL-15, IL-17A, IL4, IL-5, IL-13 in comparison to the HIV-LTBI- ( P  < 0.05 for all). The effect of LTBI on cytokines among PWH was independent of CD4 + T-cell count and ART duration. CONCLUSIONS: Despite viral suppression, persons with HIV and LTBI exhibit abnormal cytokine production accompanied by high concentrations of pro- and anti-inflammatory cytokines.

Sex modulates the association between inflammation and coronary atherosclerosis among older Ugandan adults with and without HIV.

OBJECTIVE: Inflammation is key in the pathogenesis of atherosclerotic coronary artery disease (CAD). Distinct sex-specific inflammatory mechanisms may contribute to CAD in sub-Saharan Africa (SSA), where environmental and biological determinants of systemic inflammation may differ from those in high-income settings. APPROACH AND RESULTS: We investigated sex differences in inflammatory markers and CAD in a 2-year prospective cohort of Ugandan adults enriched for cardiometabolic risk factors (RFs) and HIV. Seven plasma biomarkers were quantified at the baseline visit among 125 females and 75 males (50% with HIV) at least 45 years old at enrollment with one or more major cardiovascular RF. In year 2, coronary CT angiography (CCTA) was performed in 82 females and 50 males returning for follow-up (52% with HIV). In sex-specific models adjusted for cardiovascular RFs and HIV, tumor necrosis factor-alpha (TNF-α) RII and sCD163 predicted subsequent CAD in females, while only fibrinogen was predictive in males ( P  < 0.05). Interleukin-6 (IL-6) and sCD14 were inversely associated with CAD in males ( P  < 0.05). Sex modified the associations of TNF-α RII, sCD14, and sCD163 with CAD ( P  < 0.05 for interaction). In multivariable multiple imputation models applied to missing year 2 CCTA data to test associations between serum biomarkers in the baseline cohort ( n  = 200) and subsequent CAD, higher sCD163 was predictive in females only ( P  < 0.05). CONCLUSIONS: The positive link between inflammation and subclinical CAD was stronger among females than males in Uganda. Mechanisms by which sex modulates the relationship between inflammation and CAD should be further investigated in SSA.

Descriptive study: Feasibility of integrating hypertension screening into HIV assisted partner notification services model in Kenya.

Prevalence of hypertension (HTN) and human immunodeficiency virus (HIV) are high among men while screening rates are low. Assisted partner notification service is a strategy recommended by the World Health Organization that aims to increase HIV testing and treatment uptake and may present an opportunity to offer integrated HIV/HTN screening and treatment services. In this prospective cohort study, we assessed the feasibility of integrating HTN screening for male sexual partners of females newly tested HIV-positive in 10 health facilities in Kenya. Participants were notified of the exposure and offered HIV testing and HTN screening; if they accepted and tested positive for either HTN, HIV, or both, they were referred for care. HTN was defined as systolic blood pressure ≥ 140 mm Hg, diastolic blood pressure ≥ 90, or the use of antihypertensive medication. Among 1313 male partners traced, 99% accepted HIV testing and HTN screening. Overall, 4% were found to have HTN, 29% were in the pre-HTN stage, and 9% were HIV-positive. Only 75% had previously been screened for HTN compared to 95% who had previously tested for HIV. A majority preferred non-facility-based screening. The participants who refused HTN screening noted time constraints as a significant hindrance. HIV and HTN screening uptake was high in this hard-to-reach population of men aged 25 to 50. Although HTN rates were low, an integrated approach provided an opportunity to detect those with pre-HTN and intervene early. Strategic integration of HTN services within assisted partners services may promote and normalize testing by offering inclusive and accessible services to men.

'My people perish for lack of knowledge': barriers and facilitators to integrated HIV and hypertension screening at the Kenyatta National Hospital, Nairobi, Kenya.

INTRODUCTION: HIV and cardiovascular disease (CVD) are the two main causes of death in Kenya with hypertension as CVD's leading risk factor and HIV infection a risk factor for hypertension. We qualitatively evaluated the feasibility of integrated HIV and hypertension screening at Kenyatta National Hospital. METHODS: We conducted two focus group discussions (FGDs) in November 2020 (female FGD: n=7; male FGD: n=8) to elicit facilitators, barriers and viability of integrated diagnosis and management of both conditions at HIV testing service (HTS) facilities. Participants were selected using convenience sampling and were not pair matched. All participants had received HTS. All female clients had confirmed hypertension, while male relatives had been contacted for HIV and hypertension screening through a modified assisted partner services model-where a trained healthcare provider supports notification. Transcripts were coded independently, and the codebook was developed and revised through consensus discussion. Data were analysed using thematic content analysis. RESULTS: Main barriers to diagnosis and management included limited public awareness of hypertension risk factors and on improved treatment outcomes for those on lifelong HIV treatment, high cost of hypertension care despite free HIV care and healthcare system challenges especially medication stockouts. Strong support systems at family and healthcare levels facilitated care and treatment for both conditions. Participants recommended improved public awareness through individual-level communication and mass media campaigns, decentralised screening services for both HIV and hypertension, and either free or subsidised hypertension care services delivered alongside HIV treatment services. Most felt that an integrated HIV and hypertension service model was viable and would improve healthcare outcomes. CONCLUSION: Patient-centred care models combining HIV and hypertension services hold promise for integrated service delivery.

Association of HIV, cardiovascular risk factors, and carotid intimal media thickness: A cross-sectional study in Western Kenya.

The carotid intimal media thickness (CIMT) is a validated measure of subclinical atherosclerosis. Human immunodeficiency virus (HIV) is a risk factor for cardiovascular disease (CVD) and has been associated with CIMT in North America and Europe; however, there are limited data from Sub-Saharan Africa (SSA). In this cross-sectional study, we measured CIMT in a cohort of 262 people living with HIV (PLHIV) on antiretroviral therapy (ART) for ≥6 months and HIV-negative adults in western Kenya. Using linear regression, we examined the associations between CVD risk factors and CIMT, both overall and stratified according to the HIV status. Among the PLHIV, we examined the association between CIMT and HIV-related factors. Of 262 participants, approximately half were women. The HIV-negative group had a higher prevalence of age ≥55 years (P = .002), previously diagnosed hypertension (P = .02), treatment for hypertension (P = .03), and elevated blood pressure (BP) (P = .01). Overall prevalence of carotid plaques was low (15/262 [6.0%]). HIV-positive status was not significantly associated with a greater mean CIMT (P = .19). In multivariable regression models, PLHIV with elevated blood pressure or treatment for hypertension had a greater mean CIMT (P = .002). However, the CD4 count, viral load, and ART regimen were not associated with differences in CIMT. In the HIV-negative group, older age (P = .006), high total cholesterol levels (P = .01), and diabetes (P = .02) were associated with a greater mean CIMT. In this cross-sectional study of Kenyan adults, traditional CVD risk factors were found to be more prevalent among HIV-negative participants. After multivariable regression analysis, we found no association between HIV status and CIMT, and PLHIV had fewer CVD risk factors associated with CIMT than HIV-negative participants did. HIV-specific factors were not associated with the CIMT.

Mean Coronary Cross-Sectional Area as a Measure of Arterial Remodeling Using Noncontrast CT Imaging in Persons With HIV.

Background Persons with HIV have a higher prevalence of coronary artery disease compared with their HIV-negative counterparts. Earlier identification of subclinical atherosclerosis may provide a greater opportunity for cardiovascular disease risk reduction. We investigated coronary cross-sectional area (CorCSA) by noncontrasted computed tomography imaging as a noninvasive measure of arterial remodeling among virally suppressed persons with HIV. Methods and Results We assessed 105 persons with HIV with a spectrum of cardiometabolic health. All participants underwent computed tomography imaging to assess the mean corCSA of the proximal left anterior descending artery and 28 participants underwent additional coronary computed tomography angiography. Partial Spearman rank correlations adjusted for cardiovascular disease risk factors were used to assess relationships of corCSA with anthropometric measurements, HIV-related factors, and plasma cytokines. Mean corCSA measured by noncontrast computed tomography and coronary computed tomography angiography were strongly correlated (ρ=0.91, P<0.0001). Higher mean corCSA was present in those with coronary artery calcium (P=0.005) and it correlated with participants' atherosclerotic cardiovascular disease risk score (ρ=0.35, P=0.01). After adjusting for established cardiovascular disease risk factors, we observed an inverse relationship between corCSA and CD4+ T-cell count (ρ=-0.2, P=0.047). Removal of age from the model strengthened the relationships between corCSA and antiretroviral therapy duration (from ρ=0.19, P=0.08 to ρ=0.3, P=0.01). CorCSA was also inversely correlated with plasma IL-10 (ρ=-0.25, P=0.03) but had no relationship with IL-6 (ρ=0.11, P=0.4) or IL-1ß (ρ=0.08, P=0.5). Conclusions Positive coronary arterial remodeling, an imaging marker of subclinical atherosclerosis, is associated with a lower CD4 T-cell count, lower circulating IL-10, and possibly a longer antiretroviral therapy duration in persons with HIV. Registration Clinicaltrials.gov; Unique identifier: NCT04451980.

Cardiovascular disease risk in women living with HIV.

PURPOSE OF REVIEW: To synthesize current evidence on the impact of cardiovascular disease among women living with HIV (WLWH) with a particular focus on disease prevalence, mechanisms and prevention. RECENT FINDINGS: HIV-related cardiovascular disease risk is 1.5-fold to 2-fold higher for women than for men. Mechanisms of enhanced risk are multifactorial and include reinforcing pathways between traditional risk factors, metabolic dysregulation, early reproductive aging and chronic immune activation. These pathways influence both the presentation of overt syndromes of myocardial infarction, stroke and heart failure, as well as subclinical disease, such as microvascular dysfunction and cardiac fibrosis. Cardiovascular disease, therefore, remains a consistent threat to healthy aging among WLWH. SUMMARY: Although no specific prevention strategies exist, patient-centered risk mitigation approaches that are adaptable to the needs of aging individuals are essential to combat disparities in cardiovascular outcomes among WLWH. Further research into the optimal prevention approach for CVD among WLWH, particularly for women living in under-resourced health systems, is needed.

Interleukin-17A is associated with flow-mediated dilation and interleukin-4 with carotid plaque in persons with HIV.

OBJECTIVE: Chronic inflammation contributes to the high burden of cardiovascular disease (CVD) in persons with HIV (PWH). HIV has broad effects on innate and adaptive immune cells, including innate lymphoid cells (ILCs) and CD4+ T-helper cells. At present, the relationship between CVD and plasma cytokines reflecting ILC/T-helper responses in PWH is not well defined. We investigated relationships between plasma cytokines and subclinical atherosclerosis. DESIGN: A cross-sectional study. METHODS: We recruited 70 PWH on a single antiretroviral regimen (efavirenz, teno- fovir, and emtricitabine) with at least 12 months of suppressed viremia and 30 HIVnegative controls. We quantified plasma cytokines and chemokines, including inter- feron-g, interleukin (IL)-4, IL-13, and IL-17A, markers of macrophage activation, and markers of endothelial activation using multiplex assays and ELISA. Cytokines were grouped using Ward's hierarchical clustering. Brachial artery flow-mediated dilation (FMD) and carotid plaque burden were determined using ultrasound. Multivariable linear regression and negative binomial regression analyses were used to assess the relationships of plasma biomarkers and endpoints adjusted for CVD risk factors. RESULTS: We identified three distinct clusters in PWH, one containing Th1/Th2/ILC1/ ILC2 type cytokines, one with Th17/ILC3/macrophage-related cytokines, and a less specific third cluster. Lower FMD was associated with higher plasma IL-17A and macrophage inflammatory protein-1 a. In contrast, IL-4, a Th2/ILC2 type cytokine, was associated with carotid plaque. When HIV-negative controls were added to the models clustering was more diffuse, and these associations were attenuated or absent. CONCLUSION: Th17/ILC3 and Th2/ILC2-mediated immune mechanisms may have distinct roles in endothelial dysfunction and atherosclerotic plaque formation, respectively, in PWH.

Prevalence and factors associated with hypertension among adults with and without HIV in Western Kenya.

INTRODUCTION: The burden of cardiovascular disease (CVD) is increasing in sub-Saharan Africa with untreated hypertension being a major contributing factor. Understanding the magnitude of the problem and risk factors associated with HIV and long-term antiretroviral therapy (ART) is critically important for designing effective programs for diagnosing and treating hypertension in Kenya. METHODS: In this cross-sectional study, we enrolled 300 persons with HIV (PWH) on long term ART (≥6 months) and 298 HIV-negative adults seeking care at the Kisumu County Hospital between September 2017 and May 2018. Hypertension was defined as blood pressure of ≥140/90mmHg or a previous hypertension diagnosis. Multivariate regression was used to assess the association between hypertension and HIV adjusting for age, sex, and known CVD risk factors. RESULTS: Overall prevalence of hypertension was 22%. PWH had a lower prevalence of hypertension than HIV-negative persons (16% vs 27% respectively; p<0.002). In multivariate analyses, persons with HIV were 37% less likely to have hypertension compared to HIV-negative individuals (adjusted prevalence ratio 0.63; 95% confidence interval: 0.46-0.86). Other factors that were associated with hypertension in all participants included older age >40 years, body mass index (BMI) >25 kg/m2 and low-density lipoproteins ≥130mg/dL. Among PWH, being older than 40 years and higher BMI >30 kg/m2 were associated with hypertension. CONCLUSION: Prevalence of hypertension was high, affecting nearly one in every 4 adults, and associated with older age, higher BMI and high low-density lipoproteins. PWH on long-term ART had significantly lower prevalence of hypertension compared to HIV-negative individuals, potentially due to increased access to healthcare services and interaction with prevention messaging. Interventions to increase screening for and prevention of hypertension in the community for all adults are warranted.

Diastolic dysfunction in people with HIV without known cardiovascular risk factors in Western Kenya.

OBJECTIVES: Diastolic dysfunction (DD) has been reported to be highly prevalent in people living with HIV (PLWH) on antiretroviral therapy (ART) leading to the hypothesis that it may be an early marker of myocardial disease. Our objective was to evaluate the prevalence of DD in people living with human immunodeficiency virus without known history of diabetes or hypertension in Western Kenya. METHODS: In this cross-sectional study in western Kenya, 110 PLWH on ART and without known diabetes or hypertension were matched for age ±5 years and sex to HIV-uninfected controls. Study participants underwent a comprehensive two-dimensional echocardiogram and laboratory testing. RESULTS: The mean (SD) age in the HIV-positive group was 42.9 (8.6) years compared with 42.1 (12.9) years in the HIV-uninfected group. Mean (SD) CD4 +T cell count for the HIV-positive group was 557 (220) cells/ml. Mean systolic and diastolic blood pressures were within the normal range and comparable between the two groups. Mean body mass index was 25.2 (5.4) kg/m2 and 26.3 (5.4) kg/m2 in HIV-positive and uninfected participants, respectively. There was only 1 (0.9 %) case of DD in each group. Despite low prevalence of DD, PLWH had 5.76 g/m2 higher left ventricular mass index (p=0.01) and 2.77 mL/m2 larger left atrial volume (p=0.02) compared with the HIV-negative group after adjusting for risk factors associated with DD. CONCLUSION: Contrary to prior reports, DD in PLWH was low. Environmental and cardiovascular disease risk factors such as diabetes and hypertension may be significant modifiers for development and progression of DD in PLWH.

Participation in methadone programs improves antiretroviral uptake and HIV viral suppression among people who inject drugs in Kenya.

BACKGROUND: HIV prevalence among people who inject drugs (PWID) in Kenya is estimated to be 18% compared to 4.5% in the general population. Studies from high-income countries have demonstrated that methadone use is associated with increased uptake of antiretroviral therapy (ART) and higher rates of viral suppression among PWID with HIV. However, it is unclear whether methadone use has the same effect among African PWID living with HIV. METHODS: We performed a cross-sectional study to evaluate associations between methadone program participation and ART uptake and viral suppression (HIV RNA viral load <1000 copies/ml) among PWID with HIV in Kenya. Participants were recruited from needle and syringe programs and methadone clinics, interviewed on site, and samples were obtained and assayed for HIV viral loads. Univariate and multiple logistic regression were used to determine associations. RESULTS: Among 679 participants, median age was 37 years, 48% were female, and 24% were in a methadone program. We observed higher proportions of ART use (96% vs. 87%, p = 0.001) and HIV viral suppression (78% vs. 65%, p = 0.012) among PWID on methadone compared to those not on methadone treatment. PWID who were not participating in a methadone program were 3-fold more likely to be off ART and approximately twice as likely to be viremic compared to those in methadone programs (adjusted odds ratio [aOR] = 3.35, 95% confidence interval [CI]: 1.35-8.35 and aOR = 1.90, 95% CI: 1.03-3.52, respectively). CONCLUSIONS: In this study, Kenyan PWID living with HIV participating in a methadone treatment program were more likely to be on ART and to have achieved viral suppression. Scale-up of methadone programs may have a positive impact on HIV epidemic control for this key population.

Obesity and risk for hypertension and diabetes among Kenyan adults: Results from a national survey.

ABSTRACT: Despite the anticipated growth in the global burden of obesity especially in low-income countries, limited data exist on the contribution of obesity to cardiometabolic diseases in Africa.We examined population-based samples of Kenyan adults who participated in the 2015 national chronic disease risk factor surveillance survey. Weight and height were measured, and body mass index (BMI) was calculated and used as a measure for general obesity. Waist circumference (WC), a clinical measure of central obesity was also measured. Logistic regression was used to assess the association between obesity with hypertension, diabetes, and dyslipidemia risk.Of the 4276 participants, the median (IQR) age was 36 (27-47) years, 41% were men. One-third (37%) of the participants were centrally obese, whereas 10% were generally obese. The odds for overweight and general obesity were highest among females, adults >40 years, and those in the highest wealth quartile. Central and general obesity, assessed by WC and BMI, were associated with hypertension and dyslipidemia but not diabetes for both sexes. Compared with adults of normal weight, individuals with a BMI of ≥30 kg/m2 had an odds ratio of 2.39 (95% confidence interval [CI], 1.82-3.12) for hypertension and 2.24 (95% CI, 1.70-2.96) for dyslipidemia.Obesity prevalence is high in Kenya and is associated with hypertension and dyslipidemia but not diabetes. Our findings indicate an urgent need to develop public health interventions to address obesity and prevent the development of comorbid conditions.