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.

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.

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.

Anticytomegalovirus CD4+ T Cells Are Associated With Subclinical Atherosclerosis in Persons With HIV.

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Human Immunodeficiency Virus Is Associated With Higher Levels of Systemic Inflammation Among Kenyan Adults Despite Viral Suppression.

BACKGROUND: Systemic inflammation independently predicts future cardiovascular events and is associated with a 2-fold increase in cardiovascular disease (CVD) risk among persons living with human immunodeficiency virus (PLHIV). We examined the association between inflammatory markers, HIV status, and traditional CVD risk factors. METHODS: We conducted a cross-sectional study of Kenyan adults with and without HIV seeking care at Kisumu County Hospital. Using a multiplex immunoassay, we measured interleukin (IL) 1ß, IL-6, tumor necrosis factor α (TNF-α), and high-sensitivity C-reactive protein (hsCRP) concentrations. We compared inflammatory marker concentrations by HIV status using the Wilcoxon rank-sum test. Multivariable linear regression was used to evaluate associations between inflammatory biomarkers and HIV status, adjusting for CVD risk factors. RESULTS: We enrolled 286 PLHIV and 277 HIV-negative participants. Median duration of antiretroviral therapy for PLHIV was 8 years (interquartile range, 4-10) and 96% were virally suppressed. PLHIV had a 51% higher mean IL-6 concentration (P < .001), 39% higher mean IL-1ß (P = .005), 40% higher mean TNF-α (P < .001), and 27% higher mean hsCRP (P = .008) compared with HIV-negative participants, independent of CVD risk factors. Male sex, older age, and obesity were associated with higher concentrations of inflammatory markers. Restricting to PLHIV, viral load of ≥1000 copies/mL was associated with higher TNF-α levels (P = .013). CONCLUSIONS: We found higher levels of systemic inflammatory biomarkers among PLHIV who were virally suppressed, and this was independent of traditional CVD risk factors. Further longitudinal analyses to determine whether these inflammatory markers predict future CVD events, and are possible therapeutic targets among PLHIV, are warranted.

From HIV prevention to non-communicable disease health promotion efforts in sub-Saharan Africa: A Narrative Review.

OBJECTIVE: To synthesize published literature on noncommunicable disease (NCD) behavior change communication (BCC) interventions in sub-Saharan Africa (SSA) among persons living with HIV (PLHIV) and in the general population to inform efforts to adopt similar HIV and NCD BCC intervention activities. METHODS: We conducted a literature review of NCD BCC interventions and included 20 SSA-based studies. Inclusion criteria entailed describing a BCC intervention targeting any four priority NCDs (cardiovascular disease, type 2 diabetes, cervical cancer, and depression) or both HIV and any of the NCDs. The RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework was used to assess potential public health impact of these studies. We also solicited expert opinions from 10 key informants on the topic of HIV/NCD health promotion in five SSA countries. RESULTS: The BCC interventions reviewed targeted multiple parts of the HIV and NCD continuum at both individual and community levels. Various strategies (i.e. health education, social marketing, motivational interviewing, mobile health, and peer support) were employed. However, few studies addressed more than one dimension of the RE-AIM framework. Opinions solicited from the key informants supported the feasibility of integrating HIV and NCD BCC interventions in SSA potentially improving access, service provision and service demand, especially for marginalized and vulnerable populations. CONCLUSION: Although HIV/NCD integration can improve effectiveness of preventive services at individual and community levels, potential public health impact of such approaches remain unknown as reach, adoptability, and sustainability of both integrated and nonintegrated NCD BCC approaches published to date have not been well characterized.

Lay beliefs about hypertension among HIV-infected adults in Kenya.

OBJECTIVE: Hypertension affects 23% of Kenyans and is the most prevalent modifiable risk factor for cardiovascular disease. Despite this, hypertension awareness and treatment adherence is very low. We conducted a qualitative study to explore lay beliefs about hypertension among HIV-infected adults to inform the development of culture sensitive hypertension prevention and control program. METHODS: Eight focus group discussions were held for 53 HIV-infected adults at the HIV clinic in Kenya. RESULTS: Respondents had difficulties in describing hypertension. Hypertension was considered a temporary illness that is fatal and more serious than HIV. Stress was perceived as a main cause for hypertension with a large majority claiming stress reduction as the best treatment modality. Alcohol and tobacco use were not linked to hypertension. Obesity was cited as a cause of hypertension but weight control was not considered as a treatment modality even though the majority of our participants were overweight. Most participants did not believe hypertension could be prevented. CONCLUSION: Our findings suggest a limited understanding of hypertension among people living with HIV and points to an urgent need to integrate hypertension education programmes in HIV care facilities in Kenya. To effect change, these programmes will need to tie in the culture meaning of hypertension.

Genetic mutations in African patients with atrial fibrillation: Rationale and design of the Study of Genetics of Atrial Fibrillation in an African Population (SIGNAL).

BACKGROUND: There is an urgent need to understand genetic associations with atrial fibrillation in ethnically diverse populations. There are no such data from sub-Saharan Africa, despite the fact that atrial fibrillation is one of the fastest growing diseases. Moreover, patients with valvular heart disease are underrepresented in studies of the genetics of atrial fibrillation. METHODS: We designed a case-control study of patients with and without a history of atrial fibrillation in Kenya. Cases with atrial fibrillation included those with and without valvular heart disease. Patients underwent clinical phenotyping and will have laboratory analysis and genetic testing of >240 candidate genes associated with cardiovascular diseases. A 12-month follow-up assessment will determine the groups' morbidity and mortality. The primary analyses will describe genetic and phenotypic associations with atrial fibrillation. RESULTS: We recruited 298 participants: 72 (24%) with nonvalvular atrial fibrillation, 78 (26%) with valvular atrial fibrillation, and 148 (50%) controls without atrial fibrillation. The mean age of cases and controls were 53 and 48 years, respectively. Most (69%) participants were female. Controls more often had hypertension (45%) than did those with valvular atrial fibrillation (27%). Diabetes and current tobacco smoking were uncommon. A history of stroke was present in 25% of cases and in 5% of controls. CONCLUSION: This is the first study determining genetic associations in valvular and nonvalvular atrial fibrillation in sub-Saharan Africa with a control population. The results advance knowledge about atrial fibrillation and will enhance international efforts to decrease atrial fibrillation-related morbidity.