Cardiovascular disease in people living with HIV in Malaysia: A competing risks cohort analysis.

To synthesize recent evidence relating the gut microbiome and microbial metabolites to cardiovascular disease (CVD) in people living with HIV (PLWH). A few cross-sectional studies have reported on the gut microbiome and cardiovascular outcomes in the context of HIV, with no consistent patterns emerging. The largest such study found that gut Fusobacterium was associated with carotid artery plaque. More studies have evaluated microbial metabolite trimethylamine N-oxide with CVD risk in PLWH, but results were inconsistent, with recent prospective analyses showing null effects. Studies of other microbial metabolites are scarce. Microbial translocation biomarkers (e.g., lipopolysaccharide binding protein) have been related to incident CVD in PLWH. Microbial translocation may increase CVD risk in PLWH, but there is insufficient and/or inconsistent evidence regarding specific microbial species and microbial metabolites associated with cardiovascular outcomes in PLWH. Further research is needed in large prospective studies integrating the gut microbiome, microbial translocation, and microbial metabolites with cardiovascular outcomes in PLWH.

The aim of this study was to discuss the most recent research in the management of cardiovascular disease (CVD) in people living with HIV (PLWHIV) with a focus on screening, primary and secondary prevention. The cause of CVD in PLWHIV is complex and multifactorial and creates a demand for a multifaceted approach to screening and prevention. Current screening and management of CVD risk factors in PLWHIV is suboptimal, reasons for this are not clear and the data are still scarce both in the primary and secondary preventive setting. There are no optimal routine risk screening tools available to accurately detect early and subclinical disease; PLWHIV are undertreated with preventive drugs such as statins and aspirin and antihypertensives; there are still no programmes that have been shown significantly efficient over time with regards to improved smoking cessation, increased physical activity and optimal diet, and recent reports call for intensified focus on HIV-positive women as a particularly vulnerable subgroup. There is a need for further studies investigating barriers to optimal CVD risk factor management in PLWHIV and an increased focus of CVD prevention in HIV-positive women.

ABSTARCT Introduction: Cardiovascular disease (CVD) continues to be an essential cause of morbidity and mortality among people living with human immunodeficiency virus infection (PLWH). Since the bulk of cardiovascular risk (CVR) factors are shared between PLWH and the general population, prevention and treatment strategies are similar. However, there are CVR factors particular to PLWH, which need separate consideration. These factors are those HIV-dependent, those related to HIV-derived consequences, and combination antiretroviral therapy (cART)-dependent. Areas covered: In this review, the authors discuss the management of CVD in PLWH, with a special interest in pharmacological treatment and drug-drug interactions with cART. Expert opinion: In recent years, we have witnessed a decreased CVD morbidity and mortality in PLWH, which probably reflects an improvement in the management of CVR factors and CVD in these patients, partially thanks to new developments in antiretroviral therapy. Therefore, although there is still room for improvement, at present, the old desideratum of equaling PLWH and the general population in terms of CVD incidence and prognosis is a little closer.

Introduction of combination antiretroviral therapy (ART) has increased the life expectancy of patients with HIV infection, allowing them to live longer with this chronic medical condition and consequently experiencing conditions such as cardiovascular diseases (CVDs). Several studies have investigated the increased risk of CVD in people living with HIV (PLWH). However, less is known about the exact mechanisms involved in this increased risk. Also, specific guidelines for management of CVD in PLWH have not been developed yet. In this article, we review the recent literature on the mechanisms involved in pathogenesis of CVD in PLWH, with an emphasis on coronary artery disease (CAD). Although initial studies suspected the increased prevalence of traditional CVD risk factors and side effects of ART to be involved in the increased CVD risk in PLWH, recent studies have uncovered the important role of chronic persistent inflammation in this increased risk. In addition, biomarkers of inflammation have been associated with both CVD events and subclinical CAD in this population. Lastly, recent studies and ongoing clinical trials have been investigating medical interventions that aim to reduce inflammation and cardiovascular events. Different mechanisms of inflammation have been examined in PLWH, including subclinical viremia, microbial translocation, and coinfection with other pathogens such as cytomegalovirus. Although inflammatory biomarkers have been consistently associated with CVD and subclinical CVD outcomes, their prognostic value is unknown. Recent and ongoing trials are exploring the benefits of anti-inflammatory drugs, statins, and antimicrobial translocation drugs on both inflammation and CVD risk among PLWH.

Effect of Clonal Hematopoiesis on Cardiovascular Disease in People Living with HIV

Clonal Hematopoiesis Is More Common in People Living with HIV and May be Associated with Increased Prevalence of Cardiovascular Disease

BackgroundAntiretroviral therapy (ART) is known to reduce tuberculosis (TB) incidence among people living with HIV (PLWH). However, studies describing the impact of long-term ART and CD4 count recovery on TB incidence remain scarce due to limited follow up in previous studies. We evaluated TB incidence in a long-term cohort of PLWH on ART in Thailand.MethodsWe conducted an analysis of PLWH aged ≥ 18 years who started ART between 1996 and December 2020. Participants were followed up every 6 months for routine HIV care. TB risk factors, body mass index (BMI), physical examination and full differential blood counts were evaluated at each clinic visit, and CD4 cell counts and HIV RNA every 12 months. Participants diagnosed with TB > 3 months after starting ART were classified as incident cases. Time to event models with death as a competing risk, were used to derive the TB cumulative incidence function (CIF) after ART initiation, and assess time-updated factors associated with incident TB using a six month lag.ResultsA total of 2,636 PLWH contributing 24,229 person years (PY) of follow-up on ART were analysed. Median age was 32.0 (IQR 27.4–37.6) years; 67.5% were male. Median CD4 cell count at ART initiation was 264 (IQR 167–379) cells/mm3 and median follow-up duration was 7.6 (IQR 1.9–15.7) years. During follow-up, 113 PLWH developed TB. The probability of incident TB was 0.7%, 1.7%, 3.3% and 4.3%, at 1, 2, 5 and 7 years after ART initiation, respectively. TB CIF was highest among participants with CD4 < 50 cells/mm3. The overall crude incidence of TB was 4.66 (95% CI 3.87–5.60) per 1000 PY. Low CD4 count, BMI < 18 kg/m2, and substance use in the previous six months were significantly associated with incident TB. Incidence declined with time on suppressive ART, but remained higher than the Thai general population 7 years after ART initiation (2.2 vs 1.5/1000 PY, respectively).ConclusionDespite a marked reduction in TB incidence following ART, ongoing TB risk remains high among PLWH, despite long-term suppressive ART. Those with low CD4 cell counts, who are underweight, or currently having substance abuse should be carefully monitored.

Cardiovascular diseases in people living with HIV (PLWH) are becoming increasingly relevant as HIV/AIDS has become more treatable with the advent of highly efficacious antiretroviral therapy. Previous studies suggested that HIV infection is an independent risk factor for atrial arrhythmia. This study aims to collectively analyze these studies to elucidate the incidence and risk factors of atrial arrhythmia in PLWH. Full-text assessments and data extraction were performed from available literature. Atrial arrhythmia was defined as atrial fibrillation or atrial flutter. Incidence rate, risk, and potential risk factors of atrial arrhythmia in PLWH were catalogued, after which random-effects models were used to estimate pooled summary statistics. PRISMA standardized meta-analysis guidelines were followed. Analysis of 94,928 PLWH had an averaged incidence rate of 6.4 cases of atrial arrhythmia per 1000 person-years. Risk of atrial arrhythmia was significantly higher in PLWH than in the general population (RR 1.35; 95% CI 1.19-1.53). Sex had no association with the risk of incidental atrial arrhythmia in PLWH (RR 1.47; 95% CI 0.95-2.28). Black race (RR 0.68; 95% CI 0.47-0.97) was associated with decreased risk, whereas lower CD4 counts (RR 1.80; 95% CI 1.18-2.77) and increased viral load (RR 1.57; 95% CI 1.19-2.09) suggested increased risk of atrial arrhythmia in PLWH. HIV infection is a risk factor of atrial arrhythmia. Providers should be aware of the increased burden of atrial arrhythmia in PLWH and continue to encourage treatment of HIV infection while managing cardiovascular risk factors and screening for arrhythmias in symptomatic patients.

What Might Surviving Coronavirus Disease 2019 Look Like for People Living with HIV?

People living with HIV (PLWH) develop cardiovascular diseases (CVDs) about a decade earlier and at rates 2-3 times higher than the general population. At present, pharmacological strategies to delay the onset of CVDs in PLWH are unavailable, in part because of an incomplete understanding of its molecular causes. We and others recently uncovered elevated levels of the toxic glycolysis and inflammation-induced byproduct methylglyoxal (MG) in plasma from PLWH and from HIV-infected humanized mice (Hu-mice). We also found a reduction in expression of the primary MG-degrading enzyme glyoxalase I (Glo-I) in autopsied cardiac tissues from HIV-1-infected individuals and HIV-1-infected Hu-mice. Increasing the expression of Glo-I in HIV-1-infected Hu-mice not only attenuated heart failure but also reduced endothelial cell damage, increased the density of perfused microvessels, prevented microvascular leakage and micro-ischemia, and blunted the expression of the inflammation-induced protein vascular protein-1 (VAP-1), key mediators of CVDs. In this narrative review, we posit that elevated MG is a contributing cause for the early onset of CVDs in PLWH. Pharmacological strategies to prevent MG accumulation and delay the development of early-onset CVDs in PLWH are also discussed.

Towards evidence-based integration of services for HIV, non-communicable diseases and substance use: insights from modelling.

BackgroundTraditional cardiovascular disease (CVD) risk factors contribute to increase risk of CVD in people living with HIV (PLWH). Of all world regions, sub-Saharan Africa has the highest prevalence of HIV yet little is known about PLWH’s CVD knowledge and self- perceived risk for coronary heart disease (CHD). In this study, we assessed PLWH’s knowledge, perception and attitude towards cardiovascular diseases and their prevention.MethodsWe conducted a cross-sectional study in the largest HIV care program in western Kenya. Trained research assistants used validated questionnaires to assess CVD risk patterns. We used logistic regression analysis to identify associations between knowledge with demographic variables, HIV disease characteristics, and individuals CVD risk patterns.ResultsThere were 300 participants in the study; median age (IQR) was 40 (33–46) years and 64 % women. The prevalence of dyslipidemia, overweight and obesity were 70 %, 33 % and 8 %, respectively. Participant’s knowledge of risk factors was low with a mean (SD) score of 1.3 (1.3) out of possible 10. Most (77.7 %) could not identify any warning signs for heart attack. Higher education was a strong predictor of CVD risk knowledge (6.72, 95 % CI 1.98-22.84, P < 0.0001). Self-risk perception towards CHD was low (31 %) and majority had inappropriate attitude towards CVD risk reduction.ConclusionDespite a high burden of cardiovascular risk factors, PLWH in Kenya lack CVD knowledge and do not perceived themselves at risk for CHD. These results emphasis the need for behavior changes interventions to address the stigma and promote positive health behaviors among the high risk HIV population in Kenya.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-015-1157-8) contains supplementary material, which is available to authorized users.

Background: Human immunodeficiency virus (HIV) infection is associated with significant metabolic disruptions, and understanding how these disruptions contribute to cardiovascular disease (CVD) is essential for improving patient management and therapeutic strategies. By integrating metabolomics and transcriptomics, we aimed to elucidate the cardiometabolic disease spectrum of people living with HIV (PLWH) and to identify biomarkers and pathways associated with disease progression in this population. Methods: We conducted a cross-sectional observational study between October 2022 and June 2023 at the Third People’s Hospital of Shenzhen, China. Participants were categorized into one of four groups: HIV+ without metabolic abnormalities (healthy control [HC]), HIV + with untreated metabolic (UM) abnormalities (HIV + UM), HIV + with treated metabolic (TM) abnormalities (HIV + TM), and HIV + with CVD (HIV + CVD). Key metabolic and transcriptomic features were identified through a comparative analysis using untargeted metabolomics and RNA sequencing, followed by statistical and pathway enrichment analyses. Results: This study included 114 PLWH: HC group (n = 30), HIV + UM group (n = 19), HIV + TM group (n = 46), and HIV + CVD group (n = 19). Through comparative analyses of untargeted metabolomic and transcriptomic data across these four groups, we identified 580 dysmetabolic features (DMFs) based on significant changes between the HC group and the HIV + UM/TM groups, with no statistically significant differences in the HIV + UM/TM vs. HIV + CVD comparisons. Notably, 90.52% of these DMFs (525/580) exhibited reduced abundance in the HIV + CVD group. In contrast, 241 CVD-specific features were identified based on significant differences between the HIV + CVD group and the HIV + UM/TM groups. These features, primarily found in the HIV + CVD group, included metabolites and genes strongly associated with chronic inflammation and endothelial dysfunction—key processes in the pathogenesis of CVD among PLWH. Features that indicated a transition from metabolic abnormalities to CVD were termed escalation features (ESCFs). ESCFs included early biomarkers of lipid dysregulation, such as phosphatidylcholine (O-22:1/20:4), and upregulated genes, such as CAMP, both of which showed progressive changes from the HC group through the HIV + UM/TM groups to the HIV + CVD group. Features that indicated a reversal in expression trends—such as those increasing from the HC group to the HIV + UM/TM groups but decreasing in the HIV + CVD group, or vice versa—were termed de-escalation features (DSCFs). DSCFs included lipid species and genes involved in lipid metabolism and mitochondrial function. The integration of metabolomic and transcriptomic data revealed disruptions in pathways, such as glycerophospholipid and arachidonic acid metabolism, with concurrent upregulation of genes involved in cholesterol biosynthesis and the immune response. Receiver operating characteristic curve analysis based on the integration of metabolomic and transcriptomic data markedly improved CVD prediction among PLWH, with an area under the curve of 0.965, sensitivity of 84.2%, and specificity of 96.9%. Conclusions: This study identified key metabolic and transcriptomic alterations associated with CVD among PLWH. These alterations, primarily driven by immune activation, inflammation, and metabolic dysregulation, reflect unique molecular characteristics of CVD in PLWH. Our findings underscore the importance of early detection and tailored interventions to manage CVD risk in this population, providing insights into potential biomarkers for disease progression.

BackgroundAging people living with HIV (PLWH) have higher prevalence and increased risk of comorbidities such as cardiovascular disease (CVD). This study assessed incremental all-cause healthcare resource utilization (HCRU) and costs among PLWH with and without CVD in the US.MethodsA retrospective analysis of US administrative claims (Jan 2020-Dec 2022, Optum’s de-identified Clinformatics® Data Mart Database) examined all-cause HCRU and costs among adult (≥ 18 years) PLWH with ≥ 1 pharmacy claim for anchor antiretroviral therapy (ART) agent (NNRTI, PI, or INSTI) in 2021 (index date: earliest anchor ART claim). PLWH were followed to the earliest of 12 months or end of continuous enrollment and stratified into 2 groups based on the presence of CVD (yes/no) during baseline (12 months pre-index) using ICD-10 diagnosis codes from medical claims. Multivariable generalized linear models with negative binomial/Poisson distribution (HCRU) and gamma distribution (costs) estimated differences in all-cause per-patient-per-month (PPPM) HCRU and costs (adjusted to 2023 USD) between groups, adjusting for baseline characteristics.ResultsOf 22,402 PLWH identified, 4,917 (22%) had CVD. PLWH with vs. without CVD were older (mean age 61.45 vs. 52.86 years), more were women (22% vs. 18%) and Black (32% vs. 30%), and had higher mean Quan-Charlson Comorbidity Index scores (2.85 vs. 0.87) and baseline total costs ($5,574 vs. $3,442); all p < 0.001. Unadjusted all-cause PPPM HCRU and costs were significantly higher in PLWH with vs. without CVD (all p < 0.001; Table). In multivariable analyses, PLWH with vs. without CVD had significantly greater all-cause PPPM HCRU, total costs (9% higher), medical costs (67% higher), and inpatient costs (72.3% higher) (all p < 0.001; Table).ConclusionPLWH with CVD experience a greater HCRU and cost burden than those without CVD. Identifying modifiable CVD risk factors (e.g., hypertension, type 2 diabetes mellitus) along with providing individualized HIV care might mitigate increases in HCRU and costs while optimizing care for PLWH.DisclosuresSean P. Fleming, PhD, MSW, Merck & Co., Inc., Rahway, NJ, USA: Employee|Merck & Co., Inc., Rahway, NJ, USA: Stocks/Bonds (Public Company) Shweta Kamat, MS, PhD, Merck & Co., Inc., Rahway, NJ, USA: Contracted research Girish Prajapati, M.B.B.S., MPH , Merck & Co., Inc.: Employee|Merck & Co., Inc.: Stocks/Bonds (Private Company) Viktor Chirikov, MS, PhD, Merck & Co., Inc., Rahway, NJ, USA: Contracted research Wenying Quan, MS, Merck & Co., Inc., Rahway, NJ, USA: Contracted research Mark Bounthavong, PharmD, PhD, Merck & Co., Inc., Rahway, NJ, USA: Consultant|University of California, San Diego: Employment

In almost 4 decades since the start of the HIV epidemic, the world has witnessed an unprecedented evolution of this disease from a debilitating and rapidly fatal syndrome to a chronic condition, effectively managed with combination antiretroviral therapy (cART). Today people living with HIV (PLWH) who receive treatment have nearly the same life expectancy as HIV‐negative individuals.1 With the exception of 2 people cured by human stem‐cell transplantation,2, 3 a widely applicable cure for HIV remains elusive and infection still requires lifelong therapy for PLWH. Although effective cART suppresses viral replication, inflammation and immune activation persist for PLWH and are driven by a combination of HIV‐dependent and HIV‐independent factors.4 These immune factors contribute to an excess of non‐AIDS comorbidities in PLWH, including cardiovascular disease (CVD), frailty, malignancy, neurocognitive disease, osteoporosis, and renal and liver diseases.4 It is increasingly recognized that as the population of PLWH ages, targeting non‐AIDS comorbidities is essential to effectively care for and treat this population. CVD is the leading cause of death worldwide, accounting for 56.9 million deaths in 2016.5 The relative risk of CVD in PLWH is significantly higher than in HIV‐negative controls, including: higher rates of acute myocardial infarction6 and increased risk for ischemic stroke,7 heart failure,8 and sudden cardiac death.9 In fact, it is estimated that the HIV‐associated risk for CVD may be similar to that of traditional risk factors such as smoking, hyperlipidemia, diabetes mellitus, and hypertension.10 Despite several studies showing the higher risk of cardiovascular events in PLWH, the greatest challenge has been defining the overarching mechanisms by which HIV‐mediated immune activation and chronic inflammation increase the risk for CVD.11 This has made it difficult to identify effective interventions to target and reduce cardiovascular risk in this population despite considerable efforts. In this review, we examine the effects of HIV‐associated inflammation and immune activation on the cardiovascular system with a focus on atherosclerotic CVD and discuss existing and proposed therapeutic strategies targeting inflammation to reduce CVD risk. The factors contributing to immune activation and CVD in PLWH are summarized in Figure 1 below. Open in a separate window Figure 1 Factors contributing to immune activation and cardiovascular disease in PLWH. Solid line arrows indicate a contributory effect; dotted line arrows represent a potential yet uncertain relationship; dotted terminal line indicates an inhibitory effect. ART indicates antiretroviral therapy; CMV, cytomegalovirus; HCV, hepatitis C virus; PLWH, people living with HIV. This figure was created using http://www.biorender.com software.