Antiretroviral therapy has largely transformed HIV infection into a chronic disease condition. As such, physicians and other providers caring for individuals living with HIV infection need to be ...aware of the potential cardiovascular complications of HIV infection and the nuances of how HIV infection increases the risk of cardiovascular diseases, including acute myocardial infarction, stroke, peripheral artery disease, heart failure and sudden cardiac death, as well as how to select available therapies to reduce this risk. In this Review, we discuss the epidemiology and clinical features of cardiovascular disease, with a focus on coronary heart disease, in the setting of HIV infection, which includes a substantially increased risk of myocardial infarction even when the HIV infection is well controlled. We also discuss the mechanisms underlying HIV-associated atherosclerotic cardiovascular disease, such as the high rates of traditional cardiovascular risk factors in patients with HIV infection and HIV-related factors, including the use of antiretroviral therapy and chronic inflammation in the setting of effectively treated HIV infection. Finally, we highlight available therapeutic strategies, as well as approaches under investigation, to reduce the risk of cardiovascular disease and lower inflammation in patients with HIV infection.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
New treatments have improved outcomes and increased life expectancy for human immunodeficiency virus (HIV)–infected patients; however, their comorbidity burden has grown significantly and is greater ...than that in a matched non–HIV-infected cohort. This introduces important considerations for treatment choices and outcomes.
Abstract
Objective
Quantify proportion of human immunodeficiency virus (HIV)–infected patients with specific comorbidities receiving healthcare coverage from commercial, Medicaid, and Medicare payers.
Methods
Data from MarketScan research databases were used to select adult HIV-infected patients from each payer. Treated HIV-infected patients were matched to HIV-negative controls. Cross-sectional analyses were performed between 2003 and 2013 among HIV-infected patients to quantify the proportion with individual comorbidities over the period, by payer.
Results
Overall, 36298 HIV-infected patients covered by commercial payers, 26246 covered by Medicaid payers, and 1854 covered by Medicare payers were identified between 2003 and 2013. Essential hypertension (31.4%, 39.3%, and 76.2%, respectively), hyperlipidemia (29.2%, 22.1%, and 49.6%), and endocrine disease (21.8%, 27.2%, and 54.0%) were the most common comorbidities. Comparison of data from 2003 to data from 2013 revealed significant increases across payers in the percentage of patients with the comorbidities specified above (P < .05). Across all payers, the proportions of treated HIV-infected patients with deep vein thrombosis, hepatitis C, renal impairment, thyroid disease, and liver disease from 2003 to 2013 was significantly greater (P < .05) than for matched controls.
Conclusions
Comorbidities are common among the aging HIV-infected population and have increased over time. There should be a consideration in treatment choices for HIV infection, including the choices of antiretroviral regimens.
Although the initial reports of increased cardiovascular (CV) disease in the setting of advanced AIDS were reported approximately 30 years ago, advances in antiretroviral therapy and immediate ...initiation of therapy on diagnosis have transformed what was once a deadly infectious disease into a chronic health condition. Accordingly, the types of CV diseases occurring in HIV have shifted from pericardial effusions and dilated cardiomyopathy to atherosclerosis and heart failure. The underlying pathophysiology of HIV-associated CV disease remains poorly understood, partly because of the rapidly evolving nature of HIV treatment and because clinical endpoints take many years to develop. The gut plays an important role in the early pathogenesis of HIV infection as HIV preferentially infects CD4+ T cells, 80% of which are located in gut mucosa. The loss of these T cells damages gut mucosa resulting in increased gut permeability and microbial translocation, which incites chronic inflammation and immune activation. Antiretroviral therapy does not cure HIV infection and immune abnormalities persist. These abnormalities correlate with mortality and CV events. The effects of antiretroviral therapy on CV risk are complex; treatment reduces inflammation and other markers of CV risk but induces lipid abnormalities, most commonly hypertriglyceridemia. On a molecular level, monocytes/macrophages, platelet reactivity, and immune cell activation, which play a role in the general population, may be heightened in the setting of HIV and contribute to HIV-associated atherosclerosis. Chronic inflammation represents an inviting therapeutic target in HIV, as it does in uninfected persons with atherosclerosis.
Même si les premiers signes d’augmentation des maladies cardiovasculaires (CV) en présence du SIDA au stade avancé ont été rapportés il y a environ 30 ans, les progrès réalisés en matière de traitement antirétroviral et l’instauration immédiate du traitement au moment du diagnostic ont transformé ce qui était jadis une maladie infectieuse mortelle en problème de santé chronique. En conséquence, les types de maladies CV survenant en présence d’une infection par le VIH sont passés des épanchements péricardiques et de la cardiomyopathie dilatée à l’athérosclérose et à l’insuffisance cardiaque. La physiopathologie sous-jacente des maladies CV associées au VIH demeure mal comprise, en partie parce que le traitement du VIH a évolué rapidement et que l’élaboration des critères cliniques nécessite de nombreuses années. L’intestin joue un rôle important au début de la pathogenèse de l’infection par le VIH, car le virus infecte préférablement les lymphocytes T CD4+, dont 80 % se trouvent dans la muqueuse intestinale. La perte de ces lymphocytes T endommage la muqueuse intestinale, augmentant ainsi la perméabilité intestinale et permettant la translocation microbienne, ce qui favorise l’inflammation chronique et l’activation immunitaire. Le traitement antirétroviral ne guérit pas l’infection par le VIH, et les anomalies immunitaires persistent. Ces anomalies ont une corrélation avec la mortalité et les événements CV. Les effets du traitement antirétroviral sur le risque CV sont complexes; le traitement réduit l’inflammation et d’autres marqueurs du risque CV, mais induit des anomalies lipidiques, le plus souvent sous forme d’hypertriglycéridémie. Au niveau moléculaire, les monocytes/macrophages, la réactivité plaquettaire et l’activation des cellules immunitaires, qui jouent un rôle dans la population générale, peuvent être augmentés en présence du VIH et contribuer à l’athérosclérose associée au VIH. L’inflammation chronique représente une cible tentante dans le traitement du VIH, comme chez les personnes non infectées atteintes d’athérosclérose.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Observations on human and experimental atherosclerosis, biomarker studies, and now a large-scale clinical trial support the operation of immune and inflammatory pathways in this disease. The factors ...that incite innate and adaptive immune responses implicated in atherogenesis and in lesion complication include traditional risk factors such as protein and lipid components of native and modified low-density lipoprotein, angiotensin II, smoking, visceral adipose tissue, and dysmetabolism. Infectious processes and products of the endogenous microbiome might also modulate atherosclerosis and its complications either directly, or indirectly by eliciting local and systemic responses that potentiate disease expression. Trials with antibiotics have not reduced recurrent cardiovascular events, nor have vaccination strategies yet achieved clinical translation. However, anti-inflammatory interventions such as anticytokine therapy and colchicine have begun to show efficacy in this regard. Thus, inflammatory and immune mechanisms can link traditional and emerging risk factors to atherosclerosis, and offer novel avenues for therapeutic intervention.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A low CD4/CD8 ratio in elderly HIV-uninfected adults is associated with increased morbidity and mortality. A subset of HIV-infected adults receiving effective antiretroviral therapy (ART) fails to ...normalize this ratio, even after they achieve normal CD4+ T cell counts. The immunologic and clinical characteristics of this clinical phenotype remain undefined. Using data from four distinct clinical cohorts and three clinical trials, we show that a low CD4/CD8 ratio in HIV-infected adults during otherwise effective ART (after CD4 count recovery above 500 cells/mm3) is associated with a number of immunological abnormalities, including a skewed T cell phenotype from naïve toward terminally differentiated CD8+ T cells, higher levels of CD8+ T cell activation (HLADR+CD38+) and senescence (CD28- and CD57+CD28-), and higher kynurenine/tryptophan ratio. Changes in the peripheral CD4/CD8 ratio are also reflective of changes in gut mucosa, but not in lymph nodes. In a longitudinal study, individuals who initiated ART within six months of infection had greater CD4/CD8 ratio increase compared to later initiators (>2 years). After controlling for age, gender, ART duration, nadir and CD4 count, the CD4/CD8 ratio predicted increased risk of morbidity and mortality. Hence, a persistently low CD4/CD8 ratio during otherwise effective ART is associated with increased innate and adaptive immune activation, an immunosenescent phenotype, and higher risk of morbidity/mortality. This ratio may prove useful in monitoring response to ART and could identify a unique subset of individuals needed of novel therapeutic interventions.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BACKGROUNDThe presence and reactivation of chronic viral infections, such as EBV, CMV, and HIV, have been proposed as potential contributors to long COVID (LC), but studies in well-characterized ...postacute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited.METHODSIn a cohort of 280 adults with prior SARS-CoV-2 infection, we assessed the presence and types of LC symptoms and prior medical history (including COVID-19 history and HIV status) and performed serological testing for EBV and CMV using a commercial laboratory. We used covariate-adjusted binary logistic regression models to identify independent associations between variables and LC symptoms.RESULTSWe observed that LC symptoms, such as fatigue and neurocognitive dysfunction, at a median of 4 months following initial diagnosis were independently associated with serological evidence suggesting recent EBV reactivation (early antigen-diffuse IgG positivity) or high nuclear antigen (EBNA) IgG levels but not with ongoing EBV viremia. Serological evidence suggesting recent EBV reactivation (early antigen-diffuse IgG positivity) was most strongly associated with fatigue (OR = 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR = 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR = 0.52).CONCLUSIONOverall, these findings suggest differential effects of chronic viral coinfections on the likelihood of developing LC and association with distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted.TRIAL REGISTRATIONLong-term Impact of Infection with Novel Coronavirus; ClinicalTrials.gov NCT04362150.FUNDINGThis work was supported by NIH/National Institute of Allergy and Infectious Diseases grants (3R01AI141003-03S1, R01AI158013, and K24AI145806); the Zuckerberg San Francisco General Hospital Department of Medicine and Division of HIV, Infectious Diseases, and Global Medicine; and the UCSF-Bay Area Center for AIDS Research (P30-AI027763).
As early and effective antiretroviral therapy has become more widespread, HIV has transitioned from a progressive, fatal disease to a chronic, manageable disease marked by elevated risk of chronic ...comorbid diseases, including cardiovascular diseases (CVDs). Rates of myocardial infarction, heart failure, stroke, and other CVD manifestations, including pulmonary hypertension and sudden cardiac death, are significantly higher for people living with HIV than for uninfected control subjects, even in the setting of HIV viral suppression with effective antiretroviral therapy. These elevated risks generally persist after demographic and clinical risk factors are accounted for and may be partly attributed to chronic inflammation and immune dysregulation. Data on long-term CVD outcomes in HIV are limited by the relatively recent epidemiological transition of HIV to a chronic disease. Therefore, our understanding of CVD pathogenesis, prevention, and treatment in HIV relies on large observational studies, randomized controlled trials of HIV therapies that are underpowered to detect CVD end points, and small interventional studies examining surrogate CVD end points. The purpose of this document is to provide a thorough review of the existing evidence on HIV-associated CVD, in particular atherosclerotic CVD (including myocardial infarction and stroke) and heart failure, as well as pragmatic recommendations on how to approach CVD prevention and treatment in HIV in the absence of large-scale randomized controlled trial data. This statement is intended for clinicians caring for people with HIV, individuals living with HIV, and clinical and translational researchers interested in HIV-associated CVD.
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