HIV and cardiovascular disease - Review
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Kaku So-Armah, Laura A Benjamin, Gerald S Bloomfield, Matthew J Feinstein, Priscilla Hsue, Benson Njuguna, Matthew S Freiberg
People living with HIV have an excess risk of cardiovascular disease compared with people without HIV....Sub-Saharan Africa has a younger population, higher prevalence of elevated blood pressure, lower smoking rates, and lower prevalence of elevated cholesterol than western Europe and North America.....in 2030, by which time 78% of people with HIV will have been diagnosed with cardiovascular disease......In a recent meta-analysis,2 people living with HIV had more than twice increased risk of cardiovascular disease overall. All the cohorts analysed, except one from Tanzania, were either from western Europe or North America.
In summary, a geographical imbalance between HIV disease burden and the populations included in published HIV-related cardiovascular disease research exists. There is strong evidence linking HIV infection to myocardial infarction, stroke, and heart failure. There are scarce data that also link HIV infection to peripheral artery disease and sudden cardiac death. Although mechanisms for these associations might be the same for all people with HIV, the distribution of cardiovascular disease risk factors varies by geographical location. These variations result in different profiles of cardiovascular disease risk in low-income and middle-income countries compared with high-income countries. To reduce cardiovascular disease risk globally among people with HIV calls for thoughtful balancing of public and individual health approaches, evidence-informed strategies, expert health-care and patient opinions, and basic translational and implementation research in areas with the highest HIV burden.
A model based on the AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort showed that the median age of people with HIV on ART will increase from 43⋅9 years in 2010, to 56⋅5 years ......
.....in 2030, by which time 78% of people with HIV will have been diagnosed with cardiovascular disease. 3
The increase in relative risk of myocardial infarction among people with HIV ranges from 20% to 100%, compared with people without HIV (table 1).
First, coronary heart disease risk factor screening should be part of routine care for people with HIV.
Given few resources and the absence of cost-effective data on routine coronary heart disease risk factor screening in facility-based HIV-care programmes,
it might be advisable to reserve routine screening for people with HIV older than 40 years for whom feasibility has been shown.
We should leverage large HIV-population cohorts in sub-Saharan Africa and low-income and middle-income countries to develop tailored risk scores for stroke prevention. In regions with the highest burden of HIV infection in sub-Saharan Africa, priority should be given to developing stroke diagnostic and treatment pathways, centred around stroke units where brain imaging is available, and where complex management and rehabilitation can be provided. Government-operated stroke units are not commonplace in sub-Saharan Africa and are currently clustered in South Africa, Nigeria, and Ghana
Estimates from South Africa on peripheral artery disease suggest a prevalence of 7% in HIV populations with a mean age 46 years,20 compared with the general population with prevalence estimates of 3⋅9% in people aged 40–49 years.21 The largest study examining HIV infection as a risk factor for peripheral artery disease involved over 90 000 participants from the Veterans Aging Cohort Study in the USA and reported a 19% increase in risk of incident peripheral artery disease among people with HIV versus without HIV.10
In a recent meta-analysis, 2 people living with HIV had more than twice increased risk of cardiovascular disease overall. All the cohorts analysed, except one from Tanzania, were either from western Europe or North America. The distribution of cardiovascular disease risk factors varies by geographical location and by HIV prevalence. Sub-Saharan Africa has the greatest prevalence of HIV, along with a younger population, higher elevated blood pressure prevalence, lower tobacco smoking rates, and lower prevalence of elevated cholesterol than western Europe and North America (figure 1)
Virus-related mechanisms include pro-inflammatory effects of HIV proteins released from the HIV virus, CD4+ T-cell depletion, increased intestinal permeability, microbial translocation, and altered cholesterol metabolism (figure 2). Biomarkers of chronic inflammation, monocyte activation, and altered coagulation are elevated in people living with HIV compared with people without HIV.26 Many of these biomarkers are associated with atherogenesis, an inflammatory process, leading to atherosclerotic cardiovascular disease (eg, myocardial infarction). Importantly, sex-based differences in response to an acute HIV infection might persist into chronic infection, resulting in increased immune activation in women compared with men.16 These sex-based differences could explain higher rates of myocardial infarction among women,16 which is an important reason for greater inclusion of women and sex-stratified analyses in this field. Greater inclusivity should extend to pre-menopausal and post-menopausal women, and gender minorities for whom sex hormone profiles might (independently and synergistically with HIV) be important drivers of cardiovascular disease risk.
CD4+ T-cell depletion among people with HIV is associated with higher rates and risk of incident acute myocardial infarction, heart failure, peripheral artery disease, and ischaemic stroke (table 1).
Weakened adaptive immunity could lead to opportunistic infections, which in turn drive an inflammatory response that might lead to cardiovascular disease (eg, infectious myocarditis).27 A study by Grody and colleagues28
also suggests that HIV itself can cause cardiomyopathy via direct infection of cardiac myocytes.29
The depletion of CD4+ T cells in the gut mucosa, caused by HIV infection, damages the lining of the gut and increases its permeability to microbial translocation products. Microbial translocation is a process whereby microbial products from the gut leak across the disrupted gut lining and into the portal circulation on the way to the liver. This process leads to chronic immune activation and inflammation.30 HIV, like other viral infections, is associated with altered cholesterol metabolism resulting in atherogenic lipid and cholesterol profiles. 31
In the CNS, HIV could alter the blood–brain barrier through infected monocytes, which routinely surveil the brain from the peripheral circulation. In the closed brain compartment, HIV can infect perivascular macrophages, microglial, and mural support tissue, and establish a reservoir.
This microenvironment of HIV-infected cells can accentuate inflammatory mediators and contribute to endothelial dysfunction, and vessel wall remodelling.
Whether the mechanism in the brain differs from the periphery is yet to be established, but clinical stroke phenotypes suggest differences do exist.
Any adverse effect of ART on cardiovascular disease risk should be balanced against the life-preserving effects of ART and the effects of these drugs on reducing HIV viraemia.
Older ART regimens (eg, abacavir, lopinavir, and ritonavir) used in low-income settings had side-effect profiles detrimental to cardiovascular health such as altered glucose and lipid metabolism, mitochondrial toxicity and subsequent cardiac myopathy, or impaired left ventricular function.
Other regimens (eg, dolutegravir or atazanavir) might have less detrimental effects on cardiovascular health.
Whether these cardiotoxic-ART effects differ by sex is unclear.
Weight gain after initiation of ART and HIV viral suppression in part reflects ART side-effects and a return to health after resolution of overt HIV replication (a catabolic state).
It also reflects fluctuating trends in weight gain in low-income and high-income settings, which are not unique to HIV. Combined, these sources of weight gain have been associated with incident diabetes, a cardiovascular disease risk factor, and this association is dependent on body physique before starting ART.
People ageing with HIV have multiple chronic comorbidities often requiring multidrug regimens and resulting in polypharmacy.
The potential for drug–drug interactions increases with increasing number of medications which in turn could contribute to QT interval prolongation.
Prolonged QT intervals are associated with HIV infection and increased risk of sudden cardiac death. People with HIV have a 4-times increased risk of a sudden cardiac death compared with people without HIV.
Non-HIV specific mechanisms
Non-HIV specific mechanisms contributing to increased risk of cardiovascular disease include traditional and non-traditional cardiovascular disease risk factors. Traditional risk factors include smoking, diabetes, dyslipidaemia, hypertension, and biological sex. Although not unique to people living with HIV, populations in some regions might have greater exposure to these risk factors (figure 1). Women with HIV might have higher odds of developing metabolic syndrome than men.
When these risk factors are absent, the relative risk of acute myocardial infarction among people with HIV compared with people without HIV is still 2-times higher, but the absolute rates of acute myocardial infarction are low. Increasing exposure to these risk factors leads to an exponential increase in cardiovascular disease risk regardless of HIV status.
These risk factors in combination with HIV infection have been variably associated with subclinical atherosclerosis including carotid intima-media thickness, coronary artery calcification, and other structural and functional vascular alterations.
In addition to variability in the geographical distribution of traditional cardio-vascular disease risk factors, variability in the association of these risk factors with subclinical cardiovascular disease highlight the need for geographically diverse studies for HIV-related cardiovascular disease risk reduction globally.
Non-traditional cardiovascular disease risk factors are also accentuated in HIV and include unhealthy alcohol consumption, depression, hepatitis C, and possibly cytomegalovirus co-infection. Unhealthy alcohol consumption, independent of HIV infection, can cause microbial translocation, activating Kupffer cells, which drive chronic inflammation. Liver fibrosis can itself be associated with increased heart failure risk.
Unhealthy alcohol consumption is also associated with ART non-adherence,
which causes increased HIV viral replication and might consequently increase cardiovascular disease risk.
Major depressive disorder can affect between 5% and 10% of people with HIV. Depression is a risk factor for both acute myocardial infarction and heart failure among people with HIV.
Although the exact mechanism is unknown, some reports link depression with autonomic nervous system dysregulation, inflammation, and platelet activation.
Hepatitis C and cytomegalovirus are common co-infections among people with HIV. In many, but not all, studies, hepatitis C has been linked to incident cardiovascular disease events.
Underlying mechanisms are thought to be related to chronic inflammation, endothelial dysfunction, and exacerbating microbial translocation through hepatic damage. The role of cytomegalovirus as a risk factor for cardiovascular disease is less clear. Observational studies in the general population link cytomegalovirus antibody status to incident cardiovascular disease.
Among people with HIV, no such studies exist, although some evidence links cytomegalovirus status to immunosenescence, which might predispose to cardiovascular disease risk.
Disparities in cardiovascular care occur with studies reporting that people with HIV are less likely to receive aspirin for primary cardiovascular disease prevention, HMG-CoA reductase inhibitor therapy for diabetes, cardiovascular disease, or dyslipidaemia; and invasive procedures for myocardial infarction compared with people without HIV.
These disparities by HIV status might be worsened by substance use disorders, female sex, and among racial and ethnic minorities.
HIV and cardiovascular disease
April, 2020 - Lancet HIV - Kaku So-Armah, Laura A Benjamin, Gerald S Bloomfield, Matthew J Feinstein, Priscilla Hsue, Benson Njuguna, Matthew S Freiberg
HIV-related cardiovascular disease research is predominantly from Europe and North America. Of the estimated 37⋅9 million people living with HIV worldwide, 25⋅6 million live in sub-Saharan Africa. Although mechanisms for HIV-related cardiovascular disease might be the same in all people with HIV, the distribution of cardiovascular disease risk factors varies by geographical location. Sub-Saharan Africa has a younger population, higher prevalence of elevated blood pressure, lower smoking rates, and lower prevalence of elevated cholesterol than western Europe and North America. These variations mean that the profile of cardiovascular disease differs between low-income and high-income countries.
Research in, implementation of, and advocacy for risk reduction of cardiovascular disease in the global context of HIV should account for differences in the distribution of traditional cardiovascular disease risk factors (eg, hypertension, smoking), consider non-traditional cardiovascular disease risk factors (eg, access to antiretroviral therapy with more benign cardiovascular disease side effect profiles, indoor air pollution), and encourage the inclusion of relevant risk reduction approaches for cardiovascular disease in HIV-care guidelines.
Future research priorities include implementation science to scale up and expand integrated HIV and cardiovascular disease care models, which have shown promise in sub-Saharan Africa; HIV and cardiovascular disease epidemiology and mechanisms in women; and tobacco cessation for people living with HIV.
People living with HIV have an excess risk of cardiovascular disease compared with people without HIV.1, 2 The mechanisms driving this risk include HIV-specific, and traditional and non-traditional cardiovascular disease risk factors. Data linking HIV and clinical cardiovascular disease, risk factors, and risk assessment come predominantly from Europe and North America. Of the estimated 37⋅9 million people living with HIV worldwide, 25⋅6 million live in sub-Saharan Africa, where less is known about incidence of cardiovascular disease and the burden of risk factors driving cardiovascular disease.