Cardiovascular risk profile in the aging HIV population
Numerous observational studies investigating cardiovascular risk factors have reported that traditional risk factors have substantially higher prevalence in the HIV population as compared to the general population, irrespective of age [1–3]. Across these cohorts, current smoking is usually the risk factor with the highest prevalence, varying from 30 to 60%, depending on country of study and other factors such as social conditions and use of illicit drugs [1,2]. Recently, a Danish study shows that smoking is associated with a higher risk of myocardial infarction (MI) in the HIV-infected population than in the general population .
Three other important traditional risk factors with high prevalence include dyslipidemia (20–50%), hypertension (20–30%), and diabetes (2–8%) (Fig. 1). Age is the single most important nonmodifiable cardiovascular risk factor. Today, approximately 40 to 50% of the HIV population is 50 years or older in western countries with access to antiretroviral drugs . Familial history of CVD (20–30%) is another cardiovascular risk factor that is prevalent. Whether aging will influence the incidence of modifiable cardiovascular risk factors in the HIV population is an important question and remains under debate. In fact, in the general population, distinct cardiovascular risk profiles have been described based on accrued cardiovascular risk factors and aging. Patients younger than 50 years presenting with coronary heart disease (CHD) are predominantly smokers, dyslipidemic, and have familial history of premature CVD. Patients older than 50 years presenting with CHD are predominately hypertensive, diabetic, and have renal failure.
In our ongoing study on the prognosis of acute coronary syndrome in HIV-infected patients [PACS-HIV study]  in France, as in other studies , we compared cardiovascular risk factors at admission for acute coronary syndrome (ACS) between HIV-infected and uninfected individuals matched for age, sex, and the type of ACS. We observed that the HIV-infected group had lower BMI, higher triglycerides levels, and more illicit drug use as compared to uninfected controls. Between the two groups, no significant differences were observed in the prevalence of hypercholesterolemia, familial premature history of CVD, hypertension, or diabetes. In all observational studies published, median age at first CHD event occurrence in the HIV population is approximately 50, whereas it is significantly older in the general population at approximately 64 . Whether HIV itself is an independent cardiovascular risk factor that accelerates or accentuates premature CVD onset has been debated since the finding that CHD occurs earlier in the HIV population than the general population. However, when this finding is adjusted for the age distribution (younger than the general population in the HIV population), difference in term of age occurrence in CHD disappears .
In the Veterans Aging Cohort Study Virtual Cohort, in the USA, the authors reported an increased frequency of MI, end-stage renal disease, and non-AIDS-defining cancers in HIV-positive veterans. However, the age at onset was not different between HIV-infected and uninfected veterans . The authors of the comorbidity and aging with HIV cohort in Netherland , which compares cardiovascular risk factors and several comorbidities between HIV-infected and uninfected individuals over 45, reported that HIV-infected participants more frequently presented all noncommunicable comorbidities (MI, peripheral vascular disease, impaired renal function) and cardiovascular risk factors (hypertension, smoking) than did the HIV-uninfected participants. In this study, the age–HIV infection interaction was borderline significant. The authors suggested a stronger age effect among HIV-infected participants. However, if this effect did exist it was modest. Importantly, the authors also reported that HIV infection and prolonged duration of severe immunodeficiency, along with recognized cardiovascular risk factors, increased the risk of a higher composite noncommunicable comorbidities burden.
Recently, Rasmussen et al. reported the time trends in a range of severe age-related comorbidities in HIV-infected and uninfected individuals in Denmark. They found that all investigated comorbidities (MI, stroke, cancer, severe neurocognitive disease, chronic kidney disease (CKD), chronic liver disease, and osteoporotic fracture) were more prevalent in the HIV population as compared to the uninfected population. However, the authors observed that age-standardized and relative risks of CVD, cancer, and severe neurocognitive disease in HIV-infected individuals did not increase with time after HIV diagnosis or antiretroviral therapy (ART) initiation. This observation suggests the impact of aging on CVD in the HIV-infected population may not differ from the general population. The absence of a HIV-specific risk effect of aging was also observed in the data collection on adverse events of anti-HIV drugs (DAD) study, in which the authors found only limited evidence of age accelerating CVD risk in the HIV population compared with the general population .
It is probable, however, that individuals surviving long-term HIV exposure were treated earlier, had a shorter duration of immunosuppression, higher CD4+ cell count levels, fewer comorbidities, less illicit drug use, and fewer chronic hepatitis B and C virus co-infections. Accumulation of these protective factors may lead to a survivor bias, whereas HIV-infected individuals without these protective factors may not survive to older ages. Therefore, it is critical to identify and manage all modifiable risk factors in the ageing HIV population. This is particularly important considering the diagnosis and treatment of hypertension which is a leading cause of CVD.
Hypertension is one of the most important cardiovascular risk factors and is strongly associated with CVD including CHD, stroke, and heart failure. Prevention and treatment strategies targeting hypertension are highly beneficial and lifesaving in both developing and developed countries . The prevalence of hypertension varies between 10 and 50% in the HIV population . As in the general population, the key factors associated with higher risk of hypertension are older age, male sex, African-American, African, and Caribbean ethnicities, higher BMI, CKD, family history of hypertension, and diabetes [1,14,15]. Metabolic syndrome and lipodystrophy syndrome are also associated with hypertension . In both HIV-infected and general populations, fat redistribution (accumulated visceral fat) is associated with an increased risk of hypertension. The physiopathological mechanism may involve the stimulation of the renin–angiotensin system . Risk of hypertension has also been associated with HIV itself and certain antiretroviral drugs, notably several nucleoside reverse transcriptase inhibitors and protease inhibitors . Numerous scientific studies have observed hypertension was independently associated with duration of HIV infection, CD4+ cell count below 200/μl, and duration of ART [18,19]. Consequently, hypertension will continue to emerge as a central and highly prevalent cardiovascular risk factor in the ageing HIV population. As hypertension risk factors and hypertension prevalence continue to increase worldwide, and particularly across African contexts, cardiovascular complications due to hypertension will increase in turn. The same strategies to diagnose and treat hypertension presented in the recommendations for the general population are now warranted in the HIV population [20–22].
Coronary heart disease
The risk of CHD in the HIV population has been investigated since the end of the 90s when reports of acute MI in young HIV-infected patients became known. Several cohort studies have observed that in HIV-infected populations, increased risk of CHD was associated with both traditional cardiovascular risk factors and various HIV-related factors including HIV itself, immunodepression, chronic immune activation, and antiretroviral drugs, notably first-generation protease inhibitors (contradictory results with abacavir) . Throughout the past two decades, the risk of CHD in HIV-infected individuals was considered twice as high as in uninfected individuals of same age .
Recently, analyses of the Kaiser Permanente database in the USA showed that risk of MI was lower when current CD4+ cell count was at least 500/μl compared to CD4+ cell count below 500/μl . Other analyses of this database demonstrated that as of 2011, the risk of MI in the HIV population was not different from that in the general population . Similarly, in Denmark, Rasmussen et al. observed a decline with calendar time in the age-standardized risk of MI among both HIV-infected and HIV-uninfected populations, and also a decline in the relative risk of MI among HIV-infected relative to HIV-uninfected populations between 2006 and 2014 . This decline in the rate of CHD in both the HIV and general populations in developed countries is probably due to better preventive strategies, notably earlier treatment of HIV, smoking cessation, and prescription of statins and antihypertensive drugs.
Prognosis after a first episode of ACS has not yet been fully studied. Our group and others have observed that the HIV-infected population has a higher rate of recurrent ischemic events after a first episode of ACS as compared to the general population, yet the risk of death after long-term follow-up is not different between the two populations [6,25]. Recently, the DAD cohort reported improvements in short-term survival after MI in HIV-infected individuals, which appeared to be largely driven by increased use of drugs and coronary interventions . Another important question is whether initiation of ART at an early phase in the HIV course will decrease cardiovascular events and particularly ischemic events? The strategic timing of antiretroviral treatment (START) trial has reinforced the benefits of early initiation of ART. However, there was no benefit in terms of cardiovascular events . In the START trial, median age of the population was 36 years and median duration of ART was 2.8 years, which could explain the lack of proved benefit in such a young population with such a short period of follow-up for developing an ischemic event. Finally, this was a secondary endpoint of the study and there was no power to observe a benefit with 4685 HIV-infected patients included.
In another recent publication of the DAD cohort , the authors reported a strong relationship between confirmed CKD and CVD. As older individuals are particularly at risk for renal failure, CKD-preventive strategies to alleviate this risk are crucial. Furthermore, effective hypertension prevention is particularly important as hypertension is a recognized risk factor for both CHD and CKD. In the HIV population, two studies [6,29] observed a higher risk of developing heart failure in the HIV population as compared to the general population after ACS.
Heart failure is frequent in the ageing general population. Heart failure is becoming one of the most important CVD events in the older general population. Heart failure with preserved left ventricular function occurs at a particularly high rate. As the incidence of heart failure increases with age, largely due to the development of heart failure risk factors including hypertension and coronary artery disease, the epidemic of heart failure is likely to continue growing in the coming decades .
Before efficient antiviral therapy was available, the prevalence of left ventricular systolic dysfunction was high across the HIV-infected population, and varied between 5 and 20%. Heart failure with left ventricular systolic dysfunction in the HIV-infected population had poor prognosis and was linked to immunodeficiency . Zidovudine was associated with a higher prevalence of systolic dysfunction.
Those cardiomyopathies related to myocarditis in the context of profound immunodeficiency or to drug toxicity have completely disappeared in the antiretroviral era, but are still predominant in countries where access to antiretroviral drugs is limited. Several recent studies highlighted the risk of diastolic dysfunction in the antiretroviral era . Diastolic dysfunction prevalence varied between 20 and 60% in the HIV-infected population depending on evaluating methods and populations. The prevalence was substantially higher in the HIV-infected population than in the similar aged general population, with a prevalence at approximately 10%. In a recent meta-analysis , hypertension and older age were found to be predictors of left ventricular diastolic dysfunction in the HIV population. The pathogenesis of HIV-associated diastolic dysfunction is multifactorial and associates hypertension, increased left ventricular mass, increased aortic or vascular stiffness, and possibly inflammation. Cardiac magnetic resonance has recently shown a higher burden of left ventricular fibrosis and more diffuse fibrosis in the HIV-infected population than in the uninfected population [33,34]. Subsequently, we could speculate that in the near future, as the HIV population continues to age and the prevalence of hypertension and CKD increases, heart failure with preserved ejection fraction related to diastolic dysfunction will become a more prominent new cardiovascular complication  (Fig. 2). Exploration of the physiopathology of diastolic dysfunction and the respective implications of inflammation, hypertension, and metabolic complications such insulin resistance and lipodystrophy may improve understanding and prevention of this risk.
Other cardiovascular complications
Numerous other cardiovascular complications associated with physiological aging can occur in the HIV population. Atrial fibrillation is a notably important cardiovascular complication and has become a major health problem in the aging general population. Atrial fibrillation is associated with risk of stroke and heart failure. To date, only one retrospective cohort of more than 30 000 HIV-infected veterans has investigated the incidence of atrial fibrillation in the HIV population . Over a long-term follow-up (approximately 7 years), the authors observed the incidence of atrial fibrillation was 2.6%. Apart from aging, HIV-infected individuals with cardiovascular comorbidities, including coronary artery disease and congestive heart failure, had higher risk of developing atrial fibrillation. Additional risk factors associated with an increased risk of atrial fibrillation after multivariable adjustment included alcoholism, hypothyroidism, kidney disease, and proteinuria. Incident atrial fibrillation was associated with several HIV-related factors including CD4+ cell count below 200/μl (compared to >350/μl) and higher viral load. How HIV disease severity could influence atrial fibrillation development must be further investigated. Recently, a meta-analysis reported finding a general reduction in autonomic function with a shift toward sympathetic dominance in a young cohort of HIV-infected individuals on antiretroviral drugs. These modifications could lead to arrhythmias and atrial fibrillation, and increase the risk of heart failure and CHD .
Thromboembolic venous disease, pulmonary hypertension, sudden death, and peripheral vascular disease are also potential cardiovascular complications in the HIV population. The impact of ageing on the incidence of these events needs further evaluation in the future.
Cardiovascular disease in the ageing population in low and middle-incomes countries
More than two in three people living with HIV are on the African continent. Greater access to antiretroviral drugs in low and middle-income countries has prolonged survival of HIV-infected patients and consequently increased their risk of noncommunicable disease and CVD in particular.
Before access to HIV antiretroviral drugs, CVD in HIV-infected patients was predominantly driven by cardiomyopathy and pericarditis (tuberculosis cause). Heart failure and pericarditis remain the leading causes of cardiovascular complications in the HIV population across Africa. Two cohorts investigated causes of hospitalization in cardiac care units in sub-Saharan Africa [35–40]. In the Soweto Heart Study [38,39] in South Africa, HIV-infected individuals hospitalized for cardiovascular complications were young (mean age 39 years), predominantly female (62%), and slightly more than half the participants were taking antiretroviral drugs (54%). Thirty-eight percent presented with HIV-related cardiomyopathy, 13% with acute pericarditis, 11% with valve disease, and only 2.7% with coronary artery disease. Across low and middle-incomes countries, the shift in CVD epidemiology expected in the general population may be greater and faster in the HIV-infected population. This shift and acceleration will be largely due to easier access of antiretroviral drugs, enabling the HIV population to advance in age, and the increasing prevalence of atherosclerotic cardiovascular risk factors including hypertension, diabetes, and obesity. It has now become urgent to improve prevention, diagnosis, and management of noncommunicable diseases in HIV-infected patients living in low and middle-income countries to reduce the burden of CVD in this specific population.
Prevention of CVD in the aging HIV population should follow the same recommendations as in the general population and should maintain a focus on smoking cessation and precautions on medication prescription due to the risk of drug–drug interaction between antiretroviral and cardiovascular drugs [20,41,42]. Interventional studies aimed at reducing cardiovascular risk in HIV-infected patients are now warranted, and, for example, could address smoking cessation, increasing physical activity, and use of lipid-lowering drugs and aspirin when necessary. In fact, few studies have evaluated the efficacy and the attainment of goals for blood pressure and low-density lipoprotein (LDL)-cholesterol levels after introduction of antihypertensive drugs and/or lipid-lowering drugs, particularly statins. Recent studies have shown that the HIV-infected population is less frequently treated with aspirin in primary cardiovascular prevention and less frequently attain LDL-cholesterol goals in secondary prevention [43,44] as compared with the general population. It is essential that the HIV-infected population get the same access to CVD-prevention strategies and particularly Afro-Americans, Africans as the general population.
Drug–drug interactions and poly-pharmacy risks may be central to explaining why CVD prevention is not optimal in the HIV-infected population. Indeed, risks of potentially lethal interactions exist between certain statins (lovastatin, simvastatin) and protease inhibitors such as ritonavir (CYP3A4 inhibition). Potentially lethal interactions also exist between several antithrombotic drugs (new antiplatelet agents, new oral anticoagulant) and certain antiretroviral drugs (Table 1). The new integrase inhibitors (raltegravir, elvitegravir, dolutegravir) and maraviroc (CCR5 inhibitors) have no potential interaction with any new antiplatelet agents (e.g. P2Y12 inhibitors: ticagrelor, prasugrel, clopidogrel).
Antihypertensive drugs, in particular dihydropyridine calcium-channel-blockers, may interact with protease inhibitors and should be given at a low dose. Aspirin in primary prevention should be prescribed to high-risk patients, for example, Framingham risk score at least 20% and with controlled hypertension as recommended for the general population.
Cardiovascular health in the aging HIV population is becoming a major concern provided that the HIV population has a high prevalence of traditional risk factors (in particular smoking), and has experienced immunosuppresion, immune activation, and metabolic side effects of older generations of antiretroviral drugs (hypersinsulinemia, dyslipidemia).
Forthcoming observational studies are needed to evaluate and stratify cardiovascular risk in the aging HIV population. Who is at higher risk? What tools should be used to identify those at higher risk... which cardiovascular risk scores, infraclinic markers of atherosclerosis (coronary calcifications? coronary plaque burden using computed tomography?) or biomarkers if one exist? How to best prevent cardiovascular risk in this specific population? Should different guidelines from the general population be applied?
Interventional studies are now necessary to evaluate the benefit of preventive strategies in this high-risk population. Should we start cardiovascular prevention at an earlier time that in the general population depending on the known duration of HIV seropositivity? Although there are many complex issues at the core of improving cardiovascular health in this specific population, today we must begin to respond through adapted prevention, accurate diagnosis, and optimized treatment of cardiovascular risk factors and diseases. Scientific research is necessary to answer these inter-related and evolving questions concerning all people living with HIV, those with easy access to antiretroviral drugs, and those in developing countries where the CVD burden is increasing in the general population.
I thank Mabel Nuernberg, MSc, for critical reading of the manuscript.
Conflicts of interest
There are no conflicts of interest.
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