HIV & Aging Clinical Recommendations

Chapter 5

Preventing and Screening for Cardiovascular Disease in Older Adults with HIV

Recommendations:

  • HIV infection is associated with an excess risk of developing cardiovascular disease. Traditional and HIV-specific risk factors for CVD should be evaluated at the initial visit and reassessed over time.
     
  • While certain antiretroviral agents have been associated with greater risk of CVD and dyslipidemia in people living with HIV, traditional CVD risk factors (e.g., smoking, high blood pressure) remain the most important.
     
  • People living with HIV (PWH) should be encouraged to modify those clinical risk factors that they can. Cessation of tobacco use must be emphasized.
     
  • Newer CVD risk calculators (such as the AHA/ACC Pooled Cohort Equations CV Risk Calculator) can help assess risk in PWH but may underestimate their risk.

Cardiovascular disease (CVD) is the leading cause of death in the United States and world-wide (Kochanek, 2020). Age is a leading risk factor for CVD, and as PWH are living longer and growing older as a result of effective antiretroviral therapy (ART), the prevalence of CVD is increasing (Feinstein, 2019, Shah, 2018). Specifically, atherosclerotic cardiovascular diseases (ASCVD; e.g., coronary artery disease, myocardial infarctions, ischemic stroke) have tripled in the past two decades and are among the leading causes of hospitalizations, disability, and death among PLWH (Fleming et al., 2019; Hart et al., 2018; Shah et al., 2018).

Background

Given the increasing burden of CVD among PWH, several teams have synthesized the population-based studies examining the association between HIV, ART, and CVD. A recent synthesis reported that PLWH have a 1.5- to 2-fold increased risk of developing ASCVD (Feinstein et al., 2019).  With improved treatment and care, the risk of myocardial infarction is decreasing (Klein et al., 2015), yet a recent analysis of a large U.S. dataset (i.e., MarketScan Commercial and Medicare datasets) found an approximately 1.3-fold increase in myocardial infarction in PWH, underscoring the need for primary CVD prevention this population (Alonso et al., 2019).

In addition to aging, the major clinical risk factors for CVD include high blood pressure, hyperlipidemia, diabetes mellitus, and tobacco use. These risk factors are prevalent among PWH. The population attributable contribution of these traditional risk factors to CVD-associated mortality is high, and more than 80% of that risk is attributable to lifestyle-modifiable factors, including high blood pressure, hyperlipidemia, diabetes mellitus, and tobacco use (Althoff, 2019).

Those aging with HIV are likely to have increased exposure to traditional risk factors. For example, while the rate of smoking has declined in recent years (Frazier, 2018), the rate of smoking is higher among PWH than in the general population, and it has been suggested that the impact of smoking-related cardiovascular morbidity is greater among PWH (Raposeiras-Rubin, 2017). Insulin resistance and diabetes are also prevalent in PWH with an estimated 12% of PWH also living with diabetes, compared to 10.5% of the general American population (Kalra, 2011). Visceral fat accumulation, a poorly understood complication of ART use and HIV, continues to contribute to CVD risk in certain patients including post-menopausal women 

Additionally, rates of obesity are increasing among PWH, with ranges from 8% to 25%. Women, racial and ethnic minorities, and the initiation of some HIV medications (e.g., integrase inhibitors) are associated with increased obesity in PWH (Bailin et al., 2020; Lake, 2017). Additional lifestyle factors, including sedentary behaviors, and diet, influence both traditional CVD risk factors and the pathways between inflammation and atherosclerosis.  

The proposed pathogenesis of atherosclerosis and arterial disease in HIV infection is a multifactorial and complex process that remains incompletely understood. Dyslipidemia is a well-described independent risk factor for CVD, and it occurs in approximately 36% of PWH in high-resource settings (Wong, 2017). This dyslipidemia is caused by a combination of factors associated with HIV disease, ART regimens, and individual patient characteristics. It is well-established that HIV infection is associated with lipid abnormalities, with older PWH experiencing elevations in triglyceride (TG) levels and decreases in high-density lipoprotein (HDL) as well as in low-density lipoprotein (LDL) cholesterol and total cholesterol (TC). Increasingly, PWH are being diagnosed with high blood pressure with a recent analysis reporting that approximately 42% of PWH in high-income settings experiencing hypertension (Wong, 2017). Despite the complexities, strong evidence suggests that reducing hypertension (Casey et al., 2019), hypercholesterolemia (Grundy et al., 2019), hyperglycemia (Fox et al., 2015), and stopping all tobacco use (Barua et al., 2018) through non-pharmacological or pharmacological approaches are likely to lead to immediate improvements in CVD risk in PWH (Arnett et al., 2019).

Although modification of traditional CVD risk factors will continue to be an important focus of prevention efforts, studies have shown that these risk factors by themselves do not account for all of the observed increased CVD in PWH. A large global systematic review  of almost 800,000 PWH reported the global population attributable fraction from CVD attributable to HIV increased from 0.36% to 0.92% over the past two decades (Shah, 2018). This association may be due to a complex interaction between HIV infection, inflammation and ART that results in increased cardiovascular events in this population.

The role of ART in promoting atherosclerosis and CVD has been extensively debated; both alterations of lipid metabolism and direct detrimental effect of specific drugs have been described. In the 2000’s, the D:A:D (Data Collection in Adverse Effects of Anti-HIV Drugs) observational cohort study investigated the association of ART and CVD in PWH and identified a significant increase in MI risk with ART, especially with the use of older protease inhibitors (PI). Most of this effect may have been due to metabolic effects (e.g. hyperlipidemia, lipodystrophy and glucose intolerance) of protease inhibitors (Friis-Møller 2007). Yet, specific evaluation of individual PIs suggests that the increased risk of CVD may not be a class effect. Further, if there is any increase in CVD risk associated with ART, there is a growing consensus that it is counterbalanced by the beneficial effects (possibly anti-inflammatory) of ART on CVD risk. In fact, treating HIV with ART clearly has beneficial effects on MI risk. Consequently, as ART has evolved to have fewer toxic metabolic effects, investigations of residual CVD risk in PWH have increasingly focused on the role of inflammation. 

Despite sustained HIV suppression in PWH, sustained inflammation persists and is associated with accelerated development of CVD through vascular inflammation, endothelial dysfunction, hypercoagulability, and disrupted cholesterol transport and capacity (Hart et al., 2018; Nou et al., 2016). Inflammatory biomarkers, including D-dimer, high sensitivity C-reactive protein (hsCRP), and interleukin 6 (IL-6), are among the most studied predictors of CVD in PWH and have consistently been associated with increased CVD risk (Nou et al., 2016; Subramanya et al., 2019). While HIV public health initiatives, such as test-and-treat and the 90-90-90 goals, have helped to increase the number of PWH on effective HIV medications, they have also shortened the time between HIV infection and HIV viral suppression. This truncated time of uncontrolled HIV viremia is likely to moderate the cardiometabolic consequences of HIV infection, and may help to explain the decreasing rates of myocardial infarction among PWH in recent years.

CVD mortality trends in women living with HIV parallel those of men living with HIV, with decreasing AIDS-related mortality accompanied by increasing CVD-related mortality. In the United States, women living with HIV have an increased risk of MI, stroke and heart failure (Stone, 2017). A current area of investigation is how female sex, endogenous hormone production, and reproductive aging influence CVD risk in HIV. This gap in our understanding underscores the current need for greater effort to identify CVD risk and promote evidence-based primary prevention in women aging with HIV.

Assessment of CVD Risk

Assessing risk and preventing CVD in PWH remains challenging, as traditional risk models tend to underestimate the risk of cardiovascular events in PWH (Tirant, 2020). Both the Framingham Risk Score and the American Heart Association and American College of Cardiology (AHA/ACC) Pooled Cohort Equations CV Risk Calculator were not designed for use in HIV populations and were recently found to underestimate the risk of cardiac events in both men and women living with HIV (Feinstein, 2017).

Investigators have used data from the D:A:D study to develop a risk calculator and have compared it to the Framingham risk calculator (Friis-Moller 2010). They included some ART variables in their models in addition to the traditional Framingham risk factors and found that the D:A:D models performed similarly to Framingham in terms of discriminating risks and performed better in terms of calibrated absolute risk (predicted-to-observed CVD events) (Markowicz 2014).

While these tools may not perfectly risk stratify a patient’s risk of CVD events, they may be useful decision-making tools when helping PWH decide whether to start a new CVD therapy. Similarly, the Mayo Clinic Statin Choice Decision Aid™ can help patients and providers visualize one’s risk of CVD events and the corresponding change in risk due to a cholesterol-lowering intervention.

The IDSA/HIVMA HIV primary care guidelines recommend obtaining a baseline fasting blood glucose and/or hemoglobin A1C and a fasting lipid profile prior to and within three months after starting ART to screen for metabolic syndrome, diabetes mellitus, and dyslipidemia (Aberg 2014). The fasting lipid profile should be obtained three to six months after initiating or switching ART and then every twelve months thereafter. Standardized blood pressure (e.g. correctly fitting cuff, no talking), weight with body mass index (BMI) and waist circumference calculation should be performed at least annually.

Management of CVD Risk

Care of the older adult living with HIV includes proper management of blood pressure, diabetes, smoking cessation, obesity, and dyslipidemia to reduce the cardiovascular risk. All the available guidelines emphasize the importance of adherence to a heart-healthy lifestyle that includes regular exercise (e.g., at least 150 minutes of moderate-vigorous physical activity per week), following a low salt and low-glycemic-index diet, reducing sedentary time, maintaining BMI <25 kg/m2, and smoking cessation. After consistently taking effective ART, tobacco cessation might be the single most important factor in reducing CVD risk.

The guiding principle of CVD risk management is that a patient’s absolute CVD risk determines the intensity of interventions. The 2019 American College of Cardiology/American Heart Association (ACC/AHA) guideline on the primary prevention of cardiovascular risk in adults consolidates the most up to date evidence on cholesterol management and did identify HIV as CVD risk enhancer. The ACC/AHA guidelines address the broader outcome of clinical atherosclerotic CVD (ASCVD), which includes CVD, MI, stroke, and peripheral arterial disease, not just MI or CV death.

The ACC/AHA guidelines adopt a holistic, life course perspective of CVD prevention and emphasize lifestyle optimization to prevent CVD (Arnett, 2019). These guidelines approach CVD prevention by incorporating many aspects of lipid management, including the evaluation of patients for lipid-lowering therapy, the use and monitoring of lipid-lowering agents, and the use of treatment targets. The ACC/AHA guidelines focus on treatment of LDL-C that is based on cardiovascular risk. Risk assessment is used to identify patients to treat, and the intensity of treatment is based on clinical trials evidence. To estimate ten-year ASCVD risk in adults 40-75 years old, the ACC/AHA guidelines employ a simplified global risk-assessment tool adapted for different genders and race (non-Hispanic whites and African-Americans in the U.S.). The ASCVD Risk Estimator is relatively easy to use and can be found at http://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/. It is also available as an app for mobile devices and can be integrated into many EMR platforms.

After optimizing lifestyle approaches, medical therapy for prevention of CVD should be considered.  Recent evidence suggests a more limited role for aspirin in primary prevention of ASCVD events in the general population, with careful attention paid to assessment of both CVD and bleeding risks.  Aspirin should only be recommended if the absolute CVD risk reduction is greater than the absolute increased risk of bleeding.  In the absence of HIV specific evidence, the decision to recommend aspirin for prevention of CVD in the HIV-infected patient should be the same as for the general population.  Despite these caveats, aspirin use appears to be underutilized for PWH (Ledapo 2017). 

Statins represent the primary medical therapy for ASCVD prevention. Numerous studies among HIV-uninfected individuals without evidence of coronary heart disease have demonstrated substantial relative reductions in cardiovascular events with the use of statins. Statins remain an attractive option in PWH because, in addition to their cholesterol-lowering properties, they have anti-inflammatory effects that may further reduce CVD and all-cause mortality.

 

Table 1: Summary of key recommendations from the 2018 ACC/AHA cholesterol guideline

Groups most likely to benefit from statin therapy Recommended statin intensity
Secondary prevention for patients with clinical ASCVD High intensity
Primary prevention for LDL-C>190 mg/dL High intensity
Primary prevention for diabetics aged 40–75 years with LDL-C 70–189 mg/dL and without clinical ASCVD ≥7.5% 10-year risk—high intensity
<7.5% 10-year risk—moderate intensity
Primary prevention for non-diabetics aged 40–75 years with an estimated 10-year ASCVD risk <7.5% Moderate to high intensity if appropriate after clinician‒patient discussion

Thresholds for initiating statin therapy were derived from large randomized controlled trials. The choice of statin and dose is recommended based on estimated level of risk for a patient with HIV as a risk enhancer (Table 1). If the patient has major cardiovascular risk factors such as clinical ASCVD, LDL-C >190 mg/dL, or age 40 to 75 years with diabetes mellitus, or if the calculated ten-year risk of ASCVD was >7.5%, then the guidelines recommend moderate- to high-intensity statin therapy. The definition of high-intensity statin therapy is LDL-C reduction of >50% and that of moderate-intensity therapy is a reduction of 30% to 50%.

The efficacy of statins in HIV is not completely proven, because of small sample-size and the observational nature of many studies (Longencker, 2017). As a result, a large, multicenter, randomized, placebo-controlled trial, the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE clinicaltrials.gov: NCT02344290) was initiated in March 2015. The REPRIEVE clinical trial will randomize 7500 PWH to pitavastatin—which not metabolized via CYP3A4—or placebo. Results should provide a better understanding of the real world impact of statins on CVD events including effects on plaque and immune function (Grinspoon, 2019).

 

Table 2: Choice of Statin and Dose Intensity Options

Statin Dose and Expected LDL-C % lowering
atorvastatin (Lipitor) 10 mg 20 mg 40 mg 80 mg
39% 43% 50% 60%
pravastatin (Pravacol) 10 mg 20 mg 40 mg 80 mg
22% 32% 34% 37%
rosuvastatin (Crestor) 5 mg 10 mg 20 mg 40 mg
45% 52% 55% 63%
fluvastatin (Lescol) 20 mg 40 mg 80 mg  
22% 25% 35%  
simvastatin (Zocor) 5 mg 10 mg 20 mg 40 mg
36% 30% 38% 41%
pitavastatin (Livalo) 1 mg 2 mg 4 mg  
32% 36% 43%  
lovastatin (Mevacor) 10 mg 20 mg 40 mg 80 mg
21% 27% 31% 42%

Choice of statin and dose intensity are listed in Table 2. Statin doses that have been used in clinical trials of primary prevention include low- to moderate-intensity (pravastatin 40 mg; lovastatin 20 to 40 mg; atorvastatin 10 mg) and high-intensity (atorvastatin 40 mg; rosuvastatin 20 mg) therapy. 

In PWH, the selection of statins should take into account the relative efficacy of the statin as well as any potential drug-drug interactions and side effects. While today ART has a lower potential for drug-drug interactions compared with earlier medications, cardiovascular medications are common sources of these interactions (Courlet et al., 2019). To prevent adverse effects, each patient’s unique medical and medication history need to be considered in the context of their health goals; however, there are some general guidelines that should be considered when prescribing cardiovascular medications. 

In particular, statins are highly effective at reducing CVD, yet some—such as simvastatin and lovastatin—strongly interact with ART regimens that are boosted with a CYP3A4 inhibitor such as ritonavir or cobicistat and should therefore be avoided.  In addition, efavirenz and other non-nucleoside reverse transcriptase inhibitors induce CYP3A4 metabolism, resulting in decreased blood levels of these statins.  Weaker interactions exist for atorvastatin, rosuvastatin, and pravastatin, while pitavastatin is the lowest risk for interactions. When an interaction is present, using the lowest dose statin to reduce lipid levels is recommended (Devanathan et al., 2019). Additionally, calcium channel blockers (e.g., amlodipine, verapamil) can interact with boosted ART and may require dose adjustment (Devanathan et al., 2019). Emerging evidence suggests that antiplatelet medications (e.g., clopidogrel, prasugrel) may interact with ritonavir and cobicistat (Bravo et al., 2018). Given the increasing complexity of CVD treatment in PWH, working closely with a pharmacist and utilizing the University of Liverpool HIV Drug Interaction Checker can help minimize the risk of drug-drug interactions or adverse events (Liverpool, 2020). 

Some patients are unable to take statin medications because of side effects—most commonly myalgias and other muscular symptoms. Clinicians may consider multiple interventions to control statin myopathy (e.g., switching statin, dose reduction, alternative dosing schedules, or alternative agents). In general, clinicians should discontinue statin therapy until symptoms are evaluated. Alternative cholesterol lowering therapies such as ezetimibe or bempadoic acid could be considered. Clinicians should also consider other conditions that might increase the risk for muscle symptoms, such as hypothyroidism, kidney/liver disease, rheumatologic disorders, steroid myopathy, low Vitamin D status, or primary muscle diseases. If, after two months without statin therapy, muscle symptoms or elevated creatinine kinase levels do not resolve completely, clinicians should consider other causes of muscle symptoms.

Based on current data, there is not enough evidence to suggest that PWH need a more aggressive approach to the management of CVD risk compared with that recommended for those without HIV. But efforts to apply the newer 2019 ACC/AHA guidelines broadly should help to raise the level and intensity of CVD preventive management for aging PWH. Before initiating pharmacological CVD therapy, clinicians should help patients optimize their lifestyle factors and engage in a patient discussion of the potential for CVD risk (including family history). This discussion can also include the potential benefits of cardiovascular therapy, potential for adverse effects, medication interactions, and patient preferences.

Non-statin lipid-lowering agents such as niacin, fibrates, fish oil, and ezetimibe have shown modest benefit and have a low incidence of side effects (Grundy, 2018). Newer LDL and triglyceride lowering therapies such as PCSK9-inhibitors, bempadoic acid, icosapent ethyl, and inclisiran may increase the range of non-statin options for PWH, though costs for these newer agents remain high.  The triglyceride level is a primary target of lipid-lowering therapy only when the triglyceride level exceeds 500 mg/dL, because of the associated risk of pancreatitis. Although high triglyceride levels may be a modest independent risk factor, triglycerides are most associated with other cardiovascular risk factors (e.g., low HDL-C level, hypertension, obesity, inflammation, and insulin resistance).

For triglyceride levels below 500 mg/dL, LDL-C should be targeted to reduce CVD risk. For higher triglyceride levels, where the primary goal of treatment is to prevent pancreatitis, fibrates are the preferred initial therapy. Dietary intervention can also have a significant effect on triglyceride levels. Patients should restrict saturated fats and trans-fats, emphasize intake of omega-3 fatty acids and monounsaturated fats, limit simple carbohydrates and calories, and reduce alcohol intake. Fish oil in a dose of 4 grams per day can lower triglyceride levels substantially, and icosapent ethyl decreased cardiovascular events in a clinical trial in the general population (Bhatt, 2019).  

Summary

The prevalence of cardiovascular disease is increasing as PWH live longer, age, and acquire traditional cardiovascular disease risk factors. Recent research has clearly identified the HIV-specific increase CVD and revealed additional strategies to help mitigate this excess risk. Although lowering cardiovascular risk is focused on statin therapy and lifestyle modification, controlling the HIV virus is critical to helping this population age well.

Updated on: 
Friday, April 2, 2021
Updated by: 
Andrea Weddel

References

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