A scientific statement from the American Heart Association (AHA) was published in Circulation, with the purpose of providing a thorough review of available evidence on HIV-associated cardiovascular disease (CVD), particularly atherosclerotic CVD , as well as practical guidelines for how best to approach the prevention of CVD and the treatment of HIV considering the lack of large-scale randomized controlled trial data.
The use of early, effective antiretroviral therapy (ART) has allowed HIV to transition “from a progressive, fatal disease to a chronic, manageable disease marked by an elevated risk for chronic comorbid diseases, including CVDs.” People living with HIV (PLWHIV) have significantly higher rates of heart failure (HF), myocardial infarction (MI), stroke, and other manifestations of CVD, including hypertension and sudden cardiac death, compared with uninfected individuals.
This elevated risk persists despite HIV viral suppression and effective ART and after accounting for clinical and demographic risk factors. Although long-term outcomes for CVD in people with HIV are limited as a results of the recent transition of HIV from a fatal disease to a chronic one, these risks may be partly attributable to immune dysregulation and chronic inflammation.
Scientific understanding of the pathogenesis, prevention, and treatment of HIV is based on randomized controlled trials that are underpowered to detect cardiovascular end points, large observational studies, and small interventional studies that examine surrogate CVD end points. This document provides a review of existing evidence and offers guidelines for the prevention and management of these comorbid conditions.
HIV-Associated Atherosclerotic CVD
A range of recent international studies report that PLWHIV have an excess risk of MI and stroke. In fact, PLWHIV who achieve and sustain HIV viral suppression and have few or no CVD risk factors, demonstrate a continued increased risk for MI, compared with people without HIV. In Sub-Saharan African HIV-endemic populations, HIV is the leading risk factor for stroke in young cohorts, with both HIV viremia and immunosuppression appearing to be risk factors for stroke.
PLWHIV also have a 1.5- to 2-fold elevated risk of HF after adjusting for relevant confounders. Moreover, a >1.5-fold higher risk for HF persists in PLWHIV even after adjusting for prior MI.
Other Manifestations of CVD
Although fewer studies of HIV and CVD manifestations concern sudden cardiac death, atrial fibrillation, and peripheral artery disease, 1 study reports a 4-fold greater risk of sudden cardiac death among PLWHIV. This study also found that low CD4 counts are associated with increased incidence and prevalence of atrial fibrillation, and several other studies have reported increased risk for peripheral artery disease among PLWHIV compared with individuals without HIV.
Other risk factors in the development of atherosclerotic CVD include hypertension and cigarette smoking. A meta-analysis conducted between 2011 and 2016 demonstrated that the prevalence of hypertension in PLWHIV receiving ARTs was 35%, meanwhile in PLWHIV not receiving ARTs, the prevalence was 13%.
Elevated pulmonary artery systolic pressure has also been associated with HIV. The increased risk for pulmonary arterial hypertension (PAH), on the other hand, has been well-described since the 1990s, and the prevalence of HIV-associated PAH has not changed with ART. Considering the associations between sleep disorders such as sleep apnea and CVD, it should also be noted that HIV is generally associated with sleep impairments.
Presentation and Pathophysiology of Atherosclerotic CVD in HIV
Understanding of the underlying mechanisms behind the elevated CVD risk in PLWHIV is limited because of the interrelated nature of the disease itself, ARTs, and traditional CVD risk factors which have a high incidence and prevalence among PLWHIV.
Chronic inflammation and immune activation are strongly predictive of CVD and mortality, and though ART does reduce the levels of inflammation markers, many markers remain elevated compared with those of uninfected individuals. Inflammation is also elevated in PLWHIV coinfected with hepatitis C, and without treatment, coinfection may contribute to atherosclerosis. Despite how the Strategies for Management of Antiretroviral Therapy study demonstrated the role of chronic inflammation in HIV-associated CVD more than 10 years ago, effective therapies for lowering inflammation in those already being treated for HIV have not been found. PLWHIV have increased incidence and prevalence of metabolic complications that can contribute to CVD, such as body composition changes, dyslipidemia, and insulin resistance. The specific contributions of dyslipidemia to atherosclerotic CVD events are a particularly important area for future research.
CVD Risk Assessment in HIV
Assessing CVD risk for PLWHIV is challenging, as a model for clear best risk estimation has not been identified. Subclinical atherosclerosis can be used to refine risk of CVD, as can coronary artery calcium, as measured by noncontrast CT scans, although this may not be sufficient as PLWHIV have more noncalcified plaque compared with uninfected individuals. Noncalcified plaque can only be detected via coronary CT angiography, but this procedure is not recommended for the screening of asymptomatic patients.
Carotid intima-media thickness is a predictor of future stroke, and MI and has been associated with HIV mortality, therefore it can be assumed that selected risk enhancers identified in the 2018 American College of Cardiology/AHA cholesterol clinical practice guidelines are also likely risk enhancers in HIV.
These factors include:
- Family history of early stroke or MI
- Persistently elevated LDL-C
- Chronic kidney disease
- Premature menopause
- Subclinical atherosclerosis on imaging
- High levels of biomarkers associated with ASCVD risk
In the case of PLWHIV, these should not include elevated triglycerides, as large cohort studies have demonstrated that these are not predictive of CVD end point independent of other traditional risk factors. In addition, triglyceride levels are easily altered and sensitive to ART changes.
Prevention and Treatment of Atherosclerotic CVD and HF in HIV
A healthy lifestyle is the first step for CVD prevention among PLWHIV. Smoking cessation is crucial, especially considering the high prevalence of smoking in this population and the clear associations between smoking and CVD. Alcohol consumption should be limited, and regular physical activity and a healthy diet encouraged. Statins can reduce CVD events but should be prescribed with care due to potential interactions, which may be exacerbated by vitamin D deficiencies.
Antithrombotic agents may reduce risk but have not been thoroughly assessed in HIV. The management of hypertension and diabetes is recommended for CVD prevention in the general population, and there is no evidence to counter this for PLWHIV.
PLWHIV experiencing acute coronary syndrome appear to respond similarly to percutaneous coronary interventions, as do uninfected individuals, and yet are less likely to undergo this intervention. Coronary artery bypass graft surgery appears to be effective and safe for PLWHIV with more advanced disease and without advanced immunosuppression, although longer-term rates of major adverse cardiac events may be higher among PLWHIV.
Proprotein convertase subtilsinkexin type 9 (PCSK9) inhibitors can aggressively increase LDL-C levels and reduce clinical CVD events by 15% in uninfected individuals and may be useful in PLWHIV, who have higher levels of PCSK9, particularly with hepatitis C coinfection. A clinical trial assessing the impact of PCSK9 inhibitor therapy on inflammatory markers, lipids, and subclinical atherosclerotic CVD in HIV is currently being conducted (NCT 03207945).
In the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study, treatment with canakinumab, a monoclonal antibody targeting IL-1β, significantly lowered cardiovascular event recurrence rates, as well as the incidence of lung cancer and lung cancer mortality. However, it increased the rate of fatal infections.
An important step in rationalizing primary and secondary interventions in CVD is risk stratification tools, such as CHA2DS2-VASc and HAS-BLED scores, to estimate cardioembolic stroke and antithrombotic therapy hemorrhagic complications. However, it is unclear how reliable these scores are in PLWHIV.
Although there are no trials on thrombolysis in HIV, retrospective studies show a similar risk of death with thrombolysis for HIV infected and uninfected individuals. Endovascular treatment for patients with HIV-associated vasculopathy — which can manifest as acute stroke, driven by inflammation alone or secondary infection — can be successful, though safety data is limited.
HF Diagnosis and Treatment
Evidence-based, HIV-specific recommendations for diagnosis and treatment of HF in HIV are not possible because of uncertainty regarding the mechanisms and course of HF in this population. Nevertheless, it would be reasonable to suspect HF in PLWHIV as a result of the elevated risk for HF in HIV and to follow general population guidelines.
Disparities in Care
PLWHIV are a vulnerable population, often stigmatized, that faces a number of barriers to optimal healthcare services. Genuine progress in the understanding and management of CVD in HIV includes recognizing the systematic barriers perpetuating healthcare disparities and taking steps to address these barriers in the United States and globally.
The guideline concluded that large-scale clinical trials on the prevention and treatment of CVD in HIV are needed for informed decision-making. Researchers noted that “[i]n the meantime, a reasonable approach may be to consider [PLWHIV] at particularly elevated CVD risk and therefore more likely to benefit from CVD-preventive therapy if risk-enhancing factors that are related to HIV (eg, low current or nadir CD4 count or a history of prolonged viremia) or are more general (eg, family history of premature [atherosclerotic] CVD, chronic kidney disease, or atherosclerosis on imaging) are present. Future studies should also address gaps in implementation to ensure that [PLWHIV] who are at risk for CVD or have existing CVD are identified and provided appropriate CVD care.”
Feinstein MJ, Hsue PY, Benjamin LA, et al. Characteristics, prevention, and management of cardiovascular disease in people living with HIV: a scientific statement from the American Heart Association [published online June 3, 2019]. Circulation. doi: 10.1161/CIR.0000000000000695