Individuals living with HIV have about 1.5 to 2 times higher risk of developing cardiovascular disease (CVD) than those who do not have HIV, and they may develop earlier and more aggressive manifestations. To better manage these risks scientists are searching for HIV-specific CVD biomarkers that might better identify patients at risk and help monitor treatment effects.
A new statement from the American Heart Association (AHA) suggests there’s not enough data yet to recommend routine use of such emerging HIV-related heart risk biomarkers and instead provides an algorithm that uses more traditional CVD risk markers as well as HIV-specific risk enhancers (Circulation 2019;140:e98–124). But there is growing enthusiasm in the field that biomarker studies and the ongoing REPRIEVE trial might yield important insights on HIV-related heart disease and its management.
“The holy grail of this research is to try to figure out if we can determine in advance which [people living with HIV] are going to go on and have heart attacks, strokes, and other cardiovascular events and who would benefit from being on preventative medications or having more testing done,” explained Janine Trevillyan, MD, an infectious disease physician at Monash University in Melbourne, Australia, and an Australian National Health and Medical Research Council Fellow doing research at the University of California, Los Angeles.
HIV Heart Disease Risk Profile
As modern antiretroviral medications have turned HIV infection into a manageable, chronic disease in many settings around the globe, clinicians are working to better manage comorbidities and the consequences of both long-term antiretroviral therapies and the infection itself. Early and aggressive atherosclerotic disease and heart failure are among the most pressing of these concerns.
“Though the HIV virus is well suppressed and is typically undetectable [with antiretroviral therapy], there’s still a lot of residual inflammation,” explained Christopher deFilippi, MD, vice chairman of academic affairs at the Inova Heart and Vascular Institute in Falls Church, Virginia. He explained that changes to immune cells like macrophages and monocytes can lead to the production of inflammatory cytokines. “This is a setup for more atherosclerosis, more aggressive atherosclerosis, and more myocardial infarctions.”
Advanced immunosuppression itself or detectable viral loads may also contribute to heart problems, noted Matthew J. Feinstein, MD, MSc, chair of the writing group for the AHA statement, and an assistant professor of medicine, cardiology, and preventive medicine at the Northwestern University Feinberg School of Medicine in Chicago.
“Chronic inflammation and immune activation, even when HIV is under good control, can cause buildup of plaque in the body’s arteries (including in the heart) and also may cause dysfunction of the heart muscle,” resulting in heart attack, heart failure, and stroke, he explained.
Robert Christenson, PhD, DABCC, FADLM, professor of pathology and of medical and research technology at University of Maryland School of Medicine in Baltimore, said this “smoldering immunoreactivity” contributes to earlier emergence of age-related diseases like cancer or atherosclerosis.
According to the AHA statement, traditional heart disease risk factors like smoking, hypertension, and a family history of heart disease may also contribute. But some of these risk factors may have exaggerated effects in individuals living with HIV. For example, a smoker who has HIV has a substantially greater risk of heart attack than a smoker without HIV, noted deFilippi. Additionally, antiretroviral treatment contributes to dyslipidemia and central obesity, which are also known risk factors for heart disease. Triglyceride levels, which may be affected by antiretroviral therapy, have not been found very useful in predicting CVD risk in patients with HIV, the statement authors found.
Taking these factors into account, the statement proposes an algorithm for assessing atherosclerotic heart risk in patients with HIV using traditional heart risk calculators as well as HIV-related risk enhancers like prolonged viremia, low CD4 counts, poor treatment failure or nonadherence, dyslipidemia or other metabolic conditions, and hepatitis C virus co-infection. The writing group chose not to recommend routine imaging to measure subclinical atherosclerosis or use of inflammatory biomarkers like C-reactive protein, lipoprotein(a), and apolipoprotein B, noting there is not enough data to support it. However, the panel noted that these readings may offer some value especially for patients with HIV who have moderate risk levels.
Priscilla Hsue, MD, professor of medicine and director of the HIV Cardiology Clinic at University of California, San Francisco and vice chair of the AHA scientific statement writing group, explained that a large body of evidence links inflammatory and coagulation markers to clinical events, including CVD events. There is also evidence for the use of imaging to assess CVD risk.
“[These tools] can be used to help ascertain mechanism and disease pathogenesis in the setting of interventions and research,” Hsue explained. “However, how these tools are used in the clinical setting is less clear.”
For example, in an individual with some CVD risk factors but without a clear cut indication for statin therapy “imaging or biomarkers could be used to decide how aggressive to be with medical therapy, but this needs to be decided on a case by case basis,” she said.
Limited data are available to guide the treatment of patients with HIV who have elevated CVD risk, the statement noted. Except for simvastatin and lovastatin, “statins appear to be generally safe in HIV although more data are needed to fully understand the risks and benefits of these and other CVD-preventive therapies in HIV,” Feinstein said. “What is clear is that treating HIV with medications is far superior from an overall health as well as heart health standpoint compared with not treating HIV.”
Answers on the Horizon
The ongoing 7,700 patient Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) trial will test whether a statin (pitavastatin) prevents heart disease in patients with HIV. The REPRIEVE trial might also provide a trove of patient samples that could help researchers searching for HIV-specific CVD risk biomarkers, noted Trevillyan and deFilippi.
“There is a lot of interest in this area, and over the next five years or so there’s going to be a lot more insight into how to treat these patients so that they remain asymptomatic,” said deFilippi. He and his colleagues have used both traditional and proteomic techniques to study the effects of statins on pathways involved in CVD in patients with HIV.
“Statins may be the cure all [for heart disease in patients with HIV], but there may be unique mechanisms that are contributing to inflammation that aren’t targeted by statins, or they don’t work as efficaciously as they do in patients without HIV,” he said.
A growing body of evidence also highlights potential HIV-specific heart disease risk biomarkers. For example, N-terminal pro-B-type natriuretic peptide is used regularly in practice to assess CVD risk and has been shown to predict HIV-related heart disease risk as well, deFilippi noted. Soluble ST2 and growth differentiation factor-15 have also been linked with cardiovascular dysfunction and all-cause mortality. Recently, Trevillyan and colleagues found that individuals with HIV who have high levels of lipopolysaccharide binding protein were more likely to have a cardiac event in the next 3 months, but she noted clinical studies are needed to confirm this analyte’s usefulness. Hsue and her colleagues have also studied the link between eight biomarkers and heart failure in patients with HIV, noting that different mechanisms may be behind various heart-related HIV complications.
“We are early in our understanding of cardiovascular disease and HIV, underlying mechanisms, and optimal therapies, including use of HIV-specific treatments, anti-inflammatory strategies, and treatment of risk factors,” said Hsue, agreeing that more study is needed. Christenson concurred, noting that interventional studies demonstrating that biomarker testing improves patient outcomes would be needed.
In the meantime, deFilippi said clinicians and laboratorians should recognize that seemingly healthy, well-controlled patients living with HIV may be at risk of CVD and be alert to potentially worrisome measurements.
“If abnormal results appear, they may warrant further surveillance and follow up over time,” he stressed.
Christenson recommended that laboratorians work closely with treating physicians to assess which laboratory tests might be beneficial. This includes weighing a patient’s age and how well an individual is doing on his or her antiretroviral therapy.
As he emphasized, “It is something we have to take on a case-by-case basis until we have research that would answer some of these fundamental questions.”
Bridget M. Kuehn is a science writer in Chicago. +Email: [email protected]