With the rise of heart disease as one of the leading causes of death globally, clinicians should anticipate a significant impact of cardiovascular disease (CVD) in people living with HIV. However, in the case of HIV disease, "the pathophysiology of CVD is driven in large part by HIV-related immunologic and inflammatory changes, and current CVD prevention paradigms do not reflect this pathophysiology," according to Virginia Triant, M.D., M.P.H., of Massachusetts General Hospital.
Triant gave a state-of-the-art presentation on cardiovascular complications in people living with HIV at IDWeek 2014 in Philadelphia. This article focuses on what is now known about the context and pathophysiology of cardiovascular disease in people living with HIV -- as the understanding of these complications has evolved considerably in recent years.
The second article in the series will focus on how healthcare providers can integrate the prevention and management of CVD into HIV chronic care -- addressing both the traditional risk factors of CVD, and other risk factors that might be HIV-specific.
Context of HIV and CVD
Aging-associated non-communicable comorbidities such as hypertension, myocardial infarction, peripheral arterial disease and impaired renal function are significantly more prevalent among people living with HIV than HIV-negative people.
Several large cohort studies have found an increased risk of acute myocardial infarctions (MI) and coronary heart disease (CHD) in people living with HIV. A study that Triant presented at CROI 2014 found an elevated relative risk of major adverse cardiac events (MACE), which included myocardial infarction, stroke, angina and coronary revascularization, in people living with HIV than in HIV-negative people, across gender and age groups. The risk was increased even among those who traditionally would have been considered to be at low risk for heart disease -- which may reflect "the different distribution of CVD risk factors in HIV, with important contributions from non-traditional risk factors reflecting HIV-related immune dysregulation."
Since the advent of antiretroviral therapy, CVD has become a major cause of mortality in HIV disease -- although management practices in recent years may have lowered CVD-related mortality in the D.A.D cohort. Still, it remains the third most frequent non-AIDS-related cause of death amonth HIV-positive women.
Pathophysiology of HIV and CVD
Ever since the heightened risk of CVD began to be recognized in people living with HIV, the understanding of its causes has been evolving. A number of the traditional risk factors, such as smoking, which is far more common in people living with HIV than in HIV-negative individuals, played a role. However, these were found to only account for around 10%-25% of the heightened risk in large cohort studies.
Then much of the blame was placed on antiretroviral therapy, in particular, certain drugs, including select protease inhibitors and possibly abacavir (Ziagen). For instance, in the D.A.D. study, which was a prospective cohort study with 33,347 subjects, the relative risk of acute MI was 1.16 per year -- but the increased risk was seen on protease inhibitor-based regimens and not non-nucleoside reverse transcriptase inhibitor-containing regimens.
But, again, there is a 40%-80% increased risk of acute MI that persists despite accounting for both established CVD risk factors and antiretroviral therapy use.
Today, "the persistently increased risk is thought to be driven by HIV-specific inflammation and immune activation," said Triant, "and this is supported by extensive data."
For instance, in the SMART study (comparing continuous antiretroviral therapy versus episodic treatment) there was an increased CVD event rate in the arm given episodic antiretroviral therapy vs. the arm given continuous treatment (P = .05). A subsequent analyses of the SMART study found that, at baseline, markers of inflammation, including high-sensitivity C-reactive protein, IL-6, and d-dimer, all strongly correlated to overall mortality; and that after one month of treatment interruption, and viral replication continued, both IL-6 and d-dimer levels increased.
In addition, the increased immune activation in people living with HIV appears to be linked with a number of markers of CVD. In the Women's Interagency HIV Study, there was increased immune activation in women living with HIV vs. controls without HIV. Among those living with HIV, having a higher frequency of activated T cells was associated with an increased prevalence of carotid artery lesions -- regardless of age, antiretroviral medications, or viral load.
One possible mechanism for the chronic immune activation (despite suppressed viral loads) is believed to be the mass bacterial translocation from the gut that occurs over the course of HIV infection. Lipopolysaccharides (LPS) released by these bacteria activate monocytes and macrophages, which, in turn, are associated with increased levels of soluble CD14 -- a biomarker of monocyte activation.
Recently, an analysis of ACTG 5078, documented that both LPS and sCD14 were elevated in people living with HIV and were associated with the development of subclinical atherosclerosis. This effect was independent of traditional CVD risk factors.
Another study has found that another monocyte/macrophage activation marker, sCD163, was elevated in men living with chronic HIV infection and low or undetectable viremia when compared to HIV-negative controls -- and was associated with non-calcified coronary plaques and arterial inflammation.
A subsequent study found that relatively young people living with HIV had an increased prevalence of plaque features that are highly vulnerable to acute rupture compared to HIV-negative individuals, which could be the reason for the heightened rates of MI's and sudden cardiac death.
People living with more advanced HIV disease -- as evidenced by low CD4 cell counts and high viral loads appear to be at higher risk. For instance, an analysis of the HIV Outpatient Study found that people living with HIV with CD4 counts below 500 were at an increased risk of CVD events independently of whether they had other known CVD risk factors or were on antiretroviral therapy. Similarly, another analysis of the Partners HealthCare System cohort, found that having a CD4 count below 200 was independently associated with AMI (acute myocardial infarction). In fact, having a low CD4 count was a more important factor than any individual antiretroviral medication with respect to increased risk of AMI or viral load.
But even though viral load was not an independent risk factor in the Partner's HealthCare System Cohort, an increased viral load was a predictor of AMI risk. Other studies have found that an increased viral load was linked to ischemic stroke events, and that a detectable viral load (viral load above 50 copies/ml) was associated with increased risk of myocardial infarction.
Similarly, an analysis of the 82,459 people living with HIV in the Veterans Aging Cohort Study Virtual Cohort from April 1, 2003, through December 31, 2009 found an increased AMI risk in participants with both detectable viral loads and CD4 counts below 200. But even in patients achieving virologic suppression, there was an increased risk of AMI in contrast to people who did not have HIV.
There seems to be some elevated risk of CVD in people living with HIV regardless of treatment, viral load or immunodeficiency. This has been shown in a study of cardiovascular risk in elite controllers -- people living with HIV who have low viral loads and are immunologically stable without treatment. Despite their status as non-progressors, they have increased carotid intima-media thickness -- a surrogate marker of atherosclerosis -- compared to HIV-negative individuals.
Therefore, HIV infection, regardless of treatment, CD4 count or viral load, is associated with some degree of immune activation and an increased risk of cardiovascular disease.
In conclusion, for people living with HIV, the increased risk of cardiovascular disease is multifactorial due to traditional risk factors, HIV-related immune activation and immunodeficiency, and antiretroviral therapy may increase the risk in some ways and decrease it in others. But this complexity is not yet accounted for in how the disease is being prevented or managed.
Read Part 2 to see how providers can integrate the prevention and management of cardiovascular disease into HIV care.
Theo Smart is an HIV activist and medical writer with more than 20 years of experience. You can follow him on Twitter @theosmart.