Association Between Human Immunodeficiency Virus Infection and Cardiovascular Diseases: Finding a Solution to Double Jeopardy.

Combination antiretroviral therapy (ART) has affected the lives of human immunodeficiency virus (HIV)–infected individuals who have access to treatment and continues to narrow the gap in life expectancy between persons with HIV and the general population. Unfortunately, concomitant with this favorable outcome, noninfectious causes of morbidity and mortality, particularly cardiovascular disease (CVD), have had a disproportionately negative affect on ART-treated individuals with HIV, creating a “double jeopardy” phenomenon. Shortly after recognizing the benefits of combination ART in suppressing HIV replication, restoring immune function, and prolonging life, physicians raised concerns about possible undesired toxicities of the therapy. The appearance of dyslipidemia and lipodystrophy highlighted the issue of increased CVD in HIV-infected individuals. Large cohort studies identified an increased risk of myocardial infarction (MI), seemingly in association with long-term ART and increased rates of MI in HIV-infected individuals compared with uninfected contemporaries.1,2 However, the overall advantage of ART remains clear because large randomized clinical trials have shown that early and continuous administration of ART confers significant survival benefits, even when accounting for an increased rate of CVD.3,4 Traditional risk factors for CVD, exposure to ART, and the inherent immune activation associated with HIV infection all contribute to the increased incidence of CVD and may represent targets for intervention. Traditional CVD risk factors, such as hypertension, diabetes, smoking, and dyslipidemia, are increased among HIV-infected individuals and play a role in the development of CVD.2 For example, rates of smoking are high among HIV-infected individuals, often 2 or 3 times that of the general population. In this context, current and past smoking doubled the risk of incident MI.1 Encouraging trends showing a reduction in smoking in the general population are also reflected in persons with HIV, and observational cohorts have shown significant reductions among HIV-infected individuals in MI, CVD, and mortality following cessation of smoking.5 Hepatitis C virus (HCV) coinfection is also common in HIVinfected individuals and has been shown to increase the risk of CVD in these patients independent of other risk factors.6 Anti-HCV therapy has reduced the incidence of cardiovascular complications in HCV monoinfected patients and may provide a similar benefit to HIV coinfected patients. Future studies evaluating the long-term health benefits of newer HCV treatment regimens will illuminate the potential cardiovascular benefits of HCV clearance in the high-risk HIV-infected population. Certain antiretroviral agents have been linked to CVD and there have been efforts to minimize adverse effects through selection of ART regimens as well as active development of equally potent antiretroviral agents with more favorable toxicity profiles. First-line ART recommendations now provide options that minimize the use of agents implicated in increased CVD risk. Prospective research initiatives, such as the Data Collection on Adverse Events of Anti-HIV Drugs, a multinational cohort study that focuses on recognizing adverse events such as MI, will provide valuable data on the future relationship between incident CVD, advances in ART, and targeting CVD risk reduction in HIV infection. Independent of traditional risk factors and exposure to ART, HIV infection alone has been shown to increase the risk of CVD. Chronic inflammation and immune activation associated with HIV infection are widely felt to be key mediators of end-organ injury, including atherosclerosis, and appear to play a role in CVD even when HIV replication is seemingly wellcontrolled when receiving ART. Human immunodeficiency virus–infected individuals have significantly increased levels of inflammatory biomarkers, such as C-reactive protein, interleukin 6, D-dimer, and cystatin C, which have all been associated with CVD risk.7 Additionally, arterial inflammation in HIV has been associated with increased plasma levels of soluble cluster of differentiation 163, a monocyte/macrophage marker linked to low-grade inflammation and atherosclerosis.8 Novel imaging techniques, such as coronary computed tomographic angiography and flourodeoxyglucose positron emission tomography techniques, permit detailed quantification of coronary plaque and arterial inflammation associated with CVD. Using flourodeoxyglucose positron emission tomography, Subramanian et al8 completed a cross-sectional study of HIV-infected individuals who were receiving ART without known CVD and found increased arterial inflammation in HIVinfected individuals compared with control individuals. In this regard, inflammatory biomarkers and advances in cardiac imaging can be used as research tools to delineate the role of immune activation in the development of atherosclerosis in HIV-infected individuals and may improve our ability to predict myocardial events related to atherosclerosis in this unique population. Related article Opinion