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From 1987 until 1995, the "dark ages" of HIV treatment, only five antiretroviral medications (ARVs) were FDA approved, all nucleoside reverse transcriptase inhibitors (NRTIs, or "nukes"), and monotherapy and dual therapy were the "standards of care." 2010 is the 15th anniversary of the FDA approval of the first protease inhibitor (PI), saquinavir, as well as the advent of Highly Active Antiretroviral Therapy, or HAART, three-drug "cocktails" that are now capable of suppressing HIV replication in even the most treatment-experienced individuals.
Today we have both good news and bad news. The good news is that people with HIV/AIDS are living longer.1, 2 The Antiretroviral Therapy Cohort Collaboration (ART-CC), which includes 19 cohort studies from Europe and North America, found that if you are 20 years old and acquire HIV today, your life expectancy is now over 69 years.3 (A cohort study is an observational study in which subjects with a certain condition are monitored over time and compared with another group who don't have the condition.)
Ironically, the bad news is that people with HIV/AIDS are living longer! Accompanying this significantly increased longevity is an increase in morbidity and mortality due to non-HIV/AIDS complications such as cardiovascular disease (CVD).4, 5 The cause for concern is so great that a conference was held in 2007 with specialists from various fields of medicine, NIH members, and patient advocates to discuss HIV, CVD, and 1) metabolic abnormalities and lipodystrophy, 2) epidemiological evidence and contribution of HAART, 3) effects of HAART and HIV on the heart and blood vessels, 4) screening recommendations, 5) risk prediction models, and 6) prevention strategies.5-11
The reasons for these CV complications are not yet well understood, but we do know that living longer with HIV is accompanied by numerous metabolic and body shape, or anthropometric, abnormalities. These abnormalities may be due to HIV infection, certain ARVs or ARV classes, and/or immunological factors (such as nadir, or lowest, and current CD4 count) and include insulin resistance (IR) and abnormal lipids, as well as lipodystrophy (subcutaneous fat loss, or lipoatrophy, and/or increased visceral fat, or lipoaccumulation), all of which can increase CV risk.
Of course, as in the general population, traditional CV risk factors, such as environmental (smoking, diet, lifestyle, obesity, and exercise) and genetic factors (gender, race, age, ethnicity, family history, diabetes [DM], and hypertension [HTN]),12, 13 contribute significantly to these metabolic abnormalities and remain important CV risk factors in HIV-positive individuals.14-16
In understanding CVD and HIV, it is important to know the term metabolic syndrome (MS).17 The table, "Characteristics of Metablic Syndrome," on page 39 lists the components of MS, and when any three of the five risk factors listed are present, you are at a significantly increased risk of developing CVD.
The big question is, "Does HIV increase the risk for developing CVD?" The epidemiological evidence suggests HIV-positive individuals are at an increased risk of CVD, despite the steep drop in overall morbidity and mortality with the introduction of HAART.18 Various retrospective and prospective HIV cohort studies, randomized clinical ART studies, and administrative and clinical databases suggest anywhere from a 1.5-to 7.0-fold increase in CVD in HIV-positive versus HIV-negative individuals, although the absolute rates remain low, perhaps reflecting the age and demographics of the studied groups and the short duration of CV risk factor exposure.18-24
Traditional CV risk factors associated with MS play a significant role in the development of coronary heart disease (CHD) in HIV-positive individuals, including elevated total cholesterol (TC), low density lipoprotein (or "bad") cholesterol (LDL-C), and triglycerides, and lowered HDL-C (or "good") cholesterol, all of which worsen with lower CD4 cell counts and higher viral loads (PCR),18, 19, 25 as well as increased smoking rates in HIV-positive individuals, male sex, age, DM, and HTN.21, 22, 25-27
Nontraditional CV risk factors, such as chronic HIV inflammation, may also play a significant role in the development of CVD, as is evidenced by the unexpected increases in CV events due to HIV-viremia in the intermittent HAART dosing arm of the SMART study.28 However, impaired endothelial function (endothelial cells, the cells that line the interior surface of blood vessels, have many functions that, when impaired, contribute to the development of CV risk), and increased thickening of artery walls (increased carotid artery intima-media thickness [IMT]) were found in treated HIV patients with undetectable PCR, as well as in HIV "elite controllers" (those rare HIV-positive individuals with long-term normal CD4 cell counts and undetectable PCR without HAART).24, 29-33 Although the effects of HIV on the heart and vasculature have not been fully determined, there is evidence that HIV-associated metabolic changes, including lipoaccumulation and lipoatrophy, as well as IR, one of the factors thought to be involved in the development of lipodystrophy, also affect endothelial and myocardial (heart wall) function.34 Our prospective study utilizing nuclear exercise stress testing screening in asymptomatic individuals without prior CVD found HIV-positive individuals at six times greater odds of having subclinical coronary artery disease (CAD) that required immediate intervention, when compared to HIV-negative individuals, and abdominal lipoaccumulation was the most significant risk factor predicting CAD in the HIV group.35 Recently, T-cell activation and immunosenescence (accelerated immunologic aging) were shown to be possible mechanisms associated with inflammation and the development of subclinical carotid artery disease.36 Lastly, recent observational studies have found an association with chronic kidney disease (CKD, defined as GFR less than 60) and mild renal insufficiency (GFR 60-89),37 as well as intravenous drug and cocaine use,38 and increased rates of CVD in HIV-positive individuals.
Although no one denies the benefit of taking HAART versus not taking HAART on markers of CVD,39-43 there are many complex mechanisms whereby ART can affect the heart and vasculature, including endothelial dysfunction, increased endothelial permeability, increased oxidative stress, increased mononuclear cell adhesion, IR, accelerated lipid accumulation in vessel walls, persistent inflammation and immune activation, impaired response to vascular injury, and ART-associated lipodystrophy leading to metabolic disorders (e.g., hyperlipidemia and IR), increased systemic inflammation, and reduced circulating adiponectin (a protein hormone that regulates a number of metabolic processes).18-21, 24, 44, 49-57
The largest observational cohort study evaluating the impact of ART on cardiovascular risk, the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D), initially found that ART was associated with an overall 26% increased risk of CVD/myocardial infarction (MI),20 and, subsequently, the annual relative risk of MI increased by 16% per year for those using HAART and for those taking PIs but not non-nucleoside reverse transcriptase inhibitors (NNRTIs), possibly somewhat due to the lipid abnormalities associated with PI use.21 Controversy arose when D:A:D and SMART generated a signal that recent use of abacavir (ABC, brand name Ziagen, found in Epzicom and Trizivir) was associated with a significantly increased risk of MI in patients with moderate-to-high CV risk.43, 44, 48 The controversy surrounded the fact that while these observational trials generated banner headlines, randomized clinical trials58-61 and many other observational cohorts27, 37, 38 failed to corroborate this finding.
Additionally, despite intensive research investigating inflammation, coagulation, IR, and endothelial dysfunction biomarkers, no studies have uncovered any plausible biological mechanism to explain how ABC could cause rapid development of CAD and subsequent MI.62-65 The possibility that ABC affects platelet hyper-reactivity still needs to be explored in HIV-positive individuals, but if this mechanism is confirmed, anti-platelet therapy, such as a daily 81 mg baby aspirin (ASA), may be the simple answer (see Prevention Strategies below).
Although D:A:D failed to find an increased risk of CVD with tenofovir (TDF) use, a non-controlled study showed cumulative exposure (an average 1.5 years) to TDF/FTC (tenofovir/emtricitabine) significantly raised the risk of CVD in adolescents and young adults (average age 18.9 years), 52% of whom had MRI evidence of CAD.66 And if mild-to-moderate renal insufficiency is confirmed as a CV risk factor,37, 66 as it is in the general population, the need to monitor for renal insufficiency while taking TDF becomes critical.
The greater question that needs to be answered is whether the effects of ART on development of CVD are only modest compared to the inflammatory effect of HIV.
Screening for CVD in HIV-positive individuals has been performed with the Framingham Risk Equation (FRE), direct assessment of CAD and myocardial ischemia via exercise stress testing, and indirect assessment using inflammatory biomarkers or surrogate markers for CHD. FRE is the most commonly used tool, incorporating age, sex, BP, LDL-C, HDL-C, DM, and smoking to calculate your 10-year CHD risk. Low, intermediate, and high risk are defined as 10-year risk of CHD of 10%, 10% to 20%, and greater than 20%, respectively.
However, despite claims made by D:A:D investigators, 20, 21, 43 FRE has not been validated for use in HIV.5, 8 Our study35 showed that over 56% of HIV-positive individuals with obstructive CAD requiring intervention were low-risk and only 6% were high-risk by FRE immediately prior to their stress test.
Newer inflammatory biomarkers, such as high-sensitivity C-reactive protein (hs-CRP), the only biomarker recommended for use in clinical practice by the CDC and the AHA, may prove useful in determining if you may be at increased risk for CHD.9, 29, 68-70 An hs-CRP of 3.0-10.0 mg/L is considered high risk for developing CVD. Other biomarkers, such as D-dimer, IL-6, adiponectin, MCP-1, OPG, ICAM-1, VCAM-1, selectins E and P, and others, are being investigated but are not yet validated or commercially available.
Lastly, surrogate markers, including carotid IMT,30, 33, 70 computed tomography of coronary arteries (CT CA) to determine coronary calcium scores,71, 72 flow-mediated dilation (FMD) to assess endothelial function,73, 74 and measures of arterial stiffness75, 76 are being investigated but are not yet validated as independent predictors of CHD in HIV.
So, now that you are taking the risk of CHD seriously, what can you do to prevent or slow the development of CVD? Here is a list of risk-reducing interventions that you can implement.
This article is supported by funding from Merck.
Gary Blick, M.D., A.A.H.I.V.S., is Medical and Research Director of CIRCLE Medical, LLC, in Norwalk, Connecticut, a Comprehensive Immunology, and Research Center for Life Extension, specializing in clinical research and specialty medical care for individuals with HIV/AIDS and chronic hepatitis, as well as for the GLBT community. He also sits on the board of directors for Mid-Fairfield AIDS Project (MFAP) and the drug formulary committee for the Connecticut AIDS Drug Assistance Plan (CADAP).