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Primary, Secondary, and Tertiary Prevention of Cardiovascular Disease in Patients With HIV Disease

A Guide for Nurse Practitioners

Jones-Parker, Hazel, DNP(c), MSN, CRNP, AACRN

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Journal of the Association of Nurses in AIDS Care: March-April 2012 - Volume 23 - Issue 2 - p 124-133
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As patients with HIV infection are living longer, and a growing number of patients are infected later in life, the treatment and management of chronic comorbidities have become a major focus for health care providers who treat HIV-infected patients. For the majority of older patients, cardiovascular disease (CVD) is an important comorbidity with well-known major risk factors. These include nonmodifiable risk factors such as age, gender, race, and family history, and modifiable risk factors including, but not limited to, smoking, obesity, physical inactivity, high blood glucose, and inflammation (Chapman, Redfern, McGovern, & Giral, 2010; National Heart Lung and Blood Institute, 2001). HIV-infected people are affected by similar nonmodifiable and modifiable risk factors. However, in this population there is a greater urgency to appropriately manage these risk factors because HIV-infected patients contend with additional risk factors and an accelerated rate of CVD progression (Sharma, Messiah, Fisher, Miller, & Lipshultz, 2008).

The ranking of primary, secondary, and tertiary strategies is a useful way to organize disease prevention and treatment approaches aimed at reducing disease-associated morbidity and mortality (Institute for Work & Health, 2010). While often not formally declared, these rankings are used by primary care providers and HIV specialists to prioritize the management of multiple chronic comorbidities. Therefore, the fundamentals of this framework may be familiar to care providers who regularly manage chronic conditions such as HIV infection and CVD disease. The proposed framework (see Figure 1) is meant as a guide that care providers can use to plan a comprehensive regimen for the prevention and management of CVD in HIV-infected patients. In particular, this framework is targeted toward nurse practitioners (NPs) who will be well positioned to cost effectively fill the gap created by an influx of patients due to recent health care reforms, and a growing shortage of physicians entering the primary care field.

Figure 1. Conceptual framework for the primary, secondary, and tertiary care of HIV-infected patients with CVD risk factors and/or disease.
Figure 1. Conceptual framework for the primary, secondary, and tertiary care of HIV-infected patients with CVD risk factors and/or disease.:
NOTE: CVD = cardiovascular disease; HTN = hypertension; IR = insulin resistance; ART = antiretroviral therapy.

The framework will be presented in the context of preventing CVD progression in HIV-infected patients, noting that in HIV-infected patients, there may be additional CVD risk factors resulting from the infection itself, including, but not limited to, the effects of antiretroviral therapy (ART), direct effects of HIV viral load on arterial linings, and inflammatory consequences of the infection (Grunfeld et al., 2009; Hsue et al., 2008).


By the year 2015, a full 50% of patients infected with HIV in the United States are expected to be ages 50 or older (Kirk & Goetz, 2009). Two trends are driving this shift in the demographics. The first is the success of the pharmaceutical industry in developing potent antiretroviral (ARV) therapies for the treatment of HIV disease that, when combined into effective regimens, have dramatically extended patient life expectancy. The second is the growing number of patients who are infected later in life. For 2009, the Centers for Disease Control and Prevention (CDC) estimated that in the 40 U.S. states with confidential name-based HIV reporting, 6,963 of the newly diagnosed patients were ages 50 and older (CDC, 2011).

Another epidemiological trend that is associated with increased CVD risk is high prevalence of metabolic syndrome and obesity in the United States, with 68% of the adult U.S. population classified as overweight (including obese) and 33.8% classified as obese (Flegal, Carroll, Ogden, & Curtin, 2010), which is a significant risk factor for the development of CVD. Other lifestyle factors include cigarette smoking, a general lack of exercise, and poor diet; these also add significantly to a patient's cumulative risk for CVD (Hasse et al., 2011). Hasse and colleagues (2011) also noted that non-HIV comorbidities, particularly diabetes mellitus, CVD, non-HIV-related malignancies, and osteoporosis are increasingly important in HIV care, and most of these events are age related. In this same population, HIV-infected patients who were 65 years of age or older were more likely to be on more than four medicines for these non-HIV, age-related problems (Hasse et al., 2011), thus raising the potential for drug–drug interactions that ART design and optimization needs to consider. Therefore, a pressing question for health care providers in this era of health care reform is, “What cost effective steps can be taken to reduce CVD risk factors throughout the lives of HIV-infected patients?”


As various components of the Affordable Care Act of 2010 are implemented over the next few years, it is expected that NPs will play an ever-more important role in the management of patients with chronic diseases (Wakefield, 2010). NPs will be required to care for patients with more complex clinical presentations, such as older HIV-infected patients with multiple comorbidities including CVD. This more-advanced role will need to be consistent with recent Institute of Medicine recommendations that NPs should practice to the full extent of their education and training (Institute of Medicine, 2011). NPs with doctoral-level training are well suited to identify inefficiencies in care management strategies, streamline guidelines, and create new models such as the care management framework presented in Figure 1.

Current doctorate-of-nursing-practice (DNP) curricula include evidenced-based strategies for the promotion of well-being and disease prevention. Hence, NPs who complete this curriculum will be prepared to analyze epidemiological and environmental data to develop, test, and implement models of clinical prevention that are expected to have a positive effect on population health (Zaccagnini & White, 2011). In identifying the most cost-effective way to provide quality care to patients, an NP's ability to provide a variety of services in many clinical settings cannot be overestimated. A recent literature review identified several studies that supported the observation that NPs provide clinical care equivalent to that of physicians in many areas of nursing and medical practice, and it supported the substitution of more expensive health professionals with NPs, which would result in more cost-effective care with equivalent quality (Bauer, 2010).

The proposed framework for NP-guided care is intended as a stepwise guide to maximize CVD prevention strategies throughout the HIV-infected individual's life span. Primary prevention begins with a diagnosis of HIV infection and includes an immediate screen for CVD risk factors. Appropriate prevention strategies are then presented to the patient to manage identified modifiable risk factors. Secondary prevention strategies are employed when risk factors secondary to ART and HIV infection itself, such as higher HIV viral loads, low nadir CD4+ T cell counts, and generalized inflammation are identified. Tertiary prevention methods address multiple and chronic comorbidities and risk factors such as hyperlipidemia, hypertension (HTN), inflammation, smoking, obesity, and inactivity as chronic issues found in aging patients with HIV that may contribute to CVD progression. The implementation of this framework may be essential in the development of high-level, efficient care for this particular population.

This article presents a conceptual framework (see Figure 1) outlining primary, secondary, and tertiary CVD prevention strategies to approach CVD risk management in the setting of HIV infection. Special attention is directed to the role of the NP in the management of these comorbid conditions and to the NP's role in patient education.

Primary Prevention of CVD in HIV-Infected Patients

Primary prevention strategies focus on the prevention of disease or injury through patient education and lifestyle changes. For example, in the context of CVD progression, these strategies would include early education about lifestyle choices such as lack of exercise, poor diet, and cigarette smoking that over time can precipitate known CVD risk factors including dyslipidemias, HTN, insulin resistance (IR), and diabetes, especially type II (Becker, 2008). The goal at this stage is to prevent chronic disease before it develops.

As part of good clinical practice, addressing modifiable risk factors is important for all patients at risk for CVD. This is especially true in patients who are newly infected with HIV because patients infected with HIV are likely to develop more serious CVD (Grunfeld et al., 2009). In fact, HIV disease itself might be considered a CVD risk factor (or cluster of risk factors; El-Sadr et al., 2005). Similarly, HIV testing and early detection may have implications for CVD risk when considering the damage caused by undetected HIV disease progression. With early detection, therapeutic and lifestyle interventions will have a better chance to significantly ameliorate CVD risk factors over the long term. Given their unique roles on the health care team, NPs have key opportunities to identify and treat patients at earlier stages of HIV disease who present with higher CD4+ T cell counts. These patients generally have less-advanced CVD at this stage and are more likely to achieve long-term benefits from ongoing lifestyle modification (El-Sadr et al., 2005).

For patients infected with HIV, the current standard of care is to assess the CVD risk profile of every new adult patient as part of routine medical examination. The goal is early assessment of a patient's CVD risk profile, identification of manageable factors, design of an appropriate plan to manage medical issues, and establishment of an education strategy to promote heart-healthy lifestyle changes. Initial patient assessment should include the following: (a) documentation of patient and family medical histories, (b) a thorough physical exam, (c) identification of existing signs and symptoms that may be associated with early CVD, (d) a complete serum lipids panel, and (e) determination of the patient's Framingham Score, which considers factors including gender, age, total cholesterol and high-density lipoprotein (HDL) cholesterol, systolic blood pressure (BP), use of BP-controlling medication, and smoking status to determine overall risk of developing CVD (Turk, Tuite, & Burke, 2009).

NPs are well positioned to play a significant role in overall management of CVD risk factors by educating their patients, monitoring patient progress, and supporting changes that promote a healthy lifestyle. Lifestyle modifications include the adoption of a nutrient-rich, reduced-calorie diet and participation in a regular exercise program. Reduction of excess weight through diet and exercise has been shown to have significant beneficial effects on CVD risk factors including IR and diabetes (Bevilacqua, Dominguez, & Barbagallo, 2009), and HTN and hyperlipidemia (Randell & Moyle, 2009). NPs can also positively impact patient health by promoting smoking-cessation programs and strategies because cigarette smoking is well known to have serious health consequences, and 59%–65% of HIV-infected patients are classified as current or former smokers (Lifson et al., 2010).

Secondary Prevention of CVD in HIV-Infected Patients

Secondary prevention strategies are designed to stop or slow the progression of CVD once it is established. Additional factors that contribute to the progression of CVD in HIV-infected patients can include chronic treatment with ART, with its potential for significant untoward effects on serum lipids and endothelial inflammation due to HIV infection (Kotler, 2008; Kramer, Lazzarotto, Sprinz, & Manfroi, 2009). Increased viral load has been independently associated with greater endothelial dysfunction (Blum, Hadas, Burke, Yust, & Kessler, 2005), which can be measured by ultrasound examination of carotid intima-media thickness (CIMT), a recognized marker for CVD risk in the general population (Simon, Megnien, & Chironi, 2010). In addition, ART, especially ART including protease inhibitors (PIs), is independently associated with metabolic and other effects that can increase CVD risk (Hsue et al., 2008).

It has been reported that certain ARVs, including some nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), and especially PIs, can negatively affect serum lipid profiles (Willard, 2006). Therefore, the known risks associated with the use of these drugs in the treatment of HIV infection must be weighed against the benefits for the individual patient, especially when other risk factors are involved. For patients with established CVD, overall lifestyle, clinical presentation (lipid profiles, cardiovascular function, etc.), comorbidities (diabetes, HTN, etc.), and family medical history should all be taken into account.

For patients living with HIV disease, the benefits of early ART, including delayed disease progression and the preservation or restoration of immune function, far outweigh the associated risks (HIV-CAUSAL Collaboration, 2010). This approach has recently been validated by the demonstration of significant restoration of B cell responses to non-HIV pathogens in patients who begin ART soon after they are infected (Moir et al., 2010).

The association between certain ARTs and CVD risk has been reviewed in detail elsewhere (Aberg, 2009). In the prospective observational DAD study of 23,437 patients with HIV disease, a small but significant increase in risk of myocardial infarction (MI) was found with continued use of most PIs for 6 years or longer. The annual increase in relative risk was 10% after adjusting for serum lipids (Friis-Møller et al., 2007). In an earlier report from this study group, NNRTIs and PIs were both associated with unfavorable lipid profiles overall. The highest cholesterol levels were seen in patients who were taking both an NNRTI and a PI (currently not recommended), and the group with the next highest cholesterol level consisted of patients on a PI-containing regimen with no NNRTI component (Friis-Møller et al., 2003). Patients taking an NNRTI with no PI component were at lower risk, and patients taking only NRTIs (currently not recommended) demonstrated no difference in serum cholesterol (Friis-Møller et al., 2007).

Use of NNRTIs can increase total cholesterol (TC) levels, thereby generating unfavorable TC/HDL ratios (van Leth et al., 2004). However, the NNRTI nevirapine (NVP) has been shown to significantly increase apolipoprotein A-1 protein, which in turn increases HDL levels in the serum (Franssen et al., 2009). Therefore, clinical consideration of how ART might affect a patient's serum lipid profile could be part of a strategy to reduce overall CVD risk. Kotler (2008) has provided an excellent review with a detailed assessment of the effects of individual ARVs sorted by class.

In the setting of HIV disease, NPs can help implement appropriate changes in patient lifestyles and ART regimens with the goal of minimizing CVD risk over time (Willard, 2006). A secondary prevention approach to CVD thus combines the elements of primary prevention strategies with additional considerations to manage serum lipids and other CVD risk factors. These include use of lipid-lowering medications, if needed, and reconsideration of the ARVs chosen for the regimen, depending on side effects, including changes to serum lipid profiles, as part of an individualized approach to clinical care.

Tertiary Prevention of CVD in HIV-Infected Patients

As time with HIV disease increases, a patient's overall CVD risk also increases due to a number of factors including advancing age, long-term exposure to ART, increasing potential for virologic failure, and the cumulative effects of chronic inflammation on endothelial function (Blum et al., 2005). In this population of treatment-experienced patients, the NP must employ strategies beyond weight reduction, exercise programs, smoking cessation, and diet modification. Tertiary strategies will build on those presented in the earlier stages and include more aggressive pharmacotherapy for the management of serum dyslipidemias, HTN, and diabetes.

In the older HIV-infected patient, age-associated changes in serum lipids generally include elevated serum TC, elevated low-density lipoprotein cholesterol (LDL), reduced HDL, a higher serum TC to HDL ratio, and elevated serum triglycerides (TGs; Siervogel et al., 1998).

Depending on the presence and severity of other CVD risk factors, the patient and NP must work together to develop a long-range plan to address these comorbidities, modify risk where possible, and minimize progression to more serious disease. Patients infected with HIV must be reminded that ongoing control of existing CVD risk factors is important to achieve long-term health objectives, especially because HIV therapy has led to increased life expectancy overall (Vance, Mugavero, Willig, Raper, & Saag, 2011). To this end, patient education and counseling should include the establishment of clear goals for serum lipids in accordance with the most current National Cholesterol Education Program guidelines, which set goals for serum LDL levels according to assessed cumulative risks (National Heart Lung and Blood Institute, 2001).

The management of other significant CVD risk factors, including IR and dyslipidemia, is of increasing importance at the tertiary stage of CVD intervention in older patients. Accordingly, the proper management of serum hyperlipidemias in adults infected with HIV, as defined in treatment guidelines from the U.S. Department of Health and Human Services (Panel on Antiretroviral Guidelines for Adults and Adolescents, 2011), can be achieved through a number of approaches.

These include lifestyle changes, use of lipid-lowering drug therapies such as statins, cholesterol-binding resins and cholesterol absorption inhibitors that block cholesterol uptake, novel niacin formulations, and use of ARVs associated with minimal negative effects on serum lipid profiles (Becker, 2008). The association between particular ARVs and CVD risk has been reviewed in detail elsewhere (Aberg, 2009).

CVD risk management at this stage requires added urgency by both the patient and the health care provider. Strategies include the implementation of previous recommendations, but with more aggressive targets due to the progression of CVD as evidenced by established laboratory measures. For example, patients may be strongly encouraged to initiate a regular exercise program, which has been shown to mitigate inflammation by influencing C-reactive protein (CRP) levels (CDC, 2004) and to extend long-term survival in patients infected with HIV (Spierer et al., 2007).

Management of chronic CVD risk factors often requires multidrug therapeutic approaches to effectively control each, which can potentially complicate the treatment of both CVD and HIV. The treatment of HTN can include thiazide diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor II blockers, or beta blockers, and each of these can be considered after assessing for potential interactions with the chosen ART regimen. These patients also require aggressive management of their serum lipids, with aggressive targets including an LDL of 70 mg/dl, and an HDL of greater than 40 mg/dl for men and greater than 50 mg/dl for women (National Heart Lung and Blood Institute, 2001). In order to achieve these recommended targets, the NP may be required to manage significant dyslipidemias with additional pharmacotherapies (necessitating an even greater awareness of drug–drug interactions and the potential for side effects), while working with the patient to establish a rigorous rehabilitative diet and exercise program to maximize cardiovascular health benefits. More importantly, the NP may consider switching ARV drugs or classes with the goal of minimizing or reversing undesirable lipid effects.

In patients who have not achieved acceptable serum lipid levels through diet modification, overall lifestyle improvement (exercise, smoking cessation, etc.), and optimization of ART, more aggressive lipid control measures may be warranted. Among the most important classes of serum lipid management drugs are the statins (HMG-CoA reductase inhibitors), which are well-established agents that have significant effects on serum lipoproteins. As a group, they reduce LDL by 18%–55%, increase HDL by 5%–15%, and reduce total TG by 7%–30% (National Heart Lung and Blood Institute, 2001). While effective at significantly improving overall serum lipid numbers and reducing CVD risk and overall mortality, the use of these drugs can be limited by well-known elevations in liver enzymes (transaminitis) and myopathy (rhabdomyolysis; National Heart Lung and Blood Institute, 2001).

Bile acid sequestering agents (Davidson & Robinson, 2007) and cholesterol absorption inhibitors (Patrick et al., 2002) bind bile acids or dietary cholesterol in the gastrointestinal tract and prevent their uptake. These drugs decrease LDL by 15%–30% on average and can increase HDL by 3%–5%, with little if any effect on serum TG. While relatively benign in their mechanisms of action, the use of these drugs can be limited by side effects such as generalized gastrointestinal distress and constipation; they also can decrease the absorption of other drugs (National Heart Lung and Blood Institute, 2001), especially lipophilic agents.

Fibric acids such as clofibrate can reduce LDL by 5%–20% and increase HDL by 10%–20%, while also reducing serum TG by 20%–50%. Their use can be limited by dyspepsia, increased chance of developing gallstones, and myopathy (National Heart Lung and Blood Institute, 2001).

Niacin, or nicotinic acid, as an immediate-release or extended-release formulation, can reduce LDL by 5%–25%, increase HDL by 15%–35%, and decrease TG by 20%–50%. Side effects can include flushing, erythema, and rash (Becker, 2008).

In a recent study involving HIV-infected patients with elevated TG, fish oils were found to be effective and safe in reducing TG (Gerber et al., 2008). When given alone, fish oils achieved mean TG reduction of 46% versus the 58% reduction achieved with the use of fenofibrate. When administered in combination, the two agents were able to reduce serum TG by 65.5%. However, the fish oil supplements used in this study had no apparent effect on measured immunologic parameters (Gerber et al., 2008).

In managing HIV-infected patients over the long term, challenges may emerge, including the need to switch individual components of an ART regimen due to poor tolerance or decreased efficacy, emergent dyslipidemias or other metabolic sequelae associated with CVD or related comorbidities, and the effects of long-term polypharmacy on end-organ function (Kirk & Goetz, 2009). To better manage dyslipidemia in patients living with HIV, switching to ARVs with fewer negative lipid effects has proven an effective strategy. In a study where ART-experienced patients were switched to atazanavir (a PI) for any reason and followed for at least 1 month, this modification resulted in significant improvements in plasma lipid profiles and a modest, but significant, reduction in the normalized-for-age CVD risk score (Colafigli et al., 2008). Similar beneficial effects on patient serum lipid profile (lower TC and increased HDL) have been seen when patients switched from efavirenz (EFV) to NVP (both NNRTIs) for better management of their neuropsychiatric events (Ward & Curtin, 2006) or to manage dyslipidemia (Willard, 2006). In the SIROCCO study, patients were switched from EFV to NVP (N = 37) and found to have a statistically significant decline in LDL cholesterol at 52 weeks (Parienti, Massari, Rey, Poubeau, & Verdon, 2007). According to the Framingham Study algorithm, this decline would correspond to a 20% decrease in the 10-year relative risk for major cardiac events (Parienti et al., 2007).


Primary, secondary, and tertiary intervention strategies can be followed to prevent, minimize, and mitigate CVD risks in HIV-infected patients. Individual strategies will depend on each patient's composite CVD risk profile. Strategies should include fundamental lifestyle modifications such as diet and exercise to reduce weight, and smoking cessation, which may have the greatest impact for the HIV-infected patient to reduce overall CVD and other health risks.

Timely assessment and aggressive management of serum dyslipidemias, IR, diabetes, and HTN will prevent or slow the progression of CVD. Once a patient with HIV infection is on ART, appropriate monitoring and management, including the selection of ARV combinations with minimal negative effects on serum lipids, can help reduce the patient's overall CVD risk profile. Finally, direct control of serum lipids through the use of well-established cholesterol- and TG-lowering medications (statins, bile acid sequestering agents, cholesterol absorption inhibitors, niacin, fibric acid, and fish oils) represents an additional strategy for lowering the overall patient risk profile for a major CVD event such as a stroke or MI. With increasing age and cumulative CVD risk factors, more aggressive approaches may be needed. A balanced approach that weighs the cumulative risks and benefits to the patient is expected to have a positive impact on the overall quality of life. In light of their potential cost savings, NPs have unique roles for assessing, monitoring, and treating the patient with long-term or more advanced HIV disease and CVD risk.


Because of therapeutic advances in ART over the past decade, and also increased sexual activity and HIV transmission among older adults, the average age of people living with HIV disease in the United States is increasing (Kirk & Goetz, 2009). Chronic HIV infection increases the risk and progression of common non-HIV associated comorbidities, and these patients may require aggressive prevention measures. Selected ARVs may exacerbate some non-HIV-related conditions, but the effects may be less pronounced than those of HIV. Since older patients in general have serum lipid profiles that suggest increased risk for CVD (Kramer et al., 2009), including decreased HDL and increased LDL, TGs, and TC/HDL ratios, the appropriate management of serum lipids becomes increasingly important as the HIV-infected patient ages (Vance et al., 2011). Future research should address individual contributions of other comorbidities to the overall CVD risk profile of older patients to identify which risks are due to increasing age, ART, and chronic HIV infection. It remains difficult to manage HIV and comorbidities, and further clinical research should focus on optimal timing for HIV treatment and the management of individual comorbid conditions. Finally, we look forward to the development of updated guidelines and treatment models that are specific to the needs of older HIV-infected adults.


Although the framework presented here can be used by all health care professionals, NPs are expected to play an increasingly important role in the management of patients with multiple co-morbidities such as HIV and CVD. NPs have the opportunity to act as innovators in patient care and to design programs that specifically address CVD risk factors throughout all stages of HIV disease through the use of electronic medical records and the medical home model. The NP-led patient-centered medical home may be the most viable option to provide cost-effective care for this population (Schram, 2010).

The primary, secondary, and tertiary disease prevention framework discussed in this paper provides an innovative approach that exemplifies the full extent of NP clinical education and training. NPs will be responsible for the development and implementation of a cost-effective model that continually assesses and treats HIV-infected patients at risk for, or diagnosed with, CVD. These innovations will bring nurses with a doctoral degree (PhD, DNP) into full partnership with physicians and other health care professionals, whether they are evaluating a patient's overall CVD risk, educating patients on the need for general lifestyle changes, or monitoring the virologic efficacy and side-effects of ART regimens. Together, the health care team will determine the need to modify proposed changes in a patient's lifestyle or to intervene with direct drug therapy.

NPs have the potential to reduce CVD risk in patients infected with HIV as part of a long-term health care strategy. Applying the principles of primary, secondary, and tertiary prevention to the treatment of CVD risk factors in this population establishes a conceptual framework in which to consider HIV disease status, CVD risk management, and other factors important for optimizing long-term patient care outcomes.

Clinical Considerations

  • HIV-infected patients are at elevated risk for developing CVD.
  • CVD risks in HIV-infected patients can be due to (a) the effects of HIV infection itself, including chronic inflammation and immune activation, and (b) the effects of chronic exposure to certain antiretroviral medications.
  • NPs will play an ever-larger role in the treatment of patients with chronic HIV infection as health care paradigms continue to evolve.
  • By applying individualized primary, secondary, and tertiary prevention strategies, NPs will play a significant role in the management of CVD risk factors associated with HIV infection throughout a patient's treatment lifecycle.


Ms. Jones-Parker has participated in Speakers Bureaus for Tibotec Therapeutics, Abbott Laboratories, and Boehringer Ingelheim.


Editorial and writing assistance was provided by José L. Walewski, PhD, of Envision Scientific Solutions, which was contracted by Boehringer Ingelheim Pharmaceuticals, Inc., for these services. Ms. Jones-Parker received no compensation related to the development of the manuscript.


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cardiovascular disease; cardiovascular risk factors; HIV; primary prevention; secondary prevention; tertiary prevention

© 2012Elsevier, Inc.