Morbidity among patients with HIV who remain on antiretroviral therapy (ART) for long periods has decreased substantially in recent years, and the life expectancy of HIV-infected patients has increased considerably (Murphy et al., 2001). Unfortunately, ART can cause a variety of side effects including fat deposition or loss, dyslipidemia (abnormal levels of lipids or lipoproteins in the bloodstream), and other metabolic complications such as insulin resistance (a state in which the tissues and organs no longer respond when stimulated by insulin). Patients with multiple metabolic abnormalities of this type are said to have HIV lipodystrophy syndrome (Carr, 2003). There is evidence that hypercholesterolemia occurs in as many as 74% of patients on protease inhibitors (PIs) (Tsiodras, Mantzoros, Hammer, & Samore, 2000), whereas lipodystrophy has been observed in half of patients in the general population of HIV-infected individuals receiving ART (Heath et al., 2001). It is worth noting that although the body changes caused by lipodystrophy may have significant psychological effects on patients, the potential cardiovascular disease (CVD) risk associated with the accompanying dyslipidemia may cause them less concern.
Dyslipidemia itself has been recognized as a major CVD risk factor (Wilson et al., 1998) that often coexists with other risk factors including hypertension, insulin resistance, tobacco use, and diabetes (Bonora et al., 2003). Individuals without HIV infection who exhibit clusters of these types of lipid and nonlipid metabolic abnormalities are said to have metabolic syndrome, a simple working definition that has been recently published by the National Cholesterol Education Program (NCEP) (Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [Expert Panel, 2001). Metabolic syndrome is characterized by the presence of three of the following risk factors: abdominal obesity, elevated triglycerides, low high-density lipoprotein cholesterol (HDL-c) levels, elevated blood pressure, and increased fasting glucose (Expert Panel, 2001). Metabolic syndrome has been independently associated with increased CVD and mortality (Hu et al., 2004; Lakka et al., 2002). The similarities between the dyslipidemia and insulin resistance associated with ART and metabolic syndrome have raised considerable concern that HIV-infected patients receiving ART may be at particularly high risk of CVD.
New data from a large population-based study conducted recently in the United States provide a basis for these concerns. In this study, people with HIV infection were found to be more likely to suffer from an acute myocardial infarction as their uninfected counterparts (22% vs. 11%) (Currier et al., 2003). It is becoming clear that CVD risk may be linked to ART. This topic has been the focus of several recent reviews (Balasubramanyam, Sekhar, Jahoor, Jones, & Pownall, 2004; Green, 2002; Koutkia & Grinspoon, 2004; Mooser, 2003).
The beneficial effect of ART on the longevity of HIV-infected patients has led clinicians and patients to become increasingly concerned about long-term drug toxicities and morbidity and mortality caused by other chronic diseases. This review discusses metabolic factors involved in the CVD risk associated with HIV infection and antiretroviral treatment, issues that should be considered when implementing therapy.
Antiretroviral Therapy–Associated Dyslipidemia
Lipoproteins are proteins found in plasma and lymph that are combined with fats or other lipids. They are important for carrying lipids and cholesterol around the body and for removal of them from the bloodstream into the tissues and organs. Abnormal lipoprotein levels can alter the amount of lipids and cholesterol in circulation. Specific disturbances have been associated with CVD, including elevated levels of low-density lipoprotein cholesterol (LDL-c), low levels of HDL-c, high LDL-c/HDL-c ratios, and high total cholesterol/HDL-c ratios. It has been proposed that this last measurement may more accurately reflect CVD risk than the LDL-c/HDL-c ratio, particularly in patients with elevated triglyceride levels (Lemieux et al., 2001).
ART-associated dyslipidemia is the term commonly used to describe the condition of an abnormal lipid profile that has developed as a side effect of an antiretroviral drug regimen used to treat HIV infection. The U.S. Department of Health and Human Services guidelines for treatment recommend screening for lipid abnormalities at the initial evaluation of HIV-positive individuals.
Lipoprotein Profile Abnormalities in Antiretroviral Therapy–Associated Dyslipidemia
ART-associated dyslipidemia produces a characteristic atherogenic lipoprotein profile (Mooser, 2003). Typically, this includes the following:
- Elevated levels of very low-density lipoprotein (used to transport triglycerides)
- Elevated levels of LDL-c
- Elevated levels of lipoprotein(a) (Périard et al., 1999) (an atherogenic lipoprotein identified as a risk factor for coronary heart disease in the Framingham Heart Study [Seman et al., 1999])
- No change in or slightly decreased HDL-c
LDL-c provides cholesterol for normal body functions. However, elevated levels in the bloodstream can cause cholesterol to be deposited in arterial walls where it becomes incorporated into fatty atherosclerotic plaques. These plaques can block blood flow through the arteries and may eventually cause myocardial infarction or other cardiovascular complications. Elevated LDL-c is a major cause of coronary heart disease. The primary aim of treatment of high blood cholesterol in both uninfected and HIV-infected individuals is to lower LDL-c (Barlett, Infectious Disease Society of America, & AIDS Clinical Trials Group, 2004; Dubé et al., 2003; Grundy et al., 2004).
The relationship between ART and dyslipidemia is not straightforward. Different drug classes and individual drugs within classes have different effects on the lipoprotein profile. Many of the lipid disturbances increase CVD risk, but some may be beneficial. For example, some ART may increase levels of HDL-c (Mauss et al., 2003), which is considered protective against CVD (Expert Panel, 2001). It is this form that carries cholesterol away from the arterial walls and out of the bloodstream.
Antiretroviral Drug Classes, Dyslipidemia, and Cardiovascular Disease Risk
ART for the treatment of HIV infection typically consists of a combination of antiretroviral agents that may include nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and PIs. A single fusion inhibitor is also available.
Antiretroviral Therapy–Associated Dyslipidemia
The incidence, etiology, health risks, and treatments of dyslipidemia in ART have been reviewed in detail by Green (2002). Many initial studies focused on the detrimental metabolic effects of the PI component of ART. Overall, exposure to PIs has been associated with atherogenic dyslipidemia, specifically elevated cholesterol, and triglyceride levels. These lipid abnormalities become exacerbated the longer therapy is used (Carr, 2003; Heath et al., 2001; Périard et al., 1999), although PIs as a class, and indinavir specifically, have been associated with small increases in HDL-c (Mauss et al., 2003; Tashima, Bausserman, Alt, Aznar, & Flanigan, 2003).
The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study implicated both PIs and NNRTIs in hyperlipidemia, although NNRTIs to a lesser extent than PIs (Friis-Møller et al., 2003). This observational study determined data on more than 20,000 HIV-infected patients treated with antiretroviral therapy from 11 cohorts in 20 countries in Europe, the United States, and Australia (Friis-Møller et al., 2003). Both NNRTIs and PIs alone or in combination were associated with an atherogenic lipoprotein profile (Friis-Møller et al., 2003). The number of patients with elevated cholesterol (≥ 6.2 mmol/L) was highest among those receiving combinations containing an NNRTI plus a PI, followed by those receiving combinations containing a PI but no NNRTI. Combinations with an NNRTI but no PI were of less risk, while those containing only NRTIs had no effect at all on cholesterol levels (Friis-Møller et al., 2003). As a class, NRTIs appear to have minimal effects on lipoprotein metabolism, although exposure to stavudine has been reported to elevate triglyceride levels in some patients (Galli et al., 2002).
Antiretroviral Therapy–Associated Cardiovascular Disease Risk
The observations linking ART and dyslipidemia have raised concerns about the impact this may have on long-term CVD risk for people with HIV infection. There is now evidence that these concerns are well-founded; the risk of myocardial infarction increases with the duration of PI therapy, and myocardial infarctions are three times more common among HIV-infected patients exposed to PIs for more than 2.5 years than a comparison population (Mary-Krause et al., 2003). Further analyses have revealed that this increase was not limited to myocardial infarction, because there was a similar increase in the rate of other cardiovascular and cerebrovascular events (e.g., stroke, invasive cardiovascular procedures, deaths from other cardiovascular causes) (The Writing Committee of the D:A:D Study Group, 2004).
It is not clear whether or not PIs play a significant role in the development of atherosclerotic plaques; PIs have been associated with coronary artery calcification, higher serum cholesterol and LDL-c levels, and red blood cell abnormalities, all of which are markers of atherosclerosis (Meng et al., 2002), There is also evidence that PI therapy promotes the development of lesions in the carotid walls (Maggi et al., 2000). However, some investigators suggest that the contribution that PI therapy makes to the development of plaques may be insignificant compared with that of other risk factors such as age, elevated LDL-c levels, and cigarette smoking (Depairon et al., 2001).
Can Specific Antiretroviral Drugs Lower Cardiovascular Disease Risk?
The metabolic complications of PI therapy have been relatively well-documented, and observations have been made that some PIs may cause more severe dyslipidemia than others. For example, ritonavir has been reported to cause more severe dyslipidemia than other PIs (Fontas et al., 2004). Of particular note, atazanavir, the latest PI approved for use in combination antiretroviral therapy for the treatment of HIV infection, was shown to provide rapid and durable HIV suppression with no significant increase in total cholesterol or LDL-c levels and a decrease of 9% in triglycerides (Squires et al., 2004). Clearly, it is desirable that the CVD risk associated with atazanavir-containing ART compared with other PI- and NNRTI-containing regimens be established, because this agent may represent an important treatment option for HIV-infected patients with existing CVD risk factors. However, atazanavir is often combined with ritonavir, and research is ongoing to evaluate what the outcome will eventually be.
Nonnucleoside Reverse Transcriptase Inhibitors
The two most commonly used NNRTIs are nevirapine and efavirenz, the metabolic effects of which are not as well-understood as the PIs. Both increase total cholesterol and LDL-c levels, but they also increase HDL-c levels (van der Valk et al., 2001; van Leth et al., 2004). Although both drugs increased total cholesterol levels, nevirapine produced a larger increase in HDL-c levels and consequently a marked drop in the total cholesterol/HDL-c ratio, whereas efavirenz did not significantly change HDL-c levels (van Leth et al., 2004).
Nucleoside Reverse Transcriptase Inhibitors
First-line therapy with three (or possibly more) NRTIs may offer a means of avoiding ART-associated hyperlipidemia in some patients. Preliminary observations indicate triple therapy with zidovudine (AZT)/lamivudine/abacavir had little effect on LDL-c levels and a much lesser effect on total cholesterol levels than a combination of AZT/lamivudine/nelfinavir (10% increase vs. a 32% increase), while achieving similar virological efficacy over 48 weeks of follow-up (Kumar et al., 2002). However, the U.S. Department of Health and Human Services guidelines currently advise against a triple-NRTI regimen for initial therapy unless PI- or NNRTI-containing regimens cannot be taken because of a quick emergence of viral resistance (Panel on Clinical Practices for Treatment of HIV Infection convened by the Department of Health and Human Services [DHHS], 2004).
Changes in Lipoprotein Profiles Upon Switching Antiretroviral Therapy Regimen
The more that is known about treatment of HIV, the more the clinician understands that there are times when regimens must be changed to avoid long-term consequences. The relatively favorable effects of selected NNRTIs and NRTIs on lipoprotein metabolism have led investigators to examine the clinical utility of replacing PI-containing ART with a PI-sparing regimen as a means of reversing PI-induced dyslipidemia and reducing CVD risk. In addition, because of its minimal effects on lipoprotein levels, the new PI atazanavir is also under investigation as a substitute for traditional PI therapy.
Metabolic Effects of Switching to a Nonnucleoside Reverse Transcriptase Inhibitor
When substituted for the PI component of an ART regimen, both nevirapine and efavirenz (NNRTIs) have been shown to be highly effective for maintaining suppression of HIV infection in patients who had previously maintained a sustained virological response to PI therapy (Martinez et al., 2003). With regard to dyslipidemia, some studies have shown that HIV-infected patients who were switched from a PI- to a nevirapine-containing regimen experienced a significant reduction of total cholesterol, LDL-c, and very low density lipoprotein particles, and a significant increase in HDL-c after 24 weeks (Negredo et al., 2002). Another study compared metabolic effects in HIV-infected patients who switched from a PI- to an efavirenz- or a nevirapine-containing regimen. Both of the NNRTIs significantly raised HDL-c levels (efavirenz by 11% and nevirapine by 20%), whereas nevirapine also significantly reduced triglyceride levels (by 33%). Both PI-sparing regimens caused a significant increase in the total cholesterol/HDL-c ratio after 12 months (Fisac, Fumero, & Crespo, 2002). In further follow-up of these patients, both nevirapine and efavirenz showed similar metabolic benefits after 2 years of therapy. Total cholesterol levels were unchanged, although LDL-c levels tended to be lower. HDL-c levels were significantly increased, particularly with nevirapine (50% increase vs. 12% increase with efavirenz)] (Fisac et al., 2004). However, a downside of this is the emergence of viral resistance to nevirapine.
Metabolic Effects of Switching to Abacavir
Two studies (Clumeck et al., 2001; Katlama et al., 2003) have shown that the replacement of a PI- or NNRTI-containing ART regimen with a triple-NRTI regimen containing abacavir has provided continued virological suppression and significant improvements in triglycerides and cholesterol levels. However, others have found that a switch from a PI to abacavir had a higher virological failure rate than a switch to an NNRTI (Martinez et al., 2003). Furthermore, a meta-analysis of trials investigating the effects of switching from a PI- to an abacavir-based regimen found the risk for virological failure to be 2.5 times that of continued PI use (Bucher et al., 2003). Nevertheless, there are clear metabolic improvements among patients switching to abacavir, with significant reductions in total cholesterol (down 9%) and LDL-c (down 13%) after 12 months of follow-up (Fisac et al., 2002) that were maintained for up to 2 years (Fisac et al,. 2004).
Metabolic Effects of Switching to Atazanavir
Atazanavir is a potent PI that has minimal effects on total cholesterol, LDL-c, or triglycerides (Murphy et al., 2003). A study examining the effects of switching from nelfinavir to atazanavir in an ART regimen showed that after 6 months of therapy, switching to atazanavir was associated with significant reductions in total cholesterol (down 16%), LDL-c (down 20%), and triglycerides (down 25%). There was also a trend toward increased HDL-c (up 5%), although this was not statistically significant (Wood et al., 2004).
Metabolic Effects of Switching to Tenofovir
Tenofovir is a nucleoside reverse transcriptor that also has minimal effects on lipids. In a study in which individuals who were on stavudine for 12 weeks were switched to tenofovir, triglyceride and cholesterol levels showed significant decreases. This suggests that such a switch may reverse, at least partly, stavudine-associated dyslipidemia (Domingo et al., 2004).
Guidelines for Preventing Cardiovascular Disease Risk in HIV-Infected Patients
The high proportion of HIV-infected patients who develop ART-associated dyslipidemia warrants regular screening for lipid disorders for HIV-infected patients receiving ART. Grover, Coupal, Gilmore, and Mukherjee (2005) reported that dyslipidemia increased the risk of coronary disease by 50% over 10 years. Updated guidelines for the evaluation and management of dyslipidemia in HIV infection have recently been published by the HIV Medicine Association of the Infectious Disease Society (IDSA) of America and the Adult AIDS Clinical Trials Group (ACTG) (Barlett et al., 2004; Dubé et al., 2003). Many of the recommendations for improving the lipid profile and preventing and reducing CVD risk in HIV-infected patients are based on the NCEP Adult Treatment Panel III guidelines for the treatment of high blood cholesterol in uninfected adults (Expert Panel, 2001), which were recently updated (Stein, 2003). A basic premise for the NCEP guidelines is that risk reduction interventions should reflect the individual's absolute risk. This includes primary prevention in individuals with multiple risk factors (Expert Panel, 2001). Lowering LDL-c is still considered the primary goal of cholesterol-lowering interventions (Stein, 2003).
A general approach to managing lipid disorders in HIV-infected patients from the IDSA/ACTG guidelines is shown in Figure 1.
Screening for and Monitoring of Hyperlipidemia in HIV Infection
A complete lipoprotein profile, including total cholesterol, LDL-c, HDL-c, and triglycerides, should be performed (Expert Panel, 2001) before initiating antiretroviral therapy, again 3 to 6 months later, and then annually thereafter (Barlett et al., 2004).
Because CVD is multifactorial, a 10-year risk estimate of myocardial infarction or cardiac death should be obtained for patients who have LDL-c ≥ 100 mg/dL and two or more risk factors (Table 1). This can be estimated using an online calculator based on the Framingham Heart Study (found at http://hin.nhlbi.nih.gov/atpiii/calculator.asp) (Dubé et al., 2003). With this information, patients can be assigned a risk category that determines individual target LDL-c levels and also when to initiate cholesterol-lowering interventions (Table 2).
Recommended Approach to Treating Antiretroviral Therapy–Associated Dyslipidemia
The general sequence for initiating intervention to treat dyslipidemia in HIV infection is as follows (Barlett et al., 2004):
- Therapeutic lifestyle changes known to modify CVD risk are the first-line intervention for the treatment of ART-associated dyslipidemia (Table 3), together with active treatment of high blood pressure and diabetes and encouragement of smoking cessation.
- If these measures are ineffective or if there are extreme elevations in LDL-c levels or triglycerides (> 220 mg/dL and > 2,000 mg/dL, respectively, or triglycerides > 1,000 mg/dL plus a history of pancreatitis), initiation of drug therapy is recommended (Table 4). However, careful consideration of potential drug interactions of statins with antiretroviral agents is required (Table 5).
- Switching antiretroviral therapy in some cases (Table 6) may be preferable to using lipid-lowering agents (Dubé et al., 2003). In this case, careful consideration of the risks of toxicity of the new antiretroviral agent as well as the possibility of virological failure when switching ART is required (Barlett et al., 2004).
The Role of the Nurse Practitioner
Nurse practitioners (NPs) have been very active in the front lines of providing care to many underserved individuals. It is this author's experience that the majority of HIV care programs have at least one NP. These NPs often carry the greatest day-to-day responsibilities for the patients. Their holistic, preventative approach to care has always included primary care measures that are just now receiving recognition in the HIV care model for importance, for example the importance of smoking cessation. Therefore, the NP continues to play a vital role in the care and treatment of the dyslipidemic HIV-infected patient on ART. The following interventions are derived from recommendations for NPs treating metabolic syndrome in general (Berra, 2003). The NP should examine LDL-c levels, the primary target of treatment, along with other CVD risk factors in collaboration with the patient. With regard to education and support, the NP can help the patient to implement changes in diet and exercise. Lipid-lowering agents can be instituted as indicated. The NP should then promote continued adherence to both lifestyle modifications and pharmacologic therapy through follow-up visits and telephone calls. In a study of coronary heart disease patients, these measures were shown to result in better control of cholesterol compared with less aggressive management (Allen et al., 2002).
Most important, the use of a team approach to patient care, including the team pharmacist, nutritionist, and case management, all lend important pieces to optimizing health outcomes in the complexity of HIV treatment.
Managing patients demands an understanding of them as well as an understanding of risks and benefits of ART. While ART has provided great options, it has also provided challenges to nursing to be diligent and creative in the approach to the patient's specific needs. Prevention of disease as well as prevention of adverse responses to treatments is imperative. The very success of using ART as lifelong therapy to control HIV infection has led to improvements in quality of life, but also to concern about increased CVD risk from ART-associated dyslipidemia. New guidelines recommend screening HIV-infected patients for lipid abnormalities before the initiation of therapy, 3 to 6 months later, and with subsequent annual monitoring thereafter. When selecting ART, the impact of individual drugs on lipids and other metabolic factors that can increase cardiovascular risk should be carefully evaluated, especially when there are existing CVD risk factors. ARTs based on agents with favorable metabolic profiles such as nevirapine, abacavir, tenofovir, or atazanavir should be used if possible. In the event of dyslipidemia caused by ART, target LDL-c levels should be determined based on individual CVD risk. In the first instance, therapeutic lifestyle changes should be instituted. Expert dietary advice to help manage dietary complications is beneficial. If the target LDL-c level is not met, the options are to consider drug therapy with lipid-lowering agents or to switch antiretroviral agents to another lipid-friendly combination.
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