Brett-Major, David M. MD*; Ganesan, Anuradha MD, MPH*†‡
Increasing awareness of dyslipidemia in human immunodeficiency virus (HIV) infected patients has led to targeted trials examining its character, evaluation of its relationship to cardiovascular risk, and increasing use of serum lipid levels as a secondary outcome in therapeutic drug trials. In 2003, the Infectious Diseases Society of America (IDSA) and HIV Medicine Association (HIVMA) published guidelines regarding dyslipidemia in adult patients receiving antiretroviral therapy (ART).1 Before this effort, a 2002 international working group published recommendations on metabolic complications of ART.2 The literature on HIV and cardiovascular risk is controversial, although increasingly, it appears that HIV infection and ART may both have independent effects on cardiovascular risk3 and that conventional host factors remain relevant.
In this review, we will emphasize key points from practice guidelines and discuss implications of subsequent literature on both ART and concomitant cardiovascular risks. This review article is not intended as a substitute for reviewing the practice guidelines of IDSA/HIVMA and National Cholesterol Education Program Adult Treatment Panel III4,5 when formulating a personal practice policy, rather, it is offered as a route to framing the process.
An important starting point in this process is the understanding that regardless of the presence of dyslipidemia, treating HIV in settings when indicated is paramount.6 The addition of medications for the treatment of dyslipidemia and the selection of ART agents that prevent exacerbations or mitigate dyslipidemia if already on ART are secondary management issues.
The essential recommendations of the 2003 guidelines are (1) to recognize HIV-positive patients as an at-risk group for dyslipidemia and (2) to conform with the practice guidelines of the National Cholesterol Education Program Adult Treatment Panel III. Two dominant phenotypes are acknowledged: elevated low-density lipoproteins (LDLs) with triglycerides (TGs) of less than 500 mg/dL and severe hypertriglyceridemia (>500 mg/dL) with or without elevated LDL. Early data on ART interactions with dyslipidemia therapies were also considered in the guidelines.
Initial and then 3- to 6-months post-ART change fasting serum lipid testing are recommended. Favored 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (also known as statins) are atorvastatin and pravastatin at low dose, with fluvastatin as an alternative. Simvastatin and lovastatin are contraindicated in some settings because of drug-drug interactions, mediated through the cytochrome P450 systems. For TG-dominant disease, gemfibrozil or fenofibrate are recommended. Niacin was an alternative therapy for both LDL and TG dominant diseases, but it carried concern for increased insulin resistance. Clinical monitoring for myopathy was suggested for both monodrug and multidrug therapy for dyslipidemia, although tracking serum creatine kinase received no comment. Table 1 summarizes weighted recommendations; note the use of the conventional A-E I-III rating scheme.
At the time the guidelines were created, although dyslipidemic effects of PIs were appreciated, the role of nonnucleoside reverse transcriptase inhibitors (NNRTIs) was unclear. Ezetimibe was not discussed, although data on its use in this setting are growing.7
It is becoming increasingly recognized that the dyslipidemia seen in HIV-infected patients is a combination of HIV infection, antiretroviral drugs, and host genetics.
Effects of HIV Infection on Serum Lipids
Decreases in serum high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and LDL-C are seen with acute HIV infection.8 Serum lipids in chronic untreated HIV/acquired immunodeficiency syndrome (AIDS) patients are characterized by lower serum LDL and HDL cholesterol than age-matched controls.9,10 Analysis of LDL fractions reveals that patients with AIDS have higher levels of atherogenic small dense LDL particles,10,11 although this was not the case among a more heterogeneous HIV-infected population.12 Early in HIV infection, there are no significant changes in serum triglycerides, but later in the infection and with the development of AIDS, there is an increase in triglycerides,11 which is believed to be because of decreased TG clearance. In summary, untreated HIV infection is associated with a proatherogenic lipid profile, characterized by an increase in TG and small dense LDL concentration and decreases in serum HDL concentration.
Effects of Antiretroviral Agents on Serum Lipids
Since the first reports by Carr et al that suggest that PI-based therapy increased triglycerides and cholesterol, it has become clear that not all PIs affect serum lipids to the same extent.13 Although therapy with PIs, such as ritonavir and indinavir, resulted in increased TG and TC, some of the more recently licensed PIs, such as atazanavir, appear to have lipid sparing effects.14-17 Rollover studies have even indicated that atazanavir reverses the lipid abnormalities associated with nelfinavir use.17 Among the PIs, data from the Swiss Cohort suggest that ritonavir use is associated with the most significant elevations in TG and TC. In this cohort, treatment with indinavir and nelfinavir also were associated with increases in TC and TG; however, the magnitude of these increases was lower than that seen with ritonavir.18 Results of the 2 NN (non-nucleoside reverse transcriptase inhibitors) study suggest that use of nevirapine is associated with a better lipid profile than efavirenz.19,20 Among the NRTIs, D4T use is associated with unfavorable effects on serum lipids, whereas tenofovir and abacavir appear to have a favorable effect.21-28 Several studies where abacavir has been substituted for a nucleoside/nucleotide reverse transcriptase inhibitor (NRTI), non-nucleoside reverse trancriptase inhibitors (NNRTI), or PI have revealed beneficial lipid effects.22,25 Please refer to Table 2 for a by drug synopsis of some of the more recent studies that have evaluated different combination ART (CART) regimens and their effects on serum lipids.
Comparison of NNRTI Regimens With PI-based Therapy
In comparison with PI-based regimens, relatively lower TG increases and higher HDL levels have been observed in patients with increasing exposure to NNRTI-based regimens in contrast to PI-based regimens.18,30,31 In the D:A:D study, NNRTI use was associated with a better lipid profile, lower TC and TG, and higher HDL-C than PI therapy.30 In a study of 40 patients switching from PI-based therapy to NVP-based therapy, there were significant decreases in serum TG and increases in HDL-C in patients switching to NVP-based regimens.32
All PI Are Not Created Equal With Regard to Dyslipidemia: Ritonavir Boosting Matters
Boost dose ritonavir has been shown to cause dyslipidemia in both non-HIV-infected controls and as a component of ART in conjunction with both early and late-generation PI.33,34 Relative superiority among PI varies by study and depends greatly upon context. For instance, in 1 cohort analysis, nelfinavir use was favorable with regards to dyslipidemia, although it was contrasted to boosted lopinavir and boosted indinavir-based regimens.18 In another such analysis of a competing cohort, indinavir and saquinavir had the most favorable profiles of those compared.30 In most studies, ritonavir boosting appears to worsen dyslipidemia.
Since the publication of the 2003 guidelines, 2 PIs have been licensed and experienced greater use in the United States: atazanavir and fosamprenavir. Initial drug licensing trials revealed that atazanavir use was associated with lipid-sparing effects. Since then, several studies have confirmed these results although ritonavir boosting decreases this advantage.17,35,36 The effects of changing ART in patients with pretreatment dyslipidemia has not been well tested. Fosamprenavir licensing trials have compared fosamprenavir and nelfinavir in ART-naive patients, revealing similar dyslipidemic characteristics.37,38 The new PIs for salvage therapy, tipranavir and darunavir, have limited available data regarding their long-term dyslipidemic effects. In the RESIST trial, triple-drug regimens including boosted tipranavir had rates of severe hypertriglyceridemia and hypercholesterolemia of 30.8% and 4.3%, respectively, after 48 weeks, whereas rates for regimens with comparator boosted PI were 23.1% and 0.7%, respectively.39 Darunavir reportedly had no significant biochemical consequences in a 2-week study, although explicit data on dyslipidemia was not reported.40 Like tipranavir, it uses a higher boosting dose of ritonavir; thus, consequent dyslipidemia could be anticipated.
Protease Inhibitor and NNRTI Combination and Dual-PI Therapy
In salvage regimens, the combination of PI and NNRTI can be highly dyslipidemic. In a study of boosted indinavir with efavirenz as a salvage protocol, target viral load reductions were achieved at a cost-LDL increased by 71% and TG increased by 151%.41 Dual-PI regimens also are associated with increased rates of dyslipidemia.30
In summary, among the earlier PIs, ritonavir appears to be associated with the greatest increases in TC and TG, whereas saquinavir appears less likely to cause dyslipidemia. Among the later PIs, atazanavir probably has the least effects on lipids and may reverse dyslipidemias associated with other PIs. The classification of later and earlier is based upon their approval by the Food and Drug Administration. Ritonavir boosting probably worsens dyslipidemic profiles. Dual-PI and use of NNRTI and PIs are associated with greater increases in serum TC and TG than single-PI therapy.
Individual ART Agents May Have Markedly Different Dyslipidemic Effects Among Patient Groups: The Role of Host Genetics
A cross-sectional study of AIDS Clinical Trial Group patients demonstrated that although black patients were more likely to have lower TG and LDL levels on ART than other patients, their lipid profiles were more adversely affected from baseline on unboosted and boosted PI therapies than other patients.42 This study also correlated explicit ApoC III genotype with the predictability of dyslipidemia on ART.
Three hundred twenty-nine patients in the SWISS Cohort Study were assessed to identify whether ART in combination with common APO gene variants resulted in a worsened lipid profile.43 The presence of both APOE and APOC3 mutations in the setting of ritonavir boosting was significantly associated with a near 2-fold increase in TG levels on therapy. A variety of other gene targets have been explored.44-47 Much remains to be learned regarding the tailoring of ART to the pharmacokinetics and proteomics of individual patients.
Prevalence of Risk Factors for Coronary Artery Disease in HIV-positive Patients
Regimens that employ either a NNRTI or PI backbone are associated with dyslipidemias. Mere extrapolation of data on HIV-negative patients would suggest that these dyslipidemias would predispose HIV-positive patients to an increased risk of coronary artery disease (CAD). However, the data on HIV disease and risk for CAD are conflicting, with some studies suggesting an increased risk and one large study demonstrating a decreased risk. The following paragraphs briefly summarize recently available data on CAD, HIV infection, and ART.
The D:A:D study has tracked nearly 18,000 ART-treated HIV-positive patients since 1999, with the purpose of evaluating cardiovascular risk. A cross-sectional analysis of baseline risk factors was published in 2003.48 Treatment regimens among these patients varied significantly. Although, predictably, PI therapy provided the highest prevalence of dyslipidemias at more than 40%, more than a third of patients on NNRTI-based regimens and a quarter of patients on NRTI-only regimens also had dyslipidemia. The group with the least cardiovascular risk factors was the treatment-naive group, with a 15% rate of increased TG and only a 7.7% rate of increased TC.
Tobacco use was common, with half of the patients (51.5%) reporting current use at the time of entry into the cohort. A quarter of the patients were older than age 45 years, whereas 2.5% of the patients enrolled in this study had diabetes mellitus. In a multivariate analysis, NNRTI used as backbone therapy or in combination with a PI was statistically associated with an increased risk for diabetes in contrast to treatment-naive patients (odds ratio, 1.89; P < 0.05). Whether diabetes onset in the setting of NNRTI therapy increases cardiovascular risk to the same degree as de novo diabetes is not known. However, as diabetes is a cardiac event risk equivalent, if diabetes emerges during NNRTI therapy, alternative regimens may be considered.
The D:A:D study participants also were assessed for hypertension, which was seen in 8% of the cohort. As in non-HIV-infected patients, the risk of hypertension was associated with age, sex, and presence of obesity and not specifically to treatment regimens. Obesity was not common, and only 3.5% of the patients had a body mass index greater than 30 kg/m2. A family history of CAD was reported in 11.4% of the patients studied. Lipodystrophy was present in 25.4% of the total group, with prevalence of approximately 30% in PI or NNRTI backbone patients versus 20% in those with no ART or NRTI therapy only. At the time of the publication of this study, data from the CPCRA and the Brussels cohort had not been included in reports from the D:A:D group; however, subsequent studies include their data.
Studies Evaluating Risk of CAD in HIV Positive Patients on ART
Following the report of severe premature CAD in 2 young HIV-positive PI-treated patients in 1998, there have been several studies that have evaluated the risk of ART and CAD. The results thus far are not conclusive but seem to support the role of HAART and PI-based therapy in increased risk for CAD.3,49 The results of the DAD study suggest that the risk of MI increases with increased exposure to CART. Most of the patients in this study were treatment experienced (74.5% CART). In multivariate analysis, CART was associated with a 26% increase in the risk of MI for every additional year of CART use. The study did not have power to detect the effects of individual drugs. This study also revealed that known coronary artery risk factors such as age, smoking, and DM are also operational in HIV-positive patients.
Recent data presented by the same group suggest that exposure to PI therapy leads to a 16% increased risk of MI per year of exposure. This increased risk could not be explained by the changes in lipids due to PI therapy alone, because the risk persists even after adjustment for the serum lipids. NNRTI use was not associated with an increased risk of MI, although the numbers studied were smaller.3
In contrast to the D:A:D study, a large retrospective Veteran's Administration study has found a significant decrease in death but no increase in MI or cerebrovascular accidents across the transition to highly active ART from 1993 to 2001.50 In this study of 36,766 HIV-positive patients, with a mean follow-up of 40 months, no increased risk of CAD/CVD was observed. There were significant differences in the methodology used to ascertain outcomes in the D:A:D and the VA studies. The main outcomes in the VA study were gathered from hospital administrative databases, and deaths were ascertained using the national death index. The D:A:D study prospectively ascertained and verified the primary outcome. The most important message communicated by the VA study was that the mortality benefit of ART was so significant that CAD risk should not preclude treatment. This is consistent with current guidelines. Another large retrospective study of French HIV-positive patients observed in the mid 1990s demonstrated a PI-based therapy duration-dependent 2.56-fold relative hazard of MI. Total cases were few, however.51 A smaller but broad-based study in US clinics had similar results, with PI use being associated with a higher frequency of MI.52 Based on the above data and the recently presented data by the D:A:D group, it appears that both PI use and HIV infection may constitute independent risk factors for future coronary risk.
Studies Evaluating Surrogate Markers of Atherosclerosis
Carotid intima-media thickness (IMT) is a validated surrogate marker for cardiovascular disease.53-55 In a study comparing 148 HIV-infected subjects with 63 age- and sex-matched controls, carotid IMT was higher and progressed faster in the HIV-infected subjects.56 In multivariate analysis, factors associated with a higher baseline carotid IMT include age, duration of smoking, and LDL cholesterol, whereas Latino race and hypertension were marginally significant in this study.
A large multicenter prospective longitudinal study assessing carotid IMT for 12 months failed to show a contribution from ART.57 A smaller study in HIV-positive patients demonstrated even larger increases in IMT.58
The contribution of PI-based therapy on accelerated atherosclerosis has been difficult to define. Some studies suggest a role for PI-based therapies, whereas others do not.59-61 However, most studies were small and lacked the statistical power to define the independent role of PI therapy and atherosclerosis. In most studies done evaluating carotid IMT thus far, classical and well-recognized associations of CAD risk, such as tobacco use, age, and hypertension, appear to be strong predictors of accelerated atherosclerosis in HIV-infected persons. This suggests that aggressive management of conventional cardiac risk factors should be undertaken in this group of patients.56,57,61-63
Endothelial Function in HIV-positive Patients
Endothelial function as measured by flow-mediated vasodilation is another well-recognized marker of atherosclerosis. Studies in HIV-positive patients have demonstrated the presence of endothelial dysfunction in PI-treated patients.64 In a study of non-HIV-infected subjects, indinavir therapy was associated with endothelial dysfunction.65 This phenomenon is not restricted to adults and has been reported in children. Endothelial dysfunction has been described among HIV-infected children both on and off ART.65 Both PIs and HIV infection may play independent roles in the endothelial dysfunction observed in HIV-positive patients.
Several hypotheses have been suggested to explain this increased risk of atherosclerosis in HIV-positive patients. Inflammation is believed to initiate the atherosclerosis process. HIV infection is believed to be associated with a proinflammatory state.67 The HIV tat protein may play an important role in the atherosclerotic process. In vitro studies have examined the role of HIV proteins in atherosclerosis. The HIV tat protein decreases endothelial nitric oxide synthesis and impairs endothelium-mediated vasodilation in porcine models.68 Transduction of the tat gene into monocyte lines leads to increased production of tumor necrosis factors α and β. The tat protein acts synergistically with tumor necrosis factor α to increase adhesion of leukocytes to endothelial cells.69 Thus, it appears that there are several mechanisms by which HIV infection may promote atherogenesis.
In summary, HIV infection, ART, and host factors appear to contribute to dyslipidemia in HIV infection. Current guidelines for the management of dyslipidemia among HIV-positive patients provide useful algorithms for formulating personal practice approaches. Knowledge of ART effects on patient lipid profiles continues to grow. Stepwise assessment of HIV infection followed by cardiovascular risk is prudent at every visit.
The authors acknowledge Dr Sybil Tasker and Dr Nancy Crum Cianflone for their thorough review of this article and for their insightful comments.
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