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HIV and Antiretroviral Therapy: Lipid Abnormalities and Associated Cardiovascular Risk in HIV-Infected Patients

Kotler, Donald P MD

JAIDS Journal of Acquired Immune Deficiency Syndromes: September 1st, 2008 - Volume 49 - Issue - p S79-S85
doi: 10.1097/QAI.0b013e318186519c
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It has been demonstrated that patients on highly active antiretroviral therapy are at increased risk for developing metabolic abnormalities that include elevated levels of serum triglycerides and low-density lipoprotein cholesterol and reduced levels of high-density lipoprotein cholesterol. This dyslipidemia is similar to that seen in the metabolic syndrome, raising the concern that highly active antiretroviral therapy also potentially increases the risk for cardiovascular complications. This paper reviews the contribution of both HIV infection and the different components of highly active antiretroviral therapy to dyslipidemia and the role of these abnormalities toward increasing the risk of cardiovascular disease in HIV-infected patients; therapeutic strategies to manage these risks are also considered.

From the Division of Gastroenterology, Department of Medicine, St. Luke's-Roosevelt Hospital Center, College of Physicians & Surgeons, Columbia University, New York, NY.

Disclosure: Dr. Kotler has received grant/research support from EMD Serono, Inc., Gilead Sciences, Roche Pharmaceuticals, and Theratechnologies Inc. He is a consultant for Bristol-Myers Squibb Company, EMD Serono, Inc., Gilead Sciences, Theratechnologies Inc., and Vertex Pharmaceuticals, Inc. He is on the speakers bureau for Abbott Laboratories, Bristol-Myers Squibb Company, EMD Serono, Inc., and Gilead Sciences.

Correspondence to: Donald P. Kotler, MD, Division of Gastroenterology, Department of Medicine, St. Luke's-Roosevelt Hospital Center, S&R Rm. 1228, 1111 Amsterdam Avenue, College of Physicians & Surgeons, Columbia University, New York, NY 10025 (e-mail: dpkotler@aol.com).

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INTRODUCTION

The natural history of HIV infection changed abruptly in the developing world in 1995, subsequent to the introduction of highly active antiretroviral therapy (HAART), resulting in markedly lower mortality rates. However, treatment-associated toxicities were soon recognized, including a constellation of metabolic and body composition alterations, often referred to as HIV-associated lipodystrophy. Their development initially was ascribed solely to protease inhibitor (PI) therapy but later found to also be related to certain nucleoside reverse transcriptase inhibitors (NRTIs). The similarities of HIV-associated lipodystrophy to the metabolic syndrome suggested that cardiovascular (CV) risk may also be elevated, a concern that has been corroborated in several, but not all, analyses. The recognition of these changes has spurred the development of drugs with fewer metabolic toxicities and attempts to avoid toxicity by limiting drug exposure. The former initiative has been more successful than the latter.

The optimal management of metabolic toxicities is complicated and calls on skill sets not intrinsic to infectious disease physicians and others caring for HIV/AIDS patients. The aim of this paper is to consider the various interrelationships among HIV/AIDS, serum lipid concentrations, and cardiovascular disease (CVD). The discussion will include the association between dyslipidemia and CVD, the effects of HIV infection on serum lipid concentrations, the effects of antiretrovirals (ARVs) on serum lipid concentrations, the association between HIV infection and CVD, and the management of CVD risk associated with dyslipidemia. Whenever possible, the discussion will include the results of recent studies and will concentrate solely on metabolic and CV aspects of treatment.

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Serum Lipids and CVD

An association between dyslipidemia and myocardial infarction (MI) has long been recognized, as has the great overlap in serum cholesterol concentrations seen between those who do and do not develop symptomatic CVD. The latter observation implies the presence of other risk factors. Two general patterns of dyslipidemia are related to CVD. The first is an increase in the concentration of low-density lipoprotein cholesterol (LDL-C), usually with a genetic predisposition. A different defect leads to elevated serum triglyceride and low high-density lipoprotein cholesterol (HDL-C) concentrations and often is seen in obese patients with other components of the metabolic syndrome such as central obesity, diabetes mellitus, and hypertension. Other biologic and behavioral factors, including inflammation, may promote CVD. Some authors have considered untreated HIV infection to be an example of the type of inflammation that might promote atherosclerosis.

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Effect of HIV Infection on Serum Lipid Concentrations

Clinical observations have documented dyslipidemia in patients with AIDS and symptomatic HIV infection. The earliest alterations recognized, in terms of disease stage, were decreases in HDL-C and LDL-C concentrations.1 Hypertriglyceridemia was seen in HIV-infected patients and those with symptomatic disease.2 In addition, an early study of zidovudine therapy in patients with AIDS/AIDS-related complex documented a treatment-associated decrease in triglyceride concentrations.3 Studies in experimental models of inflammation demonstrated associations between lipid changes and proinflammatory cytokine activities. In one study, serum triglyceride concentrations were more closely associated with serum concentrations of bioactive α-interferon than other cytokines.2 An analysis of data from the Multicenter AIDS Cohort Study (MACS) corroborated and extended these findings. This was a study of MACS subjects who became HIV infected and developed progressive immune depletion, eventually requiring HAART, all during follow-up.4 A decrease in total cholesterol (TC), HDL-C, and LDL-C concentrations was noted (triglyceride data were not reported because nonfasting bloods were analyzed). Importantly, initiation of HAART led to an increase in total and LDL-C, but only to baseline (preinfection) values for LDL-C. There was very little change in serum HDL-C concentrations.

These data are important because they illustrate how data collection affects data analysis. The observed rise in TC within the first 18 months of HAART therapy was 50 mg/dL, and the rise in LDL-C was approximately 21 mg/dL. However, the immediate pre-HAART TC was 30 mg/dL, and LDL-C was 22 mg/dL lower than the preseroconversion value. If the first time point analyzed is just before initiating HAART, as is the case in all clinical trials, then the impression would be that treatment increased serum LDL-C concentrations as a metabolic toxicity. However, when preinfection values are known, the actual interpretation is that a rise in LDL-C in the average patient represents a return to prior metabolic health, which may or may not have been normal. Thus, the results of clinical treatment studies performed in ARV-naive subjects must be interpreted in a way that accounts for this level of treatment-associated elevations in lipids. It is even likely that treatment-associated changes are related to baseline clinical status because progressive hypocholesterolemia is a common finding in malnourished patients with a variety of diseases. On the other hand, studies of treatment switches may or may not show similar changes, depending on whether or not there is viral suppression at the time of the switch.

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Effect of ARV Regimens on Lipid Levels

Clinical observations, the results of clinical trials, and the results of studies in healthy adult volunteers have documented metabolic effects on lipid metabolism by PIs, NRTIs, and nonnucleoside reverse transcriptase inhibitors (NNRTIs). There are also intraclass differences in the propensity for individual drugs to cause development of dyslipidemia. The PI effect is related to an increase in hepatic very low-density lipoprotein secretion. One study found that ritonavir inhibited an intracellular protease responsible for intracellular regulation, including the degradation of apolipoprotein B (apoB), resulting in an increase in apoB available for very low-density lipoprotein assembly and secretion.5 The NNRTI effect may be related to an increase in the hepatic synthesis of apoA1 and the capacity for lipoprotein secretion.6 In contrast, the effect of NRTIs seems to be indirect, has been ascribed to mitochondrial toxicity, and is often observed in patients with other clinical evidence of mitochondrial toxicity. There is substantial individual variation in the response to specific antiviral agents, which is related to both genetic susceptibility7-10 and environmental factors (eg, concomitant medications). In individual patients, extreme alterations in serum lipids are likely related to genetic interactions. In addition, the development of dyslipidemia may be related to weight gain during HAART therapy,11 so that avoidance of weight gain may be protective.

Recent studies have provided a wealth of data from which to approach initial ARV treatment, including consideration of potential treatment-associated dyslipidemia. It is important to recognize that, although specific compounds are compared, the actual comparison occurs between treatment regimens whose backbones may differ among studies. In studies of treatment-naive individuals, most recent studies have reproduced the MACS data, with treatment-associated rises of 10-61 mg/dL for TC and 4-28 mg/dL for LDL-C (Table 1). In addition, treatment is associated with rises in HDL-C concentrations of 7-15 mg/dL, which is greater than in the MACS experience. Elevation of triglyceride levels seems to be related, in part, to the boosting dose of ritonavir, ranging from 10 to 70 mg/dL for 100 mg daily and from 14 to 78 mg/dL for 100 mg bid, and 130 for one study using ritonavir 200 mg daily (Table 1). Treatment-associated changes in lipids typically are lower in salvage studies. In general, for initial ARV treatment, the results are relatively similar for the different PIs, with mean and median values usually within clinically acceptable ranges. These results do not reflect outliers, however, who are the patients in whom serious dyslipidemia may occur, requiring treatment.

TABLE 1

TABLE 1

For the first generation of NNRTIs, treatment-associated elevations in TC are higher, in general, than for PIs, though the elevations in LDL-C are similar (Table 2). Treatment-associated elevations in HDL-C concentrations are the most prominent changes and, when calculated, the ratio of TC to HDL-C decreases modestly, suggesting an overall benefit in terms of CV risk. The second-generation NNRTIs rilpivirine and etravirine seem to have lesser effects on lipids than do the older NNRTIs (Table 2). For NRTIs, studies show that both stavudine and zidovudine increase lipids compared with tenofovir, with effects on both triglycerides and cholesterol. On the other hand, zidovudine and abacavir had similar effects on serum lipids whereas abacavir raised lipids more than did tenofovir (Table 3). The fusion inhibitor enfuvirtide, the integrase inhibitor raltegravir, or the CCR5 antagonist maraviroc seem to affect serum lipid concentrations (Table 4).

TABLE 2

TABLE 2

TABLE 3

TABLE 3

TABLE 4

TABLE 4

In summary, these studies seem to show that the average patient initiating ARV therapy in the modern era is likely to experience only a moderate rise in serum lipids. Several studies have suggested that genetic effects or other factors, such as central obesity or diabetes, may influence serum lipids; as a result, the approach to patients must be individualized and based on the response to initial treatment.

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Evidence for an Association Between HIV/AIDS and Symptomatic CVD and Cardiac Risk

Several case reports of HIV-infected patients with MI were published around the time the lipodystrophy syndrome was first identified.33 Within 2 years, the results of the first analyses of CV risk were presented.34,35 The results of cohort studies are conflicting; 5 cohort studies in the United States and Europe, including over 60,000 subjects, showed a relative increase in CV events in patients on ARVs or PIs, with or without a concomitant increase in stroke.34-38 Interestingly, more recent follow-up has suggested that the relative increase peaked in 2001-2002.39-41 The change in natural history might be related either to changes in ARV therapy or overall patient management, especially related to CV risk. In contrast, a single study of over 36,000 patients from the VA Health Care System seemed to show the opposite result, with a decrease in all-cause mortality, including heart attack and stroke, as a result of HAART. Of note, the follow-up on therapy was relatively short.42

The Data Collection on Adverse Events of Anti-HIV Drugs Study is a prospective, multinational, observational study including 11 cohorts from 21 countries that has analyzed over 150,000 person-years of follow-up on ARV therapy. Its initial purpose was to determine the prevalence of risk factors for MI among HIV-infected persons and to investigate any association between risk factors, stage of HIV disease, and use of antiretroviral therapy (ART). The study noted a high prevalence of risk factors-particularly smoking-for CVD at baseline. Continued follow-up for more than 7 years has shown a progressive increase in the risk of MI, though the absolute risk is not very high as yet.43,44 CV risk was related to drug class, with PI-based therapy conferring an increased risk compared with NNRTI therapy. The difference was related, in part, to differences in serum lipid concentrations.

Other factors also affect the risk of developing an MI, including traditional risk factors and other behavioral factors that are not evaluated in classic risk calculations (eg, cocaine use). HIV disease stage, as measured by CD4-lymphocyte numbers, was associated with overall risk of death in the Data Collection on Adverse Events of Anti-HIV Drugs Study.43,45

The role of HIV infection itself in the development and progression of CVD has been elucidated in recent clinical studies. Following initial reports of endothelial dysfunction in HIV infection and the potential adverse effects of PIs,46 several groups have contributed to this rapidly growing body of literature. In cross-sectional studies, it has been difficult to find significant associations with HIV-related variables because the strongest effects were related to traditional risk factors. An important contribution was made in the A5152s substudy of AIDS Clinical Trials Group Study 5142. In this class-sparing study, the effects of initial treatment choice on both efficacy and safety were evaluated. Brachial artery flow-mediated dilation, an objective measure of endothelial function, was evaluated in a subset of subjects. The major findings were that endothelial function was impaired in the ARV-naive subjects, endothelial function improved with therapy, similar improvements were seen despite widely disparate treatments, and the major predictor of improvement was the fall in HIV RNA content.47 Several presentations at the 2008 Conference on Retroviruses and Opportunistic Infections evaluated the CV effects of HIV infection48,49 and intermittent ARV treatment (STACCATO Study50 and SMART Study51). The results indicate that treatment initiation is associated with decreased inflammation and lower levels of vascular adhesion molecules and procoagulant molecules.

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Management of HIV-Infected Patients to Decrease CV Risk

The goals for CV risk prevention should be the same for HIV-infected and -uninfected individuals. The Data Collection on Adverse Events of Anti-HIV Drugs Study found general agreement between observed and predicted rates of MI, analyzed by length of ART exposure.52 In terms of lipids, a reasonable approach is to measure lipids before starting ART and every 6-12 months thereafter, assess CV risk in each patient, intervene with lifestyle modifications in patients at risk, and, if lifestyle modifications do not achieve lipid goals, modify the ARV regimen or use lipid-lowering therapy.

There have been relatively few studies comparing the effects of switching ARVs versus treating dyslipidemia. In a study reported by Calza et al,53 treatment with a fibrate or statin lowered TC and triglyceride concentrations more than did switching from a PI- to an NNRTI-based regimen. Such a result could have been predicted from the studies of PI-based HAART (Table 1). However, switching a PI to abacavir (NEFA Study),54 unboosted atazanavir (SWAN Study),55 or even boosted atazanavir (from lopinavir/ritonavir, ATAZIP Study)56 did result in a fall in lipid concentrations. In addition, switching from stavudine to tenofovir resulted in a reduction in serum lipid concentrations (Study 903E).57

There are few data concerning the dietary management of dyslipidemia. A study by Moyle et al58 suggested that, after 24 weeks, dietary management can be expected to lower serum TC by approximately 4% from baseline values compared with 17% when pravastatin is added to the treatment regimen. At the 2007 International AIDS Society meeting, Lazzaretti et al presented the results of a randomized study using the National Cholesterol Education Program dietary intervention guidelines to evaluate the effects of diet plus education by a dietician, in adults initiating ART. The results indicated that the National Cholesterol Education Program intervention prevented a treatment-associated rise in serum lipids and led to reduced fat and caloric intake, reduced body mass index, and increased dietary fiber intake.11

A second indication for aggressive dietary treatment of dyslipidemia is for patients with severely elevated serum triglycerides (eg, >1000 mg/dL). In this circumstance, the short-term risk is acute pancreatitis rather than CVD. In virtually all cases, patients with triglycerides >1000 mg/dL have circulating chylomicrons. It is important to remember that the lipids within chylomicrons are of dietary origin because they are produced by intestinal epithelial cells. However, the appropriate diet is one with extremely low fat, on the order of 20-30 g/d, which is at the lower limits of palatability. The pharmacologic drug of choice for severe hypertriglyceridemia is fenofibrate. For hypercholesterolemia with more modest elevations in triglycerides, most experts would recommend targeting LDL-C (or non-HDL-C) in an attempt to reduce CV risk.59 The results of clinical studies suggest that niacin, omega-3 fatty acids, and ezetimibe all may provide adjunctive benefit.60-62

Much has been written about drug-drug interactions between antihypercholesterolemic agents and ARVs, especially PIs.10 The propensity for adverse reactions by statins metabolized by CYP3A4 (eg, simvastatin and lovastatin) is well known, with lesser effects seen for atorvastatin and rosuvastatin and none for pravastatin. However, recent studies have suggested that darunavir interacts with pravastatin, leading to increased patient exposure to the statin, with lesser effects seen for atorvastatin and rosuvastatin.63 Other observations have shown that the NNRTI efavirenz may accelerate the metabolism of statins, thereby reducing their effect.

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CONCLUSIONS

This discussion concentrates specifically on the role of lipids in CVD risk in HIV infection. However, the approach to managing CV risk in patients should be more comprehensive and focus on the most important modifiable risk factors, such as cigarette smoking. Although developments in ARV drug therapy have led to many agents that cause little dyslipidemia in the average patient, the clinician should continue to maintain vigilance for HIV-infected patients with exaggerated lipid response and other metabolic risk factors and for the clinical expression of CVD, irrespective of serum lipid concentrations.

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                                  Keywords:

                                  antiretroviral therapy; cardiovascular disease; dyslipidemia; lipodystrophy; myocardial infarction; HAART

                                  © 2008 Lippincott Williams & Wilkins, Inc.