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Hyperlipidemia and HIV
Alison D. Schecter, MD*
Human immunodeficiency virus–acquired immunodeficiency syndrome (HIV-AIDS) is a devastating disease responsible for more than 100,000 deaths in the United States alone between 1987 and 1999.1 Patients with HIV-AIDS are commonly treated with a combination of 3 or 4 drugs from the 3 available classes that can inhibit the replication of HIV: nucleoside analogue reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). This is referred to as highly active antiretroviral therapy (HAART). The use of HAART, coupled with effective prophylaxis for opportunistic infections, has led to a dramatic increase in survival of patients with HIV infection. Unfortunately, HAART regimens have serious adverse effects, such as metabolic derangements that unfavorably alter cardiovascular risk profiles. Given that chronic disease processes including atherosclerosis may be more prevalent among people with HIV infection, increased cardiovascular risk in this population is a growing clinical concern. This editorial reviews the cardiac risk factors that specifically affect HIV-infected patients, the impact of the various antiretroviral therapies on lipids, and possible pathogenetic mechanisms for accelerated vascular disease in this population.
HIV-AIDS and Cardiac Risk
One question that remains unanswered is the relative role of HIV infection itself in the pathogenesis of atherosclerosis compared with the individual’s intrinsic cardiac risk profile and the potential metabolic and lipid derangements that are associated with treatment. There is evidence that HIV may target the vasculature. In the preprotease era, 2 studies, examining coronary arteries from patients with AIDS (23 to 32 years old) at autopsy, found evidence of accelerated atherosclerosis and arteriopathy.2,3 In pathologic studies involving small and medium-size arteries from pediatric patients with AIDS, intimal fibrosis, fragmentation of the elastic tissue, and fibrosis and calcification of the media with variable luminal narrowing are described, suggesting a distinct HIV-associated arteriopathy.4,5 There is also evidence that HIV infection itself, in the absence of therapy, can affect lipids. A recent observational study, examining the baseline cardiac risk factors in more than 17,000 HIV-infected patients, showed that total cholesterol levels vary inversely with HIV viral load, independent of antiretroviral therapy.6 Hypertriglyceridemia is a common finding in patients with AIDS, and triglyceride levels increase as viral load increases.7
Regardless of etiology, the preponderance of data indicates that people infected with HIV have multiple and interrelated cardiac risk factors stemming from the infection itself, its treatment, and their intrinsic risk factor profiles. In terms of HIV treatment strategies, the use of HAART itself is associated with dyslipidemia, insulin resistance, fat redistribution, and hypertension.8 Optimal treatment and cardiac risk evaluation of these patients are further complicated by the fact that the risk for adverse effects varies from drug to drug, from drug class to drug class, and from patient to patient.9 Features of the dyslipidemia associated with HAART include severe hypertriglyceridemia, low levels of high-density lipoprotein cholesterol (HDL-C), and elevated low-density lipoprotein cholesterol (LDL-C) levels. The dyslipidemia is more profound among those receiving PIs and in those with fat redistribution. An increase in insulin resistance without the manifestation of frank diabetes is also common. The Data Collection on Adverse Events of Anti-HIV Drugs study (DADS) found that the use of NNRTIs and PIs, alone and especially in combination, was associated with dyslipidemia.10 In this study, almost a third of the patients receiving combination therapy including a PI had total cholesterol levels above 240 mg/dL, and almost 40% of this group had triglyceride levels above 200mg/dL.10 In a longitudinal assessment of male HIV-infected seroconverters, there was a decrease in total cholesterol, HDL-C, and LDL-C at the time of infection, before treatment. With the initiation of HAART, total cholesterol and LDL-C increased to preinfection levels, but low HDL-C levels persisted.11
In terms of actual risk of events, a large prospective observational study10 demonstrated that combination antiretroviral therapy (4 to 6 years) was independently associated with a 26% relative increase in the rate of myocardial infarction (MI) per year of exposure; however, the absolute risk for MI was low. Other studies failed to demonstrate a dramatic increase in MI risk during the first year of PI therapy.12 Therefore, cardiac risk must be balanced with the marked benefits of antiretroviral treatment.
Managing Cardiac Risk in Patients With HIV-AIDS
The practitioner should perform a thorough risk assessment, determining
1. Whether the patient has a family history of cardiovascular or cerebrovascular events
2. Whether the patient has a history of diabetes or thyroid disease
3. The patient’s level of physical activity
4. The patient’s use of alcohol or of other medications that might adversely affect lipid levels (hormone replacement therapy, birth control pills, second-generation antipsychotics, etc)
Treatment plans should include annual fasting lipid level measurements, risk assessment, and intervention based on National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines13 and their recently proposed modifications.14 The latter, based on clinical trial results released after the 2002 publication of the NCEP ATP III, refined the panel’s risk stratification and treatment algorithm, with more aggressive LDL-C treatment goals for patients in each risk category and even lower “optional” goals for some. In light of the evidence that HIV infection is an additional cardiac risk factor, clinicians might, at their discretion, consider these optional LDL-C goals for their patients with HIV-AIDS.
Lipid levels should be rechecked 4 to 6 weeks after antiretroviral therapy is initiated and after any change in the antiretroviral regimen. Appropriate lifestyle modifications should be instituted. World Health Organization definitions (fasting glucose ≥ 126 mg/dL defines diabetes; fasting glucose ≥ 110 mg/dL and < 126 mg/dL defines impaired fasting glycemia) should be used to characterize glucose abnormalities in HIV-positive patients.15 HIV-infected patients with known cardiovascular disease should be treated aggressively. In general, a hydroxymethylglutaryl–coenzyme A reductase inhibitor (statin) should be used to treat isolated hypercholesterolemia, and a fibrate should be used to treat isolated hypertriglyceridemia.16 Drug interactions, especially those between specific protease inhibitors and statins, should always be considered (Table).17,18 It is important to measure baseline liver enzyme and creatinine kinase levels before and after titration of any lipid-lowering therapy because of potential cytochrome P-450–mediated toxicity.
HIV-infected people are living longer, have a high prevalence of tobacco use,19 and are at risk for metabolic complications such as dyslipidemia, insulin resistance, and altered fat distribution (reviewed in Grinspoon and Carr18) secondary to HAART. Until adequate clinical evidence becomes available, practitioners face a complex task in identifying, evaluating, and calculating the cardiovascular risk of HIV-infected patients. While the number of actual cardiac events in this population may be relatively low, this is likely to change with longer exposure to HAART therapy and an aging HIV-infected population. An emphasis on individualized and intensive cardiac risk factor evaluation and preventive interventions for all HIV-infected adults and adolescents is warranted.
References
1. Selik RM, Byers RH, Jr, Dworkin MS. Trends in diseases reported on U.S. death certificates that mentioned HIV infection, 1987-1999. J Acquir Immune Defic Syndr. 2002;29:378-387.
2. Tabib A, Leroux C, Mornex JF, Loire R. Accelerated coronary atherosclerosis and arteriosclerosis in young human-immunodeficiency-virus-positive patients. Coron Artery Dis. 2000;11:41-46.
3. Paton P, Tabib A, Loire R, Tete R. Coronary artery lesions and human immunodeficiency virus infection. Res Virol. 1993;144:225-231.
4. Joshi VV, Pawel B, Connor E, et al. Arteriopathy in children with acquired immune deficiency syndrome. Pediatr Pathol. 1987;7:261-275.
5. Joshi VV. Pathology of acquired immunodeficiency syndrome (AIDS) in children. Keio J Med. 1996;45:306-312.
6. Friis-Møller N, Weber R, Reiss P, et al. Cardiovascular disease risk factors in HIV patients—association with antiretroviral therapy. Results from the DAD study. AIDS. 2003;17:1179-1193.
7. Grunfeld C, Kotler DP, Hamadeh R, Tierney A, Wang J, Pierson RN. Hypertriglyceridemia in the acquired immunodeficiency syndrome. Am J Med. 1989;86:27-31.
8. Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet. 2000;356:1423-1430.
9. Montessori V, Press N, Harris M, Akagi L, Montaner JS. Adverse effects of antiretroviral therapy for HIV infection. Cmaj. 2004;170:229-238.
10. Friis-Møller N, Sabin CA, Weber R, et al. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med. 2003;349:1993-2003.
11. Riddler SA, Smit E, Cole SR, et al. Impact of HIV infection and HAART on serum lipids in men. Jama. 2003;289:2978-2982.
12. Coplan PM, Nikas A, Japour A, et al. Incidence of myocardial infarction in randomized clinical trials of protease inhibitor-based antiretroviral therapy: an analysis of four different protease inhibitors. AIDS Res Hum Retroviruses. 2003;19:449-455.
13. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143-3421.
14. Grundy SM, Cleeman JI, Merz NB, et al; for the Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239.
15. Kamin DS, Grinspoon SK. Cardiovascular disease in HIV-positive patients. Aids. 2005;19:641-652.
16. Calza L, Manfredi R, Chiodo F. Statins and fibrates for the treatment of hyperlipidaemia in HIV-infected patients receiving HAART. Aids. 2003;17:851-859.
17. Fichtenbaum CJ, Gerber JG, Rosenkranz SL; NIAID AIDS Clinical Trials Group. Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG study A5047. AIDS. 2002;16:569-577.
18. Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med. 2005;352:48-62.
19. Vittecoq D, Escaut L, Merad M, Teicher E, Monsuez JJ, Chironi G. Coronary heart disease in HIV-infected individuals. Adv Cardiol. 2003;40:151-162.
Table
*Alison D. Schechter, MD
Assistant Professor
Zena and Michael A. Wiener Cardiovascular Institute
Center for Immunobiology
Mount Sinai School of Medicine
New York, New York
Biographical Sketch
Alison D. Schechter, MD, is an assistant professor in the Zena and Michael A. Wiener Cardiovascular Institute, the Department of Medicine, and the Center for Immunobiology at Mount Sinai School of Medicine in New York, New York. Dr. Schecter received an MD degree from SUNY Health Science Center at Brooklyn in 1990. She completed an internal medicine internship and residency at Johns Hopkins Hospital in Baltimore and cardiology fellowships at Massachusetts General Hospital in Boston and Mount Sinai School of Medicine.
Dr. Schecter is the cofounder of the Women’s CARE (Cardiac Evaluation and Risk Assessment) Program, which was created at Mount Sinai through her interest in women’s cardiovascular disease prevention. Dr. Schecter has appeared on numerous network and cable television stations such as CBS, ABC, and the Oxygen Network in an effort to educate laypeople about potentially lifesaving lifestyle modifications.
Dr. Schecter’s research interest focuses on the relationship between inflammation and thrombosis. Her laboratory recently identified the chemokine receptor CCR5, a coreceptor for HIV, in arterial smooth muscle cells and atherosclerotic plaque. In collaboration with Drs. Mary E. Klotman and Adriane B. Berman, she is investigating the role of CCR5 in both HIV-related vasculopathies and Kaposi’s sarcoma.
Faculty Disclosure
Dr. Schecter has disclosed that she has served as a speaker/faculty for Merck & Co, Inc.
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