Introduction
The development and use of antiretroviral medications to treat patients infected with HIV have dramatically changed the course of this disease from one that was fatal to a chronic and more manageable condition. However, with antiretroviral therapy (ART) came a new spectrum of diseases brought about by metabolic changes related to the virus, side effects of ART, and the fact that people with HIV were living to ages at which cardiovascular disease (CVD) was more prevalent.

Recent epidemiologic studies have shown that people infected with HIV have an increased risk of CVD at all ages compared to the general population, and that it remains even after control of traditional risk factors.1 This population also has higher rates of smoking, behavioral, and social factors that increase risk.2,3 It is anticipated that CVD will become the leading cause of morbidity and mortality in this patient population, making diagnosis and management of CVD risk factors — in particular, dyslipidemia — essential to patient care.4,5

There have been no specific and comprehensive guidelines or risk stratification schemes for management of dyslipidemia in patients infected with HIV. The National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 2 will include management recommendations for this patient population.

This review presents background information to understand the interactions of HIV, antiretroviral therapy, and dyslipidemia in patients living with HIV.

Background: Human Immunodeficiency Virus
The virus infects cells in the immune system, specifically CD4+ T cells, which are white blood cells. After entering the CD4+ T cell, the viral RNA genome is converted (a process known as “reverse transcription”) into double-stranded DNA that becomes integrated into the cell nucleus and rapidly replicates. The virus has a high mutation rate, making treatment – and finding a vaccine – challenging.7,8

HIV and Risk for Cardiovascular Disease
Infection with HIV produces a cardiometabolic syndrome consisting of insulin resistance, lipodistrophy (fat maldistribution, including increase in abdominal visceral fat), and abnormal lipids (elevated triglycerides [TG] and low high-density lipoprotein cholesterol [HDL- C]). Therapy with ART can exacerbate these abnormalities.6,9,10 The mechanisms of these metabolic abnormalities are complex and interdependent with the impaired glucose metabolism and dyslipidemia, due in part to abnormal fat distribution (especially abdominal fat) and inflammation.11,12

More research is needed to better define the role of inflammation in HIV and how this influences CVD risk. The National Institutes of Health (NIH) has initiated the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) study, a multi- center, prospective, randomized clinical trial of HIV-infected individuals who are at low risk according to the 2013 American College of Cardiology American Heart Association (ACC/AHA) Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults.13 Participants will be randomized to either statin therapy (pitavastatin) or placebo and followed to investigate how statins may reduce the risk for CVD through non-low-density lipoprotein (LDL)-lowering benefits, including anti-inflammatory properties. The study is sponsored by the National Heart, Lung and Blood Institute (NHLBI) in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID).14

Antiretroviral Therapy
There currently is no cure for HIV. ART provides viral suppression, but not elimination of the virus, and allows the body to maintain higher CD4 counts and better immune function. There is less likelihood of the virus being transmitted while a patient is on ART with viral suppression. The classes of ART prevent viral replication in different ways and are used in combination. Newer drugs with higher potency, lower toxicity, better dosing, and fewer side effects now exist, facilitating early and long-term treatment. Treatment progress is monitored by measuring CD4 count and viral load. CD4 counts of ≥300 cells/µL were found to be associated with good immune function.15 Healthy people who are not infected with HIV generally have CD4 counts in the range of 800 to 1,200 cells/µL. Viral suppression is achieved when plasma RNA levels are below detectable limits.16

The different classes of ART each interfere with a different step in the replication of the virus. These classes include entry inhibitors, fusion inhibitors, nucleoside/nucleotide reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), integrase inhibitors, and protease inhibitors (PI). Combination regimens are standard.

As noted above, infection with HIV confers metabolic changes that may be exacerbated by ART. Protease inhibitors are the agents that produce the most adverse effects, but non-nucleoside/nucleotide reverse transcriptase inhibitors also influence lipids.9,16-18

Lipid Changes with HIV Infection and ART
Acute infection lowers LDL-C19  but levels may return to baseline after virologic suppression with ART.20,21  Chronically, there often is a pattern of low HDL and elevated TG that results from the metabolic changes clustered in these patients22,23  and often worsened by specific antiretrovirals, many of which are now less commonly prescribed.17,24 The magnitude of these changes also is reflective of ethnicity, race, gender, lifestyle factors, and genomic traits.25  As noted above, PI and NNRTI are the ART that most significantly influence lipid levels.

Risk Stratification and Scores
No validated risk score or stratification scheme currently exists for patients infected with HIV, although two groups have proposed scoring systems. The Data Collection on Adverse Effects of Anti-HIV Drugs (D:A:D) Study group has developed a risk calculator that includes both traditional risk factors and exposure to individual antiretroviral drugs.26 The Veterans Aging Cohort Study (VACS) was used to develop the “VACS Index” to predict overall mortality. The index includes age, CD4 count, viral load, hemoglobin, aspartate, and alanine transaminase, platelets, creatinine, and hepatitis C status. The VACS Index has been used in studies predicting coronary heart disease (CHD) risk but has not been validated for this use.27

Use of the Framingham  Risk Score, although not validated in patients with HIV, is endorsed by the HIV Medical Association (HIVMA) of the Infectious Diseases Society of America (IDSA)28 and the European  AIDS Clinical Society (EACS).29 However, it is unclear if Framingham and other risk scores are appropriate for this patient population. At this time, it is reasonable to use the National Cholesterol Education Program’s Adult Treatment Panel III- (NCEP ATP III-) and Framingham-based algorithms with consideration for increasing one risk category for patients infected with HIV.

Lipid Targets for Patients Living With HIV LDL-Cholesterol
Treatment of and targets for dyslipidemia for the general population traditionally have been focused on low-density lipoprotein cholesterol (LDL-C) and based on risk stratification, with lower targets for those with greater risk.

More recent guidelines for management of dyslipidemia in the general population have introduced the concept of “residual risk.”30  LDL-C is highly associated with CVD but does not reflect the total amount of atherosclerotic particles,31-33 meaning all particles that have an apolipoprotein  B (apoB). Measures of residual risk, including non-HDL-C (total cholesterol minus HDL- C), apo B or LDL particle number (LDL-P) better predict risk for CVD than LDL-C with apo B and LDL-P, performing better than non-HDL-C.31,32  Certain populations of patients, such as those with diabetes, are felt to have discordance between LDL-C and these other measures, which may result in under- or over-treatment.31,34 Patients infected with HIV also may have a discordance between measures, with LDL-C lower than LDL-P and apo B, therefore underestimating risk and treatment targets.35,36  Although measures of residual risk are being increasingly incorporated into diagnosis and management plans, LDL-C continues to be used in the general population and for patients infected with HIV.

Existing recommendations for patients infected with HIV include the European AIDS Clinical Society (EACS), where a target of < 155 mg/dL for total cholesterol and < 80 mg/dL for LDL-C is identified.29 Recently issued guidelines by HIVMA of the IDSA for primary care of patients with HIV state that lipid testing and targets should be based on the NCEP’s ATP III guidelines with consideration for more stringent targets.28 Metabolic syndrome is considered in ATP III to be a risk factor. Because this is prevalent in patients infected with HIV, clinicians should assess for metabolic syndrome and, if present, incorporate it in the risk stratification and identification of target for LDL-C.24

Triglycerides
Because of the lack of evidence for treating in this patient population, the EACS does not recommend treatment of moderately elevated TG in patients infected with HIV.29 Guidelines for the general population consider values ≥ 150 mg/dL as high and ≥ 500 mg/dL as very high and a risk for pancreatitis.37 Dyslipidemia in patients with HIV is characterized by elevated TG (greater than 150 mg/ dL) and reduced HDL-C because of HIV infection itself and ART-induced metabolic disturbances, such as impaired glucose tolerance with insulin resistance, visceral adiposity, and peripheral lipoatrophy.38,39

HDL-Cholesterol
ATP III identifies HDL < 40 as being low.30 Viral suppression, treatment of co-morbid conditions (central adiposity, diabetes) and lowering TG with medication and lifestyle changes can help raise HDL-C. Medications to specifically raise HDL-C consist of the niacin preparations, but these medications often are poorly tolerated and may exacerbate the cluster of metabolic abnormalities, including insulin resistance in patients with HIV. Treatment aimed specifically for low HDL-C is not recommended at this time for patients infected with HIV.

Conclusion
It is important to understand that attainment of targets for LDL-C and TG may not be reached, although there is incremental benefit to optimizing lipids and lipoproteins. Care for patients living with HIV is complex, with side effects of medications, problems with adherence to a multi-drug regimen, and co-morbidities that impact on lipids. Review of all medical conditions and medications with the patient’s other providers can help to identify priorities for the patient. Viral suppression generally is considered foremost, although treatment of other conditions also may merit priority. Part II of the NLA Recommendations will provide more information on the diagnosis and management of dyslipidemia for patients living with HIV.

Disclosure statement: Dr. Myerson has received consulting fees from Gilead and Kowa; an educational grant from Gilead, Kowa, and LipoScience; and research funds from LipoScience.

References:

1. Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endo-crinol Metab. 2007;92(7):2506-2512.
2. Myerson M, Poltavskiy E, Armstrong EJ, Kim S, Sharp V, Bang H. Prevalence, Treatment and Control of Dyslipidemia and Hyperten-sion in 4,278 HIV Outpatients. Journal of Acquired Immune Defi-ciency Syndrome. 2014.
3. Petoumenos K, Worm S, Reiss P, et al. Rates of cardiovascular disease following smoking cessation in patients with HIV infection: Results from the D:A:D study(*). HIV Medicine. 2011;12(7):412-421.
4. Smith CJ, Ryom L, Weber R, et al. Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): A multico-hort collaboration. Lancet. 2014;384(9939):241-248.
5. Esser S, Gelbrich G, Brockmeyer N, et al. Prevalence of cardiovascu-lar diseases in HIV-infected outpatients: Results from a prospective, multicenter cohort study. Clinical Research in Cardiology : Official Journal of the German Cardiac Society. 2013;102(3):203-213.
6. Grinspoon SK, Grunfeld C, Kotler DP, et al. State of the science conference: Initiative to decrease cardiovascular risk and increase quality of care for patients living with HIV/AIDS: Executive sum-mary. Circulation. 2008;118(2):198-210.
7. Taylor BS, Hammer SM. The challenge of HIV-1 subtype diversity. The New England Journal of Medicine. 2008;359(18):1965-1966.
8. Ackerman M, Alter G. Mapping the journey to an HIV vaccine. The New England Journal of Medicine. 2013;369(4):389-391.
9. Galescu O, Bhangoo A, Ten S. Insulin resistance, lipodystrophy and cardiometabolic syndrome in HIV/AIDS. Reviews in Endocrine & Metabolic Disorders. 2013;14(2):133-140.
10. Reyskens KM, Essop MF. The maladaptive effects of HIV protease inhibitors (lopinavir/ritonavir) on the rat heart. International Journal of Cardiology. 2013;168(3):3047-3049.
11. Magkos F, Mantzoros CS. Body fat redistribution and metabolic abnormalities in HIV-infected patients on highly active antiretroviral therapy: Novel insights into pathophysiology and emerging op-portunities for treatment. Metabolism: Clinical and Experimental. 2011;60(6):749-753.
12. Brown TT, Tassiopoulos K, Bosch RJ, Shikuma C, McComsey GA. Association between systemic inflammation and incident diabetes in HIV-infected patients after initiation of antiretroviral therapy. Diabetes Care. 2010;33(10):2244-2249.
13. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Athero-sclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology. 2013.
14. https://clinicaltrials.gov/ct2/show/NCT02344290
15. Gale HB, Gitterman SR, Hoffman HJ, et al. Is frequent CD4+ T-lymphocyte count monitoring necessary for persons with counts >=300 cells/muL and HIV-1 suppression? Clinical Infectious Dis-eases : An Official Publication of the Infectious Diseases Society of America. 2013;56(9):1340-1343.
16. Gunthard HF, Aberg JA, Eron JJ, et al. Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel. JAMA. 2014;312(4):410-425.
17. Friis-Moller N, Reiss P, Sabin CA, et al. Class of antiretroviral drugs and the risk of myocardial infarction. New England Journal of Medi-cine. 2007;356(17):1723-1735.
18. Reyskens KM, Fisher TL, Schisler JC, et al. Cardio-metabolic ef-fectsof HIV protease inhibitors (lopinavir/ritonavir). PloS One. 2013;8(9):e73347.
19. Stein JH, Komarow L, Cotter BR, et al. Lipoprotein Changes in HIV-Infected Antiretroviral-Naive Individuals after Starting Antiretroviral Therapy: ACTG Study A5152s Stein: Lipoprotein Changes on An-tiretroviral Therapy. Journal of Clinical Lipidology. 2008;2(6):464-471.
20. Riddler SA, Li X, Chu H, et al. Longitudinal changes in serum lipids among HIV-infected men on highly active antiretroviral therapy. HIV Medicine. 2007;8(5):280-287.
21. Riddler SA, Smit E, Cole SR, et al. Impact of HIV infection and HAART on serum lipids in men. JAMA. 2003;289(22):2978-2982.
22. Jarrett OD, Wanke CA, Ruthazer R, Bica I, Isaac R, Knox TA. Metabolic syndrome predicts all-cause mortality in persons with human immunodeficiency virus. AIDS Patient Care and STDs. 2013;27(5):266-271.
23. Alencastro PR, Fuchs SC, Wolff FH, Ikeda ML, Brandao AB, Barcel-los NT. Independent predictors of metabolic syndrome in HIV-in-fected patients. AIDS Patient Care and STDs. 2011;25(11):627-634.
24. Martin Lde S, Pasquier E, Roudaut N, et al. Metabolic syndrome: a major risk factor for atherosclerosis in HIV-infected patients (SHIVA study). Presse Medicale (Paris, France : 1983). 2008;37(4 Pt 1):579-584.
25. Malvestutto CD, Aberg JA. Management of dyslipidemia in HIV-infected patients. Clinical Lipidology. 2011;6(4):447-462.
26. Friis-Moller N, Thiebaut R, Reiss P, et al. Predicting the risk of cardiovascular disease in HIV-infected patients: The data collection on adverse effects of anti-HIV drugs study. European Journal of Cardiovascular Prevention and Rehabilitation. 2010;17(5):491-501.
27. Justice AC, Freiberg MS, Tracy R, et al. Does an index composed of clinical data reflect effects of inflammation, coagulation and mono-cyte activation on mortality among those aging with HIV? Clinical Infectious Diseases. 2012;54(7):984-994.
28. Aberg JA, Gallant JE, Ghanem KG, Emmanuel P, Zingman BS, Hor-berg MA. Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clinical Infectious Diseases. 2014;58(1):e1-34.
29. Lundgren JD, Battegay M, Behrens G, et al. European AIDS Clinical Society (EACS) guidelines on the prevention and management of metabolic diseases in HIV. HIV Medicine. 2008;9(2):72-81.
30. 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. Circu-lation. 2002;106(25):3143-3421.
31. Otvos JD, Mora S, Shalaurova I, Greenland P, Mackey RH, Goff DC Jr. Clinical implications of discordance between low-density lipopro-tein cholesterol and particle number. Journal of Clinical Lipidology. 2011;5(2):105-113.
32. Cromwell WC, Otvos JD, Keyes MJ, et al. LDL Particle Number and Risk of Future Cardiovascular Disease in the Framingham Offspring Study – Implications for LDL Management. Journal of Clinical Lipi-dology. 2007;1(6):583-592.
33. Manickam P, Rathod A, Panaich S, et al. Comparative prognostic utility of conventional and novel lipid parameters for cardiovascular disease risk prediction: Do novel lipid parameters offer an advan-tage? Journal of Clinical Lipidology. 2011;5(2):82-90.
34. Malave H, Castro M, Burkle J, et al. Evaluation of low-density lipo-protein particle number distribution in patients with type 2 diabe-tes mellitus with low-density lipoprotein cholesterol <50 mg/dl and non-high-density lipoprotein cholesterol <80 mg/dl. The American Journal of Cardiology. 2012;110(5):662-665.
35. Myerson M, Lee R, Varela D, et al. Lipoprotein Measurements in Patients Infected with HIV: Is Cholesterol Content of HDL and LDL Discordant with Particle Number? Journal of Clinical Lipidology. 2014;8(3):332-333.
36. Swanson B, Sha BE, Keithley JK, et al. Lipoprotein Particle Profiles by Nuclear Magnetic Resonance Spectroscopy in Medically-Underserved HIV-Infected Persons. Journal of clinical lipidology. 2009;3(6):379-384.
37. Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardio-vascular disease: a scientific statement from the American Heart Association. Circulation. 2011;123(20):2292-2333.
38. Bucher HC, Richter W, Glass TR, et al. Small dense lipoproteins, apolipoprotein B, and risk of coronary events in HIV-infected patients on antiretroviral therapy: the Swiss HIV Cohort Study. Journal of Acquired Immune Deficiency Syndromes (1999). 2012;60(2):135-142.
39. Anastos K, Lu D, Shi Q, et al. Association of serum lipid levels with HIV serostatus, specific antiretroviral agents, and treatment regi-mens. Journal of Acquired Immune Deficiency sSyndromes (1999). 2007;45(1):34-42.