Lipid Abnormalities

SUPPLEMENT ARTICLE

Lipid Abnormalities

Michael Dube1 and Marcy Fenton2 1Indiana University School of Medicine, Wishard Memorial Hospital, Division of Infectious Diseases, Indianapolis, Indiana; and 2AIDS Project Los Angeles HIV Nutrition Program, Los Angeles, California

Dyslipidemia is an important clinical problem in individuals infected with human immunodeﬁciency virus (HIV) who are receiving antiretroviral therapy. Data suggest that increased cardiovascular disease is occurring in this population. HIV-infected individuals should undergo evaluation and treatment regimens based on the current National Cholesterol Education Program guidelines. In most situations, the ﬁrst interventions should be nonpharmacological and should include diet, exercise, and management of other hygienic risk factors. If pharmacologic therapy becomes necessary, the choices of lipid-lowering agents should be limited to agents with the least likelihood of adverse drug interactions.

PREVALENCE with disease progression. During therapy with PIs, increases in serum triglycerides may be extreme [6], par- Abnormalities of lipid metabolism are common in HIV- ticularly with ritonavir therapy. In contrast to the pre- infected patients and tend to be accentuated in those PI era, increases in cholesterol have occurred with PIs receiving antiretroviral therapy, particularly with pro- [1, 2, 7–9]. A mean increase in serum cholesterol of 32 tease inhibitors (PIs). Forty-seven percent of PI recip- mg/dL (23%) and a 27% increase in LDL-C occurred ients at one clinic had lipid abnormalities, according 3.4 months after initiation of therapy with a PI [8]. In to the National Cholesterol Education Program HIV-negative volunteers, ritonavir therapy increased (NCEP) guidelines for intervention [1]. Behrens et al. total cholesterol by 24% and triglycerides by 137% [2] reported that 56 (57%) of 98 PI recipients expe- within 2 weeks [10]. In addition, signiﬁcant elevations rienced hyperlipidemia. Among those, 19% had ele- of both total cholesterol and HDL-C have also occurred vation of low-density lipoprotein cholesterol (LDL-C) during therapy with the nonnucleoside reverse tran- alone, 44% had hypertriglyceridemia alone, and 37% scriptase inhibitors (NNRTI) efavirenz [11] and nevi- had both abnormalities. Thus, dyslipidemia is a com- rapine [12]. Whether these increases in HDL-C are ben- mon problem among HIV-infected individuals receiv- eﬁcial remains speculative. ing treatment.

POTENTIAL FOR CARDIOVASCULAR ETIOLOGY MORBIDITY AND MORTALITY Abnormalities of lipid metabolism reported before the Anecdotal reports suggest that serious premature vas- use of HIV-1 PIs include increases in serum triglycer- cular events may be related to PI therapy and abnormal ides [3, 4] and decreases in total and high-density li- lipids [2, 13–15]. The incidence of cardiovascular mor- poprotein cholesterol (HDL-C) [4, 5] that occurred bidity was increased among HIV-infected subjects in general but not among PI recipients, in one abstract [16]. However, duration of PI use was positively as- Reprints or correspondence: Dr. Michael Dube, Indiana University School of Medicine, Wishard Memorial Hospital, Division of Infectious Diseases, 1001 W. sociated with cardiac events in another preliminary re- 10th St., Suite OPW-430, Indianapolis, IN 46202-2879 ([email protected]). port [17]. Although there is currently no deﬁnitive ev- Clinical Infectious Diseases 2003;36(Suppl 2):S79–83 2003 by the Infectious Diseases Society of America. All rights reserved. idence that antiviral drug–associated lipid disturbances 1058-4838/2003/3607S2-0005$15.00 will result in increased cardiovascular morbidity and

Lipid Abnormalities • CID 2003:36 (Suppl 2) • S79 mortality, many experts speculate that HIV treatment-related factor for cardiovascular disease, even when values are only dyslipidemia will increase the atherogenic tendency, particularly modestly elevated (200–400 mg/dL) [23]. When triglyceride when combined with other HIV-associated metabolic abnor- levels exceed 200 mg/dL, calculation of non–HDL-C (total cho- malities such as insulin resistance [7, 8, 18], visceral adiposity lesterol minus HDL-C) should be performed and considered [19], impaired ﬁbrinolysis [20], and chronic infection and im- a secondary target for intervention [22]. In addition, the high mune activation. Consequently, rationales exist for intervention frequency of low HDL-C in persons with HIV warrants atten- in many individuals. tion [2].

EVALUATION OF CARDIOVASCULAR DISEASE MANAGEMENT: DIET AND NONDRUG RISKS THERAPIES

Evaluation of serum lipids should be performed after fasting Nondrug interventions should be the first approach for man- for a minimum of 8 h, and preferably 12 h. The standard agement of abnormal lipid levels. Clinicians should consult with screening lipid profile should include measurement of total dietary specialists as a first step, when initial attempts at dietary cholesterol, HDL-C, and triglycerides, with calculation of LDL- intervention fail to achieve the desired effects, or when intensive C, and should be obtained before therapy [21]. This should be dietary modification becomes necessary. Other nondrug ther- repeated 3–6 months after the initiation of HAART, and then apies are expected to be beneficial, as they are in persons with- yearly. All patients should be screened for other cardiovascular out HIV. For example, structured exercise plus diet resulted in risk factors including family history, smoking, hypertension, a 21% decrease in triglyceride levels in HIV-infected patients menopausal status, physical inactivity, obesity, and diabetes, in [1], and resistance training improved triglyceride levels [24]. addition to potential exacerbating factors such as certain med- Smoking cessation and weight reduction for obesity also im- ical illnesses and medications [22]. prove the overall cardiovascular risk profile. Diet. After assessment of existing dietary habits, the Ther- apeutic Lifestyle Changes (TLC) diet should be prescribed (table THRESHOLDS FOR TREATMENT INTERVENTION 2). For many patients, these changes can be achieved without Dyslipidemia in patients with well-controlled HIV should have radical alterations in dietary habits. These diets also reduce similar, and perhaps greater, long-term consequences for car- serum triglycerides. For patients with low HDL-C, reduction diovascular complications compared with the general popu- of dietary fat will further reduce HDL-C. Monounsaturated fats lation. For the purposes of initiating therapy for dyslipidemia, (e.g., canola and olive oil) should be substituted for saturated the Panel recommends that the NCEP guidelines [22] should fats. Moreover, if carbohydrate intake is increased as ingestion generally be followed for HIV-infected patients. Of note, the of fat is reduced, this may increase triglyceride levels. The man- new NCEP guidelines now include a category termed coronary agement of severe hypertriglyceridemia and hyperchylomicro- heart disease (CHD) “risk equivalents,” which include diabetes nemia requires a very–low-fat diet and avoidance of simple mellitus, other atherosclerotic disease, and multiple risk factors sugars (i.e., use of low–glycemic-index carbohydrates) and al- that confer a 10-year risk of CHD of 120%. Because of the cohol. Fish oils (omega-3 fatty acid supplements) variably de- high risk of CHD in these groups, these individuals should be crease triglyceride synthesis and may be tried in patients with treated as aggressively as those with established CHD [22]. The severe hypertriglyceridemia. NCEP guidelines target primarily LDL-C (table 1). However, Weight reduction. In subjects with central (abdominal) elevated triglyceride levels also represent an independent risk obesity, weight reduction through diet modifications and in-

Table 1. Target goals for LDL cholesterol in patients with HIV.

LDL-C level, mg/dL Initiate therapeutic Consider Risk Goal lifestyle changes drug therapy 0–1 risk factors for CHD !160 у160 у190 у2 risk factors for CHD !130 у130 у160 (10-y risk р0%) With CHD, or CHD risk equivalent !100 у100 у130 (100–129, (10-y risk 120%) drug optional)

NOTE. Adapted from [22]. CHD, coronary heart disease; LDL-C, low-density lipoprotein cholesterol. See text for deﬁnition of CHD risk equivalent.

S80 • CID 2003:36 (Suppl 2) • Dube and Fenton Table 2. National Cholesterol Education Program Therapeutic Lifestyle Changes (TLC) diet.

Nutrient Recommendation Total calories Adjust to achieve desired weight Total fat 25%–35% of total calories; keep trans fatty acids low Saturated fat !7% of total calories Polyunsaturated fat Up to 10% of total calories Monounsaturated fat Up to 20% of total calories Cholesterol !200 mg/d Carbohydrates 50%–60% of total calories, predominantly complex carbohydrates Protein ∼15% of total calories

NOTE. Adapted from [22]. creased physical activity is an important element of therapy for due to increased levels of lipid-lowering drugs and reduced abnormal lipid levels. Weight reduction enhances the LDL-C efficacy of antiretroviral drugs are a concern. lowering that can be achieved by diet alone. Both weight re- Drug therapy for elevated LDL-C or non–HDL-C. The duction and intensive aerobic exercise also reduce serum tri- hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase in- glycerides, raise HDL-C, lower blood pressure, and decrease hibitors, or statins, reduce the risk of CHD in patients without the risk for diabetes mellitus [25]. However, the effects of weight previous CHD (primary prevention) and risk of recurrent CHD reduction on peripheral adipose tissues stores have not been events (secondary prevention) [27] in patients without HIV. established in patients with HIV but are expected to be minimal On the basis of limited pharmacokinetic data [28] and the in the presence of central obesity because intra-abdominal fat likelihood of significant interactions, the Panel recommends is more sensitive to lipolysis than peripheral fat [26]. that when statin therapy is necessary, low initial dosages of Patients with CHD or CHD risk equivalents. The goal either pravastatin (20 mg daily) or atorvastatin (10 mg daily) ! for LDL-C is 100 mg/dL in patients with CHD or CHD risk be used, along with careful clinical monitoring. Fluvastatin is equivalents. In contrast to subjects without CHD, prolonged an alternative statin, but there are no data on fluvastatin in- attempts to lower LDL-C with diet may not be desirable before teractions with PIs. Therapy with lovastatin and simvastatin 1 initiation of drug therapy. If LDL-C is 130 mg/dL, diet and should be avoided. lipid-lowering therapy may be instituted simultaneously in The fibrates (gemfibrozil and fenofibrate) are well-tolerated these high-risk individuals. alternative agents when hypercholesterolemia is accompanied Monitoring the response to therapy. In patients without by elevated triglycerides, but fibrates are less effective than sta- CHD, after initiation of the therapeutic diet, lipids should be tins for reducing LDL-C. Niacin lowers LDL-C and triglyceride measured and adherence to the diet assessed after 4 to 6 weeks levels but produces frequent cutaneous flushing and pruritus. and again after 3 months. Because niacin causes insulin resistance [29, 30], niacin should be avoided as first-line therapy in patients receiving PIs or in patients with fat redistribution, because both conditions are MANAGEMENT: LIPID-LOWERING DRUGS associated with reduced insulin sensitivity. Bile-sequestering As for patients without HIV, if lipid levels remain above the resins are not recommended because their effects on antiviral target after intensive dietary and lifestyle interventions have drug absorption are not known. been attempted for at least 12 weeks, drug therapy should be Drug therapy for elevated triglycerides. The absolute value considered. In the absence of other CHD risk factors, especially at which drug therapy should be given for isolated hypertrig- in patients !35 years of age, a longer period of nondrug ther- lyceridemia has not been defined, but in the absence of CHD apies may be appropriate. Shorter periods of time may be con- risk factors or hypercholesterolemia, elevations 1500 mg/dL sidered in patients with severe elevations of LDL-C (1220 mg/ (unresponsive to nondrug therapies) carry an increased risk of dL) or with multiple risk factors. Drug therapy should only be pancreatitis. Drug therapy should therefore be considered for added to dietary therapy, never substituted for it. these individuals. For patients with extreme elevations (i.e., Lipid-lowering therapies for HIV-infected patients with dys- triglycerides 12000 mg/dL), drug therapies may be initiated lipidemia are conceptually problematic because of the potential concurrently with nondrug interventions. for drug interactions (reviewed in [21]). Both increased toxicity Fibrates should be prescribed if drug therapy is necessary for

Lipid Abnormalities • CID 2003:36 (Suppl 2) • S81 hypertriglyceridemia. Treatment is with gemfibrozil [1] (600 dystrophy, hyperlipidaemia and insulin resistance due to HIV protease inhibitors. AIDS 1998; 12:F51–8. mg bid) or fenofibrate (54–160 mg once daily). If treatment 8. Mulligan K, Grunfeld C, Tai VW, et al. Hyperlipidemia and insulin with a fibrate results in inadequate lowering of serum triglyc- resistance are induced by protease inhibitors independent of changes erides, or if LDL-C levels remain elevated, a cautious trial of in body composition in patients with HIV infection. J Acquir Immune niacin or a statin (see above) may be considered, with careful Defic Syndr 2000; 23:35–43. 9. Periard D, Telenti A, Sudre P, et al. Atherogenic dyslipidemia in HIV- monitoring for symptoms of skeletal muscle toxicity. infected individuals treated with protease inhibitors. the Swiss HIV cohort study. Circulation 1999; 100:700–5. 10. Purnell JQ, Zambon A, Knopp RH, et al. Effect of ritonavir on lipids CONSIDERATION FOR SWITCHING and post-heparin lipase activities in normal subjects. AIDS 2000; 14: 51–7. ANTIRETROVIRAL THERAPIES 11. Tashima K, Stryker R, Skiest D, et al. Lipid profiles and clinical lipodystrophy in study 006 patients [abstract 1304]. In: Program and Where virologically appropriate, substitution of a new antiviral abstracts of the 39th Interscience Conference on Antimicrobial Agents agent with a lesser tendency to induce dyslipidemia for an and Chemotherapy (San Diego). Washington, DC: American Society for Microbiology, 1999; 501. existing agent with a greater tendency may be considered. In 12. van der Valk M, Kastelein JJ, Murphy RL, et al. Nevirapine-containing NNRTI-naive patients, substitution of nevirapine for a PI im- antiretroviral therapy in HIV-1 infected patients results in an anti- proves serum lipids in some studies [31] but not in others [32, atherogenic lipid profile. AIDS 2001; 15:2407–14. 13. Henry K, Melroe H, Huebsch J, et al. Severe premature coronary artery 33]. The substitution of efavirenz for a PI has not consistently disease with protease inhibitors. Lancet 1998; 351:1328. had a beneficial effect [34]. Improvement in lipid levels have 14. Gallet B, Pulik M, Genet P, Chedin P, Hiltgen M. Vascularcomplications also been reported with the substitution of abacavir for PIs [35, associated with use of HIV protease inhibitors. Lancet 1998; 351: 36]. Rates of virologic relapse when an NNRTI or abacavir is 1958–9. 15. Vittecoq D, Escaut L, Monsuez JJ. Vascular complications associated substituted for PIs have been acceptable. When triglyceride with use of HIV protease inhibitors. Lancet 1998; 351:1959. levels remain markedly elevated despite aggressive interven- 16. Klein D, Hurley L, Sorel M, Sidney S. Do protease inhibitors increase tions, it may be reasonable to change ritonavir to another PI the risk for coronary heart disease among HIV positive patients? Fol- low-up through June 2000 [abstract 655]. In: Program and abstracts or non–PI-based regimen or to select the lowest effective dose of the 8th Conference on Retroviruses and Opportunistic Infections of ritonavir when it is used to increase the levels of other PIs. (Chicago). Washington, DC: Foundation for Retrovirology and Human To our knowledge, there are no studies that compare the Health; 2001. effects of switching antiretroviral treatment with the effects of 17. Mary-Krause M, Cotte L, Partisani M, Simon A, Costagliola D. Impact of treatment with protease inhibitor (PI) on myocardial infarction (MI) adding lipid-lowering agents to ongoing successful therapy. Cli- occurrence in HIV-infected men [abstract 657]. In: Program and ab- nicians will need to weigh the potential risks of new treatment- stracts of the 8th Conference on Retroviruses and Opportunistic In- related toxicities and the possibility of virologic relapse when fections (Chicago). Washington, DC: Foundation for Retrovirology and switching antiviral drugs against the potential risks of drug Human Health; 2001. 18. Walli R, Herfort O, Michl GM, et al. Treatment with protease inhibitors interactions and toxicities from lipid-lowering agents added to associated with peripheral insulin resistance and impaired oral glucose antiretroviral drug regimens. tolerance in HIV-1–infected patients. AIDS 1998; 12:F167–73. 19. Miller KD, Jones E, Yanovski JA, Shankar R, Feuerstein I, Falloon J. Visceral abdominal-fat accumulation associated with use of indinavir. Lancet 1998; 351:871–5. References 20. Hadigan C, Meigs JB, Corcoran C, et al. Metabolic abnormalities and 1. Henry K, Melroe H, Huebesch J, Hermundson J, Simpson J. Ator- cardiovascular disease risk factors in adults with human immunode- vastatin and gemfibrozil for protease-inhibitor–related lipid abnor- ficiency virus infection and lipodystrophy. Clin Infect Dis 2001; 32: malities. Lancet 1998; 352:1031–2. 130–9. 2. Behrens G, Dejam A, Schmidt H, et al. Impaired glucose tolerance, 21. Dube´ MP, Sprecher D, Henry WK, et al. Preliminary guidelines for beta cell function and lipid metabolism in HIV patients under treat- the evaluation and management of dyslipidemia in HIV-infected adults ment with protease inhibitors. AIDS 1999; 13:F63–70. receiving antiretroviral therapy. Recommendations of the Adult ACTG 3. Grunfeld C, Kotler DP, Shigenaga JK, et al. Circulating interferon- Cardiovascular Disease Focus Group. Clin Infect Dis 2000; 31:1216–24. alpha levels and hypertriglyceridemia in the acquired immunodefi- 22. Expert Panel on Detection Evaluation and Treatment of High Blood ciency syndrome. Am J Med 1991; 90:154–62. Cholesterol in Adults. Executive summary of the third report of the 4. Grunfeld C, Pang M, Doerrler W, Shigenaga JK, Jensen P, Feingold National Cholesterol Education Program (NCEP) Expert Panel on De- KR. Lipids, lipoproteins, triglyceride clearance, and cytokines in human tection, Evaluation, and Treatment of High Blood Cholesterol in Adults immunodeficiency virus infection and the acquired immunodeficiency (Adult Treatment Panel III). JAMA 2001; 285:2486–97. syndrome. J Clin Endocrinol Metab 1992; 74:1045–52. 23. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for 5. Shor Posner G, Basit A, Lu Y, et al. Hypocholesterolemia is associated cardiovascular disease independent of HDL cholesterol level: a meta- with immune dysfunction in early human immunodeficiency virus-1 analysis of population-based prospective studies. J Cardiovasc Risk infection. Am J Med 1993; 94:515–9. 1996; 3:213–9. 6. Danner SA, Carr A, Leonard JM, et al. A short-term study of the safety, 24. Yarasheski KE, Tebas P, Stanerson B, et al. Resistance exercise training pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 pro- reduces hypertriglyceridemia in HIV-infected men treated with anti- tease. N Engl J Med 1995; 333:1528–33. viral therapy. J Appl Physiol 2001; 90:133–8. 7. Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipo- 25. Franz MJ, Horton ES, Bantle JP, et al. Nutrition principles for the

S82 • CID 2003:36 (Suppl 2) • Dube and Fenton management of diabetes and related complications. Diabetes Care Lahoz J. Risks and beneﬁts of replacing protease inhibitors by nevi- 1994; 17:490–518. rapine in HIV-infected subjects under long-term successful triple com- 26. Smith SR, Zachwieja JJ. Visceral adipose tissue: a critical review of bination therapy. AIDS 2000; 14:807–12. intervention strategies. Int J Obes Relat Metab Disord 1999; 23:329–35. 33. Tebas P, Yarasheski K, Powderly WG, et al. A prospective, open-label 27. LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary pilot trial of a maintenance nevirapine-containing regimen in patients disease: a meta-analysis of randomized controlled trials. JAMA 1999; with undetectable viral loads on protease inhibitor regimens for at least 282:2340–6. 6 months [abstract 45]. In: Program and abstracts of the 7th Conference 28. Fichtenbaum CJ, Gerber JG, Rosenkranz SL, et al. Pharmacokinetic on Retroviruses and Opportunistic Infections (San Francisco). Wash- interactions between protease inhibitors and statins in HIV seroneg- ington, DC: Foundation for Retrovirology and Human Health; 2000. ative volunteers: ACTG Study A5047. AIDS 2002; 16:569–77. 34. Martinez E, Garcia-Viejo MA, Blanco JL, et al. Impact of switching 29. Garg A, Grundy SM. Nicotinic acid as therapy for dyslipidemia in non- from human immunodeﬁciency virus type 1 protease inhibitors to insulin-dependent diabetes mellitus. JAMA 1990; 264:723–6. efavirenz in successfully treated adults with lipodystrophy. Clin Infect 30. Kahn SE, Beard JC, Schwartz MW, et al. Increased B-cell secretory Dis 2000; 31:1266–73. capacity as a mechanism for islet cell adaptation to nicotinic acid- 35. Walli RK, Michl GM, Bogner JR, Goebel FD. Improvement of HAART- induced insulin resistance. Diabetes 1989; 38:562–8. associated insulin resistance and dyslipidemia after replacement of pro- 31. Martinez E, Conget I, Lozano L, Casamitjana R, Gatell JM. Reversion tease inhibitors with abacavir. Eur J Med Res 2001; 6:413–21. of metabolic abnormalities after switching from HIV-1 protease in- 36. Carr A, Hudson J, Chuah J, et al. HIV protease inhibitor substitution hibitors to nevirapine. AIDS 1999; 13:805–10. in patients with lipodystrophy: a randomized, controlled, open-label, 32. Barreiro P, Soriano V, Blanco F, Casimiro C, de la Cruz JJ, Gonzalez- multicentre study. AIDS 2001; 15:1811–22.

Note added in proof. Since submission of this paper, the following articles have been published with regard to cardiovascular disease outcomes and HIV: (1) Bozzette SA, Ake CF, Tam HK, Chang SW, Louis TA. Cardiovascular and cerebrovascular events in patients treated for human immunodeficiency virus infection. N Engl J Med 2003;702–10; (2) Holmberg SSD, Moorman AC, Williamson JM, et al. Protease inhibitors and cardiovascular outcomes in patients with HIV-1. Lancet 2002;360:1747–8; and (3) Klein D, Hurley LB, Quesenberry CP Jr, Sidney S. Do protease inhibitors increase the risk for coronary heart disease in patients with HIV-1 infection? JAIDS J Acquired Immune Defic Syndr 2002;30: 471–7. The following reports of controlled clinical trials of lipid-lowering drugs in HIV-infected subjects have also been recently published: (1) Doser N, Ku¨bli S, Telentic A, et al. Efficacy and safety of fluvastatin in hyperlipidemic protease inhibitor–treated HIV-infected patients. AIDS 2002;16:1982–3; and (2) Miller J, Brown D, Amin J, et al. A randomized, double-blind study of gemfibrozil for the treatment of protease inhibitor–associated hypertriglyceridaemia. AIDS 2002;16:2195–200.

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