Hyperlipidaemia in Patients with HIV-1 Infection Receiving Highly Active Antiretroviral Therapy: Epidemiology, Pathogenesis, Clinical Course and Management

International Journal of Antimicrobial Agents 22 (2003) 89/99 www.ischemo.org Review Hyperlipidaemia in patients with HIV-1 infection receiving highly active antiretroviral therapy: epidemiology, pathogenesis, clinical course and management

Leonardo Calza *, Roberto Manfredi, Francesco Chiodo

Department of Clinical and Experimental Medicine, Section of Infectious Diseases, University of Bologna Alma Mater Studiorum, S. Orsola Hospital, Via G. Massarenti 11, Bologna 40138, Italy

Abstract

A wide range of abnormalities of lipid metabolism have been recently described in HIV-infected patients receiving a protease inhibitor (PI)-based highly active antiretroviral therapy, including hypertriglyceridaemia and hypercholesterolaemia. The increase of plasma lipid concentrations may involveupto70/80% of HIV-positive subjects treated with a PI-containing regimen and are frequently (but not always) associated with the fat redistribution or the lipodystrophy syndrome. Multiple pathogenetic mechanisms by which antiretroviral agents lead to dyslipidaemia have been hypothesized, but they are still controversial. The potential clinicopathological consequences of HIV-associated hyperlipidaemia are not completely known, but several anecdotal observations report an increased risk of premature coronary artery diseases in young HIV-positive individuals receiving PIs, besides peripheral atherosclerosis and acute pancreatitis. A limited-to-significant improvement of increased triglyceride and cholesterol plasma levels was described in patients who replaced PIs with nevirapine, efavirenz or abacavir, but the risks of long-term toxicity and virological relapse of this treatment switching are not completely defined. A hypolipidaemic diet and regular physical exercise may act favorably on dyslipidaemia, but pharmacological therapy becomes necessary when hyperlipidaemia is severe or persists for a long time. The choice of hypolipidaemic drugs is problematic because of potential pharmacological interactions with antiretroviral compounds and other antimicrobial agents, associated with an increased risk of toxicity and intolerance. Statins are considered the first-line therapy for the PI-related hypercholesterolaemia, while fibrates are the cornerstone of drug therapy when predominant hypertriglyceridaemia is of concern. # 2003 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved.

Keywords: HIV infection; Highly active antiretroviral therapy; Protease inhibitors; Hypertriglyceridaemia; Hypercholesterolaemia

1. Introduction The fat redistribution syndrome or lipodystrophy (characterized by either localized fat loss in the face or Despite the profound impact of protease inhibitor limbs, or fat accumulation in the abdomen, breasts or (PI)-based antiretroviral treatment (highly active anti- dorso-cervical region), hyperlipidaemia, insulin resis- retroviral therapy or HAART) on the natural history of tance and hyperglycaemia have been extensively re- human immunodeficiency virus type 1 (HIV-1) infec- ported in subjects treated with PIs and nucleoside tion, leading to a remarkable decrease of its morbidity reverse transcriptase inhibitors (NRTIs). However, it and mortality, this pharmacological association has remains uncertain if the occurrence of hyperlipidaemia, frequently been associated with a wide range of clinical abnormal body fat distribution and glucose metabolism and metabolic complications. alteration are interrelated and associated with PI clinical

use only [1/4]. Classification of morphological and metabolic ab- * Corresponding author. Tel.: /39-51-6363355; fax: /39-51- 343500. normalities following PI administration is summarized E-mail address: [email protected] (L. Calza).

0924-8579/03/$30 # 2003 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. doi:10.1016/S0924-8579(03)00115-8 90 L. Calza et al. / International Journal of Antimicrobial Agents 22 (2003) 89/99

Table 1 elevation may exacerbate reductions in total, HDL and Classiﬁcation of morphological and metabolic alterations under LDL cholesterol serum concentrations. On the other antiretroviral therapy proposed by the Antiretroviral-associated Lipo- hand, significant interleukin-1 (IL-1) plasma levels are dystrophy European Comparative Study (ALECS) Group usually undetectable in the circulation of subjects with Type Main morphological Subclassification AIDS and they do not seem to be associated with features decreased cholesterolaemia or increased triglyceridae-

I Fat loss (lipoatrophy) (a) Without Bichat fat pad reduction mia [6,9/11]. (b) With Bichat fat pad reduction Hypocholesterolaemia and hypertriglyceridaemia II Fat accumulation (c) Involvement of 1 site were also considered a marker of HIV disease progres- (lipohypertrophy) (excluding lipoma) sion, with both frequency and severity of dyslipidaemia (d) Involvement of /1 site (e) Lipomatosis inversely related to decreased CD4/ lymphocyte count. III Combined form (a/b)/(c/d/e) Particularly, patients with a CD4/ cell count below 200 IV Isolated metabolic lymphocytes/mm3 show significantly lower total choles- alterations terol levels than the HIV-negative subjects and those below 400 lymphocytes/mm3 have significantly higher triglyceride concentrations, when compared with in Table 1, while the severity of metabolic alterations is matched HIV-negative controls. A multivariate analysis reported in Table 2. performed in HIV-positive individuals naı¨ve to all Although lipid metabolism imbalances have been antiretroviral agents showed that the hypertriglyceri- increasingly recognized since the introduction of daemia was correlated to acute opportunistic infections HAART in clinical practice, disturbances in lipid and to IFN-a levels, while reduced serum LDL choles- metabolism during the course of HIV infection and terol concentration was associated with hypoalbuminae- acquired immunodeficiency syndrome (AIDS) had been mia [11]. observed long before the advent of new PI-based Moreover, nutritional alterations are commonly ob- antiretroviral regimens [2,5]. Briefly, this therapy-un- served in patients with advanced HIV infection long related dyslipidaemia was characterized by initial de- before the usual PI administration, including in most creased plasma levels of total, HDL and LDL cases weight loss with protein and body cell mass cholesterol, followed by elevations in triglyceride levels depletion. The development of malnutrition was gen- during advanced stages of HIV disease. These plasma erally multifactorial and occurred through changes in lipid level alterations are comparable with those ob- calorie intake, nutrient absorption or energy expendi- served in chronic infections sustained by bacteria, ture. Clinically, malnutrition usually led to cachexia and parasites and other viruses, and are associated with an was often favored by concurrent hormonal alterations increased blood concentration of the cytokine inter- [9,12]. feron-a (IFN-a). Therefore, circulating levels of IFN-a The clinical course of HIV infection and AIDS may are elevated in the advanced phase of HIV disease and be complicated by a variety of endocrine abnormalities probably correlate with an increased production and a such as hypocortisolaemia, hypotestosteronaemia and reduced clearance of triglyceride, even though it is thyroid dysfunction (hypothyroidism or thyroiditis with unclear whether IFN-a directly affects the lipid meta- thyrotoxicosis). Endocrine function could be altered bolism or whether it is an indirect marker of these because of the complex relationship between immune metabolic disturbances [1,2,6/8]. and endocrine systems or through the direct involve- At the same time, tumour necrosis factor (TNF) is ment of these glands by HIV itself, opportunistic likely to be involved in HIV-related dyslipidaemia. infections (Pneumocystis carinii, Toxoplasma gondii, Although TNF levels are not elevated during HIV mycobacteria, cytomegalovirus) or malignancies (Kapo- infection, they increase during concomitant opportunis- si’s sarcoma, lymphoma). Hormonal alterations occur- tic infections occurring in patients with AIDS and this ring during HIV disease may lead also to extensive

Table 2 Grading of severity in metabolic abnormalities associated with antiretroviral therapy

Severity Serum cholesterol levels (fasting) (mg/dl) Serum triglyceride level (fasting) (mg/dl) Serum glucose levels (fasting) (mg/dl)

Grade 0 (normal) Total B/200, LDL B/160 B/200 B/110 Grade 1 (mild) Total 200/239, LDL 160/189 200/399 110/125 (intermittent) Grade 2 (moderate) Total 240/300, LDL 190/220 400/1000 110/125 (persistent) Grade 3 (severe) Total /300, LDL /220 /1000 /125 L. Calza et al. / International Journal of Antimicrobial Agents 22 (2003) 89/99 91 metabolic and nutritional abnormalities, aside from On the other hand, none of the following predictors is antiretroviral treatment [11/14]. usually associated with the appearance of hypercholesterolaemia: lipid levels at the start of the PI treatment,

gender, age, mean CD4/ lymphocyte count, mean 2. Risk factors for HAART-associated hyperlipidaemia plasma viral load, weight or body mass index [2]. Nevertheless, some authors pointed out an association A wide range of anomalies of lipid metabolism has of increased cholesterol concentration with higher been increasingly recognized among HIV-infected per- values of age, body mass index and CD4/ cell count sons since the introduction of HAART in current [22,32,33]. Therefore, epidemiological, clinical and la- clinical practice [2,4,15/17].Even though therapy with boratory risk factors for the PI-related hyperlipidaemia zidovudine, lamivudine, stavudine or non-nucleoside are still controversial today when comparing different reverse transcriptase inhibitors (NNRTIs) has been published researches. sometimes associated with the occurrence of dyslipidae- Even though elevations in serum triglyceride and mia, abnormalities of plasma lipid levels appear to be a cholesterol levels have been associated with all the prevalent condition among patients receiving a PI-based available PIs, hypertriglyceridaemia seems more fre- regimen [3,4,16,18,19]. quent in patients receiving a ritonavir, ritonavir/saqui- The scenario of concurrent and/or related lipid metabolism alterations includes hypertriglyceridaemia, navir or ritonavir/lopinavir combination therapy, hypercholesterolaemia (or rather increased total and compared with indinavir-, nelfinavir- and amprenavir- LDL cholesterol levels) and decreased serum HDL based ones, and may sometimes be extreme, reaching a cholesterol levels, besides other metabolic or clinical triglyceride plasma concentration /1000 mg/dl in abnormalities such as insulin resistance with hyperinsu- subjects on ritonavir therapy [3,4,32,34/40]. At the linaemia, raised C-peptide concentrations, diabetes same time, a mild to moderate increase of cholesterol mellitus and the lipodystrophy syndrome [4,16,20/22]. levels seems more frequent among patients treated with In patients receiving a PI-containing antiretroviral ritonavir and probably nelfinavir, as opposed to in- regimen, the prevalence of hyperlipidaemia ranges from dinavir [35,41,42]. In a retrospective analysis, indinavir 28 to 80% and it includes hypertriglyceridaemia in the seems PI associated with the lowest risk of hypercho- majority of cases (40/80%), followed by hypercholes- lesterolaemia and hypertriglyceridaemia [2]. terolaemia (10/50%) and hyperglycaemia/hyperinsuli- The development of hyperlipidaemia during PI ad- naemia (5/30%), with the prevalence of fat ministration appears to be dose- and probably time- redistribution syndrome ranging from 10 to 80% in related. Serum lipid abnormalities occur shortly after different studies [4,15,16,22/24]. The so-called lipody- beginning therapy, usually between 3 and 12 months, strophy syndrome is frequently (but not always) asso- but their onset may be faster in subjects receiving a ciated with dyslipidaemia; although metabolic ritonavir-containing regimen (weeks to months) alterations are more common among patients with [2,19,20]. Ritonavir, alone or in combination with lipodystrophy, they are also present in those without saquinavir or lopinavir, appears to be associated with these morphological changes. It has been observed that the most frequent and severe lipid level elevations, while metabolic abnormalities usually precede the body fat available data are limited and remain insufficient to redistribution [17,22,25]. Particularly, fat depletion or evaluate the real effect of indinavir, nelfinavir, saquina- lipoatrophy syndrome is often related to the hypertri- vir and amprenavir on plasma lipid concentrations glyceridaemia, while fat accumulation or lipohypertro- [2,4,40,42]. phy syndrome is accompanied by dyslipidaemia, In recent studies, hyperlipidaemia was also related to peripheral insulin resistance, raised C-peptide levels a longer cumulative exposure to stavudine, although the and diabetes mellitus in an elevated number of cases exact effect of NRTIs on lipid metabolism is still being [26/28]. In several studies, hypertriglyceridaemia has been debated [22,32,33]. Moreover, some authors have found found in association with the following factors: male out that hypertriglyceridaemia is more frequent among patients with concurrent hyperglycaemia or diabetes gender, more advanced age (/36 years), higher body mellitus [43], while chronic hepatitis C virus infection mass index, greater weight (/65 kg), being homosex- seems inversely associated with the development of ual, diagnosis of AIDS, higher mean CD4/ lymphocyte count, and elevated cholesterol and triglyceride plasma hypercholesterolaemia [22,44]. Finally, lipid metabolism levels prior to the PI therapy initiation [1,9,22,29/31]. alterations have also been frequently reported in HIV- However, in some studies, gender, baseline lipid levels, infected paediatric patients receiving HAART. Hyperli- stage of HIV disease and body weight do not appear to pidaemia was found in 70% of children treated with be related to the occurrence of hypertriglyceridaemia ritonavir and in approximately 50% of those receiving [2,17,32]. nelfinavir [45]. 92 L. Calza et al. / International Journal of Antimicrobial Agents 22 (2003) 89/99

3. Pathophysiology tion in hepatic cells for key enzymes involved in the triglyceride biosynthetic pathway, leading to the hepatic

The broad spectrum possibly supporting pathogenetic accumulation of triglyceride-rich lipoparticles [3,50/52]. pathways that potentially underlie PI-associated dysli- A recent report hypothesizes that mitochondrial pidaemia is not fully understood. The most convincing alterations found in HIV-infected patients receiving proposed mechanism is based upon the structural HAART could also play a role in the development of similarity between the catalytic region of HIV-1 protease antiretroviral therapy-related lipodystrophy and dysli- and two homologous human proteins involved in the pidaemia. It could be speculated that HAART (espe- lipid metabolism: cytoplasmic retinoic acid-binding cially when conducted with multiple NRTIs) would protein type 1 (CRABP-1) and low-density lipopro- cause mitochondrial abnormalities by inhibiting the tein-receptor-related protein (LRP). The amino acid mitochondrial DNA polymerase g, leading to a mito- sequence of the C-terminal region of CRABP-1 is 58% chondrial DNA depletion, a respiratory chain dysfunc- homologous to the catalytic region of HIV-1 protease, tion and a reduced cell energy production. while LRP shares 63% amino acid homology with the Mitochondrial respiratory chain inhibition could be viral protease. responsible for several abnormalities in different cell CRABP-1 usually binds intracellular retinoic acid and types, such as adipocytes, promoting lipodystrophy presents it to cytochrome P450 (CYP) 3A enzymes, syndrome and increased plasma lipid levels. Moreover, which convert retinoic acid to cis-9-retinoic acid. This interference between PIs and cellular protease could also molecule subsequently binds to a heterodimer (including trigger the development of metabolic alterations, be- retinoid X receptor (RXR) and peroxisome-proliferator- cause some proteases are essential for mitochondrial activated receptor type g (PPARg)) in adipocyte nuclei. biogenesis and metabolic function [53].

The heterodimer RXR/PPARg associated with the cis- Finally, PI-related dyslipidaemia probably involves a 9-retinoic acid inhibits adipocyte apoptosis and stimu- genetic predisposition, too. Recent experimental lates adipocyte proliferation and differentiation. searches document an evident association between PIs probably bind to CRABP-1 which is homologous hypertriglyceridaemia (with low serum HDL cholesterol to the viral protease and erroneously inhibit the forma- levels) and several polymorphisms found in the apo C- tion of cis-9-retinoic acid, leading to a reduced RXR/ III gene. Variations at nucleosides /455 and /482 are PPARg activity, increased apoptosis and diminished both associated with increased levels of triglyceride- proliferation of peripheral adipocytes. Such events containing lipoproteins (VLDL) and low HDL values. would cause peripheral lipoatrophy syndrome and Carriers of the /455 genetic variant had 30% lower hyperlipidaemia because of adipocyte loss, decreased levels of HDL cholesterol for those without this poly- lipid storage and lipid release into the bloodstream [2/ morphism and plasma lipid concentrations increase 4]. according to the number of these variant alleles [54]. Another possible mechanism underlying these meta- In conclusion, pathogenetic mechanisms underlying bolic abnormalities involves the inhibition of CYP 3A PI-related dyslipidaemia are very complex and probably induced by PIs and particularly by ritonavir, which is involve multiple drug-induced lipid metabolism anoma- the most potent inhibitor of these enzymes and proves lies, in association with a broad range of hormonal and associated with the most frequent and severe hyperlipi- immunological imbalances and genetic predisposing daemia. The inhibition of CYP 3A would be responsible factors. for a reduced formation of cis-9-retinoic acid and a decreased activity of RXR/PPARg enzymes [4,46]. During normal lipid metabolism, LRP is bound to 4. Clinical course and complications lipoprotein lipase (LPL) on capillary endothelium and this LRP/LPL complex cleaves fatty acids from trigly- Since the introduction of HAART into clinical cerides, thereby promoting free fatty acid accumulation practice has remarkably changed the natural history of in peripheral adipocytes. Some authors hypothesize that HIV disease and led to a notable extension of life

PIs binding to LRP may inhibit the LRP/LPL complex expectancy, prolonged metabolic alterations could sig- normal function and interfere with fatty acid storage, nificantly act on the long-term prognosis and outcome leading to hyperlipidaemia [2/4]. The elevation in of HIV-infected persons. Therefore, these metabolic cholesterol levels is principally in the LDL and VLDL imbalances are causing increasing concern, particularly cholesterol fractions, since fatty acids released into the those linked with elevated risk of cardiovascular com- bloodstream subsequently reach the liver and promote a plications. secondary hepatic synthesis of triglycerides and VLDL The potential clinicopathological consequences of

[4,21,47/49]. Moreover, new experimental results sug- HIV-associated hyperlipidaemia are still not completely gest that PIs may directly stimulate hepatic triglyceride known and controlled studies have not yet demon- synthesis. Several PIs up-regulate the mRNA produc- strated an increased risk of cardiovascular events in L. Calza et al. / International Journal of Antimicrobial Agents 22 (2003) 89/99 93 association with the PI-based antiretroviral therapy. 5. Non-pharmacological management However, some anecdotal observations reported an increased incidence of premature coronary artery dis- Prior to instituting an antihyperlipidaemic pharma- ease and myocardial infarction in young HIV-infected cological treatment, clinicians should exclude secondary individuals treated with HAART, besides peripheral causes of dyslipidaemia, such as familial hyperlipidae- atherosclerosis, acute pancreatitis and cutaneous xanto- mia, drug therapy (b-blockers, diuretics, steroid deriva- tives and oral contraceptives), diabetes mellitus, obesity, mas [16,36/38,55/61]. Hypertriglyceridaemia, elevated total and LDL cho- alcoholism, hypothyroidism, and liver or kidney chronic lesterol levels, decreased HDL cholesterol levels, insulin diseases. resistance syndrome, diabetes mellitus and truncal Attention must be given to other correctable risk adiposity are known to increase cardiovascular risk in factors for cardiovascular diseases, such as cigarette the HIV-negative population, and may similarly predis- smoking, physical inactivity, arterial hypertension and concomitant medications. For women with early meno- pose HIV-infected subjects to accelerated coronary pause, oestrogen or oestrogen/progestin replacement illness [58/61]. therapy can be considered where appropriate and may A large proportion of the middle-aged HIV-infected lead to a reduced LDL and increased HDL serum individuals examined by high-resolution B-mode ultra- cholesterol levels, but can exacerbate hypertriglyceri- sound arterial imaging had one or more atherosclerotic daemia and should be used with great caution. plaques within the femoral or carotid arteries. However, A hypolipidaemic diet and an increased physical some authors have observed that the presence of exercise may act favorably on dyslipidaemia, but they peripheral atherosclerosis within this population was are often inadequate to correct metabolic alterations, not associated with the use of PIs, but rather with other and other pertinent interventions are generally re- classic cardiovascular risk factors such as hyperlipidae- quested. However, hypolipidaemic nourishment and mia and smoking [62,63]. At the same time, two recent regular physical activity should be general and usual studies have showed that premature carotid artery components of a healthy life style for all HIV-infected lesions (such as arterial calcifications) and an increased individuals. erythrocyte volume have a higher prevalence in HIV- Switching from the PI-based treatment to a PI- positive subjects treated with PIs, compared with PI- sparing regimen (including two NRTIs associated with naı¨ve patients [64,65]. nevirapine, efavirenz or abacavir) or a different PI are Even though an increased risk of coronary artery two options that have been evaluated. Several clinical events has not yet been demonstrated in patients treated studies have shown that, for the antiretroviral-naı¨ve with HAART, subjects receiving PI-based antiretroviral HIV-infected patients, antiretroviral combinations in- regimens frequently present a rapid deterioration of a cluding one NNRTI or abacavir and two NRTIs are at pre-existing coronary artery illness, which often be- least as potent as PI-based regimens [67/70]. comes symptomatic only after the initiation of antire- These PI-sparing antiretroviral associations contain- troviral treatment [61]. ing nevirapine, efavirenz or abacavir are being employed The constellation of metabolic abnormalities (includ- to reduce toxicity and complexity of HAART and to ing dyslipidaemia and hyperinsulinaemia) suggestiveof improve the long-term therapeutic adherence. Prelimin- a significant insulin resistance syndrome among HIV- ary searches support the role of NNRTIs and abacavir for therapy simplification strategies and metabolic positive patients with concurrent fat redistribution correction in patients receiving PI-based treatments, syndrome leads to a notable increase of cardiovascular but most of these studies have been uncontrolled and disease risk factors already known in HIV-negative relatively short [71/76]. population. On the other hand, these predisposing A lot of studies have demonstrated that an antire- factors are markedly lower in patients without lipody- troviral regimen in which a PI is replaced with nevir- strophy syndrome [60]. In addition, prolonged and apine, efavirenz or abacavir in patients with long-lasting extremely high triglyceride concentrations (/1000 mg/ viral suppression has antiviral activity similar to that of dl), such as those following the ritonavir administration, prior PI-based combination. In the great majority of are associated with the occurrence of acute pancreatitis, cases, full plasma HIV-RNA suppression is maintained especially in patients with a history of alcoholism and and a significant increase in the CD4/ lymphocyte gallstones [59,66]. count is reported [67/69,72/74,76]. Efavirenz in parti- Further, enlarged studies with extensive follow-up cular has shown the greatest antiviral efficacy in periods are certainly required in order to determine the switched patients (with undetectable plasma viral load true risk of cardiovascular diseases and other clinical maintained in 92/100% of cases) [68,72,77/80], fol- complications associated with the prolonged PI admin- lowed by abacavir (85/90%) [76,81,82] and nevirapine istration. (79/90%) [71,72,74,83]. 94 L. Calza et al. / International Journal of Antimicrobial Agents 22 (2003) 89/99

However, the rate of virological failure might even- retroviral regimen from ritonavir, ritonavir/saquinavir tually increase among patients who have previously or indinavir to nelfinavir. These authors have reported received prolonged non-suppressive antiretroviral regi- that switching to nelfinavir leads to a significant mens such as dual NRTI therapy. According to current decrease of the concurrent hypertriglyceridaemia after knowledge, patients previously treated with isolated a 6- or 12-month follow-up, without significant varia- NRTI therapy may eventually harbor drug-resistant tions in the viral suppression drug activity [85,86]. virus variants with multiple mutations in the reverse transcriptase gene, despite subsequent prolonged viral suppression during the HAART administration. There- fore, because of the intrinsically low genetic barrier of 6. Drug therapy the NNRTI class, the safest strategy is probably to replace PI with nevirapine, efavirenz or abacavir only in A pharmacological hypolipidaemic therapy becomes patients with prolonged undetectable plasma HIV-RNA necessary when the HAART-related hyperlipidaemia is levels and who have previously exclusively received a PI- remarkable or persists for a long time and if dietary based antiretroviral association [71,77]. changes, physical exercise and switching treatment are With regard to the lipid metabolism alterations, ineffective or not applicable. several authors have reported similar results in patients Drug therapy for dyslipidaemia in HIV-infected switched from HAART to a PI-sparing regimen, which persons receiving HAART is problematic, because of is generally able to significantly improve the concurrent potential drug interactions, toxicity, intolerance and hyperlipidaemia. The nevirapine-containing simplifica- decreased patient adherence to multiple drug regimens. tion therapies have obtained the most remarkable 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-Co reductions both in triglyceride and in cholesterol plasma A) reductase inhibitors, or statins, are considered the levels after a 12-month follow-up. The efavirenz- or current first-line therapy for primary hypercholestero- abacavir-based associations also lead frequently to a laemia. Considerable evidence demonstrates their bene- significant improvement of hyperlipidaemia [70/ ficial effects in reducing both total and LDL cholesterol 74,76,77,79/82]. On the other hand, the effect of the levels in HIV-negative population, leading to a de- replacement of a PI with an NNRTI or abacavir on the creased risk of coronary artery events, in the primary HAART-related lipodystrophy syndrome is still con- and secondary prevention of the heart diseases [87]. troversial. Even though some studies have reported an These compounds inhibit the key rate-controlling improvement in the fat redistribution syndrome [72/74], enzyme in the de novo synthesis of cholesterol, respon- the majority of authors failed to detect any significant sible for production of /50% of total body cholesterol. change in morphological alterations after the switch By the inhibition of HMG-Co A reductase, statins can from HAART to a PI-sparing regimen [71,75,77,84]. also promote an increased synthesis of hepatic LDL Results of the most recent studies concerning switch receptors and a reduced production of VLDL lipopro- therapy with nevirapine, efavirenz or abacavir are teins. Most statin agents may provide comparable summarized in Table 3. lowering of LDL cholesterol, even though simvastatin To conclude, two studies have also evaluated the and atorvastatin can more remarkably influence these effects on dyslipidaemia of switching a PI-based anti- cholesterol levels [87/89].

Table 3 Metabolic, morphologic and virologic results obtained in most recent published studies about the switching from a PI-based to a nevirapine-, efavirenz- or abacavir-containing antiretroviral regimen

Authors Drug used Number of Follow-up (months) Virological relapse (%) Effect on Effect on patients hyperlipidaemia lipodystrophy

Barreiro et al. [74] NVP 104 6 11 Unchanged Reduced Ruiz et al. [71] NVP 52 12 21 Reduced Unchanged Martinez et al. [72] NVP 23 6 4 Reduced Reduced Negredo et al. [77] NVP 25 12 4 Reduced Unchanged Moyle [68] EFV 26 12 0 Reduced Reduced Negredo et al. [77] EFV 25 12 8 Unchanged Unchanged Martinez et al. [72] EFV 20 6 5 Reduced Reduced Opravil et al. [76] ABC 84 8 15 Reduced Unchanged Clumeck et al. [81] ABC 105 12 13 Reduced Unchanged Walli et al. [82] ABC 16 12 12 Reduced Unchanged

NVP, nevirapine; EFV, efavirenz; ABC, abacavir. L. Calza et al. / International Journal of Antimicrobial Agents 22 (2003) 89/99 95

Most of these compounds are metabolized by cyto- Treatment with gemfibrozil (600 mg twice daily), chrome P450 3A4 and may cause clinically relevant bezafibrate (400 mg daily) or fenofibrate (200 mg daily) interactions with other agents that are changed by this generally results in a significant reduction in triglyceride enzymatic complex, such as cyclosporin, erythromycin, and cholesterol levels in HIV-infected patients receiving itraconazole, ketoconazole, oral anticoagulants, PIs and a PI-containing therapy, with a more evident improve- NNRTIs. An additional complicating feature is that ment of hypertriglyceridaemia [91,101,103]. With regard individual statins are metabolized to differing degrees, in to other hypolipidaemic agents, niacin should be some cases producing active metabolites. They are also avoided as first-line therapy in subjects treated with substrates for P-glycoprotein, a drug transporter present PIs, because it often causes cutaneous rash, pruritus and in the small intestine, which may influence their oral insulin resistance. Bile sequestering resins should be bioavailability [87,88]. discouraged because they may produce elevated trigly- Simvastatin, lovastatin and atorvastatin are exten- ceride levels and bind several co-administered medica- sively metabolized by CYP 3A4: co-administration of tions, with a reduction in their oral bioavailability. Fish ritonavir plus saquinavir to HIV-negative volunteers oils (omega-3 fatty acid supplements) show a variable resulted in an increased exposure to simvastatin by effect on plasma triglyceride concentrations and their 3059% and to atorvastatin by 347%. These notable drug efficacy has not been fully demonstrated [91,101/104]. interactions cause elevated plasma levels of statins, The National Cholesterol Education Program leading to a significantly increased risk of liver and (NCEP) Guidelines for the pharmacological treatment skeletal muscle toxicity (acute hepatitis, myopathy and of PI-related hypercholesterolaemia focus on LDL rhabdomyolysis). On the other hand, fluvastatin is cholesterol levels, as summarized in Table 4. Suggested metabolized by CYP 2C9 and pravastatin is not cholesterol levels for dietary and drug interventions are significantly metabolized by the CYP enzyme system, variable according to the presence of cardiovascular with a very low risk of drug interactions [88/90]. disease risk factors (including men age ]/45 years, Consequently, it is reasonable to recommend the use women age ]/55 years, familial history of coronary of pravastatin as first-line treatment for hypercholester- artery disease, cigarette smoking, arterial hypertension, olaemia in PI-treated patients and the use of fluvastatin serum HDL cholesterol level B/35 mg/dl and diabetes (characterized by a slightly lower efficacy) as second-line mellitus). The first-line therapy is represented by pra- regimen. vastatin or fluvastatin; fibrates are reasonable alterna- Given these potential interactions, it is opportune to administer low initial doses of either pravastatin (10 mg tive agents [91,98]. Hypertriglyceridaemia requires drug treatment in daily) or fluvastatin (20 mg daily), with a monthly monitoring of plasma aminotransferase and creatine- patients with a plasma triglyceride level of /1000 mg/ phosphokinase levels in patients who are taking PIs. On dl, but subjects with a history of pancreatitis may the other hand, simvastatin, lovastatin and atorvastatin represent a group for whom a lower threshold of should be avoided, because they present a great risk of triglyceride increase is opportune, such as /500 mg/ dl. Fibrates are considered the cornerstone of drug pharmacological interactions with PIs [91/98]. More- over, in a recent study, pravastatin had the lowest therapy for the hypertriglyceridaemia, while statins binding to plasma proteins of the statin agents and represent the second-choice treatment [91,96,100].A dietary advice associated with this statin compound hypolipidaemic diet and a regular aerobic physical significantly reduced total cholesterol levels in HIV- exercise should be always recommended in association infected patients treated with HAART, without signifi- with this pharmacological treatment. cant adverse events [99]. Fibrates represent the cornerstone of drug therapy for hypertriglyceridaemia and mixed hyperlipidaemia. Table 4 These compounds are characterized by an extended NCEP Guidelines for the dietary and pharmacological treatment of activity on the hepatic synthesis of both triglycerides hypercholesterolaemia according to different values of plasma LDL cholesterol and cholesterol, LPL and acetil-CoA-carboxylase, as well as the favorable effects on peripheral lipolysis Risk factors for Hypolipidaemic Drug therapy inhibition and glycaemic control. Fibrates are also cardiovascular diseases diet (mg/dl) (mg/dl) metabolized by hepatic cytochrome P450 enzymes, but Without CAD they appear primarily to affect only CYP 4A and do not B/2 risk factors LDL ]/160 LDL ]/190 show clinically relevant interactions with PIs. However, ]/2 risk factors LDL ]/130 LDL ]/160 concomitant use of both fibrates and statins can increase With CAD LDL ]/100 LDL ]/130 the risk of skeletal muscle toxicity and should be avoided CAD, coronary artery disease; LDL, plasma LDL cholesterol [100/103]. concentration. 96 L. Calza et al. / International Journal of Antimicrobial Agents 22 (2003) 89/99

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