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Georg Behrens and Reinhold E. Schmidt

The HIV lipodystrophy syndrome, which includes metabolic complications and altered fat distribution, is of major importance in HIV therapy. The metabolic abnormalities may harbor a significant risk of developing cardiovascular disease, with as yet unknown consequences. In addition, several studies report a reduced quality of life in patients with body habitus changes leading to reduced treatment adherence. Despite the impact of lipodystrophy syndrome on HIV management, little is known about the pathogenesis, its prevention, diagnosis and treatment. Current data indicate a rather multifactorial pathogenesis where HIV infection, its therapy, and patient-related factors are major contributors. The lack of a clear and easy definition reflects the clinical heterogeneity, limits a clear diagnosis and impairs the comparison of results among clinical studies. Therapeutic and prevention strategies have so far been of only limited clinical success. Thus, general recommendations include dietary changes and life style modifications, altering antiretroviral drug therapy (replacement of protease inhibitors with NNRTI or replacement of stavudine and zidovudine with e.g. abacavir or tenofovir), and finally, the use of metabolically active drugs. Here we summarize the pathogenesis, diagnosis and treatment options of the HIV lipodystrophy syndrome.

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Clinical manifestation Lipodystrophies were originally described as acquired or inherited disorders characterized by regional or generalized loss of subcutaneous fat. The non-HIV-associated forms, such as congenital or familial partial lipodystrophy, have a very low prevalence. Generally, these forms are associated with complex metabolic abnormalities and are difficult to treat. The term "lipodystrophy syndrome" in association with HIV, was introduced to describe a complex medical condition including the apparent abnormal fat redistribution and metabolic disturbances seen in HIV-patients receiving protease inhibitor therapy (Carr 1998). But, even years after its first description, there is still no consensus on a case definition for lipodystrophy syndrome in HIV patients. Thus, the diagnosis of lipodystrophy in clinical practice often relies on a more individual interpretation than on an evaluated classification. Finally, changes in the fat distribution have to be considered as being rather dynamic processes. In most cases, lipoatrophy is clinically diagnosed when significant fat loss has already occurred. HIV-associated lipodystrophy includes both clinical and metabolic alterations (Behrens 2000). The most prominent clinical sign is a loss of subcutaneous fat (lipoatrophy) in the face (periorbital, temporal), limbs, and buttocks. Prospective studies have demonstrated an initial increase in limb fat during the first months of therapy, followed by a progressive decline over the ensuing years (Mallon 2003). Peripheral fat loss can be accompanied by an accumulation of visceral fat, which can cause mild gastrointestinal symptoms. Truncal fat increases initially after therapy and then remains stable (Mallon 2003). Visceral obesity, as a singular feature of abnormal fat redistribution, appears to occur in only a minority of patients. The study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM), a large cross-sectional analysis of HIV-positive and control men, reported that peripheral lipoatrophy was more frequent in HIV-positive men than in controls (38.3% vs. 4.6%, p=0.001), whereas central lipohypertrophy was less frequent (40.2% vs.55.9%, p=0.001). Among HIV-positive men, the presence of central lipohypertrophy was not positively associated with peripheral lipoatrophy (odds ratio = 0.71, 95%CI: 0.47 to 1.06, p= 0.10). HIV-positive men (age 33-45 years) both with and without lipoatrophy had less subcutaneous adipose tissue (SAT) than controls, with legs and lower trunk more affected than upper trunk. Fat accumulation may also be found locally as dorsocervical fat pads ("buffalo hump") or dissiminated within the muscle and the liver. Female HIV patients sometimes complain about painful breast enlargement, which has been attributed to the lipodystrophy syndrome. There is now accumulating evidence that the major clinical components - lipoatrophy, central adiposity and the combination of both - result from different pathogenetic developmental processes. The prevalence of lipodystrophy syndrome has been estimated to be between 30 and 50 %, based on cross-sectional studies. A prospective study over an 18-month period after initiation of therapy revealed a prevalence of 17 %. Lipodystrophy, and in particular lipoatrophy, has been observed most frequently in patients receiving a combination regimen of nucleoside analogues and protease inhibitors, although almost all antiretroviral drug combinations can be associated with fat redistribution. The risk of the syndrome increases with the duration of treatment, the age of the patient and the level of immunodeficiency. Lipodystrophy has been observed during the therapy of both the acute and chronic states of HIV infection and even following post-exposure prophylaxis. Children can be affected, like adults, with clinical fat redistribution shortly after initiation or change of antiretroviral therapy. The evolution of the individual clinical components of the lipodystrophy syndrome is variable. Subcutaneous fat loss has been observed during exclusive therapy with NRTIs. The nucleoside analogues linked most strongly to lipoatrophy are zidovudine and stavudine, the latter particularly when used in combination with didanosine. Tenofovir combined with lamivudine and efavirenz is associated with less loss of limb fat than stavudine in a similar combination in therapy-naïve HIV patients. Frequently, complex metabolic alterations are associated with the described body shape alterations. These include peripheral and hepatic insulin resistance, impaired glucose tolerance, type 2 diabetes, hypertriglyceridemia, hypercholesterolemia, increased free fatty acids (FFA), and decreased high density lipoprotein (HDL). Often these metabolic abnormalities appear or deteriorate before the manifestation of fat redistribution. The prevalence of insulin resistance and glucose intolerance has been reported in the literature at 20 to 50% depending on the study design and measurement methods. Frank diabetes is less frequent with a prevalence of between 1 and 6 %. Lipodystrophic patients present with the highest rates of metabolic disturbances. Hyperlipidemias are a frequently observed side effect of antiretroviral therapy, especially in combinations that include protease inhibitors. Given that many HIV patients present with already decreased HDL levels, these are not further reduced by antiretroviral drugs. Hypertriglceridemias, especially in patients with evidence of body-fat abnormalities, are the leading lipid abnormality either alone or in combination with hypercholesterinemia. Several weeks after initiation or change of HIV therapy, lipid levels usually reach a plateau and remain stable. All protease inhibitors can potentially lead to hyperlipidemia, although to different extents. For example, atazanavir (Reyataz™) appears to be less frequently associated with dyslipidemia and insulin resistance. In contrast, ritonavir (Norvir™) often leads to hypertriglyceridemia correlating to the drug levels. The therapy-induced dyslipidemias are characterized by increased triglyceride-rich very low density lipoproteins (VLDL) and to a lesser extend by raising low density lipoproteins (LDL). Detailed characterization revealed an increase of apoplipoprotein B, CIII and E. Raised levels of lipoprotein(a) have been described in protease inhibitor recipients. Mild hypercholesterolemia can occur during therapy with efavirenz (Sustiva™) but is not typical under therapy with nevirapine (Viramune™). Stavudine-based, antiretroviral therapy is associated with early and statistically significant increases in total triglycerides and cholesterol. It is important to note that HIV infection itself is associated with disturbed lipid metabolism. During disease progression, the total cholesterol, LDL, and HDL levels decline and the total triglyceride level rises. It has been postulated that the raised LDL-cholesterol levels after initiation of HIV-therapy reflect rather a reconstitution of LDL-cholesterol concentration as before HIV-infection than an independent increase in LDL-cholesterol by antiretroviral regimens. HAART, lipodystrophy syndrome and cardiovascular risk The fat redistribution and disturbances in glucose and fat metabolism resemble a clinical situation that is known as the "metabolic syndrome" in HIV-negative patients. This condition includes symptoms such as central adipositas, insulin resistance and hyperinsulinemia, hyperlipidemia (high LDL, Lp(a) hypertriglyceridemia and low HDL) and hypercoagulopathy. Given the well-established cardiovascular risk resulting from this metabolic syndrome, there is growing concern about a potential therapy-related increased risk of myocardial infarction in HIV patients. These fears are further sustained by reports of arterial hypertension on HAART, a high rate of smoking among HIV patients and increased levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) in patients with lipodystrophy. Although many of the, mainly retrospective, studies dealing with this issue are inconclusive, data from a large international study (D:A:D study) provide evidence for an increased relative risk of myocardial infarction during the first 7 years of HAART (Friis-Møller 2003). The incidence of myocardial infarction increased from 1.39/1,000 patient years in those not exposed to HAART, to 2.53/1,000 patient years in those exposed for < 1 year, to 6.07/1,000 patient years in those exposed for = 6 years (RR compared to no exposure: 4.38 [95 % CI 2.39 to 8.04], p = 0.0001). After adjustment for other potential risk factors, there was a 1.17-fold [1.11 to 1.24] increased risk of myocardial infarction per additional year of combined ART exposure. It is, however, of note that older age, male gender, smoking, diabetes mellitus, and pre-existing coronary artery disease were still associated with a higher risk of sustaining cardiovascular events than HAART in this study. Although the CHD risk profile in D:A:D patients worsened over time, the risk of myocardial infarction decreased over time after controlling for these changes. More recently, further analyses of the D:A:D cohort proposed an independent contribution of protease inhibitor therapy to the development of coronary heart disease. After adjustment for exposure to the other drug class and established cardiovascular risk factors (excluding lipid levels), the relative rate of myocardial infarction per year of protease-inhibitor exposure was 1.16 (95% confidence interval [CI], 1.10 to 1.23), whereas the relative rate per year of exposure to non-nucleoside reverse-transcriptase inhibitors was 1.05 (95% CI, 0.98 to 1.13). Adjustment for serum lipid levels further reduced the effect of exposure to each drug class to 1.10 (95% CI, 1.04 to 1.18) and 1.00 (95% CI, 0.93 to 1.09), respectively (Friis-Møller 2003). Data of the SMART study revealed that episodic antiretroviral therapy guided by the CD4 cell count significantly increased the risk of opportunistic disease or death from any cause, as compared with continuous antiretroviral therapy. Surprisingly, the hazard ratio for the drug conservation group vs. the viral suppression group was 1.6 (95% CI, 1.0 to 2.5; P=0.05) for fatal or non-fatal cardiovascular disease. These data may provide evidence for the role of the immune system and/or viral replication in the occurence of cardiovascular events in HIV-patients (El Sadr 2007). Several other studies used ultrasonography to measure the thickness of the carotid intima media or endothelial function to predict the cardiovascular risk. Some of these investigations found abnormal test results (e.g. reduced flow-mediated dilation) that correlated either with the use of protease inhibitors or the presence of dyslipidemia (Currier 2003). While there is some indication of an increased rate of coronary artery disease during HAART, the benefit of suppressed viral replication and improved immune function resulting in reduced morbidity and mortality, clearly argues for the use of antiretroviral drugs according to current international guidelines. It seems obvious however, that pre-existing cardiovascular risk factors in individual patients need to be considered more carefully before starting or switching HAART. Recommendations such as the National Cholesterol Education Program (NECP) have been proposed for non-HIV-infected patients with similar risk constellations. These guidelines are being proposed by some authors for HIV patients as well (Dube 2003, Schambelan 2002, Grinspoon 2005). According to these recommendations, the overall cardiovascular risk in HIV-infected patients can be determined from specific risk factors by using the Framingham equation. Prediction of coronary heart disease using this equation, however, may have some limitations. A 10-year CHD risk estimation at any time point is determined by the individual's past and expected future lipid levels (best assessed as area under the curve). Hyperlipidemia in many treated HIV patients, however, does not follow the 10-year time course seen in the "normal population" due to frequent therapy changes that may lower total cholesterol, increase HDL, and improve atherogenic risk. Thus, the validity of this calculation for the long-term cardiovascular risk assessment in young patients with changing lipid levels and medication regimens requires further studies. Clearly, more clinical studies are necessary to assess whether these recommendations are also applicable in the presence of HIV and to determine the clinical value of lipid lowering drug therapy in these patients. Most importantly, the information about drug interactions of lipid lowering and antiretroviral drugs is still incomplete. The accumulation of pre-existing and drug-related risk factors will get more clinical attention, because, by improving the HIV-associated morbidity and mortality, HAART consequently increases an additional relevant cardiovascular risk factor: the age of patients who are effectively treated with antiretroviral drugs. Pathogenesis For a better understanding of the pathogenesis of the complex metabolic abnormalities, it is useful to separate individual aspects of the lipodystrophy syndrome: adipocytes/fat redistribution, lipid metabolism, and carbohydrate metabolism. Studies published during recent years provide evidence for two fundamental assumptions: firstly, lipoatrophy and lipoaccumulation result from divergent or only partially overlapping pathogenetic reasons. Secondly, NRTIs, NNRTIs, PIs, and even drugs within each class contribute to the lipodystrophy syndrome and its individual features by different, probably overlapping and certainly synergistic mechanisms. NRTI and lipodystrophy The patterns of fat redistribution in patients who are exclusively receiving NRTIs are unlike those observed in patients during PI therapy. Peripheral fat loss is the major symptom observed in NRTI therapy (particularly using stavudine and didanosine combinations), although a few clinical studies have described a minimal intra-abdominal fat increase in these patients, which is clearly less than under PIs. Given that, commonly, only a mild increase in triglycerides has been observed, exclusive NRTI therapy seems to be of minor impact on lipid metabolism. Postprandially elevated FFA in patients with lipodystrophy, together with in vitro experiments, have led to the hypothesis that NRTIs could impair fatty acid binding proteins (FABP) which are responsible for cellular fat uptake and intracellular fat transport. In contrast, addition of stavudine (Zerit™) to a dual PI regimen does not result in a further increase in the total cholesterol or triglyceride levels. It is well established that long-term NRTI therapy can cause mitochondrial toxicity. The clinical manifestation of this side effect presents in symptoms such as hepatic steatosis, severe hyperlactatemia, and polyneuropathy. As an explanation for these symptoms, the "pol-? hypothesis" has been proposed, which was later extended to reveal the lipoatrophy observed under NRTIs (Brinkmann 1999). To maintain an adequate bioenergetic level for accurate cell function, all metabolically active cells depend on a persistent polymerase ?-mediated mitochondrial (mt) DNA synthesis. Mitochondria require a constant supply of nucleosides for this process. The mitochondrial DNA polymerase ? retains both DNA- as well as RNA-dependent DNA polymerase activity. The latter is perhaps responsible for the HIV reverse transcriptase activity and therefore its susceptibility for interactions with NRTIs. Experimental data revealed that, for NRTI uptake into mitochondria, the subsequent phosphorylation and then incorporation into the DNA, certain pharmacodynamic requirements need to be fulfilled. These requirements, which include thymidine kinase activity and deoxynucleotide transport specificity of the mitochondrial membrane, are apparently different for zidovudine (Retrovir™) and stavudine (Zerit™), which partially explains the prevailing association between lipoatrophy and stavudine therapy. The postulated mechanisms of NRTI-induced mitochondrial dysfunction consist of competitive inhibition, incorporation into the mtDNA resulting in mtDNA depletion, impairment of mitochondrial enzymes, uncoupling of oxidative phosphorylation and induction of apoptosis. Depletion of mtDNA and structural changes in the mitochondria, resulting in increased rates of apoptosis in subcutaneous adipocytes, have been confirmed by some studies. Despite the experimental link between mitochondrial toxicity and fat tissue as one potential target organ, the degree to which mitochondrial damage contributes to fat distribution abnormalities and its specificity remains unknown. In contrast, mitochondrial damage is widely believed to be responsible for other NRTI-related side effects, such as myopathy, hyperlactatemia, microvesicular steatosis, and steatohepatitis with lactic acidosis (Nolan & Mallal 2004). Protease inhibitors and lipodystrophy PIs account for the majority of metabolic abnormalities associated with lipodystrophy syndrome. Numerous studies report increases in the levels of total triglycerides and triglyceride-rich lipoproteins (VLDL) accompanied by raised LDL levels after initiation of PI therapy (Walli 1998). Conversely, these parameters improved substantially in most studies after discontinuation of the PI or on switching to abacavir (Ziagen™) or nevirapine (Viramune™). The hyperlipidemic changes are frequently associated with hyperinsulinemia and/or insulin resistance. It has been proposed, based on in vitro experiments, that PIs such as saquinavir (Invirase™), indinavir (Crixivan™), and ritonavir (Norvir™) are able to inhibit proteasomal degradation of apolipoprotein B leading to intracellular stockpiling of this lipoprotein and excessive release in response to FFA (Liang 2001). Using stable isotopes in vivo, other authors demonstrate a dramatic increase in FFA turnover together with increased lipolysis and decreased clearance of triglyceride-rich VLDL and chylomicrons (Shekar 2002). These conditions point towards an impaired postprandial insulin-mediated lipid metabolism, since insulin, on the one hand, normally inhibits lipolysis and, on the other hand, increases uptake of FFA, triglyceride synthesis, and fat oxidation in favor of glucose oxidation. So far, it remains unclear whether impaired insulin action eventually leads to dyslipidemia, or whether hyperlipidemia is responsible for reduced insulin function and insulin resistance in the periphery. Presumably, both mechanisms are important given that some PIs (e.g. indinavir) have been shown to induce insulin resistance without changes occurring in lipid metabolism after short-term administration (Noor 2001, Noor 2002), whereas other PIs (e.g. ritonavir) have been demonstrated to cause mainly hypertriglyceridemia due to increased hepatic synthesis without major changes occurring in glucose metabolism. However, comparative clinical studies on the association of different PIs with insulin resistance are still lacking. It is reasonable to speculate that lipid abnormalities and, in particular increased FFA levels, contribute substantially to the peripheral and central insulin resistance of skeletal muscles and the liver, presumably due to the increased storage of lipids in these organs (Gan 2002). Given this hypothesis, the visceral adiposity could reflect the adaptation of the body in response to raised FFA concentrations and an attempt to minimize the lipotoxic damage to other organs. Several in vitro experiments have indicated that almost all PIs can potentially lead to insulin resistance in adipocytes. Short-term administration of indinavir caused an acute and reversible state of peripheral insulin resistance in healthy volunteers, which was determined in an euglycemic-hyperinsulinemic clamp. These effects are most likely caused by the inhibition of glucose transport mediated by GLUT-4, the predominant transporter involved in insulin-stimulated cellular glucose uptake in humans (Murata 2002). A common structural component found in most PIs has been proposed to cause GLUT-4 inhibition. In some patients with lipodystrophy, additional impairment of glucose phosphorylation may contribute to insulin resistance (Behrens 2002). This is presumably due to an impaired insulin-mediated suppression of lipolysis and subsequently increased FFA levels (Behrens 2002, van der Valk 2001) and accumulation of intramyocellular lipids. Peripheral insulin resistance may also account for an increase in the resting energy expenditure in HIV lipodystrophy and a blunted insulin-mediated thermogenesis. Indinavir may also induce insulin resistance by inhibiting the translocation, processing or phosphorylation of the sterol regulatory element-binding protein 1c (SREBP-1c) (Caron 2001, Bastard 2002). Either directly or via the peroxisome proliferator activated receptor ? (PPAR?), SREBP-1 regulates FFA uptake and synthesis, adipocyte differentiation and maturation, and glucose uptake by adipocytes. Similarly, the function of these factors has been proposed to be disturbed in inherited forms of lipodystrophy. Finally, hypoadiponectinemia, as found in patients with abnormal fat distribution, may contribute to insulin resistance (Addy 2003). Diagnosis Both the lack of a formal definition and uncertainty about the pathogenesis and possible long-term consequences, leads to a continuing discussion about appropriate guidelines for the assessment and management of HIV lipodystrophy syndrome and its metabolic abnormalities. Outside clinical studies, the diagnosis relies principally on the occurrence of apparent clinical signs and the patient reporting them. A standardized data collection form may assist in diagnosis (Grinspoon 2005). This appears sufficient for the routine clinical assessment, especially when the body habitus changes develop rather rapidly and severely. For clinical investigations however, especially in epidemiological and interventional studies, more reliable measurements are required. But so far, no technique has demonstrated sufficient sensitivity, specificity or predictive value to definitively diagnose the HIV lipodystrophy syndrome by comparison with results obtained from a "normal" population. A recent multicenter study to develop an objective and broadly applicable case definition proposes a model including age, sex, duration of HIV infection, HIV disease stage, waist-to-hip ratio, anion gap, serum HDL cholesterol, trunk to peripheral fat ratio, percentage leg fat, and intra-abdominal to extra-abdominal fat ratio. Using these parameters, the diagnosis of lipodystrophy had a 79 % sensitivity and 80 % specificity (Carr 2003). Although this model is largely for research and contains detailed body composition data, alternative models and scoring systems, incorporating only clinical and metabolic data, also gave reasonable results (for more information, see http://www.med.unsw.edu.au/nchecr). Despite individual limitations, several techniques are suitable for measuring regional fat distribution. These include dual energy x-ray absorptiometry (DEXA), computer tomography (CT), magnetic resonance imaging (MRI) and sonography. Anthropometric measurements are safe, portable, cheap and much easier to perform than imaging techniques. Waist circumference alone, as well as sagittal diameter, are more sensitive and specific measures than waist-to-hip ratio. Repeated measurements of skin fold thickness can be useful for individual long-term monitoring but need to be performed by an experienced person. The main imaging techniques (MRI, CT, DEXA) differentiate tissues on the basis of density. Single-slice measurements of the abdomen and extremities (subcutaneous adipose tissue = SAT, visceral adipose tissue = VAT) and more complex three-dimensional reconstructions have been used to calculate regional or total body fat. Limitations of these methods include most notably their expense, availability and radiation exposure (CT). Consequently, CT and MRI should only be considered in routine clinical practice for selected patients (e.g. extended dorso-cervical fat pads, differential diagnosis of non-benign processes and infections). DEXA is appropriate for examining appendicular fat, which is comprised almost entirely of SAT, and has been successfully employed in epidemiological studies. However, SAT and VAT cannot be distinguished by DEXA, which therefore limits the evaluation of changes in truncal fat. Application of sonography to measure specific adipose compartments, including those in the face, requires experienced investigators and has been minimally applied in HIV infection so far. Bioelectrical impedance analysis estimates the whole body composition and cannot be recommended for measurement of abnormal fat distribution. Patients should routinely be questioned and examined for cardiovascular risk factors, such as smoking, hypertension, adiposity, type 2 diabetes, and family history. For an accurate assessment of blood lipid levels, it is recommended to obtain blood after a fasting of at least 8 hours. Total cholesterol and triglycerides together with LDL and HDL cholesterol should be obtained prior to the initiation of, or switch to, a new potent antiretroviral therapy and repeated 3 to 6 months later. Fasting glucose should be assessed with at least a similar frequency. The oral glucose tolerance test (OGTT) is a reliable and accurate instrument for evaluating insulin resistance and glucose intolerance. An OGTT may be indicated in patients with suspected insulin resistance such as those with adipositas (BMI > 27 kg/m2), a history of gestational diabetes and a fasting glucose level of 110 to 126 mg/dl (impaired fasting glucose). The diagnosis of diabetes is based on fasting glucose levels > 126 mg/dl, glucose levels of > 200 mg/dl independent of fasting status, or a 2-hour OGTT glucose level above 200 mg/dl. Additional factors that could lead to or assist in the development of hyperlipidemia and/or insulin resistance always need to be considered (e.g. alcohol consumption, thyroid dysfunction, liver and kidney disease, hypogonadism, concurrent medication such as steroids, ß-receptor blockers, thiazides, etc.). Therapy and Prevention So far, most attempts to improve or even reverse the abnormal fat distribution by modification of the antiretroviral treatment have shown only modest clinical success. In particular, peripheral fat loss appears to be resistant to most therapeutic interventions. The metabolic components of the syndrome may be easier to improve (Table 3) and more detailed information can be obtained form the Guidelines on the Prevention and Management of Metabolic Diseases in HIV by the European AIDS Clinical Society (www.eacs.eu) Given the inadequate treatment options to resolve lipoatrophy, much attention has been given to prevent the development of abnormal fat distribution in HIV-patients. Unfortunately, many of these studies so far have not sufficient follow-up periods to fully assess the impact of the respecitve antiretroviral drug combinations on body composition. ACTG 5142 is a multi-centre open-label randomized 96-week study (Haubrich 2007). The study compared the development of lipoatrophy, defined as a 20% loss of peripheral fat from baseline, at week 98 in therapy-naïve patients receiving either two nucleoside analogues + lopinaivr/r, two nucleoside analogues + efavirenz, or lopinavir/r + efavirenz only. The results again identified stavudine and zidovudine as major culprits leading to peripheral fat wasting but surprisingly, in a univariate analysis all patients on lopinavir/r-containing regimens had significantly less lipoatrophy (17%) in comparison to efavirenz-containing regimens (32%) independent of the nucleoside analogues that were combined with these drugs. Patients receiving lopinavir/r + efavirenz had lowest rates of lipoatrophy (9%) at week 96. Whether efavirenz had an independent effect on the development of lipoatrophy or whether lopinavir/r exerts some protective effects, remains unclear. Longer follow-up with more detailed statistical analysis of this trial is required before definite conclusions can be drawn. Lifestyle changes Dietary interventions are commonly accepted as the first therapeutic option for hyperlipidemia, especially hypertriglyceridemia. Use of NCEP guidelines may reduce total cholesterol and triglycerides by 11 or 21 %, respectively. Whenever possible, dietary restriction of the total fat intake to 25-35 % of the total caloric intake should be a part of the treatment in conjunction with lipid-lowering drugs. Consultation with professional and experienced dieticians should be considered for HIV-infected patients and their partners. Patients with excessive hypertriglyceridemia (>1000 mg/dl) may benefit from a very low fat diet and alcohol abstinence to reduce the risk of pancreatitis, especially if there is a positive family history or concurrent medications that may harbor a risk of developing pancreatitis. Regular exercise may have beneficial effects, not only on triglycerides and insulin resistance, but probably also on fat redistribution (reduction in truncal fat and intramyocellular fat) and should be considered in all HIV-infected patients (Driscoll 2004). All patients should be advised and supported to cease smoking in order to reduce the cardiovascular risk. Cessation of smoking is more likely to reduce cardiovascular risk than any choice or change of antiretroviral therapy or use of any lipid-lowering drug. Table 3. Therapeutic options for HIV-associated lipodystrophy and related metabolic complications Lifestyle changes (reduce saturated fat and cholesterol intake, increase physical activity, cease smoking) Change antiretroviral therapy [replacement of PI, replacement of stavudine (Zerit™) or zidovudine (Retrovir™)] Statins [e.g. Atorvastatin (Sortis™), Pravastatin (Pravasin™), Fluvastatin (Lescol™)] Ezetimibe (Ezetrol™) Fibrates [e.g. Gemfibrozil (Gevilon™) or Bezafibrat (Cedur™)] Metformin (e.g. Glucophage™) Thiazolidinediones [rosiglitazone (Avandia™), pioglitazone (Actos™)] Recombinant human growth hormones (e.g. Serostim™) Surgical intervention Specific interventions Given the extensive indications that PIs are the culprits substantially contributing to the metabolic side effects, numerous attempts have tried to substitute the PI component of a regimen with nevirapine, efavirenz, or abacavir. Similarly, given the close association of stavudine-based therapy with lipoatrophy, replacement of this thymidine nucleoside analogue by, for example, abacavir or tenofovir has been evaluated in several studies. Indeed, these "switch studies" have demonstrated substantial improvement, although not normalization, of serum lipids (total and LDL cholesterol, triglycerides) and/or insulin resistance in many patients. In patients with hyperlipidemia, substitution of PIs with alternative PIs that have less metabolic side effects (e.g. atazanavir) has also been proven to be a successful strategy (Martinez 2005, Moebius 2005). Protease inhibitor cessation has not been shown to improve lipoatrophy. However, stopping administration of the thymidine nucleoside analogue stavudine or zidovudine usually leads to a slow recovery (over months and years) measured by DEXA and moderate clinical increase in limb fat (Moyle 2005). Under restricted inclusion criteria and study conditions, most patients maintained complete viral suppression after changes to the HAART regimen, but not all of these studies included control groups with unchanged antiretroviral therapy. The MITOX study showed that, in addition to limb fat gains, switching to abacavir had no significant effect on HIV-1 RNA, fasting lipids or glucose after 24 weeks (51; 56). Modest but significant increases in limb fat were observed in those switching to abacavir over 2 years (mean increases of 0.39 kg and 1.26 kg at weeks 24 and 104, respectively); the benefits on limb fat mass were largely restricted to individuals switching away from stavudine. Other randomized studies confirmed these findings and have suggested that switching therapy may also prevent limb fat loss. Recently, a pilot study evaluating the effect of uridine (NucleomaxX™) on lipoatrophy in HIV patients continuing their HAART regimen described a significant increase in subcutaneous fat after only three months (Sutinen 2005). Further studies with uridine, a sugar cane extract, will be necessary to fully assess the effectiveness and safety of this compound for patients with the lipodystrophy syndrome. Other advantageous changes of metabolic parameters have been observed after replacement of the PI by nevirapine or abacavir. This option is, however, not always suitable, and the clinical benefit of effective viral suppression and improved immune function needs to be considered in view of the drug history, current viral load, and resistance mutations. When options are limited, antiretroviral drugs that may lead to elevation of lipid levels should not be withheld for fear of further exacerbating lipid disorders. Table 4. Preliminary treatment recommendations and LDL cholesterol goals for HAART-associated hyperlipidemias Recommendations Risk Category "aimed for" LDL diet if LDL Lipid-lowering drugs if LDL CHD or risk equivalent < 100 mg/dl = 100 mg/dl = 130 mg/dl = 2 RF and 10-years risk £ 20% 10-year risk 10-20% < 130 mg/dl = 130 mg/dl = 130 mg/dl 10-year risk <10% < 130 mg/dl = 130 mg/dl = 160 mg/dl 0-1 risk factors < 160 mg/dl = 160 mg/dl = 190 mg/dl Coronary heart disease (CHD) includes history of myocardial infarction, unstable angina, stable angina, coronary artery procedures, or evidence of clinically significant myocardial ischemia. CHD risk equivalents include clinical manifestations of non-coronary forms of atherosclerotic disease, diabetes, and >2 risk factors with 10-year risk for hard CHD >20 %. Risk factors (RF) include: age (male = 45 years, female = 55 years or premature menopause without hormone replacement), positive family history for premature CHD (in first-degree relatives < 55 years and first-degree female relatives < 65 years), cigarette smoking, hypertension (blood pressure = 140/90 mmHg or taking antihypertension drugs), HDL < 40 mg/dl (1.0 mmol/l). If HDL cholesterol is over > 60 mg/dl (1.6 mmol/l), subtract one risk factor from the total (adapted from Dubé 2000 and Schambelan 2002). Lipid lowering agents should be considered for the treatment of severe hypertriglyceridemia, elevated LDL or a combination of both. The clinical benefit, however, of lipid lowering or insulin-sensitizing therapy in HIV patients with lipodystrophy remains to be demonstrated. In light of the potentially increased cardiovascular risk to recipients of antiretroviral therapy, an American AIDS clinical trial group (ACTG) published recommendations based on the National Cholesterol Education Program (NCEP) for primary and secondary prevention of coronary artery disease in seronegative patients (Table 4). In addition, more detailed recommendations by the European AIDS Clinical Society (www.eacs.eu) have been published recently. However, these recommendations should be considered as being rather preliminary, given the so far limited numbers, sizes and durations of the clinical studies they are based on. It appears reasonable to measure fasting lipid levels annually before and 3-6 months after antiretroviral therapy is initiated or changed. Whenever possible, the antiretroviral therapy least likely to worsen lipid levels should be selected for patients with dyslipidemia. Decision on lipid lowering therapy can be based on estimating the 10-year risk for myocardial infarction according to the Framingham equation (http://hin.nhlbi.nih.gov/atpiii/calculator.asp or http://cphiv.dk/tools.aspx). HMG-CoA reductase inhibitors have been successfully used in combination with dietary changes in HIV patients with increased total and LDL cholesterol. These drugs may decrease total and LDL cholesterol by about 25 % (Grinspoon 2005) and even more effective decrease in lipids have been described when combined with ezetimibe. Many of the statins (as well as itraconazole, erythromycin, diltiazem, etc.) share common metabolization pathways with PIs via the cytochrome P450 3A4 system, thereby potentially leading to additional side effects due to increased plasma levels of statins which can then cause liver and muscle toxicity. Based on limited pharmacokinetic and clinical studies, atorvastatin (Sortis™), fluvastatin (Lescol™), and pravastatin (Pravasin™), carefully administered at increasing doses, are the preferred agents for a carefully monitored therapy in HIV-infected patients on HAART. Lovastatin (Mevinacor™) and simvastatin (Zocor™) should be avoided due to their potential interaction with PIs. Fibric acid analogues such as gemfibrozil or fenofibrate are particularly effective in reducing the triglyceride levels by up to 50 % (Rao 2004, Badoui 2004, Miller 2002, Calza 2003) and should be considered in patients with severe hypertriglyceridemia (>1000 mg/dl). Omega 3 acid ester may be considered as alternative agents. Fibric acid analogues retain a supportive effect on lipoprotein lipase activity and can thereby lower LDL levels. Despite their potentially synergistic effect, co-administration of fibric acid analogues and statins in patients on HAART should only be used carefully in selected individuals, since both can cause rhabdomyolysis. Niacinic acid has been shown to only minimally improve the hyperlipidemia induced by HAART. It does, however, increase peripheral insulin resistance (Gerber 2004). Extended-release niacin (Niaspan™) has been shown to have beneficial effects mainly on triglycerides and was well tolerated at a dose of 2,000 mg daily in a study with 33 individuals. Finally, it should be stressed that the long-term effects of lipid-lowering agents and their impact on cardiovascular outcomes, especially in HIV patients with moderate or severe hypertriglyceridemia, are unknown. Metformin has been evaluated for the treatment of lipodystrophy syndrome. Some studies have revealed a positive effect on the parameters of insulin resistance and the potential reduction of intra-abdominal (but also subcutaneous) fat, although not clinically obvious. Together with exercise training, metformin has been described to reverse the muscular adiposity in HIV-infected patients (Driscoll 2004). Metformin, like all biguanides, can theoretically precipitate lactic acidosis but this adverse interaction has not been described. Use of metformin should be avoided in patients with creatinine levels above 1.5 mg/dl, increased aminotransferase levels, or hyperlactatemia. Thiazolidinediones, such as rosiglitazone (Avandia™) or pioglitazone (Actos™), exhibit the potency to improve insulin sensitivity via stimulation of the PPAR? and other mechanisms. Rosiglitazone has been successfully used to treat abnormal fat distribution in genetic lipodystrophies. Three published studies on HIV patients, however, revealed no or only a minimal improvement in the abnormal fat distribution. But, insulin sensitivity was increased at the expense of increased total cholesterol and triglycerides (Carr 2004, Hadigan 2004, Sutinen 2003, Cavalcanti 2005). Thus, at least rosiglitazone cannot be recommended for general treatment of lipoatrophy in HIV patients at this time (Grinspoon 2005). It also reduces the bioavailability of nevirapine, but not of efavirenz and lopinavir (Oette 2005). Recently, a randomized double-blind placebo-controlled trial (ANRS 113) revealed a significant increase in subcutaneous fat 48 weeks after treatment with pioglitazone 30 mg once daily without demonstrating negative effects on lipid parameters (Slama 2006). Recombinant growth hormone (e.g. Serostim™) at doses of 4-6 mg/d sc over a time course of 8-12 weeks has been demonstrated in some small studies to be a successful intervention for reducing visceral fat accumulation, but it also reduces subcutaneous fat (Kotler 2004). Unfortunately, these improvements have been shown to consistently reverse after the discontinuation of growth hormone therapyThe possible side effects associated with growth hormone therapy include arthralgia, peripheral edema, insulin resistance and hyperglycemia. The FDA declined to approve Serostim for the treatement of the lipoadystrophy syndrome in July 2007. Surgical intervention (liposuction) for the treatment of local fat hypertrophy has been successfully performed, but appears to be associated with an increased risk of secondary infection, and recurrence of the fat accumulation is possible. 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