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Lipodystrophy, Metabolic Disorders and Cardiovascular Risk - Complications of Antiretroviral Therapy

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Abstract

Introduction During the last decade, antiretroviral (ARV) combination therapy has dramatically reduced the mortality of HIV-infected individuals in the countries where these treatments are available. 1,2 Due to the substantially expanded life expectancy and the long-term use of antiretroviral therapy (ART), complications of these highly successful treatment strategies has gained much more attention. The two main complications today associated with antiretroviral therapy are the HIV-associated lipodystrophy and metabolic alterations affecting the lipid and glucose metabolism, which are often but not necessarily found to be associated (see Table 1).

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Table 1: Preliminary Classification of Symptoms of the HIV-associated Lipodystrophy Syndrome

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HIV-associated Lipodystrophy

Clinical Features and Diagnosis
For the affected patient, the most unpleasant adverse event of antiretroviral therapy is the change in body fat called HIVassociated lipodystrophy. The changes in adipose tissue, peripheral subcutaneous fat loss, visceral or dorsocervical fat accumulation or enlargement of the breast have a marked social and psychological impact and can be perceived as disfiguring and stigmatising (see Figures 1, 2a and 2b). Despite more than 10 years of previous experience with antiretroviral therapy, changes in body fat, as distinct from wasting, were only first reported in 1997. 3,4,5 Overall the prevalence has been reported as high as 80% in antiretroviral-experienced patients.


Figure 1: Facial lipoatrophy characterised by sunken cheeks and hollow temples due to buccal and subcutaneous fat loss

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In patients with pronounced fat loss, particularly in the presence of historical comparison (see Figures 1, 2a and 2b, long-term patient-physician relationship), the diagnosis is easy to make. However, although computed tomography, dual-energy X-ray absorptiometry and magnetic resonance imaging (MRI) are suitable methods of measuring body fat in different compartments, the establishment of clear, cross-sectional applicable diagnostic criteria is difficult since body shape varies greatly according to constitutional characteristics, nutritional status, age, race and sex, making a clear definition of pathological fat distribution problematical. Furthermore, to date, no normal values for reference populations exist. A case definition study for lipodystrophy using complex multifactorial modelling including imaging procedures and laboratory tests reached a sensitivity and specificity of about 80%, which stresses the problems in establishing a precise, objective diagnosis. 6

Figure 2a: Visceral fat accumulation, before antiretroviral therapy
Figure 2b: Visceral fat accumulation, four months after initiation of antiretroviral therapy

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Risk Factors and Aetiology
As the HIV-associated lipodystrophy syndrome is almost invariably found in antiretrovirally treated patients, antiretroviral therapy is considered to be a major risk factor. Treatment with dual nucleoside reverse transcriptase inhibitors (NRTIs) or protease inhibitors appears to be associated with a lower prevalence of HIV-associated lipodystrophy compared with triple drug regimens including an HIV-protease inhibitor or stavudine. 7-9 Dual NRTI regimens containing stavudine are reported to have a higher prevalence compared with zidovudine-containing regimens (see Figure 3). 8,10 For non-NRTI (NNRTI)-containing regimens, controlled, prospective studies are not available. The cross-sectional data reported does not allow definite conclusions about the contribution of these agents to the development of lipodystrophy. The same accounts for newer agents such as the nucleotide reverse transcriptase inhibitor tenofovir and atazanavir, an HIV-protease inhibitor with a favourable metabolic profile. In general, no specific antiretroviral regimen has yet been demonstrated not to be associated with the development of the HIV-associated lipodystrophy.

Figure 3: Incidence of lipoatrophy in stavudine-containing regimen versus zidovudine-containing regimen
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Additional factors linked with the development of the HIV-associated lipodystrophy syndrome include: duration of antiretroviral therapy, the nadir of CD4- positive cells, higher age, Caucasian race, elevated C-peptide levels and elevated triglycerides.

A causative mechanism has not been described so far, although current hypotheses include mitochondrial toxicity or interaction of antiretroviral agents with key proteins of lipid metabolism leading to apoptosis of subcutaneous fat cells and growth of visceral fat as a compensatory reaction. 11

Approaches to Treatment
The natural history of visceral fat accumulation may result in spontaneous regression. In contrast, this has only rarely been observed in subcutaneous fat loss.

Since the lipodystrophic changes were first considered to be caused by HIV-protease inhibitors, studies were initiated in which the protease inhibitor was replaced, usually with an NNRTI. Partial improvements, in particular a regression of visceral fat accumulation, but less objective improvement of peripheral fat atrophy, have been reported. 12,13 After stavudine was identified as a major risk factor for the development of subcutaneous fat loss, interruption of stavudine was reported to partially reverse subcutaneous fat atrophy. 14 Modest but continuous increases in subcutaneous fat were reported in lipoatrophic patients after replacement of stavudine or zidovudine by abacavir. 15 However, the facial changes in particular often do not show as much improvement as required to make a substantial change in appearance. As a result, a variety of surgical procedures has been applied. Repeated injection of polylactic acid is, to date, regarded as the safest approach. However, treatment failures occur and, in most cases, the effect is at least partially reversible over time. 16 Subcutaneous fat accumulations such as dorsocervical fat pads were successfully removed by liposuction, but recurrence may occur. 17,18 Visceral fat accumulation, on the other hand, cannot be treated by liposuction.

In a pilot study, exercise training showed modest benefits in the reduction of trunk fat. (19) Recombinant human growth hormone was reported to reduce visceral fat to a marked extent, leading to symptomatic improvement in severe cases after a treatment period of eight to 12 weeks (see Figure 4). 20-22 The effect is, however, reversible after discontinuation of treatment. Possible adverse effects of therapy with recombinant human growth hormone include arthralgia, oedema and hyperglycaemia. The dose used is usually 6mg per day, based on the therapy of HIV-associated wasting. Lower doses may also be effective, substantially decreasing costs and optimising tolerability.

In patients with signs of insulin resistance and visceral fat accumulation, treatment with metformin achieved a reduction in visceral fat of more than 30%. 23,24 In contrast, no effect of metformin on adipose tissue distribution was seen in patients with normal glucose tolerance. 25

A similar observation was reported from rosiglitazone. In a controlled study in patients with normal glucose tolerance, no change in lipodystrophy was observed, 26 whereas a pilot study in patients with a compromised insulin sensitivity showed a gain in subcutaneous fat and a loss of visceral fat. 27

Dyslipidaemia, Insulin Resistance and Cardiovascular Risk Insulin Resistance
Reported disturbances in glucose homeostasis range from subclinical insulin resistance to overt diabetes mellitus, thus showing a pattern similar to Type 2 diabetes. The prevalence of insulin resistance as determined by an intravenous insulin tolerance test seems to be as high as 66% in patients on an HIVprotease- inhibitor-containing regimen, compared with approximately 25% in patients on dual NRTIs and less than 5% in patients without ART. 28 The predominant pathophysiological mechanism is the direct inhibition of glucose transporter 4, but interactions with sterol-regulating element-binding protein (SREBP)-1c may also play a role. Data from switch studies indicates an improvement in insulin sensitivity after changing an HIV-protease inhibitor to nevirapine or abacavir. 29,30

Table 2: Prevalence of pathological glucose tolerance in HIV-positive patients with and without antiretroviral therapy



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Key: PI = protease inhibitor; RTI = reverse transcriptase inhibitor; ART = antiretroviral therapy. p
In agreement with the results from the insulinresistance studies, a pathological glucose tolerance is found more frequently in patients on HIV-protease inhibitor-containing regimen than in patients on reverse transcriptase inhibitors only or those without ART (see Table 2). 31 In contrast, the prevalence of overt diabetes mellitus only appears to be moderately elevated in HIV-positive patients on ARVs. 7

Dyslipidaemia

HIV Infection and Dyslipidaemia
Dyslipoproteinaemia and hyperlipidaemia are welldescribed consequences of advanced HIV infection (see Figure 1). 32,33 These changes are characterised by a decrease in high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol and an increase in triglycerides. An increase in endogenous interferon production, as known from other chronic viral infections such as hepatitis C, was suggested as a pathophysiological explanation. 34

In a small series of autopsies with matched HIVseronegative controls before the introduction of ARV combination therapy, an increased arterial intima media thickness was reported, which was regarded as related to an increased cardiovascular risk with HIV infection itself. 35 However, during this period, the death toll due to AIDS was high and long-term metabolic considerations seemed not clinically relevant.

This has changed considerably during the last years. With a marked decline of the HIV-associated death rate, the importance of other causes of death has become increasingly important. In the general US population aged 35 to 44 years, the incidence of death due to cardiovascular disease is today higher than the incidence of death due to AIDS (see Figure 5). As a result of this and the ageing of the HIVseropositive community, cardiovascular disease and death will become more visible in the future. In addition, as shown in numerous cohort studies, HIVpositive patients smoke more frequently compared with the general population. 36-38


Figure 5: Hyperlipidaemia in HIV Disease

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ARVs and Dyslipideamia
On this background, the changes in lipid and lipoprotein pattern observed in patients undergoing ARV combination therapy, particularly HIVprotease- inhibitor-containing regimens, raised additional concerns (see Table 3). A common observation is that treatment with HIV-proteaseinhibitor- based regimens increase triglycerides, total cholesterol, LDL cholesterol and very LDL (VLDL) cholesterol and may increase HDL cholesterol compared with pre-treatment values in a substantial proportion of patients. This change in lipid pattern seems to be more pronounced in ritonavir-based regimens and absent in regimens containing unboosted atazanavir. 39,40 However, if French HIVseropositive patients from a cohort treated with HIVprotease inhibitors were compared with the agematched general population from the World Health Organization (WHO) Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) Project, HIV-seropositive patients did show higher triglycerides and a lower HDL cholesterol, but not a higher total or LDL cholesterol (see Table 4). 36


Table 3: Lipoprotein pattern in HIV-seropositive subjects with and without antiretroviral therapy

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* p


Treatment with NNRTIs, i.e. efavirenz or nevirapine, increases HDL cholesterol and, to a lesser extent, LDL cholesterol, resulting in an improvement of the LDL: HDL ratio. 41 NRTIs are usually considered without major influence on lipid patterns, but recent reports suggest an association between an increase in cholesterol and triglyceride levels and treatment with stavudine. 42


Table 4: Coronary risk factors in French HIV+ men
35-44 years treated with protease inhibitor compared with the general population

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Source: C Leport, M Saves, P Ducimetiere, et al., “Coronary Heart Disease Risk (CHD) in French HIV-infected Men Started on a Protease Inhibitor (PI)-containing Regimen Compared to the General Population”, 9th CROI 2002 [abstract 697-T].

Pathophysiology
The current pathophysiological explanations for the ARV-associated hyperlipidaemia are an increase in the hepatic production of VLDLs, the inhibition of lipoprotein lipase, the interaction of HIV-protease inhibitors with SREBP 1-c HIV-protease inhibitors with SREBPs or the apoptosis of subcutaneous fat cells leading to a reduced storage capacity for the circulating lipoproteins. 11,43,44 The majority of the cholesterol in HIV-associated dyslipidaemia is found in the VLDL fraction showing in a relevant proportion of patients a pattern with large VLDL particles similar to familial hypertriglyceridaemia, a rather benign lipid disorder with a low cardiovascular risk (see Figure 5). 45 However, in some patients, the lipoprotein profile may resemble more the classic cardiovascular risk profile with an increase in small LDL particles. 46

Cardiovascular Risk Assessment
In principle, dyslipidaemia associated with an increase in cholesterol and/or triglycerides suggests an increased cardiovascular risk. The clinical data, however, is still conflicting. Studies assessing the carotid intima media thickness as a surrogate marker for an increased cardiovascular risk have identified treatment with HIV-protease inhibitors as a risk factor. 47,48 Other studies could not support this finding, but reported HIV infection itself to be an independent risk factor for atherosclerosis49 or identified classical proatherogenic risk factors only. 50

Clinical end-point studies also provide no clear picture. The preliminary results of two cohort studies suggest an increased cardiovascular disease rate in patients treated with HIV-protease inhibitors compared with patients on non-protease-inhibitor regimens 51 or on ARV combination therapy in general. 52 Neither studies had an HIV-seronegative cont
ol or control for the duration of HIV infection. A multivariate analysis from the latter study suggested a strong influence of classical risk factors such as smoking, age and diabetes mellitus on the cardiovascular risk. 52 In contrast, no increase in cardiovascular morbidity or mortality was reported from another large cohort study in patients with ART compared with patients without ARVs. 38 To further increase the confusion, a large retrospective cohort study found a higher prevalence of cardiovascular disease in HIV-seropositive individuals compared with HIV-seronegative controls independent from ART status. 53

Treatment Strategies
From a clinical standpoint, a switch to drugs with a more favourable lipid profile or treatment with lipidlowering agents of patients with active cardiovascular disease, of older age with the presence of multiple classical risk factors such as smoking, hypertension, diabetes mellitus, history of cardiovascular events in close relatives and high LDL cholesterol with or without a decreased HDL cholesterol may be justified. However, in patients with no additional cardiovascular risk factors, or those below 35 years, a transient increase in cholesterol due to ART may not represent a relevant cardiovascular risk factor. In addition, in patients with limited treatment options and advanced HIV infection, the control of HIV easily outweighs the cardiovascular risk.

In general, dietary restriction of total fat (25% to 35% of total calories), saturated fat (54,55

Figure 6: Trends in annual rates of death from leading causes of death among persons 25 to 44 years old

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Lipid-lowering agents should be considered for treatment of severe hypertriglyceridaemia (> 800mg/dl) or markedly elevated cholesterol that do not respond to modification of lifestyle or ARV treatment, or for patients in whom such modifications are not appropriate. Fibrates are the preferred agents for lowering of hypertriglyceridaemia. Statins are the medication of choice to treat LDLhypercholesterolaemia. Both statins and fibrates have been shown to lower lipid levels in hyperlipidaemia associated with HIV-protease inhibitors. 55-57 Restoration of lipid levels according to the current NCEP guidelines may, however, be difficult to achieve. 58 Combining statins with fibrates is associated with an increased risk of rhabdomyolysis and should only be used after a thorough risk-benefit analysis in individual cases. 59 Based on data from interaction studies with HIV-protease inhibitors pravastatin and atovarstatin are the preferred agents and simvastatin or lovastatin should be avoided, because of high drug levels. 60 In addition, pravastatin has no major influence on the drug levels of HIVprotease inhibitors themselves. 61 It must be mentioned that the long-term effect of lipidlowering agents and their impact on cardiovascular outcomes when used in the treatment of ARVinduced hyperlipidaemia are unknown.


Figure 7: Hypothesis of highly active antiretroviral therapy-associated hyperlipidaemia

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In conclusion, being HIV-infected may constitute a cardiovascular risk factor by itself. Treatment of HIV infection may consequently reduce this cardiovascular risk. A relevant proportion of ARV-induced hyperlipidaemia may be transient, because of the sequencing of different ARV regimens. In addition, in a number of patients, ARV-induced hyperlipidaemia seems not to be LDL- but VLDLcholesterol- driven, which may represent a different cardiovascular risk. Ideally, the individual lipid profile should be assessed before starting or switching ART and a second time thereafter in addition to the assessment of the individual cardiovascular risk factors. On this basis, a decision in favour of or against modifying ARV treatment, recommending dietary restrictions or initiating treatment with lipid-lowering agents should be made. In general, hyperlipidaemia due to ART should not lead to undertreatment with ARVs or overtreatment with statins or fibrates. Given the overall low number of cardiovascular events, an individualised approach seems adequate.

Conclusion
The current approach to ART is not only driven by maximising the antiviral efficacy as in previous years, but by reducing the current complications of the available treatments. Whereas lipodystrophic body changes are the most visible and psychological harmful adverse events for the patient, the metabolic alterations induced by ARVs, which may possibly increase the cardiovascular risk for at least a subgroup of patients, have drawn much attention during recent years from treating physicians. With new ARV agents available, the development of less toxic combinations will be a major challenge for the near future and will be an important criterion influencing the choice of which ARV regimen to begin with and which to switch to."

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