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Nutrition and the HIV-associated lipodystrophy syndrome

Published online by Cambridge University Press:  23 November 2012

Cathríona Rosemary Loonam
Affiliation:
Diabetes and Nutritional Sciences Division, School of Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, LondonSE1 9NH, UK
Anne Mullen*
Affiliation:
Diabetes and Nutritional Sciences Division, School of Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, LondonSE1 9NH, UK
*
*Corresponding author: Dr Anne Mullen, fax +44 20 7848 4171, email anne.mullen@kcl.ac.uk
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Abstract

HIV-associated lipodystrophy syndrome (HALS), comprising metabolic and morphological alterations, is a known side effect of highly active antiretroviral therapy (HAART). Evidence for the role of nutrition in the management of the systemic parameters of HALS is currently limited. In the present paper we review the current knowledge base surrounding HALS, focusing particularly on the role of nutrition in mitigating the systemic parameters of the syndrome. Reported prevalence of HALS was found to vary from 9 to 83 % due to lack of a standardised definition, as well as variations in assessment methods and in the study population used. HALS is associated with both morphological (lipoatrophy, lipohypertrophy) and metabolic (dyslipidaemia, glucose intolerance, diabetes, hypertension, endothelial dysfunction and atherosclerosis) alterations, which may occur singly or in combination, and are associated with an increased risk of CVD. HAART-induced adipocyte inflammation, oxidative stress and macrophage infiltration, as well as altered adipocyte function and mitochondrial toxicity, have been shown to be central to the development of HALS. The adipocyte, therefore, represents a plausible target for treatment. Pharmacological and surgical treatment interventions have shown effect. However, their use is associated with numerous adverse effects and complications. Targeted lifestyle interventions may provide a useful alternative for managing HALS owing to their safety and tolerability. A Mediterranean-style diet has been found to be effective in improving the systemic parameters of HALS. Furthermore, the effects of n-3 PUFA supplementation are encouraging and future randomised controlled trials investigating the beneficial effects of n-3 PUFA in HALS are justified.

Type
Review Article
Copyright
Copyright © The Authors 2012

Introduction

The number of individuals living with HIV/AIDS has increased globally(Reference Reynolds and Quinn1), with a current estimated global prevalence of 33·3 million(2). In the UK alone, the incidence of HIV/AIDS has almost doubled in the past decade and there are now an estimated 86 200 individuals living with HIV/AIDS(3). This represents less than 1 % of the global HIV/AIDS population, while Sub-Saharan Africa remains most severely affected by the HIV pandemic, with 67 % of the global HIV/AIDS population located here(2).

A significant turning point in the management of HIV came with the introduction of the nucleoside RT inhibitor (NRTI) zidovudine (ZDV), the first antiretroviral drug approved by the Food and Drug Administration in 1987(4). For those with access to antiretroviral therapy (ART), HIV infection no longer represented an immediate threat to mortality(Reference de Béthune5), and was, in many cases, transformed into a chronic condition.

The development of subsequent antiretroviral drugs zalcitabine (ddC), didanosine (ddI) and stavudine (d4T) led to combination ART (cART), the first of which was ZDV and ddC(Reference McLeod and Hammer6). cART, commonly referred to as highly active ART, consists of at least two antiretrovirals, most usually from one of three main drug classes: NRTI and nucleotide RT inhibitors (NtRTI), protease inhibitors (PI) and non-nucleoside RT inhibitors (NNRTI)(Reference Shafer and Vuitton7). NRTI and NtRTI interact with the substrate-binding site of the HIV RT enzyme(Reference De Clercq8), which halts the production of new virions(Reference Kakuda9, 10). NNRTI bind specifically with a non-substrate-binding site of RT, disrupting the enzyme's catalytic site(Reference De Clercq8, Reference Wynn, Zapor and Smith11); PI inhibit the protease enzyme, thus preventing the host cell from cleaving the viral proteins into active viral particles(Reference Wynn, Zapor and Smith11); fusion inhibitors prevent viral capsid entry into the host cell by blocking the attachment, co-receptor binding and fusion of the viral particle(Reference Greenberg and Cammack12); C-C chemokine receptor type-5 (CCR5) inhibitors prevent viral entry into the host cell by inhibiting CCR5 signalling, which allows the virus to enter its target cell(Reference Dorr, Westby and Dobbs13); integrase inhibitors, a new class of antiretrovirals, inhibit the insertion of the HIV pro-viral DNA into the host cell genome(Reference De Clercq14).

Shortly after the introduction of PI, which were in the context of sole use or cART, case reports of disorders of glucose metabolism(Reference Dubé, Johnson and Currier15) and alterations in body fat distribution(Reference Deeks16Reference Viraben and Aquilina19) began to appear in the literature. HIV-associated lipodystrophy syndrome (HALS) was the term subsequently used to define these metabolic and morphological alterations, and was first described in 1998 by Carr et al. (Reference Carr, Samaras and Burton20). Though ART, particularly PI and NRTI, are the main drivers of HALS, the virus itself and host genetics also contribute to its pathogenesis(Reference Mallon21).

HALS comprises peripheral lipoatrophy (LA) and central lipohypertrophy (LH)(Reference Omolayo and Sealy22), which can occur together or separately(Reference Lichtenstein, Balasubramanyam and Sekhar23), dyslipidaemia(Reference Worm, Friis-Møller and Bruyand24), insulin resistance(Reference Samaras, Wand and Law25), type 2 diabetes mellitus (T2DM)(Reference Lumpkin26Reference Brown, Cole and Li28), hypertension(Reference Samaras, Wand and Law25), endothelial dysfunction(Reference Masiá, Padilla and García29), and altered cytokine and adipokine production(Reference Masiá, Padilla and García29). Collectively these abnormalities have been associated with an increased risk of CVD in this population(Reference Friis-Møller, Sabin and Weber30Reference Mondy, Overton and Grubb32). HALS has been associated with risk factors for premature CVD and premature myocardial infarction (MI)(Reference Vittecoq, Escaut and Chironi33Reference Guaraldi, Zona and Alexopoulos38).

Nutrition plays a key role in maintaining health in HIV infected individuals(39). According to a recent consensus statement from the American Dietetic Association(39), evidence on the role of diet in mitigating systemic parameters in HALS is limited. There are a number of studies that have generally investigated the area by cross-sectional analysis of diet and systemic parameters of HIV-positive adults with and without HALS. Existing evidence indicates the potential benefit of a diet high in fibre(Reference Hendricks, Dong and Tang40, Reference Shah, Tierney and Adams-Huet41) and Ca(Reference Leite and Sampaio42), which includes polyunsaturated fat(Reference Hadigan, Jeste and Anderson43), and which corresponds with a Mediterranean-style dietary pattern(Reference Tsiodras, Poulia and Yannakoulia44, Reference Turčinov, Stanley and Rutherford45) in lowering the risk of metabolic and morphological abnormalities in HALS.

In the present article, we aim to review the existing knowledge base surrounding HALS, including epidemiology, associated metabolic and morphologic complications, potential molecular mechanisms involved in its pathogenesis, as well as strategies used in the management of the condition, focusing particularly on the potential role of nutrition in mitigating the complications of the syndrome.

Prevalence and definition

The prevalence of HALS has been shown to vary widely from 9 to 83 % depending on the assessment criteria used (Table 1). Furthermore, the study populations used to assess prevalence of the condition may also account for the observed differences in published prevalence. The majority of studies recruit only HIV-infected individuals receiving ART or those receiving ART and ART-naive comparisons. Five studies compare those with HIV infection with those without HIV infection(Reference Carr, Samaras and Burton20, Reference Mondy, Overton and Grubb32, Reference Jacobson, Tang and Spiegelman46Reference Tien, Cole and Williams48), and only one of these compares prevalence rates between HIV-infected individuals receiving PI, those who were PI-naive and healthy men(Reference Carr, Samaras and Burton20).

Table 1 Prevalence of the HIV-associated lipodystrophy syndrome (HALS)

CS, cross-sectional; HIV+, HIV-positive; F, female; Anthro, anthropometry; Biochem, biochemical assessment; ART, antiretroviral therapy; P, prospective study; SHCS, Swiss HIV Cohort Study; LA, lipoatrophy; LH, lipohypertrophy; M, male; RCT, randomised controlled trial; CREATE, Cardiovascular Risk Evaluation and Antiretroviral Therapy Effects; IDF, International Diabetes Federation; NCEP ATP III, National Cholesterol Education Program Adult Treatment Panel III; LipolCoNa, substudy of the Italian Cohort Naive Antiretrovirals; DXA, dual-energy X-ray absorptiometry; CSOS, cross-sectional observational study; APROCO, Antiprotéases Cohorte; OB, observational study; T2DM, type 2 diabetes mellitus; RT, randomised trial; BIA, bioelectrical impedance analysis; NIH, National Institutes of Health; HIV − , HIV-negative; PI, protease inhibitor; CC, case–control study; CT, computed tomography; NHANES, National Health and Nutrition Examination Survey; HOPS, HIV Out-Patient Study; PCS, prospective cross-sectional study; EU, European Union; POB, prospective observational study; DAD, Data Collection on Adverse Effects of Anti-HIV Drugs.

* Long-term follow-up of a randomised controlled trial.

Based on the ‘Report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to Definition’(Reference Grundy, Brewer and Cleeman91).

The methods used to identify HALS also greatly affect prevalence estimates. Currently used methods include patient self-report, physician examination/report, a combination of these, anthropometric indices, biochemical indices, dual-energy X-ray absorptiometry, computed tomography (CT) and MRI. Patient self-report and physician report are commonly used methods; however, the accuracy of these subjective methods has not been evaluated(Reference Norris and Dreher49), and physician and patient assessments of HALS have been shown to vary(Reference Benn, Ruff and Cartledge50).

Carter et al. (Reference Carter, Hoy and Bailey51) showed that differences in the definition of the syndrome can contribute to a variation in prevalence of between 19 and 65 %. Existing definitions include LA or LH(Reference Tien, Cole and Williams48, Reference Boufassa, Lascaux and Meyer52Reference Kalyanasundaram, Jacob and Hemalatha62), LA alone(Reference Carr, Samaras and Burton20, Reference Seminari, Tinelli and Minoli61Reference Zannou, Denoeud and Lacombe75), LH alone(Reference Seminari, Tinelli and Minoli61Reference Paton, Earnest and Ng68, Reference Pujari, Dravid and Naik70Reference Heath, Hogg and Chan78), or a combination of LA and LH(Reference Boufassa, Lascaux and Meyer52, Reference Galli, Cozzi-Lepri and Ridolfo54, Reference Galli, Veglia and Angarano55, Reference Seminari, Tinelli and Minoli61, Reference Kalyanasundaram, Jacob and Hemalatha62, Reference Thiébaut, Daucourt and Mercié64, Reference Heath, Singer and O'Shaughnessy66Reference Paton, Earnest and Ng68, Reference van Griensven, De Naeyer and Mushi71Reference Zannou, Denoeud and Lacombe75, Reference Martínez, Mocroft and García-Viejo79Reference van der Valk, Gisolf and Reiss85). The main definitions for the metabolic alterations associated with HALS (abdominal obesity, dyslipidaemia, raised blood pressure, insulin resistance and a pro-inflammatory, prothrombotic state) are the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III criteria(86), used by the majority of researchers(Reference Worm, Friis-Møller and Bruyand24, Reference Samaras, Wand and Law25, Reference Mondy, Overton and Grubb32, Reference Sobieszczyk, Hoover and Anastos47, Reference Jevtovic, Dragovic and Salemovic73, Reference Jericó, Knobel and Montero87, Reference Elgalib, Aboud and Kulasegaram88), the International Diabetes Federation (IDF) Guidelines(89) used in one study(Reference Zannou, Denoeud and Lacombe75), a combination of NCEP and IDF used in three studies(Reference Samaras, Wand and Law25, Reference Elgalib, Aboud and Kulasegaram88, Reference Gkrania-Klotsas and Klotsas90), the ‘Report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to Definition’(Reference Grundy, Brewer and Cleeman91) used in one study(Reference Jacobson, Tang and Spiegelman46), and the US National Institutes of Health Division of AIDS definition (2004 version)(92) used in one study(Reference Han, Zhou and Saghayam93). In addition to metabolic definitions, anthropometric techniques have been used in the identification of central adiposity in HALS(Reference Mutimura, Stewart and Rheeder59). The use of anthropometry in detecting small changes in fat distribution in HIV patients is, however, limited, as it is associated with inter-individual differences in the measurement of fat distribution in HIV patients(Reference Wanke, Polsky and Kotler94).

Carr et al. (Reference Carr, Emery and Law82) have attempted to objectively define HALS and developed an objective case definition for the syndrome based on age, sex, duration of HIV infection, HIV disease stage, waist:hip ratio, anion gap, serum HDL concentration, trunk:peripheral fat ratio, percentage leg fat, and intra-abdominal:extra-abdominal fat ratio. This definition is 79 % sensitive and 80 % specific for the diagnosis and intensity of the syndrome. However, the definition requires anthropometric variables from dual-energy X-ray absorptiometry and CT, reducing its utility in clinical practice(Reference Benn, Ruff and Cartledge50).

Research has also focused on grading the severity of the components of HALS. The HIV Outpatient Study scale was one of the first methods used to assess the severity of HALS in different areas of the body, including the abdomen, arms, legs, hips/buttocks and face(Reference Lichtenstein, Ward and Moorman65). Abnormalities in each area were graded from ‘subtle’ (noticeable only if looked for; no change in clothing fit), to ‘moderate’ (easily noticed by patient or physician; clothing has become tight or loose) and ‘severe’ (obvious to the casual observer; has required a change in clothing size). All changes were graded both subjectively (patient self-report) and objectively (physician examination)(Reference Lichtenstein, Ward and Moorman65). Subsequently, Carr & Law(Reference Carr and Law95) developed a severity grading scale based on their objective case definition of HALS; however, in the same paper they recommended abandoning the assessment of lipodystrophy severity, and suggested the lipodystrophy case definition score provided the best objective measure of severity. Recently, Fontdevila et al. (Reference Fontdevila, Serra-Renom and Raigosa96) have developed a CT-validated grading system for determining the severity of facial LA based on the loss of facial bone and muscle structures. This grading system is recommended for use when comparing the efficacy of fat grafting procedures and, therefore, may not be ideal in routine clinical practice.

In the absence of a clear definition for HALS, the incidence and prevalence of the syndrome remain uncertain(Reference Guaraldi and Baraboutis97). It is clear that the definition and diagnostic criteria for HALS are poor, epidemiological data on its prevalence and incidence are also lacking, and as a result Guaraldi & Baraboutis(Reference Guaraldi and Baraboutis97) question whether HALS ‘is over?’. In this paper, the authors suggest replacing the definition of HALS with the non-infectious co-morbidities that develop as a result of HIV infection.

Morphological alterations

In their original paper, Carr et al. (Reference Carr, Samaras and Burton20) refer to lipodystrophy as ‘fat wasting of the face, limbs and upper trunk’. Further research by the same authors acknowledged lipid accumulation as another feature of HALS(Reference Carr, Samaras and Thorisdottir98). A review, published the same year, concluded that LA and LH are distinct entities with individual pathophysiological mechanisms underlying their development(Reference Safrin and Grunfeld99). Although these early findings separate LA and LH in the definition of HALS, recent findings conclude that the abnormalities associated with HALS, including LA and LH, can occur singly or in combination(Reference Omolayo and Sealy22); for the purposes of the present review they will be discussed separately.

Lipoatrophy

LA, characterised by loss of subcutaneous fat(Reference Saint-Marc, Partisani and Poizot-Martin100), is distinctly different from the traditional HIV wasting syndrome, characterised by a disproportionate decrease in lean body mass(Reference Grinspoon, Corcoran and Miller101). LA, as a side effect of ART, is seen mainly in the face (facial LA) and the extremities (peripheral LA)(Reference Saint-Marc, Partisani and Poizot-Martin63). Fat wasting of the face usually presents as malar or temporal wasting(Reference Omolayo and Sealy22). Peripheral fat wasting typically occurs in the arms, shoulders, buttocks and legs(Reference Engelson, Kotler and Tan102). The latter type of fat wasting is often accompanied by prominent superficial veins, which contribute to the emaciated appearance observed in these individuals(Reference Bergersen, Sandvik and Ellingsen103).

Initial reports attributed the development of LA to PI(Reference Carr, Samaras and Burton20); however, it is now known that the use of NRTI such as d4T is more strongly linked with its development(Reference Seminari, Tinelli and Minoli61, Reference Nolan, Hammond and James104). Some NRTI combinations, such as d4T and didanosine (ddI), are contraindicated as a result of their severe lipoatrophic side effects(Reference Grinspoon and Carr105). In addition to type of ART, a number of other risk factors for LA have been identified including older age(Reference Grinspoon and Carr105), a decrease in BMI before ART(Reference Lichtenstein, Delaney and Armon69), white race(Reference Lichtenstein, Delaney and Armon69), use of PI for greater than 2 years(Reference Carr, Samaras and Thorisdottir98), and factors relating to disease progression including lower CD4 cell count(Reference Lichtenstein, Delaney and Armon69), duration and severity of HIV infection(Reference Lichtenstein, Ward and Moorman65, Reference Jacobson, Knox and Spiegelman106) and prior diagnosis of AIDS(Reference Lichtenstein, Ward and Moorman65).

Lipohypertrophy

LH is characterised by adipose tissue accumulation mainly in the intra-abdominal (‘Crix belly’)(Reference Viraben and Aquilina19, Reference Carr, Samaras and Burton20, Reference Engelson, Kotler and Tan102, Reference Miller, Jones and Yanovski107, Reference Dinges, Chen and Snell108) and dorsocervical (‘buffalo hump’) regions(Reference Hengel, Watts and Lennox17, Reference Roth, Kravcik and Angel18, Reference Lo, Mulligan and Tai109). Other characteristic features of LH include breast enlargement, observed in both males and females(Reference Mutimura, Stewart and Rheeder59, Reference Paton, Earnest and Ng68, Reference Goujard, Boufassa and Deveau77, Reference Bernasconi, Boubaker and Junghans80, Reference Savès, Raffi and Capeau81), accumulation of adipose tissue on the anterior region of the neck(Reference Palella, Chmiel and Riddler110), side of the neck(Reference Mutimura, Stewart and Rheeder59, Reference Paton, Earnest and Ng68), under the axillae(Reference Palella, Chmiel and Riddler110) and in the suprapubic region(Reference Guaraldi, Orlando and Squillace111), and localised or generalised lipomas(Reference Miller, Carr and Emery56). LH is distinct from simple visceral fat accumulation, as it is associated with a decrease, rather than an increase, in subcutaneous fat(Reference Gkrania-Klotsas and Klotsas90, Reference Dinges, Chen and Snell108). It is worth noting that abdominal LH is the most commonly identified lipohypertrophic change in HALS patients(Reference Boufassa, Lascaux and Meyer52, Reference Miller, Carr and Emery56, Reference Puttawong, Prasithsirikul and Vadcharavivad57, Reference Mutimura, Stewart and Rheeder59, Reference Paton, Earnest and Ng68, Reference Goujard, Boufassa and Deveau77Reference Savès, Raffi and Capeau81, Reference Engelson, Kotler and Tan102).

Risk factors associated with the development of LH in the context of HIV and ART include age, female sex, having a BMI of greater than 25 kg/m2(Reference Manfredi, Calza and Chiodo260), and having a low CD4 cell count(Reference Lichtenstein, Ward and Moorman65, Reference Lichtenstein, Delaney and Armon69). The type of ART has also been shown to play a role in the pathogenesis of LH. Jacobson et al. (Reference Jacobson, Tang and Spiegelman46) demonstrated that LH was observed in both patients who have and have not been exposed to PI, indicating that PI are not the only cause of LH. Thymidine analogues in particular have been shown to increase the risk of developing LH(Reference van Griensven, De Naeyer and Mushi71). Novel drugs, such as the peptidic HIV-1 fusion inhibitor enfuvirtide, have also recently been implicated in the development of LH(Reference Cooper, Cordery and Reiss112). In addition to the type of ART, a longer duration of treatment has been associated with an increased risk of developing LH(Reference Martínez, Mocroft and García-Viejo79).

Metabolic alterations

Dyslipidaemia

Before the advent of ART, evidence suggested that HIV infection itself caused abnormalities of blood lipids(Reference Grunfeld, Kotler and Hamadeh113, Reference Grunfeld, Kotler and Shigenaga114). One study investigating lipid abnormalities associated with seroconversion in men found that HIV infection was associated with a reduction in total cholesterol, LDL and HDL(Reference Riddler, Smit and Cole115). Subsequent initiation of ART in the same subjects led to a significant increase in total cholesterol and LDL concentrations from baseline to follow-up, confirming the role of ART in the pathogenesis of dyslipidaemia in HIV(Reference Riddler, Smit and Cole115).

The prevalence of lipid disorders in HIV-infected individuals treated with ART has been shown to vary from 24 to 72 %(Reference Chêne, Angelini and Cotte53, Reference Thiébaut, Daucourt and Mercié64, Reference Pujari, Dravid and Naik70, Reference Zannou, Denoeud and Lacombe75, Reference Elgalib, Aboud and Kulasegaram88, Reference Tomažič, Silič and Karner116, Reference Lesi, Soyebi and Eboh117). Characteristic lipid abnormalities associated with HALS include elevated total cholesterol and LDL, elevated TAG(Reference Carr, Samaras and Burton20) and reduced HDL(Reference Friis-Møller, Weber and Reiss118). Early studies attributed the development of dyslipidaemia to PI therapy(Reference Carr, Samaras and Chisholm119, Reference Periard, Telenti and Sudre120). Subsequent studies have, however, shown that both NRTI and NNRTI are involved in the development of lipid abnormalities in HIV(Reference van Leth, Phanuphak and Stroes121, Reference Jones, Sawleshwarkar and Michailidis122). Furthermore, both in vitro and in vivo studies have demonstrated an association between cART and the development of more pronounced lipid abnormalities(Reference Friis-Møller, Weber and Reiss118, Reference Kosmiski, Miller and Klemm123). A recent UK study found that impaired postprandial TAG clearance in HIV patients receiving ART was exacerbated by a combination of NRTI and PI(Reference Ware, Jackson and Wootton124). A recent retrospective cohort study from Brazil found that PI increased serum TAG but not total cholesterol concentrations in 102 HIV-infected patients(Reference Monnerat, Cerutti Junior and Caniçali125). In the same study NNRTI were associated with an increase in total cholesterol with no significant effect on TAG levels. Similarly, Walmsley et al. (Reference Walmsley, Cheung and Fantus72) in their prospective cohort study of HIV patients found that after 12 months of treatment with NNRTI, only total cholesterol concentrations increased significantly. Results pertaining to the duration of ART and risk of lipodystrophy are inconsistent, with some showing that increased duration increases risk of dyslipidaemia(Reference Savès, Raffi and Capeau81, Reference Friis-Møller, Weber and Reiss118), while other studies have shown no effect of duration on the risk of dyslipidaemia(Reference Mondy, Overton and Grubb32).

A number of factors have been identified which are associated with an increased risk of dyslipidaemia in patients receiving ART. Similar to the general population, dyslipidaemia in HIV has been shown to occur to a greater extent in female patients(Reference Pernerstorfer-Schoen, Jilma and Perschler126). Although African-Americans in the general population have been shown to have a lower prevalence of hypertriacylglycerolaemia(Reference Gaillard, Schuster and Osei127), Foulkes et al. (Reference Foulkes, Wohl and Frank128) found that exposure to PI induced the greatest increase in TAG concentrations in black compared with white and Hispanic populations. This may indicate a role for race/ethnicity in increasing the risk of dyslipidaemia in HIV. It is important to note, however, that this study had, according to the authors, limited power, making it difficult to detect small interaction effects within these racial/ethnic groups. A number of polymorphisms of genes including APOA5, APOC3, APOE, sterol-regulatory element-binding protein-1c (SREBP1c) and TNF have also been associated with an increased risk of dyslipidaemia in HIV-infected individuals(Reference Guardiola, Ferré and Salazar129Reference Tarr Philip, Taffé and Bleiber133).

It has been suggested that the diagnosis of dyslipidaemia in HIV-infected individuals should be made using recommendations for non-HIV-infected individuals(Reference Gkrania-Klotsas and Klotsas90). For the general population, dyslipidaemia is diagnosed using a fasting lipid profile and defined using the NCEP ATP III criteria. Ideally, fasting lipid profiles should be offered to patients before initiation of ART in order to gain an insight into the exact changes caused thereafter by ART(Reference Gkrania-Klotsas and Klotsas90). LDL levels are the primary target of the NCEP ATP III guidelines, which recommend that lifestyle modifications be trialled first, followed by statins, to lower LDL(86).

Glucose abnormalities

Before the ART era, the development of T2DM in HIV-infected individuals was attributed to the anti-microbial medication pentamidine(Reference Abourizk, Lyons and Madden134) and was relatively uncommon(Reference Bradbury and Samaras135). Following the introduction of PI, however, a greater number of reported glucose disorders began to emerge in HIV-infected individuals(Reference Dubé, Johnson and Currier15, Reference Eastone and Decker136, Reference Visnergarwala, Krause and Musher137).

Abnormalities in fasting blood glucose concentration have been found in up to 20 % of patients(Reference Thiébaut, Daucourt and Mercié64, Reference Walmsley, Cheung and Fantus72, Reference Mercier, Gueye and Cournil74, Reference Elgalib, Aboud and Kulasegaram88), while prevalence figures for impaired fasting glucose(Reference Mutimura, Stewart and Rheeder59, Reference Mercier, Gueye and Cournil74, Reference Zannou, Denoeud and Lacombe75, Reference Savès, Raffi and Capeau81, Reference Elgalib, Aboud and Kulasegaram88) and impaired glucose tolerance(Reference Puttawong, Prasithsirikul and Vadcharavivad57, Reference Walmsley, Cheung and Fantus72, Reference Jevtovic, Dragovic and Salemovic73, Reference Savès, Raffi and Capeau81, Reference Carr, Samaras and Thorisdottir98, Reference Tomažič, Silič and Karner116) have been shown to vary from 3·8 to 18 % and from 7 to 37 %, respectively. In comparison, the prevalence of impaired glucose tolerance and impaired fasting glucose in the general population is 8·4 and 6·3 %, respectively(Reference van Dieren, Beulens and van der Schouw138).

Puttawong et al. (Reference Puttawong, Prasithsirikul and Vadcharavivad57) and Tomažič et al. (Reference Tomažič, Silič and Karner116) identified the prevalence of insulin resistance in 30 and 38 % of their HIV subjects, respectively. The prevalence of diabetes in the general population has been shown to be 9·8 % for men and 9·2 % for women(Reference Danaei, Finucane and Lu139), while in patients receiving ART, prevalence has been shown to range from 7 to 27 %(Reference Jevtovic, Dragovic and Salemovic73, Reference Savès, Raffi and Capeau81, Reference Carr, Samaras and Thorisdottir98, Reference Tomažič, Silič and Karner116). Although the aforementioned studies have shown a relationship between ART and glucose abnormalities in HALS, a number of studies have failed to show a relationship with either glycaemic parameters(Reference Sobieszczyk, Hoover and Anastos47, Reference Chêne, Angelini and Cotte53, Reference Carr, Hudson and Chuah140) or insulin resistance(Reference Dubé, Parker and Tebas141), highlighting the inconsistencies that currently exist in the literature.

Risk factors for the development of glucose abnormalities in the context of HIV and ART have been recently reviewed and were found to include older age, existing LA, non-white race, family history of T2DM, and disease factors, such as co-infection with hepatitis C(Reference Gkrania-Klotsas and Klotsas90). Furthermore, a recent study from Bangkok found that the risk of pre-diabetes in HIV-infected patients receiving ART increased with each 5 kg increase in body weight(Reference Srivanich, Ngarmukos and Sungkanuparph142). In the same study, the NNRTI nevirapine was found to be protective for pre-diabetes. Both in vitro and in vivo studies have demonstrated the negative effect of PI on glucose homeostasis in HIV(Reference Behrens, Dejam and Schmidt27, Reference Lee, Seneviratne and Noor143, Reference Woerle, Mariuz and Meyer144). Results from the Women's Interagency HIV Study showed that longer-term exposure to NRTI increased the incidence of T2DM, indicating their role in increasing the risk of glucose abnormalities in HALS(Reference Tien, Schneider and Cole145).

Diagnosis of glucose disorders in HALS is similar to the general population and has been made on the basis of guidelines from the International Diabetes Federation(89) and the American Diabetes Association(146). According to these guidelines, fasting plasma glucose greater than 5·6 mmol/l is defined as impaired glucose tolerance and a value greater than 7 mmol/l is indicative of frank diabetes. The American Diabetes Association criteria for diagnosing abnormalities of glucose metabolism state that patients must present with symptoms (polyuria, polydipsia, weight loss) and a random glucose of greater than 11·1 mmol/l for a diagnosis of diabetes to be made. Furthermore, Wohl et al. (Reference Wohl, McComsey and Tebas147) recommend follow-up with fasting blood glucose every 3–6 months for at-risk patients and those undergoing changes in their ART regimen.

Hypertension

Both LA and LH have been shown to be independently associated with hypertension in HIV-infected individuals receiving ART(Reference Crane, Grunfeld and Harrington148). As for the general population, hypertension in HIV patients is associated with an increased risk of CVD(Reference de Arruda Junior, Lacerda and Moura149). A recent UK study of HIV patients with the metabolic syndrome found that raised systolic blood pressure was associated with risk factors such as being male, higher BMI and higher CD4 cell count and viral load(Reference Elgalib, Aboud and Kulasegaram88, Reference Sattler, Qian and Louie150). Crane et al. (Reference Crane, Grunfeld and Harrington148) suggest that increased BMI may be involved in mediating hypertension associated with LH in HALS. When the authors adjusted for BMI, patients with LA had an increased risk of hypertension compared with those without anthropometric abnormalities(Reference Crane, Grunfeld and Harrington148). The role of ART in mediating hypertension is somewhat unclear. A study by Thiébaut et al. (Reference Thiébaut, El-Sadr and Friis-Møller151) showed that ART was not independently associated with any negative effects on blood pressure; in fact, use of NNRTI was associated with a lower risk of hypertension in this group.

Carotid artery intima thickness

Arterial stiffness has been shown to be an independent predictor of cardiovascular morbidity and mortality in the general population(Reference Franklin152). Exposure to ART in HIV-infected individuals is associated with thickening of the carotid artery intima and arterial stiffness(Reference van Vonderen, Smulders and Stehouwer153, Reference Vigano, Bedogni and Cerini154). Recent findings from the Women's Interagency HIV Study and the Multicenter AIDS Cohort found a significant association between HIV-related immunosuppression and increased carotid artery stiffness, independent from the impact of ART or other traditional atherosclerotic risk factors(Reference Seaberg, Benning and Sharrett155). These results suggest that disease factors may predict the development of arterial stiffness and subsequent atherosclerosis in HALS.

Endothelial dysfunction

Endothelial dysfunction is a critical initial step in the progression of atherosclerosis in HIV-infected individuals(Reference Shankar and Dubé156). A recent prospective study showed that the presence of lipodystrophy predicted endothelial dysfunction in fifty-five HIV-infected patients, independent of other CVD risk factors(Reference Masiá, Padilla and García29). Contrary to initial findings, different classes of ART have been implicated in the pathogenesis of endothelial dysfunction in HALS(Reference Masiá, Padilla and García29). Currently, results appear conflicting, some showing that use of ART contributes to endothelial dysfunction(Reference Stein, Klein and Bellehumeur157), some showing no association between ART and endothelial function(Reference Dubé, Shen and Mather158), and others showing improved endothelial function following treatment in previously ART-naive subjects(Reference Torriani, Komarow and Parker159). Interestingly, recent in vitro work has shown increased oxidative stress and cellular senescence in human coronary artery endothelial cells following long-term exposure to ritonavir and lopinavir–ritonavir(Reference Lefèvre, Auclair and Boccara160), highlighting a potential mechanism for PI-associated endothelial dysfunction. Larger long-term prospective studies are, however, required to determine the effect of ART on endothelial dysfunction in vivo.

Atherosclerosis

Patients with lipodystrophy have been shown to be at a higher risk of atherosclerosis(Reference Coll, Parra and Alonso-Villaverde161). Calza et al. (Reference Calza, Manfredi and Pocaterra162) recently reviewed the link between HIV infection, ART and the development of premature atherosclerosis. Similar to the general population, the most commonly identified risk factors associated with atherosclerosis were age, smoking, increased BMI, hypertension and dyslipidaemia. Of nine studies, four found an association between the use of PI and premature atherosclerosis. Furthermore, three of five studies showed that HIV infection itself was associated with atherosclerosis. This, coupled with the association between risk of atherosclerosis and CD4 cell count(Reference Kaplan, Kingsley and Gange163), indicates that disease factors play an important role in the pathogenesis of atherosclerosis.

CVD

It has been well established that ART contributes to a ‘metabolic syndrome’ encompassing abdominal obesity, atherogenic dyslipidaemia, insulin resistance, endothelial dysfunction and inflammation, known as HALS. In recent years, therefore, research has begun to focus on the deleterious effects of ART on risk of CVD(Reference Bradbury and Samaras135).

Early reports of CVD appeared in peer-reviewed literature shortly after the introduction of PI(Reference Henry, Melroe and Huebsch164, Reference Vittecoq, Escaut and Monsuez165). Evidence for the association between ART and increased risk of CVD is, at present, inconsistent. Some studies show no association between the use of ART and risk of CVD or cerebrovascular disease(Reference Bozzette, Ake and Tam166), while others show a positive association for PI(Reference Friis-Møller, Sabin and Weber30, Reference Friis-Møller, Weber and Reiss118, Reference Sabin, Worm and Weber167, Reference Barbaro, Di Lorenzo and Cirelli168). Research has shown that between 5 and 31 % of patients with HIV/AIDS are at risk for cardiovascular events(Reference Jevtovic, Dragovic and Salemovic73, Reference Mallewa, Higgins and Garbett169, Reference Alvarez, Salazar and Galindez170), and, similar to the general population, patients with the metabolic syndrome have a greater risk than those without(Reference Alvarez, Salazar and Galindez170).

Variations in observed risk could be explained by differences in the risk factors of the study population. Commonly identified risk factors for MI or cardiovascular events include AIDS before ART initiation, age over 40 years, cigarette smoking(Reference Jevtovic, Dragovic and Salemovic73), family history of CVD, diagnosis of dyslipidaemia, hypertension, lipodystrophy or T2DM(Reference Sabin, Worm and Weber167) or pre-existing vascular disease(Reference Bozzette, Ake and Tam35). Unlike the general population, Bozzette et al. (Reference Bozzette, Ake and Tam35) showed that risk of serious cardiovascular events was lower for African-American subjects, indicating that race/ethnicity may also be a risk factor. It has also been found that the prevalence of CVD is higher for patients receiving a combination of PI and NNRTI(Reference Friis-Møller, Weber and Reiss118). In a recent review, Schafer et al. (Reference Schafer, Short and Squires171) referred to studies which show an increased risk of CVD associated with recent, but not cumulative, use of abacavir, a NRTI. However, a recent 96-week randomised controlled trial did not find an association between the NRTI combination abacavir–lamivudine and cardiovascular morbidity and mortality in HIV-infected individuals(Reference Martin, Amin and Cooper172). These researchers suggest that differences in results may be attributed to variations in pre-study viral load among patients. The increased longevity observed in the HIV population as a result of advanced drug therapy has also been associated with an increase in the incidence of CVD(Reference Schillaci, Pucci and De Socio173). Evidence indicates that disease progression and associated immune deficiency in HIV patients are associated with an increased CVD risk(Reference Seaberg, Benning and Sharrett155). Recent evidence that a low CD4 cell count was associated with an increased prevalence of carotid artery lesions in HIV patients further supports this finding(Reference Kaplan, Kingsley and Gange163). Paradoxically, interruption of ART has been shown to increase CVD risk(Reference Phillips, Carr and Neuhaus174), suggesting that HIV infection itself may play a role in increasing the risk of CVD. A recent treatment interruption trial in Thai HIV-infected patients demonstrated an association between markers of CVD, including increased vascular cell adhesion molecule-1, decreased adiponectin, and increased HIV RNA replication(Reference Calmy, Gayet-Ageron and Montecucco175), which further supports this finding.

Currently, risk-prediction models such as the Framingham score are recommended for use in estimating CVD risk(Reference Calza, Manfredi and Pocaterra162). The Framingham equations, developed over a decade ago for use in non-HIV-infected individuals(Reference Anderson, Odell and Wilson176), have been used to estimate CVD risk in HIV-infected subjects(Reference Jevtovic, Dragovic and Salemovic73, Reference Martin, Amin and Cooper172, Reference Calmy, Gayet-Ageron and Montecucco175); however, studies assessing the accuracy of this model in HIV-infected patients are limited(Reference Friis-Møller and Worm177). Friis-Møller et al. (Reference Friis-Møller, Weber and Reiss118), in a large prospective cohort, used CVD risk-scoring estimates for the general population to determine cut-offs to define HIV patients at ‘high risk’ of CVD. More recently, May et al. (Reference May, Sterne and Shipley178) have developed another risk model for predicting the risk of MI or death from CHD in HIV-infected men. These researchers use data from five cardiovascular cohorts of HIV-uninfected men and adapt the model for the known risk factors observed in HIV patients following initiation of ART. However, the authors state that only a modest change in CHD risk factors may be detected using the risk model. In addition, the model does not take into account changes in CHD risk attributable to lifestyle changes. To the best of the current authors' knowledge, this model has also not yet been evaluated.

Underlying molecular mechanisms

Altered adipocyte inflammatory status

Studies of human adipose tissue from HIV-infected patients receiving ART have demonstrated an increase in the expression of genes relating to inflammation. In particular, HALS has been associated with an increase in pro-inflammatory cytokine expression(Reference Hammond, McKinnon and Nolan179), in addition to increased systemic pro-inflammatory cytokine activity(Reference Johnson, Albu and Engelson180). Increased circulating levels of TNF-α, IL-6 and IL-1β have been shown in both in vitro (Reference Lagathu, Eustace and Prot181, Reference Kim, Wilson and Wabitsch182) and ex vivo studies(Reference Johnson, Albu and Engelson180, Reference Jan, Cervera and Maachi183, Reference Sievers, Walker and Sevastianova184). IL-6 has been shown to mediate insulin resistance and may modulate insulin signalling in adipose tissue(Reference Bastard, Maachi and van Nhieu185). A large body of research has focused on the hypersecretion of TNF-α, which has a number of pathophysiological effects including mediating insulin resistance via reduction of insulin receptor kinase activity, inducing apoptosis and lipolysis(Reference Domingo, Vidal and Domingo186, Reference Kovsan, Ben-Romano and Souza187), and down-regulating insulin receptor kinase substrate (IRS)-1 and GLUT-4(Reference Domingo, Vidal and Domingo186, Reference Mallewa, Wilkins and Vilar188). These effects may occur via a number of mechanisms including: a reduction in insulin signalling, attenuating the anti-lipolytic action of insulin(Reference Rudich, Ben-Romano and Etzion189); down-regulation of inhibitory G-protein-coupled receptors, leading to enhanced cyclic AMP levels(Reference Zhang, Halbleib and Ahmad190); down-regulation of lipoprotein lipase(Reference Domingo, Vidal and Domingo186); and down-regulation of the function and expression of perilipin, a lipid droplet-associated protein, which protects the adipocyte from the hydrolytic action of cellular lipases(Reference Rydén, Arvidsson and Blomqvist191). This increased cytokine production in HALS has also been suggested to induce a stress response in adipocytes, which may lead to physical damage of the cell(Reference Lagathu, Eustace and Prot181, Reference Adler-Wailes, Guiney and Koo192).

In addition to an increase in inflammatory cytokine production, HALS has been associated with a reduced expression of adiponectin in both plasma and adipose tissue(Reference Giralt, Domingo and Guallar193). Adiponectin is a potent insulin sensitiser and, hence, its down-regulation contributes to insulin resistance(Reference Kim, Wilson and Wabitsch182). In vitro and ex vivo studies have shown reduced expression, secretion and release of adiponectin from adipose tissue(Reference Lagathu, Eustace and Prot181, Reference Jan, Cervera and Maachi183), while in vivo studies in HALS patients have identified the presence of hypoadiponectinaemia, which is a risk factor for cardiovascular impairment(Reference Bezante, Briatore and Rollando194). Inhibition of adipocyte differentiation, such as that caused by PI, has been shown to down-regulate adiponectin expression(Reference Körner, Wabitsch and Seidel195). Furthermore, down-regulation of adiponectin expression by NRTI has been suggested to occur as a result of the reduction in fat mass associated with NRTI use(Reference Pacenti, Barzon and Favaretto196, Reference Lindegaard, Keller and Bruunsgaard197). Mallewa et al. (Reference Mallewa, Wilkins and Vilar188) also refer to the negative feedback loop that exists between cytokines, whereby high levels of TNF-α and IL-6 may inhibit the expression of adiponectin, which may also account for the observed reduction in adiponectin in HALS.

Adipose tissue macrophage infiltration, resulting in chronic low-grade inflammation, has also been suggested to contribute to the development of HALS(Reference Sevastianova, Sutinen and Kannisto198). Macrophage infiltration of adipose tissue has been shown to be greater in HALS patients compared with healthy controls(Reference Jan, Cervera and Maachi183). Recently, Hammond et al. (Reference Hammond, McKinnon and Nolan179) demonstrated an increase in adipose tissue macrophage count associated with thymidine NRTI treatment.

Altered adipocyte functionality

Microarray analysis of gene expression during adipogenesis has revealed numerous effects of ART on genes involved in adipocyte lipid and glucose metabolism(Reference Pacenti, Barzon and Favaretto196). In a recent study, Sievers et al. (Reference Sievers, Walker and Sevastianova184) showed that NRTI caused a general decrease in the expression of genes involved in adipocyte differentiation and lipid and glucose metabolism within the cell (CCAAT/enhancer-binding protein-α (C/EBPA), C/EBPB, cyclo-oxygenase-3 (COX3), GLUT4, hexokinase-1 (HEXOK1), perilipin (PLIN), SREBP1c), and an increase in markers of cell proliferation and genes involved in mitochondrial transcription (COX4, lamin-B (LAMINB), lamin A/C (LAMINA), proliferating cell nuclear antigen (PCNA), PPAR-γ co-activator-1b (PGC1B)).

Similarly, a number of in vitro studies have demonstrated changes in gene expression following exposure of adipocytes to antiretroviral drugs. Both PI and NRTI have been shown to down-regulate the expression of adipocyte differentiation genes such as Pparg, Cebpa, adiponectin (Adipoq), leptin (Lep), the scavenger receptor CD36 (Cd36), adipocyte lipid-binding protein-2 (Ap2), fatty acid synthase (fasn) and acetyl-coenzyme A carboxylase (Acc)(Reference Pacenti, Barzon and Favaretto196, Reference Caron, Auclair and Lagathu199). In particular, the NRTI d4T and ZDV have been found to cause a reduction in mRNA expression of adipogenic markers involved in lipid accumulation including fatty acid synthase, acetyl-coenzyme A carboxylase and adipocyte lipid-binding protein-2(Reference Lagathu, Eustace and Prot181, Reference Pacenti, Barzon and Favaretto196, Reference Caron, Auclair and Lagathu199, Reference Grigem, Fischer-Posovszky and Debatin200). Pacenti et al. (Reference Pacenti, Barzon and Favaretto196) demonstrated that NRTI modulate the expression of various transcription factors, such as Aebp1, Pou5f1 and Phf6, which may play a role in determination of the adipocyte phenotype.

Adiponectin plays a role in glucose and lipid metabolism within the adipocyte(Reference Kim, Wilson and Wabitsch182) and a number of in vitro studies have shown a reduction in adiponectin expression following exposure of 3T3-L1 murine and Simpson–Golabi–Behmel syndrome (SGBS) human adipocytes to PI(Reference Kim, Wilson and Wabitsch182, Reference Pacenti, Barzon and Favaretto196, Reference Grigem, Fischer-Posovszky and Debatin200). These alterations in gene expression correspond with findings of altered adipocyte function including reduced capacity of insulin to activate lipogenesis(Reference Caron, Auclair and Lagathu199), decreased lipid accumulation(Reference Caron, Auclair and Lagathu199) and reduced adipocyte lipid content(Reference Lagathu, Eustace and Prot181, Reference Kim, Wilson and Wabitsch182).

Two ex vivo studies have investigated gene expression in subcutaneous adipose tissue samples from HALS patients and found reduced nuclear mRNA expression of mitochondrial proteins (PGC-1α), transcription factors (PPAR-γ) and adipocyte metabolic markers (GLUT-4, lipoprotein lipase)(Reference Giralt, Domingo and Guallar193, Reference Kim, Leclercq and Lanoy201). Further support for these findings comes from results by Kim et al. (Reference Kim, Leclercq and Lanoy201), which showed that the expression of PPAR-γ increased after PI withdrawal. Moreover, mRNA expression of uncoupling protein-3 and preadipocyte factor-1, both inhibitors of adipocyte differentiation and metabolism, has been shown to be increased in HALS(Reference Giralt, Domingo and Guallar193). As with the work of Sievers et al. (Reference Sievers, Walker and Sevastianova184), these findings suggest that ART impair mitochondrial biogenesis, adipocyte differentiation and metabolism, and are involved in the down-regulation of adipogenic transcription factors.

Mitochondrial toxicity

ART-mediated inhibition of mitochondrial DNA-polymerase-γ, leading to mitochondrial toxicity, has been suggested to not only be involved in cell death and loss of fat mass, but in the aetiology of alterations in adipose tissue function(Reference Hammond, McKinnon and Nolan179). As a result of these defects in adipose tissue function, the liver and skeletal muscles are exposed to increased concentrations of fatty acids, which has been associated with the development of the metabolic alterations seen in HALS(Reference Villarroya, Domingo and Giralt202). Studies examining the effect of ART on mitochondrial toxicity are somewhat conflicting, with some showing limited or no effect of certain ART regimens on mitochondrial toxicity(Reference Venhoff, Setzer and Melkaoui203, Reference Birkus, Hitchcock and Cihlar204), while others found effects for both single ART and cART(Reference Hammond, McKinnon and Nolan179, Reference Caron, Auclair and Lagathu199, Reference Viengchareun, Caron and Auclair205). According to Walker et al. (Reference Walker, Setzer and Venhoff206), mitochondrial toxicity is sometimes more pronounced with use of cART. A recent study examining the effect of switching from d4T to tenofovir found improvements in mitochondrial toxicity after just 1 month(Reference Ribera, Paradiñeiro and Curran207). Mallewa et al. (Reference Mallewa, Wilkins and Vilar188) suggest that these observed differences may be due to differing levels of affinity of the active metabolites of the drugs for mitochondrial DNA-polymerase-γ. Furthermore, PI and NRTI have been associated with increased oxidative stress, which has been shown to induce mitochondrial dysfunction in 3T3-F442A adipocytes(Reference Caron, Auclairt and Vissian208, Reference Walker, Auclair and Lebrecht209). This PI- and NRTI-associated mitochondrial dysfunction and oxidative stress have also been shown to trigger premature senescence in a number of cell models, including primary human fibroblasts(Reference Caron, Auclairt and Vissian208), human coronary artery endothelial cells and peripheral blood mononuclear cells(Reference Lefèvre, Auclair and Boccara160). In the context of HIV and ART, it has been suggested that premature senescence may contribute to accelerated cellular ageing, which might increase the risk of premature CVD as observed in HALS(Reference Lefèvre, Auclair and Boccara160).

Treatment

Pharmacological and surgical management

A number of pharmacological and surgical interventions have been used in the management of HALS. Pharmacological interventions include switching to more ‘lipid-friendly’ antiretrovirals(Reference Sension, de Andrade Neto and Grinsztejn210), use of synthetic growth hormone analogues to reduce excess visceral adipose tissue(Reference Sivakumar, Mechanic and Fehmie211), statins to improve dyslipidaemia(Reference Tungsiripat and Aberg212Reference Fichtenbaum, Gerber and Rosenkranz214) and anti-diabetic drugs(Reference Feldt, Oette and Kroidl215Reference van Wijk, Hoepelman and de Koning218) to improve glucose abnormalities. A number of adverse events are associated with these pharmacological interventions, which range from drug–drug interactions(Reference Jiménez-Nácher, Alvarez and Morello219) to more serious side effects such as a higher virologic failure(Reference Martínez220, Reference van Vonderen, Gras and Wit221) and increased risk of MI(Reference Psaty and Furberg222) (Table 2).

Table 2 Adverse events associated with the pharmacological and surgical management of the HIV-associated lipodystrophy syndrome

PI, protease inhibitor; NRTI, nucleoside RT inhibitor.

To correct the morphological abnormalities associated with HALS, patients often undergo surgical procedures. These include liposuction(Reference Hultman, McPhail and Donaldson223) and excisional lipectomy(Reference Warren and Borud224) for LH and silicone gluteal prostheses(Reference Moreno, Miralles and Negredo225), facial fillers(Reference Skeie, Bugge and Negaard226Reference Narciso, Bucciardini and Tozzi228), facial grafting(Reference Fontdevila, Serra-Renom and Raigosa96) and fat transplantation(Reference Guaraldi, Squillace and De Fazio229) for LA. Surgical interventions such as these are radical interventions and are associated with numerous adverse events, which often offset their success (Table 2).

Lifestyle interventions

Although pharmacological and surgical interventions have a role to play in the management of HALS, lifestyle interventions are increasingly being trialled as first-line strategies in the management in HALS, due to their greater safety and tolerability.

Exercise

A number of studies have investigated the role of exercise in improving the systemic parameters in HALS and have shown mixed results. One study failed to show an effect of exercise and resistance training in improving lipid parameters in HALS(Reference Terry, Sprinz and Stein230), while four have shown a beneficial effect, particularly in reducing central fat accumulation and in increasing body weight and limb girth(Reference Roubenoff, Weiss and McDermott231Reference Fillipas, Cherry and Cicuttini234). A recent cross-sectional study investigated the effect of leisure time physical activity on central fat accumulation in adults receiving ART and showed a significant negative correlation between leisure time physical activity and central fat(Reference Florindo and Jaime235). As for the general population, exercise in HALS patients has proven effective in improving lipid parameters and insulin resistance. Yarasheski et al. (Reference Yarasheski, Tebas and Stanerson236) investigated the effect of exercise on dyslipidaemia and showed that progressive weight-lifting reduced serum TAG levels in eighteen men receiving ART. Furthermore, a recent study of twenty men receiving supervised strength and endurance training demonstrated increases in insulin-mediated glucose uptake and hence improved insulin sensitivity after 16 weeks of training(Reference Lindegaard, Hansen and Hvid237). Overall, it appears that exercise has a beneficial effect in improving lipid parameters and central adiposity in HALS.

Nutrition

Relatively little is known about the influence of diet on the metabolic complications of HIV and associated lipodystrophy(Reference Hadigan238). There are a number of studies that have generally investigated the area by cross-sectional analysis of diet and systemic parameters of HIV-positive adults with and without lipodystrophy. Dietary fibre intake has been shown to be positively associated with metabolic health in HIV-positive adults(Reference Hendricks, Dong and Tang40, Reference Shah, Tierney and Adams-Huet41, Reference Hadigan, Jeste and Anderson43). In another study, fibre had no association(Reference Gavrila, Tsiodras and Doweiko239). A recent Brazilian cross-sectional study found that individuals with HIV who consumed more than two servings of dairy food per d had a lower BMI, waist circumference and blood pressure than those who consumed less than this amount(Reference Leite and Sampaio42). The authors of this study suggest that Ca intake may be involved in mediating these changes. In most cross-sectional studies no association was found between saturated fat(Reference Shah, Tierney and Adams-Huet41, Reference Gavrila, Tsiodras and Doweiko239, Reference Batterham, Garsia and Greenop240), total fat(Reference Shah, Tierney and Adams-Huet41, Reference Gavrila, Tsiodras and Doweiko239, Reference Batterham, Garsia and Greenop240) or other fat subclasses(Reference Gavrila, Tsiodras and Doweiko239), with the exception of trans-fatty acids(Reference Shah, Tierney and Adams-Huet41), and metabolic health in HIV-positive adults. Samaras et al. (Reference Samaras, Wand and Law241) in their study of men with HALS showed that saturated fat intake was significantly positively associated with percentage body fat. Weak evidence suggests that polyunsaturated fat intake is positively associated with insulin sensitivity in HIV-infected individuals(Reference Hadigan, Jeste and Anderson43). Contrary to these findings, Samaras et al. (Reference Samaras, Wand and Law241) demonstrated that fat subtype did not relate to fasting insulin, insulin resistance, total cholesterol, HDL, TAG, glucose or adiponectin concentrations in HALS.

Turčinov et al. (Reference Turčinov, Stanley and Rutherford45) cross-sectionally investigated the diets of 136 HIV-positive Croatian adults on ART. Adherence to a Mediterranean diet was assessed by a 150-item questionnaire and a point scale that stratified subjects as having low or moderate to high adherence. Although HALS was not an inclusion factor in the study, it was determined that Croatians who did not smoke and moderately or highly adhered to the Mediterranean diet were least likely to have LA and LH. In another cross-sectional study, adherence to a Mediterranean-style diet was positively correlated with HDL and marginally negatively correlated with TAG levels(Reference Tsiodras, Poulia and Yannakoulia44).

Interestingly, a negative association between total and supplemental vitamin E intake and diastolic blood pressure has been shown among HIV-positive adults(Reference Gavrila, Tsiodras and Doweiko239). Two association studies have shown that dietary energy intake is not associated with metabolic dysregulation among HIV-positive adults(Reference Shah, Tierney and Adams-Huet41, Reference Gavrila, Tsiodras and Doweiko239), and one has shown significant positive associations(Reference Batterham, Garsia and Greenop240).

A number of intervention studies have investigated the effects of diet in mitigating the metabolic and morphological abnormalities of HALS (Table 3). Barrios et al. (Reference Barrios, Blanco and Garcia-Benayas242) showed that adherence to a low-fat diet for 6 months reduced total cholesterol by 10 % and TAG by 23 % among HIV-positive adults with hyperlipidaemia. Contrary to these findings, Ng et al. (Reference Ng, Chan and Li243) in a recent pilot randomised controlled trial found that HIV-infected individuals who adhered to a low-fat diet did not have reduced cholesterol levels and in fact had increased TAG levels after 1 year. The same authors found that HIV-infected individuals adopting a modified Mediterranean diet had significantly increased cholesterol levels after 9 and 12 months, while serum TAG levels in the same individuals remained unchanged over the same period(Reference Ng, Chan and Li243). In a case report, Roubenoff et al. (Reference Roubenoff, Schmitz and Bairos244) found that a moderate-fat, low-GI, high-fibre diet, in combination with exercise, reduced total and trunk fat, LDL, fasting glucose and insulin resistance in one male HALS patient. Similarly, another study found that a low-fat diet and aerobic exercise significantly reduced body weight, body fat and waist:hip ratio in HALS patients(Reference Terry, Sprinz and Stein230). One study investigated the effect of altering the fatty acid composition of the diet from medium- to long-chain fatty acids in HALS, and showed improvements in lipid profile after 3 months(Reference Vázquez, Reyes and Alcaraz245). Owing to conflicting results, further randomised controlled trials are necessary before dietary recommendations can be made in this area.

Table 3 Intervention trials investigating the effect of nutrition in the HIV-associated lipodystrophy syndrome (HALS)

PI, prospective intervention; HIV+, HIV-positive; ART, antiretroviral therapy; TC, total cholesterol; ↓ , decrease; CT, control trial; M, male; HALS+, HIV patients with HALS; HALS − , HIV patients without HALS; REE, resting energy expenditure; ↑ , increase; RCT, randomised controlled trial; CR, case report; GI, glycaemic index; WHR, waist:hip ratio; MCT, medium-chain TAG; OLRT, open-label randomised trial; RIT, randomised intervention trial; NRTI, nucleoside RT inhibitor; RDBPCT, randomised double-blind placebo-controlled trial; PR, prospective randomised trial; t.d.s., ter die sumendum (three times per d); POL, prospective open label study.

* 10 d per month for 24 weeks.

16-week intervention followed by 16-week washout.

A number of studies have examined the effect of supplements, such as l-acetylcarnitine, uridine and niacin, on the metabolic and morphological abnormalities in HALS. l-Acetylcarnitine has been suggested to be involved in regulating fatty acid oxidation(Reference Famularo, Moretti and Marcellini246) and in one study of HALS subjects supplementation with 4 g/d resulted in increased lipid oxidation, decreased intramyocellular TAG content, decreased plasma NEFA and lower insulin sensitivity compared with controls after 8 months(Reference Benedini, Perseghin and Terruzzi247). Three interventions have trialled dietary uridine supplementation, which has been shown in vitro to prevent and treat mitochondrial toxicity(Reference McComsey, O'Riordan and Setzer248). One study showed no effect on changes in fat or blood mitochondrial DNA levels(Reference McComsey, O'Riordan and Setzer248), while the other two studies showed conflicting results – one finding no significant increase in limb fat mass following 24 weeks of supplementation(Reference Calmy, Bloch and Wand249), while the other showed a significant increase in subcutaneous fat mass following 3 months of supplementation in lipoatrophic patients(Reference Sutinen, Walker and Sevastianova250). Both studies used the same level of supplementation. Niacin, which has been shown to modulate lipoprotein metabolism and inhibit TAG synthesis(Reference Kamanna and Kashyap251), was used in one study examining the effect of combination therapy with diet, exercise and niacin in patients with highly active ART-associated dyslipidaemia. Treatment with a low-saturated fat diet, exercise and niacin significantly increased HDL concentrations, and total cholesterol:HDL ratio compared with controls after 24 weeks(Reference Balasubramanyam, Coraza and Smith252).

An interesting set of studies by Kosmiski et al. (Reference Kosmiski, Bessesen and Stotz253Reference Kosmiski, Bessesen and Stotz255) has shown that lipodystrophy in HIV is associated with an increase in resting energy expenditure (REE) per kg lean body mass. Furthermore, 3 d of eu-energetic feeding, which normally would not induce a change in REE, resulted in a significant increase in REE among HIV-positive adults with lipodystrophy compared with HIV-positive adults without lipodystrophy and healthy controls(Reference Kosmiski, Bessesen and Stotz253). The same researchers found that 3 d of hypo-energetic feeding induced a significant drop in REE and 3 d of hyper-energetic feeding induced a significant increase in REE in HIV-positive adults with lipodystrophy compared with HIV-positive adults and healthy controls(Reference Kosmiski, Bessesen and Stotz253, Reference Kosmiski, Bessesen and Stotz255). The group concluded that lipodystrophic subjects have higher REE per kg lean body mass than non-lipodystrophic subjects, that short-term over-feeding increases REE among lipodystrophic subjects and that short-term energy restriction reduces REE among lipodystrophic subjects. The authors suggest that hypermetabolism associated with lipodystrophy, and a form of adaptive thermogenesis invoked to dissipate energy that cannot be stored in a normal manner underlie these observations.

Despite weak support from observational studies, a number of intervention trials focusing on the role of n-3 long-chain PUFA (n-3 LC-PUFA) in mitigating the metabolic abnormalities in HALS patients have been pursued. In the pre-ART era, intervention trials investigating the immunomodulatory effects of EPA and DHA as an adjunct therapy in HIV patients were pursued(Reference Razzini and Baronzio256). Their hypothesis was based on the immunomodulatory effects of EPA and DHA previously documented. Evidence strongly supports a role for n-3 LC-PUFA in HIV therapy, but in lipid lowering rather than immune regulation.

In a study of 120 HIV-positive adults on ART, 8 weeks of supplementation with 6 g n-3 LC-PUFA per d induced a 25·5 and 38·7 % reduction in plasma TAG concentrations among moderate and severe hypertriacylglycerolaemics, respectively(Reference De Truchis, Kirstetter and Perier257). Similarly, plasma TAG concentrations decreased by 25 % following 4 weeks of supplementation with 1750 mg EPA and 1150 mg DHA per d among fifty-two HIV-positive adults with moderately raised TAG(Reference Wohl, Tien and Busby258). In a study of 100 HIV-positive adults with hypertriacylglycerolaemia, fish oil supplements taken at 6 g/d for 8 weeks reduced TAG concentrations by 46 %, fenofibrates reduced TAG concentrations by 58 %, and the combination of fish oil and fenofibrates by 65·5 %(Reference Gerber, Kitch and Fichtenbaum259). Manfredi et al. (Reference Manfredi, Calza and Chiodo260) showed that rates of TAG normalisation were non-significantly different, at 25·9 and 34 %, between HIV-positive subjects with raised TAG supplemented with ethyl esters of n-3 LC-PUFA or treated with pharmaceutical lipid-lowering therapy, respectively. Salmon oil, administered at 3 g/d, significantly reduced TAG concentrations after 12 to 24 weeks of supplementation in fifty-eight HIV-positive adults on ART(Reference Baril, Kovacs and Trottier261). The TAG-lowering effects of the n-3 LC-PUFA among HIV-positive adults are supported by three smaller prospective studies(Reference Ranieri262Reference Carter, Woolley and Jolley264), although Virgili et al. (Reference Virgili, Farriol and Castellanos265) showed no significant effect among nine HIV-positive subjects receiving 1120 mg EPA and 720 mg DHA daily for 6 weeks. A review of 237 hospital charts from HIV-positive adults with hypertriacylglycerolaemia showed that the use of n-3 LC-PUFA supplements was associated with a 32 % reduction in TAG concentrations(Reference Normén, Yip and Montaner266). Furthermore, at baseline 11 % of subjects used these dietary supplements, whereas at 6 months 25 % of subjects used the supplements(Reference Normén, Yip and Montaner266). This demonstrates an enthusiasm and acceptance of these dietary supplements by HIV-positive adults with hypertriacylglycerolaemia. The effects of n-3 LC-PUFA on lipoprotein concentrations in HIV-positive adults are unclear, with no effect(Reference Ranieri262), 11 % raised HDL(Reference Normén, Yip and Montaner266) and 22·4 % raised LDL(Reference Wohl, Tien and Busby258) reported.

EPA and DHA have been shown to have anti-inflammatory effects in vitro via their role as PPAR-γ ligands(Reference Calder267) and modulation of the NF-κB signalling system(Reference Weldon, Mullen and Loscher268, Reference Mullen, Loscher and Roche269). Despite the strength of evidence to support anti-inflammatory effects of EPA and DHA in vitro, studies investigating the effects of n-3 LC-PUFA supplementation on cytokine production in HIV-positive adults are limited. One study found no effects on the concentration of the soluble TNF-α receptor following 6 months of dietary supplementation with a product containing 1·7 g n-3 LC-PUFA and 7·4 g arginine(Reference Pichard, Sudre and Karsegard270). Another study demonstrated that among ten subjects consuming a bar containing 1·96 g n-3 LC-PUFA, PGF-1α secretion was decreased, and IL-1β and IL-6 secretion increased, from peripheral blood mononuclear cells(Reference Bell, Chavali and Bistrian271). Overall, n-3 LC-PUFA appear to have beneficial TAG-lowering effects; however, their role in modulating inflammation in HALS remains to be elucidated.

Conclusion

There is a clear disparity in the reported prevalence of HALS owing to lack of a standardised definition, use of different methods for diagnosing the syndrome, as well as variations in the study population. It has been suggested that the search for a standardised definition for HALS should be abandoned and instead replaced with a description of the non-infectious co-morbidities associated with HIV, a condition that is slowly and globally acquiring chronic disease status. HALS is associated with fat maldistribution and metabolic complications such as dyslipidaemia, insulin resistance, hypertension, endothelial dysfunction and atherosclerosis, which lead to a rise in the incidence of CVD among this population group. Alterations in adipocyte inflammatory status and functionality, as well as mitochondrial toxicity, have been shown to underlie the development of HALS. Although current pharmacological and surgical interventions are effective in the treatment of HALS, their use is not without limitations. Targeted lifestyle interventions, such as exercise, may provide a useful alternative for managing non-infectious co-morbidities in HIV patients. Diet, particularly in the context of what we currently consider cardioprotective, appears to offer a safe, tolerable and effective treatment strategy for HALS, with evidence accumulating to supporting the use of n-3 LC-PUFA in future interventions.

Acknowledgements

The present review received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. C. L. completed the review; A. M. advised in relation to the review content and approach and critically evaluated the manuscript. Both authors approved the final review. The authors declare no conflicts of interest.

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