Skip to main content Accessibility help
Hostname: page-component-55597f9d44-2qt69 Total loading time: 3.367 Render date: 2022-08-16T19:10:46.544Z Has data issue: true Feature Flags: { "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true, "useRatesEcommerce": false, "useNewApi": true } hasContentIssue true

Nutrition and the HIV-associated lipodystrophy syndrome

Published online by Cambridge University Press:  23 November 2012

Cathríona Rosemary Loonam
Diabetes and Nutritional Sciences Division, School of Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, LondonSE1 9NH, UK
Anne Mullen*
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
Rights & Permissions[Opens in a new window]


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.

Review Article
Copyright © The Authors 2012


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.


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).


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


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.


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.


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.


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).


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.


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.


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.


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.


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.


1Reynolds, S & Quinn, T (2010) Setting the stage: current state of affairs and major challenges. Clin Infect Dis 50, Suppl. 3, S71S76.CrossRefGoogle ScholarPubMed
2World Health Organization (2010) Fast facts on HIV. Scholar
3Health Protection Agency (2010) HIV in the United Kingdom: 2010. Scholar
4Food and Drug Administration (2011) Antiretroviral drugs used in the treatment of HIV infection. Scholar
5de Béthune, MP (2010) Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: a review of the last 20 years (1989–2009). Antiviral Res 85, 7590.CrossRefGoogle Scholar
6McLeod, GX & Hammer, SM (1992) Treatment of HIV infection: the antiretroviral nucleoside analogues. Nucleoside analogues: combination therapy. Hosp Pract 27, 1425.CrossRefGoogle ScholarPubMed
7Shafer, RW & Vuitton, DA (1999) Highly active antiretroviral therapy (HAART) for the treatment of infection with human immunodeficiency virus type 1. Biomed Pharmacother 53, 7386.CrossRefGoogle ScholarPubMed
8De Clercq, E (1998) The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection. Antiviral Res 38, 153179.CrossRefGoogle ScholarPubMed
9Kakuda, TN (2000) Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin Ther 22, 685708.CrossRefGoogle ScholarPubMed
10Gilead Sciences Inc. (2001) VIREAD (tenofovir): highlights of prescribing information. Scholar
11Wynn, GH, Zapor, MJ, Smith, BH, et al. (2004) Antiretrovirals, part 1: overview, history, and focus on protease inhibitors. Psychosomatics 45, 262270.CrossRefGoogle ScholarPubMed
12Greenberg, ML & Cammack, N (2004) Resistance to enfuvirtide, the first HIV fusion inhibitor. J Antimicrob Chemother 54, 333340.CrossRefGoogle ScholarPubMed
13Dorr, P, Westby, M, Dobbs, S, et al. (2005) Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Ch 49, 47214732.CrossRefGoogle Scholar
14De Clercq, E (2010) Antiretroviral drugs. Curr Opin Pharmacol 10, 507515.CrossRefGoogle ScholarPubMed
15Dubé, MP, Johnson, DL, Currier, JS, et al. (1997) Protease inhibitor-associated hyperglycaemia. Lancet 350, 713714.CrossRefGoogle ScholarPubMed
16Deeks, SG (1997) HIV-1 protease inhibitors. A review for clinicians. JAMA 227, 145153.CrossRefGoogle Scholar
17Hengel, RL, Watts, NB & Lennox, JL (1997) Benign symmetric lipomatosis associated with protease inhibitors. Lancet 350, 1596.CrossRefGoogle ScholarPubMed
18Roth, VR, Kravcik, S & Angel, JB (1998) Development of cervical fat pads following therapy with human immunodeficiency virus type 1 protease inhibitors. Clin Infect Dis 27, 6567.CrossRefGoogle ScholarPubMed
19Viraben, R & Aquilina, C (1998) Indinavir-associated lipodystrophy. AIDS 12, F37F39.CrossRefGoogle ScholarPubMed
20Carr, A, Samaras, K, Burton, S, et al. (1998) A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS 12, F51F58.CrossRefGoogle ScholarPubMed
21Mallon, PW (2007) Pathogenesis of lipodystrophy and lipid abnormalities in patients taking antiretroviral therapy. AIDS Rev 9, 315.Google ScholarPubMed
22Omolayo, O & Sealy, PL (2008) HIV lipodystrophy syndrome. Hosp Physician 44, 714.Google Scholar
23Lichtenstein, K, Balasubramanyam, A, Sekhar, R, et al. (2007) HIV-associated adipose redistribution syndrome (HARS): definition, epidemiology and clinical impact. AIDS Res Ther 4, 16.CrossRefGoogle ScholarPubMed
24Worm, SW, Friis-Møller, N, Bruyand, M, et al. (2010) High prevalence of the metabolic syndrome in HIV-infected patients: impact of different definitions of the metabolic syndrome. AIDS 24, 427435.CrossRefGoogle ScholarPubMed
25Samaras, K, Wand, H, Law, M, et al. (2007) Prevalence of metabolic syndrome in HIV-infected patients receiving highly active antiretroviral therapy using International Diabetes Foundation and Adult Treatment Panel III criteria. Diabetes Care 30, 113119.CrossRefGoogle ScholarPubMed
26Lumpkin, MM (1997) Reports of diabetes and hyperglycemia in patients receiving protease inhibitors for the treatment of human immunodeficiency virus (HIV). Scholar
27Behrens, G, Dejam, A, Schmidt, H, et al. (1999) Impaired glucose tolerance, β cell function and lipid metabolism in HIV patients under treatment with protease inhibitors. AIDS 13, F63F70.CrossRefGoogle ScholarPubMed
28Brown, TT, Cole, SR, Li, X, et al. (2005) Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the Multicenter AIDS Cohort Study. Arch Intern Med 165, 11791184.CrossRefGoogle ScholarPubMed
29Masiá, M, Padilla, S, García, N, et al. (2010) Endothelial function is impaired in HIV-infected patients with lipodystrophy. Antivir Ther 15, 101110.CrossRefGoogle ScholarPubMed
30Friis-Møller, N, Sabin, CA, Weber, R, et al. (2003) Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 349, 19932003.Google ScholarPubMed
31Salyer, J, Lyon, DE, Settle, J, et al. (2006) Coronary heart disease risks and lifestyle behaviors in persons with HIV infection. J Assoc Nurses AIDS Care 17, 317.CrossRefGoogle ScholarPubMed
32Mondy, K, Overton, E, Grubb, J, et al. (2007) Metabolic syndrome in HIV-infected patients from an urban, midwestern US outpatient population. Clin Infect Dis 44, 726734.CrossRefGoogle ScholarPubMed
33Vittecoq, D, Escaut, L, Chironi, G, et al. (2003) Coronary heart disease in HIV-infected patients in the highly active antiretroviral treatment era. AIDS 17, Suppl. 1, S70S76.CrossRefGoogle ScholarPubMed
34Matetzky, S, Domingo, M, Kar, S, et al. (2003) Acute myocardial infarction in human immunodeficiency virus-infected patients. Arch Intern Med 163, 457460.CrossRefGoogle ScholarPubMed
35Bozzette, SA, Ake, CF, Tam, HK, et al. (2008) Long-term survival and serious cardiovascular events in HIV-infected patients treated with highly active antiretroviral therapy. J Acquir Immune Defic Syndr 47, 338341.Google ScholarPubMed
36Khunnawat, C, Mukerji, S, Havlichek, D Jr, et al. (2008) Cardiovascular manifestations in human immunodeficiency virus-infected patients. Am J Cardiol 102, 635642.CrossRefGoogle ScholarPubMed
37Friis-Møller, N, Thiébaut, R, Reiss, P, et al. (2010) Predicting the risk of cardiovascular disease in HIV-infected patients: the data collection on adverse effects of anti-HIV drugs study. Eur J Cardiovasc Prev Rehabil 17, 491501.CrossRefGoogle ScholarPubMed
38Guaraldi, G, Zona, S, Alexopoulos, N, et al. (2009) Coronary aging in HIV-infected patients. Clin Infect Dis 49, 17561762.CrossRefGoogle ScholarPubMed
39American Dietetic Association (2010) Position of the American Dietetic Association: nutrition intervention and human immunodeficiency virus infection. J Am Diet Assoc 110, 11051119.CrossRefGoogle Scholar
40Hendricks, KM, Dong, KR, Tang, AM, et al. (2003) High-fiber diet in HIV-positive men is associated with lower risk of developing fat deposition. Am J Clin Nutr 78, 790795.CrossRefGoogle ScholarPubMed
41Shah, M, Tierney, K, Adams-Huet, B, et al. (2005) The role of diet, exercise and smoking in dyslipidaemia in HIV-infected patients with lipodystrophy. HIV Med 6, 291298.CrossRefGoogle ScholarPubMed
42Leite, LHM & Sampaio, ABMM (2010) Dietary calcium, dairy food intake and metabolic abnormalities in HIV-infected individuals. J Hum Nutr Diet 23, 535543.CrossRefGoogle ScholarPubMed
43Hadigan, C, Jeste, S, Anderson, EJ, et al. (2001) Modifiable dietary habits and their relation to metabolic abnormalities in men and women with human immunodeficiency virus infection and fat redistribution. Clin Infect Dis 33, 710717.CrossRefGoogle ScholarPubMed
44Tsiodras, S, Poulia, K-A, Yannakoulia, M, et al. (2009) Adherence to Mediterranean diet is favorably associated with metabolic parameters in HIV-positive patients with the highly active antiretroviral therapy-induced metabolic syndrome and lipodystrophy. Metabolism 58, 854859.CrossRefGoogle ScholarPubMed
45Turčinov, D, Stanley, C, Rutherford, G, et al. (2009) Adherence to the Mediterranean diet is associated with a lower risk of body-shape changes in Croatian patients treated with combination antiretroviral therapy. Eur J Epidemiol 24, 267274.CrossRefGoogle ScholarPubMed
46Jacobson, DL, Tang, AM, Spiegelman, D, et al. (2006) Incidence of metabolic syndrome in a cohort of HIV-infected adults and prevalence relative to the US population (National Health and Nutrition Examination Survey). J Acquir Immune Defic Syndr 43, 458466.CrossRefGoogle Scholar
47Sobieszczyk, ME, Hoover, DR, Anastos, K, et al. (2008) Prevalence and predictors of metabolic syndrome among HIV-infected and HIV-uninfected women in the Women's Interagency HIV Study. J Acquir Immune Defic Syndr 48, 272280.CrossRefGoogle ScholarPubMed
48Tien, PC, Cole, SR, Williams, CM, et al. (2003) Incidence of lipoatrophy and lipohypertrophy in the Women's Interagency HIV Study. J Acquir Immune Defic Syndr 34, 461466.CrossRefGoogle ScholarPubMed
49Norris, A & Dreher, HM (2004) Lipodystrophy syndrome: the morphologic and metabolic effects of antiretroviral therapy in HIV infection. J Assoc Nurses AIDS Care 15, 4664.CrossRefGoogle ScholarPubMed
50Benn, P, Ruff, C, Cartledge, J, et al. (2003) Overcoming subjectivity in assessing facial lipoatrophy: is there a role for three-dimensional laser scans? HIV Med 4, 325331.CrossRefGoogle Scholar
51Carter, V, Hoy, J, Bailey, M, et al. (2001) The prevalence of lipodystrophy in an ambulant HIV-infected population: it all depends on the definition. HIV Med 2, 174180.CrossRefGoogle Scholar
52Boufassa, FDA, Lascaux, AS, Meyer, L, et al. (2001) Lipodystrophy in 685 HIV-1-treated patients: influence of antiretroviral treatment and immunovirological response. HIV Clin Trials 2, 339345.CrossRefGoogle ScholarPubMed
53Chêne, G, Angelini, E, Cotte, L, et al. (2002) Role of long-term nucleoside-analogue therapy in lipodystrophy and metabolic disorders in human immunodeficiency virus-infected patients. Clin Infect Dis 34, 649657.CrossRefGoogle ScholarPubMed
54Galli, M, Cozzi-Lepri, A, Ridolfo, AL, et al. (2002) Incidence of adipose tissue alterations in first-line antiretroviral therapy: The LipoICoNa Study. Arch Intern Med 162, 26212628.CrossRefGoogle ScholarPubMed
55Galli, M, Veglia, F, Angarano, G, et al. (2003) Gender differences in antiretroviral drug-related adipose tissue alterations: women are at higher risk than men and develop particular lipodystrophy patterns. J Acquir Immune Defic Syndr 34, 5861.CrossRefGoogle ScholarPubMed
56Miller, J, Carr, A, Emery, S, et al. (2003) HIV lipodystrophy: prevalence, severity and correlates of risk in Australia. HIV Med 4, 293301.CrossRefGoogle ScholarPubMed
57Puttawong, S, Prasithsirikul, W & Vadcharavivad, S (2004) Prevalence of lipodystrophy in Thai-HIV infected patients. J Med Assoc Thai 87, 605611.Google ScholarPubMed
58Young, J, Rickenbach, M, Weber, R, et al. (2005) Body fat changes among antiretroviral-naive patients on PI- and NNRTI-based HAART in the Swiss HIV Cohort Study. Antivir Ther 10, 7381.Google ScholarPubMed
59Mutimura, EM, Stewart, AP, Rheeder, PMD, et al. (2007) Metabolic function and the prevalence of lipodystrophy in a population of HIV-infected African subjects receiving highly active antiretroviral therapy. J Acquir Immune Defic Syndr 46, 451455.CrossRefGoogle Scholar
60Nguyen, A, Calmy, A, Schiffer, V, et al. (2008) Lipodystrophy and weight changes: data from the Swiss HIV Cohort Study, 2000–2006. HIV Med 9, 142150.CrossRefGoogle ScholarPubMed
61Seminari, E, Tinelli, C, Minoli, L, et al. (2002) Evaluation of the risk factors associated with lipodystrophy development in a cohort of HIV-positive patients. Antivir Ther 7, 175180.Google Scholar
62Kalyanasundaram, AP, Jacob, SM, Hemalatha, R, et al. (2012) Prevalence of lipodystrophy and dyslipidemia among patients with HIV infection on generic ART in Rural South India. J Int Assoc Physicians AIDS Care (Chic) 11, 329334.CrossRefGoogle ScholarPubMed
63Saint-Marc, T, Partisani, M, Poizot-Martin, I, et al. (2000) Fat distribution evaluated by computed tomography and metabolic abnormalities in patients undergoing antiretroviral therapy: preliminary results of the LIPOCO study. AIDS 14, 3749.CrossRefGoogle ScholarPubMed
64Thiébaut, R, Daucourt, V, Mercié, P, et al. (2000) Lipodystrophy, metabolic disorders, and human immunodeficiency virus infection: Aquitaine Cohort, France, 1999. Clin Infect Dis 31, 14821487.CrossRefGoogle Scholar
65Lichtenstein, KA, Ward, DJ, Moorman, AC, et al. (2001) Clinical assessment of HIV-associated lipodystrophy in an ambulatory population. AIDS 15, 13891398.CrossRefGoogle Scholar
66Heath, KV, Singer, J, O'Shaughnessy, MV, et al. (2002) Intentional nonadherence due to adverse symptoms associated with antiretroviral therapy. J Acquir Immune Defic Syndr 31, 211217.CrossRefGoogle ScholarPubMed
67Mauss, S, Corzillius, M, Wolf, E, et al. (2002) Risk factors for the HIV-associated lipodystrophy syndrome in a closed cohort of patients after 3 years of antiretroviral treatment. HIV Med 3, 4955.CrossRefGoogle Scholar
68Paton, NI, Earnest, A, Ng, YM, et al. (2002) Lipodystrophy in a cohort of human immunodeficiency virus-infected Asian patients: prevalence, associated factors, and psychological impact. Clin Infect Dis 35, 12441249.CrossRefGoogle Scholar
69Lichtenstein, KA, Delaney, KM, Armon, C, et al. (2003) Incidence of and risk factors for lipoatrophy (abnormal fat loss) in ambulatory HIV-1-infected patients. J Acquir Immune Defic Syndr 32, 4856.CrossRefGoogle Scholar
70Pujari, SN, Dravid, AM, Naik, E, et al. (2005) Lipodystrophy and dyslipidemia among patients taking first-line, World Health Organization-recommended highly active antiretroviral therapy regimens in Western India. J Acquir Immune Defic Syndr 39, 199202.Google ScholarPubMed
71van Griensven, J, De Naeyer, L, Mushi, T, et al. (2007) High prevalence of lipoatrophy among patients on stavudine-containing first-line antiretroviral therapy regimens in Rwanda. Trans R Soc Trop Med Hyg 101, 793798.CrossRefGoogle ScholarPubMed
72Walmsley, S, Cheung, A, Fantus, G, et al. (2008) A prospective study of body fat redistribution, lipid, and glucose parameters in HIV-infected patients initiating combination antiretroviral therapy. HIV Clin Trials 9, 314323.CrossRefGoogle ScholarPubMed
73Jevtovic, D, Dragovic, G, Salemovic, D, et al. (2009) The metabolic syndrome, an epidemic among HIV-infected patients on HAART. Biomed Pharmacother 63, 337342.CrossRefGoogle ScholarPubMed
74Mercier, S, Gueye, NFN, Cournil, A, et al. (2009) Lipodystrophy and metabolic disorders in HIV-1-infected adults on 4- to 9-year antiretroviral therapy in Senegal: a case–control study. J Acquir Immune Defic Syndr 51, 224230.CrossRefGoogle ScholarPubMed
75Zannou, DM, Denoeud, L, Lacombe, K, et al. (2009) Incidence of lipodystrophy and metabolic disorders in patients starting non-nucleoside reverse transcriptase inhibitors in Benin. Antivir Ther 14, 371380.Google ScholarPubMed
76Gervasoni, C, Ridolfo, AL, Trifiro, G, et al. (1999) Redistribution of body fat in HIV-infected women undergoing combined antiretroviral therapy. AIDS 13, 465471.CrossRefGoogle ScholarPubMed
77Goujard, C, Boufassa, F, Deveau, C, et al. (2001) Incidence of clinical lipodystrophy in HIV-1-infected patients treated during primary infection. AIDS 15, 282284.CrossRefGoogle Scholar
78Heath, KV, Hogg, RS, Chan, KJ, et al. (2001) Lipodystrophy-associated morphological, cholesterol and triglyceride abnormalities in a population-based HIV/AIDS treatment database. AIDS 15, 231239.CrossRefGoogle Scholar
79Martínez, E, Mocroft, A, García-Viejo, MA, et al. (2001) Risk of lipodystrophy in HIV-1-infected patients treated with protease inhibitors: a prospective cohort study. Lancet 357, 592598.CrossRefGoogle ScholarPubMed
80Bernasconi, E, Boubaker, K, Junghans, C, et al. (2002) Abnormalities of body fat distribution in HIV-infected persons treated with antiretroviral drugs: The Swiss HIV Cohort Study. J Acquir Immune Defic Syndr 31, 5055.CrossRefGoogle ScholarPubMed
81Savès, M, Raffi, F, Capeau, J, et al. (2002) Factors related to lipodystrophy and metabolic alterations in patients with human immunodeficiency virus infection receiving highly active antiretroviral therapy. Clin Infect Dis 34, 13961405.CrossRefGoogle ScholarPubMed
82Carr, A, Emery, S, Law, M, et al. (2003) An objective case definition of lipodystrophy in HIV-infected adults: a case–control study. Lancet 361, 726735.CrossRefGoogle ScholarPubMed
83Galli, M, Ridolfo, AL, Adorni, F, et al. (2003) Correlates of risk of adipose tissue alterations and their modifications over time in HIV-1-infected women treated with antiretroviral therapy. Antivir Ther 8, 347354.Google ScholarPubMed
84Fellay, J, Ledergerber, B, Bernasconi, E, et al. (2001) Prevalence of adverse events associated with potent antiretroviral treatment: Swiss HIV Cohort Study. Lancet 358, 13221327.CrossRefGoogle ScholarPubMed
85van der Valk, M, Gisolf, EH, Reiss, P, et al. (2001) Increased risk of lipodystrophy when nucleoside analogue reverse transcriptase inhibitors are included with protease inhibitors in the treatment of HIV-1 infection. AIDS 15, 847855.CrossRefGoogle ScholarPubMed
86National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) (2002) Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106, 31433421.Google Scholar
87Jericó, C, Knobel, H, Montero, M, et al. (2005) Metabolic syndrome among HIV-infected patients: prevalence, characteristics, and related factors. Diabetes Care 28, 132137.CrossRefGoogle ScholarPubMed
88Elgalib, A, Aboud, M, Kulasegaram, R, et al. (2011) The assessment of metabolic syndrome in UK patients with HIV using two different definitions: CREATE 2 study. Curr Med Res Opin 27, 6369.CrossRefGoogle ScholarPubMed
89International Diabetes Federation (2005) Global guideline for type 2 diabetes. Scholar
90Gkrania-Klotsas, E & Klotsas, A-E (2007) HIV and HIV treatment: effects on fats, glucose and lipids. Br Med Bull 84, 4968.CrossRefGoogle ScholarPubMed
91Grundy, SM, Brewer, HB Jr, Cleeman, JI, et al. (2004) Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 109, 433438.CrossRefGoogle ScholarPubMed
92US National Institutes of Health (2004) DAIDS HIV Vaccines and Research Program NIoH. Division of AIDS (DAIDS) revised toxicity tables for grading the severity of adult and pediatric adverse events experiences, version 1.0. Washington, DC. Scholar
93Han, SH, Zhou, J, Saghayam, S, et al. (2011) Prevalence of and risk factors for lipodystrophy among HIV-infected patients receiving combined antiretroviral treatment in the Asia-Pacific region: results from the TREAT Asia HIV Observational Database (TAHOD). Endocr J 58, 475484.CrossRefGoogle Scholar
94Wanke, C, Polsky, B & Kotler, D (2002) Guidelines for using body composition measurement in patients with human immunodeficiency virus infection. AIDS Patient Care STDS 16, 375388.CrossRefGoogle ScholarPubMed
95Carr, A, Law, M & HIV Lipodystrophy Case Definition Study Group (2003) An objective lipodystrophy severity grading scale derived from the lipodystrophy case definition score. J Acquir Immune Defic Syndr 33, 571576.CrossRefGoogle ScholarPubMed
96Fontdevila, J, Serra-Renom, JM, Raigosa, M, et al. (2008) Assessing the long-term viability of facial fat grafts: an objective measure using computed tomography. Aesthet Surg J 28, 380386.CrossRefGoogle ScholarPubMed
97Guaraldi, G & Baraboutis, I (2009) Evolving perspectives on HIV-associated lipodystrophy syndrome: moving from lipodystrophy to non-infectious HIV co-morbidities. J Antimicrob Chemother 64, 437440.CrossRefGoogle ScholarPubMed
98Carr, A, Samaras, K, Thorisdottir, A, et al. (1999) Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 353, 20932099.CrossRefGoogle ScholarPubMed
99Safrin, S & Grunfeld, C (1999) Fat distribution and metabolic changes in patients with HIV infection. AIDS 13, 24932505.CrossRefGoogle ScholarPubMed
100Saint-Marc, T, Partisani, M, Poizot-Martin, I, et al. (1999) A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. AIDS 13, 16591667.CrossRefGoogle ScholarPubMed
101Grinspoon, S, Corcoran, C, Miller, K, et al. (1997) Body composition and endocrine function in women with acquired immunodeficiency syndrome wasting. J Clin Endocrinol Metab 82, 13321337.Google ScholarPubMed
102Engelson, ES, Kotler, DP, Tan, Y, et al. (1999) Fat distribution in HIV-infected patients reporting truncal enlargement quantified by whole-body magnetic resonance imaging. Am J Clin Nutr 69, 11621169.CrossRefGoogle ScholarPubMed
103Bergersen, B, Sandvik, L, Ellingsen, I, et al. (2005) Lipoatrophic men 44 months after the diagnosis of lipoatrophy are less lipoatrophic but more hypertensive. HIV Med 6, 260267.CrossRefGoogle Scholar
104Nolan, D, Hammond, E, James, I, et al. (2003) Contribution of nucleoside-analogue reverse transcriptase inhibitor therapy to lipoatrophy from the population to the cellular level. Antivir Ther 8, 617626.Google ScholarPubMed
105Grinspoon, S & Carr, A (2005) Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med 352, 4862.CrossRefGoogle ScholarPubMed
106Jacobson, DL, Knox, T, Spiegelman, D, et al. (2005) Prevalence of, evolution of, and risk factors for fat atrophy and fat deposition in a cohort of HIV-infected men and women. Clin Infect Dis 40, 18371845.CrossRefGoogle Scholar
107Miller, KD, Jones, E, Yanovski, JA, et al. (1998) Visceral abdominal-fat accumulation associated with use of indinavir. Lancet 351, 871875.CrossRefGoogle ScholarPubMed
108Dinges, WL, Chen, D, Snell, PG, et al. (2005) Regional body fat distribution in HIV-infected patients with lipodystrophy. J Investig Med 53, 1525.CrossRefGoogle ScholarPubMed
109Lo, JC, Mulligan, K, Tai, VW, et al. (1998) “Buffalo hump” in men with HIV-1 infection. Lancet 351, 867870.CrossRefGoogle ScholarPubMed
110Palella, FJ Jr, Chmiel, JS, Riddler, SA, et al. (2006) A novel pattern of lipoaccumulation in HIV-infected men. JAMA 296, 766768.CrossRefGoogle ScholarPubMed
111Guaraldi, G, Orlando, G, Squillace, N, et al. (2007) Prevalence of and risk factors for pubic lipoma development in HIV-infected persons. J Acquir Immune Defic Syndr 45, 7276.CrossRefGoogle ScholarPubMed
112Cooper, DA, Cordery, DV, Reiss, P, et al. (2011) The effects of enfuvirtide therapy on body composition and metabolic parameters over 48 weeks in the TORO body imaging substudy. HIV Med 12, 3139.CrossRefGoogle ScholarPubMed
113Grunfeld, C, Kotler, DP, Hamadeh, R, et al. (1989) Hypertriglyceridemia in acquired immunodeficiency syndrome. Am J Med 86, 2731.CrossRefGoogle ScholarPubMed
114Grunfeld, C, Kotler, DP, Shigenaga, JK, et al. (1991) Circulating interferon-α levels and hypertriglyceridemia in the acquired immunodeficiency syndrome. Am J Med 90, 154162.CrossRefGoogle ScholarPubMed
115Riddler, SA, Smit, E, Cole, SR, et al. (2003) Impact of HIV infection and HAART on serum lipids in men. JAMA 289, 29782982.CrossRefGoogle ScholarPubMed
116Tomažič, J, Silič, A, Karner, P, et al. (2004) Lipodystrophy and metabolic abnormalities in Slovenian HIV-infected patients. Wien Klin Wochenschr 116, 755759.CrossRefGoogle ScholarPubMed
117Lesi, OA, Soyebi, KS & Eboh, CN (2009) Fatty liver and hyperlipidemia in a cohort of HIV-positive Africans on highly active antiretroviral therapy. J Natl Med Assoc 101, 151155.CrossRefGoogle Scholar
118Friis-Møller, N, Weber, R, Reiss, P, et al. (2003) Cardiovascular disease risk factors in HIV patients – association with antiretroviral therapy. Results from the DAD study. AIDS 17, 11791193.CrossRefGoogle ScholarPubMed
119Carr, A, Samaras, K, Chisholm, DJ, et al. (1998) Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet 351, 18811883.CrossRefGoogle ScholarPubMed
120Periard, D, Telenti, A, Sudre, P, et al. (1999) Atherogenic dyslipidemia in HIV-infected individuals treated with protease inhibitors. Circulation 100, 700705.CrossRefGoogle ScholarPubMed
121van Leth, F, Phanuphak, P, Stroes, E, et al. (2004) Nevirapine and efavirenz elicit different changes in lipid profiles in antiretroviral-therapy-naive patients infected with HIV-1. PLoS Med 1, e19.CrossRefGoogle ScholarPubMed
122Jones, R, Sawleshwarkar, S, Michailidis, C, et al. (2005) Impact of antiretroviral choice on hypercholesterolaemia events: the role of the nucleoside reverse transcriptase inhibitor backbone. HIV Med 6, 396402.CrossRefGoogle ScholarPubMed
123Kosmiski, LA, Miller, HL & Klemm, DJ (2006) In combination, nucleoside reverse transcriptase inhibitors have significant effects on 3T3-L1 adipocyte lipid accumulation and survival. Antivir Ther 11, 187195.Google Scholar
124Ware, LJ, Jackson, AG, Wootton, SA, et al. (2009) Antiretroviral therapy with or without protease inhibitors impairs postprandial TAG hydrolysis in HIV-infected men. Br J Nutr. 102, 10381046.CrossRefGoogle ScholarPubMed
125Monnerat, BZ, Cerutti Junior, C, Caniçali, SC, et al. (2008) Clinical and biochemical evaluation of HIV-related lipodystrophy in an ambulatory population from the Hospital Universitário Cassiano Antonio de Morais, Vitória, ES, Brazil. Braz J Infect Dis 12, 364368.CrossRefGoogle Scholar
126Pernerstorfer-Schoen, H, Jilma, B, Perschler, A, et al. (2001) Sex differences in HAART-associated dyslipidaemia. AIDS 15, 725734.CrossRefGoogle ScholarPubMed
127Gaillard, T, Schuster, D & Osei, K (2009) Metabolic syndrome in black people of the African diaspora: the paradox of current classification, definition and criteria. Ethn Dis 19, Suppl. 2, S2-1–S2-7.Google ScholarPubMed
128Foulkes, AS, Wohl, DA, Frank, I, et al. (2006) Associations among race/ethnicity, ApoC-III genotypes, and lipids in HIV-1-infected individuals on antiretroviral therapy. PLoS Med 3, e52.CrossRefGoogle Scholar
129Guardiola, M, Ferré, R, Salazar, J, et al. (2006) Protease inhibitor-associated dyslipidemia in HIV-infected patients is strongly influenced by the APOA5-1131T → C gene variation. Clin Chem 52, 19141919.CrossRefGoogle ScholarPubMed
130Fauvel, J, Bonnet, E, Ruidavets, J-B, et al. (2001) An interaction between apo C-III variants and protease inhibitors contributes to high triglyceride/low HDL levels in treated HIV patients. AIDS 15, 23972406.CrossRefGoogle ScholarPubMed
131Miserez, AR, Muller, PY, Barella, L, et al. (2001) A single-nucleotide polymorphism in the sterol-regulatory element-binding protein 1c gene is predictive of HIV-related hyperlipoproteinaemia. AIDS 15, 20452049.CrossRefGoogle ScholarPubMed
132Nolan, D, Moore, C, Castley, A, et al. (2003) Tumour necrosis factor-α gene -238G/A promoter polymorphism associated with a more rapid onset of lipodystrophy. AIDS 17, 121123.CrossRefGoogle ScholarPubMed
133Tarr Philip, E, Taffé, P, Bleiber, G, et al. (2005) Modeling the influence of APOC3, APOE, and TNF polymorphisms on the risk of antiretroviral therapy-associated lipid disorders. J Infect Dis 191, 14191426.CrossRefGoogle Scholar
134Abourizk, NN, Lyons, RW & Madden, GM (1993) Transient state of NIDDM in a patient with AIDS. Diabetes Care 16, 931933.CrossRefGoogle Scholar
135Bradbury, RA & Samaras, K (2008) Antiretroviral therapy and the human immunodeficiency virus – improved survival but at what cost? Diabetes Obes Metab 10, 441450.CrossRefGoogle ScholarPubMed
136Eastone, JA & Decker, CA (1997) New-onset diabetes mellitus associated with use of protease inhibitor. Ann Intern Med 127, 948.CrossRefGoogle ScholarPubMed
137Visnergarwala, F, Krause, KL & Musher, DM (1997) Severe diabetes associated with protease inhibitors. Ann Intern Med 127, 947.CrossRefGoogle Scholar
138van Dieren, S, Beulens, JWJ, van der Schouw, YT, et al. (2010) The global burden of diabetes and its complications: an emerging pandemic. Eur J Cardiovasc Prev Rehabil 17, Suppl. 1, s3s8.Google Scholar
139Danaei, G, Finucane, MM, Lu, Y, et al. (2011) National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2·7 million participants. Lancet 378, 3140.CrossRefGoogle ScholarPubMed
140Carr, A, Hudson, J, Chuah, J, et al. (2001) HIV protease inhibitor substitution in patients with lipodystrophy: a randomized, controlled, open-label, multicentre study. AIDS 15, 18111822.CrossRefGoogle ScholarPubMed
141Dubé, MP, Parker, RA, Tebas, P, et al. (2005) Glucose metabolism, lipid, and body fat changes in antiretroviral-naive subjects randomized to nelfinavir or efavirenz plus dual nucleosides. AIDS 19, 18071818.CrossRefGoogle ScholarPubMed
142Srivanich, N, Ngarmukos, C & Sungkanuparph, S (2010) Prevalence of and risk factors for pre-diabetes in HIV-1-infected patients in Bangkok, Thailand. J Int Assoc Physicians AIDS Care 9, 358361.CrossRefGoogle ScholarPubMed
143Lee, GA, Seneviratne, T, Noor, MA, et al. (2004) The metabolic effects of lopinavir/ritonavir in HIV-negative men. AIDS 18, 641649.CrossRefGoogle ScholarPubMed
144Woerle, H, Mariuz, PR, Meyer, C, et al. (2003) Mechanisms for the deterioration in glucose tolerance associated with HIV protease inhibitor regimens. Diabetes 52, 918925.CrossRefGoogle ScholarPubMed
145Tien, PC, Schneider, MF, Cole, SR, et al. (2007) Antiretroviral therapy exposure and incidence of diabetes mellitus in the Women's Interagency HIV Study. AIDS 21, 17391745.CrossRefGoogle ScholarPubMed
146American Diabetes Association, Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (2003) Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 26, Suppl. 1, S5S20.CrossRefGoogle Scholar
147Wohl, DA, McComsey, G, Tebas, P, et al. (2006) Current concepts in the diagnosis and management of metabolic complications of HIV infection and its therapy. Clin Infect Dis 43, 645653.CrossRefGoogle ScholarPubMed
148Crane, HM, Grunfeld, C, Harrington, RD, et al. (2009) Lipoatrophy and lipohypertrophy are independently associated with hypertension. HIV Med 10, 496503.CrossRefGoogle ScholarPubMed
149de Arruda Junior, ER, Lacerda, HR, Moura, LCRV, et al. (2010) Risk factors related to hypertension among patients in a cohort living with HIV/AIDS. Braz J Infect Dis 14, 281287.CrossRefGoogle Scholar
150Sattler, FR, Qian, D, Louie, S, et al. (2001) Elevated blood pressure in subjects with lipodystrophy. AIDS 15, 20012010.CrossRefGoogle ScholarPubMed
151Thiébaut, R, El-Sadr, WM, Friis-Møller, N, et al. (2005) Data collection of adverse events of anti-HIV Drugs Study Group. Predictors of hypertension and changes of blood pressure in HIV-infected patients. Antivir Ther 10, 811823.Google Scholar
152Franklin, SS (2008) Beyond blood pressure: arterial stiffness as a new biomarker of cardiovascular disease. J Am Soc Hypertens 2, 140151.CrossRefGoogle ScholarPubMed
153van Vonderen, MGA, Smulders, YM, Stehouwer, CDA, et al. (2009) Carotid intima-media thickness and arterial stiffness in HIV-infected patients: the role of HIV, antiretroviral therapy, and lipodystrophy. J Acquir Immune Defic Syndr 50, 153161.CrossRefGoogle ScholarPubMed
154Vigano, A, Bedogni, G, Cerini, C, et al. (2010) Both HIV-infection and long-term antiretroviral therapy are associated with increased common carotid intima-media thickness in HIV-infected adolescents and young adults. Curr HIV Res 8, 411417.CrossRefGoogle ScholarPubMed
155Seaberg, EC, Benning, L, Sharrett, AR, et al. (2010) Association between human immunodeficiency virus infection and stiffness of the common carotid artery. Stroke 41, 21632170.CrossRefGoogle ScholarPubMed
156Shankar, SS & Dubé, MP (2004) Clinical aspects of endothelial dysfunction associated with human immunodeficiency virus infection and antiretroviral agents. Cardiovasc Toxicol 4, 261269.CrossRefGoogle ScholarPubMed
157Stein, JH, Klein, MA, Bellehumeur, JL, et al. (2001) Use of human immunodeficiency virus-1 protease inhibitors is associated with atherogenic lipoprotein changes and endothelial dysfunction. Circulation 104, 257262.CrossRefGoogle ScholarPubMed
158Dubé, MP, Shen, C, Mather, KJ, et al. (2010) Relationship of body composition, metabolic status, antiretroviral use, and HIV disease factors to endothelial dysfunction in HIV-infected subjects. AIDS Res Hum Retroviruses 26, 847854.CrossRefGoogle ScholarPubMed
159Torriani, FJ, Komarow, L, Parker, RA, et al. (2008) Endothelial function in human immunodeficiency virus-infected antiretroviral-naive subjects before and after starting potent antiretroviral therapy: The ACTG (AIDS Clinical Trials Group) Study 5152s. J Am Coll Cardiol 52, 569576.CrossRefGoogle Scholar
160Lefèvre, C, Auclair, M, Boccara, F, et al. (2010) Premature senescence of vascular cells is induced by HIV protease inhibitors. Arterioscler Thromb Vasc Biol 30, 26112620.CrossRefGoogle ScholarPubMed
161Coll, B, Parra, S, Alonso-Villaverde, C, et al. (2006) HIV-infected patients with lipodystrophy have higher rates of carotid atherosclerosis: the role of monocyte chemoattractant protein-1. Cytokine 34, 5155.CrossRefGoogle ScholarPubMed
162Calza, L, Manfredi, R, Pocaterra, D, et al. (2008) Risk of premature atherosclerosis and ischemic heart disease associated with HIV infection and antiretroviral therapy. J Infect 57, 1632.CrossRefGoogle ScholarPubMed
163Kaplan, RC, Kingsley, LA, Gange, SJ, et al. (2008) Low CD4+ T-cell count as a major atherosclerosis risk factor in HIV-infected women and men. AIDS 22, 16151624.CrossRefGoogle ScholarPubMed
164Henry, K, Melroe, H, Huebsch, J, et al. (1998) Severe premature coronary artery disease with protease inhibitors. Lancet 351, 1328.CrossRefGoogle ScholarPubMed
165Vittecoq, D, Escaut, L & Monsuez, JJ (1998) Vascular complications associated with use of HIV protease inhibitors. Lancet 351, 1959.CrossRefGoogle ScholarPubMed
166Bozzette, SA, Ake, CF, Tam, HK, et al. (2003) Cardiovascular and cerebrovascular events in patients treated for human immunodeficiency virus infection. N Engl J Med 348, 702710.CrossRefGoogle ScholarPubMed
167Sabin, CA, Worm, SW, Weber, R, et al. (2008) Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet 371, 14171426.Google Scholar
168Barbaro, G, Di Lorenzo, G, Cirelli, A, et al. (2003) An open-label, prospective, observational study of the incidence of coronary artery disease in patients with HIV infection receiving highly active antiretrovial therapy. Clin Ther 25, 24052418.CrossRefGoogle Scholar
169Mallewa, JE, Higgins, SP, Garbett, S, et al. (2009) Cardiovascular disease risk management in HIV patients, experiences from Greater Manchester. Int J STD AIDS 20, 425426.CrossRefGoogle ScholarPubMed
170Alvarez, C, Salazar, R, Galindez, J, et al. (2010) Metabolic syndrome in HIV-infected patients receiving antiretroviral therapy in Latin America. Braz J Infect Dis 14, 256263.CrossRefGoogle ScholarPubMed
171Schafer, JJ, Short, WR & Squires, KE (2010) Association between abacavir exposure and increased risk for cardiovascular disease in patients with human immunodeficiency virus. Pharmacotherapy 30, 10721083.CrossRefGoogle ScholarPubMed
172Martin, A, Amin, J, Cooper, D, et al. (2010) Abacavir does not affect circulating levels of inflammatory or coagulopathic biomarkers in suppressed HIV: a randomized clinical trial. AIDS 24, 26572663.CrossRefGoogle ScholarPubMed
173Schillaci, G, Pucci, G & De Socio, GVL (2009) HIV infection and antiretroviral treatment: a two-hit model for arterial stiffness. Am J Hypertens 22, 817818.CrossRefGoogle ScholarPubMed
174Phillips, AN, Carr, A, Neuhaus, J, et al. (2008) Interruption of antiretroviral therapy and risk of cardiovascular disease in persons with HIV-1 infection: exploratory analyses from the SMART trial. Antivir Ther 13, 177187.Google ScholarPubMed
175Calmy, A, Gayet-Ageron, A, Montecucco, F, et al. (2009) HIV increases markers of cardiovascular risk: results from a randomized, treatment interruption trial. AIDS 23, 929939.CrossRefGoogle ScholarPubMed
176Anderson, KM, Odell, PM, Wilson, PWF, et al. (1991) Cardiovascular disease risk profiles. Am Heart J 121, 293298.CrossRefGoogle ScholarPubMed
177Friis-Møller, N & Worm, SW (2007) Editorial commentary: can the risk of cardiovascular disease in HIV-infected patients be estimated from conventional risk prediction tools? Clin Infect Dis 45, 10821084.CrossRefGoogle ScholarPubMed
178May, M, Sterne, JA, Shipley, M, et al. (2007) A coronary heart disease risk model for predicting the effect of potent antiretroviral therapy in HIV-1 infected men. Int J Epidemiol 36, 13091318.CrossRefGoogle ScholarPubMed
179Hammond, E, McKinnon, E & Nolan, D (2010) Human immunodeficiency virus treatment-induced adipose tissue pathology and lipoatrophy: prevalence and metabolic consequences. Clin Infect Dis 51, 591599.CrossRefGoogle ScholarPubMed
180Johnson, JA, Albu, JB, Engelson, ES, et al. (2004) Increased systemic and adipose tissue cytokines in patients with HIV-associated lipodystrophy. Am J Physiol Endocrinol Metab 286, E261E271.CrossRefGoogle ScholarPubMed
181Lagathu, C, Eustace, B, Prot, M, et al. (2007) Some HIV antiretrovirals increase oxidative stress and alter chemokine, cytokine or adiponectin production in human adipocytes and macrophages. Antivir Ther 12, 489500.Google ScholarPubMed
182Kim, RJ, Wilson, CG, Wabitsch, M, et al. (2006) HIV protease inhibitor-specific alterations in human adipocyte differentiation and metabolism. Obesity 14, 9941002.CrossRefGoogle ScholarPubMed
183Jan, V, Cervera, P, Maachi, M, et al. (2004) Altered fat differentiation and adipocytokine expression are inter-related and linked to morphological changes and insulin resistance in HIV-1-infected lipodystrophic patients. Antivir Ther 9, 555564.Google ScholarPubMed
184Sievers, M, Walker, UA, Sevastianova, K, et al. (2009) Gene expression and immunohistochemistry in adipose tissue of HIV type 1-infected patients with nucleoside analogue reverse transcriptase inhibitor-associated lipodystrophy. J Infect Dis 200, 252262.CrossRefGoogle Scholar
185Bastard, J-P, Maachi, M, van Nhieu, JT, et al. (2002) Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro. J Clin Endocrinol Metab 87, 20842089.CrossRefGoogle ScholarPubMed
186Domingo, P, Vidal, F, Domingo, JC, et al. (2005) Tumour necrosis factor α in fat redistribution syndromes associated with combination antiretroviral therapy in HIV-1-infected patients: potential role in subcutaneous adipocyte apoptosis. Eur J Clin Invest 35, 771780.CrossRefGoogle ScholarPubMed
187Kovsan, J, Ben-Romano, R, Souza, SC, et al. (2007) Regulation of adipocyte lipolysis by degradation of the perilipin protein. J Biol Chem 282, 2170421711.CrossRefGoogle ScholarPubMed
188Mallewa, JE, Wilkins, E, Vilar, J, et al. (2008) HIV-associated lipodystrophy: a review of underlying mechanisms and therapeutic options. J Antimicrob Chemother 62, 648660.CrossRefGoogle ScholarPubMed
189Rudich, A, Ben-Romano, R, Etzion, S, et al. (2005) Cellular mechanisms of insulin resistance, lipodystrophy and atherosclerosis induced by HIV protease inhibitors. Acta Physiol Scand 183, 7588.CrossRefGoogle ScholarPubMed
190Zhang, HH, Halbleib, M, Ahmad, F, et al. (2002) Tumor necrosis factor-α stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP. Diabetes 51, 29292935.CrossRefGoogle ScholarPubMed
191Rydén, M, Arvidsson, E, Blomqvist, L, et al. (2004) Targets for TNF-α-induced lipolysis in human adipocytes. Biochem Biophys Res Commun 318, 168175.CrossRefGoogle ScholarPubMed
192Adler-Wailes, D, Guiney, EL, Koo, J, et al. (2008) Effects of ritonavir on adipocyte gene expression: evidence for a stress-related response. Obesity 16, 23792387.CrossRefGoogle ScholarPubMed
193Giralt, M, Domingo, P, Guallar, JP, et al. (2006) HIV-1 infection alters gene expression in adipose tissue, which contributes to HIV-1/HAART-associated lipodystrophy. Antivir Ther 11, 729740.Google ScholarPubMed
194Bezante, GP, Briatore, L, Rollando, D, et al. (2009) Hypoadiponectinemia in lipodystrophic HIV individuals: a metabolic marker of subclinical cardiac damage. Nutr Metab Cardiovasc Dis 19, 277282.CrossRefGoogle ScholarPubMed
195Körner, A, Wabitsch, M, Seidel, B, et al. (2005) Adiponectin expression in humans is dependent on differentiation of adipocytes and down-regulated by humoral serum components of high molecular weight. Biochem Biophys Res Commun 337, 540550.CrossRefGoogle ScholarPubMed
196Pacenti, M, Barzon, L, Favaretto, F, et al. (2006) Microarray analysis during adipogenesis identifies new genes altered by antiretroviral drugs. AIDS 20, 16911705.CrossRefGoogle ScholarPubMed
197Lindegaard, B, Keller, P, Bruunsgaard, H, et al. (2004) Low plasma level of adiponectin is associated with stavudine treatment and lipodystrophy in HIV-infected patients. Clin Exp Immunol 135, 273279.CrossRefGoogle ScholarPubMed
198Sevastianova, K, Sutinen, J, Kannisto, K, et al. (2008) Adipose tissue inflammation and liver fat in patients with highly active antiretroviral therapy-associated lipodystrophy. Am J Physiol Endocrinol Metab 295, E85E91.CrossRefGoogle ScholarPubMed
199Caron, M, Auclair, M, Lagathu, C, et al. (2004) The HIV-1 nucleoside reverse transcriptase inhibitors stavudine and zidovudine alter adipocyte functions in vitro. AIDS 18, 21272136.CrossRefGoogle ScholarPubMed
200Grigem, S, Fischer-Posovszky, P, Debatin, KM, et al. (2005) The effect of the HIV protease inhibitor ritonavir on proliferation, differentiation, lipogenesis, gene expression and apoptosis of human preadipocytes and adipocytes. Horm Metab Res 37, 602609.CrossRefGoogle ScholarPubMed
201Kim, MJ, Leclercq, PE, Lanoy, E, et al. (2007) A 6-month interruption of antiretroviral therapy improves adipose tissue function in HIV-infected patients: the ANRS EP29 Lipostop Study. Antivir Ther 12, 12731283.Google ScholarPubMed
202Villarroya, F, Domingo, P & Giralt, M (2010) Drug-induced lipotoxicity: lipodystrophy associated with HIV-1 infection and antiretroviral treatment. BBA-Mol Cell Biol L 1801, 392399.CrossRefGoogle ScholarPubMed
203Venhoff, N, Setzer, B, Melkaoui, K, et al. (2007) Mitochondrial toxicity of tenofovir, emtricitabine and abacavir alone and in combination with additional nucleoside reverse transcriptase inhibitors. Antivir Ther 12, 10751085.Google ScholarPubMed
204Birkus, G, Hitchcock, MJM & Cihlar, T (2002) Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother 46, 716723.CrossRefGoogle ScholarPubMed
205Viengchareun, S, Caron, M, Auclair, M, et al. (2007) Mitochondrial toxicity of indinavir, stavudine and zidovudine involves multiple cellular targets in white and brown adipocytes. Antivir Ther 12, 919929.Google ScholarPubMed
206Walker, UA, Setzer, B & Venhoff, N (2002) Increased long-term mitochondrial toxicity in combinations of nucleoside analogue reverse-transcriptase inhibitors. AIDS 16, 21652173.CrossRefGoogle ScholarPubMed
207Ribera, E, Paradiñeiro, JC, Curran, A, et al. (2008) Improvements in subcutaneous fat, lipid profile, and parameters of mitochondrial toxicity in patients with peripheral lipoatrophy when stavudine is switched to tenofovir (LIPOTEST Study). HIV Clin Trials 9, 407417.CrossRefGoogle Scholar
208Caron, M, Auclairt, M, Vissian, A, et al. (2008) Contribution of mitochondrial dysfunction and oxidative stress to cellular premature senescence induced by antiretroviral thymidine analogues. Antivir Ther 13, 2738.Google ScholarPubMed
209Walker, UA, Auclair, M, Lebrecht, D, et al. (2006) Uridine abrogates the adverse effects of antiretroviral pyrimidine analogues on adipose cell functions. Antivir Ther 11, 2534.Google ScholarPubMed
210Sension, M, de Andrade Neto, JL, Grinsztejn, B, et al. (2009) Improvement in lipid profiles in antiretroviral-experienced HIV-positive patients with hyperlipidemia after a switch to unboosted atazanavir. J Acquir Immune Defic Syndr 51, 153162.CrossRefGoogle ScholarPubMed
211Sivakumar, T, Mechanic, O, Fehmie, D, et al. (2011) Growth hormone axis treatments for HIV-associated lipodystrophy: a systematic review of placebo-controlled trials. HIV Med 12, 453462.CrossRefGoogle ScholarPubMed
212Tungsiripat, M & Aberg, JA (2005) Dyslipidemia in HIV patients. Clev Clin J Med 72, 11131120.CrossRefGoogle ScholarPubMed
213Dubé, MP, Stein, JH, Aberg, JA, et al. (2003) Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: recommendations of the HIV Medicine Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group. Clin Infect Dis 37, 613627.CrossRefGoogle Scholar
214Fichtenbaum, C, Gerber, JG, Rosenkranz, SL, et al. (2002) Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047. AIDS 16, 569577.CrossRefGoogle ScholarPubMed
215Feldt, T, Oette, M, Kroidl, A, et al. (2006) Evaluation of safety and efficacy of rosiglitazone in the treatment of HIV-associated lipodystrophy syndrome. Infection 34, 5561.CrossRefGoogle ScholarPubMed
216Raboud, JM, Diong, C, Carr, A, et al. (2010) A meta-analysis of six placebo-controlled trials of thiazolidinedione therapy for HIV lipoatrophy. HIV Clin Trials 11, 3950.CrossRefGoogle ScholarPubMed
217Hadigan, C, Corcoran, C, Basgoz, N, et al. (2000) Metformin in the treatment of HIV lipodystrophy syndrome: a randomized controlled trial. JAMA 284, 472477.CrossRefGoogle ScholarPubMed
218van Wijk, JPH, Hoepelman, AIM, de Koning, EJP, et al. (2011) Differential effects of rosiglitazone and metformin on postprandial lipemia in patients with HIV-lipodystrophy. Arterioscler Thromb Vasc Biol 31, 228233.CrossRefGoogle ScholarPubMed
219Jiménez-Nácher, I, Alvarez, E, Morello, J, et al. (2011) Approaches for understanding and predicting drug interactions in human immunodeficiency virus-infected patients. Expert Opin Drug Metab Toxicol 7, 457477.CrossRef