Review
Metabolic disease in HIV infection

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Summary

The treatment of metabolic disease is becoming an increasingly important component of the long-term management of patients with well controlled HIV on antiretroviral therapy (ART). Metabolic diseases probably develop at the intersection of traditional risk factors (such as obesity, tobacco use, and genetic predisposition) and HIV-specific and ART-specific contributors (including chronic inflammation and immune activation). This Review discusses present knowledge on adipose tissue dysfunction, insulin–glucose homoeostasis, lipid disturbances, and cardiovascular disease risk in people with HIV on ART. Although new antiretroviral drugs are believed to induce fewer short-term metabolic perturbations than do older drugs, the long-term effects of these drugs are not fully understood. Additionally, patients remain at increased risk of cardiovascular disease and other metabolic comorbidities. Research and treatment should focus on selection of ART that is both virologically effective and has minimum metabolic effects, minimisation of traditional risk factors for metabolic disease, and development of novel therapies to treat metabolic disease in patients with HIV, including use of anti-inflammatory and immunomodulatory drugs.

Introduction

Comorbid disease management is becoming increasingly important in the long-term management of patients with well controlled HIV on antiretroviral therapy (ART). Metabolic disease in HIV probably develops in the setting of traditional risk factors (such as obesity, tobacco use, and genetic predisposition) and HIV-specific and ART-specific contributors (including chronic inflammation and immune activation). In this Review, we discuss present data on the pathophysiology of and treatment options for the management of adipose tissue dysfunction, disorders of insulin–glucose homoeostasis, dyslipidaemia, and cardiovascular disease in patients with HIV, with a focus on the contributions of ART to these comorbid states.

Section snippets

Pathogenesis of adipose tissue dysfunction

Lipoatrophy and lipohypertrophy are clinically significant problems in patients with long-term HIV treated with ART, especially in people given older antiretroviral drugs; however, our knowledge of how lipodystrophic and non-lipodystrophic adipose tissue function differently remains incomplete, with few available treatments options for patients with lipodystrophy. Additionally, whether adipose tissue dysfunction in the absence of clinically apparent fat changes contributes to the development of

Epidemiology and pathogenesis of glucose disorders

Disorders of insulin–glucose homoeostasis are common in people with HIV, with estimates of prevalence of diabetes mellitus in ART-naive people at 3%,54, 55 of diabetes mellitus in patients on highly active ART up to 10%, and up to 25% for any disorder of insulin–glucose homoeostasis.56 Glucose disorders have been associated with traditional risk factors in addition to HIV-associated factors such as lipodystrophy and ART.56, 57, 58, 59 Although obesity plays a part in development of diabetes

Effects of ART on lipids in adults

Lipid changes after ART initiation partly reflect a return to health after treatment of HIV infection.88 However, increased lipid concentrations might require intervention (especially in patients with other cardiovascular risk factors), and expected lipid disturbances could be an important consideration when selecting ART. Fortunately, measurement of fasting lipid concentrations has become a standard component of clinical trials assessing new antiretroviral drugs, and new drugs show minimum

Effects of ART of cardiovascular risk

Whether specific lipid changes associated with individual antiretroviral drugs affect cardiovascular risk remains uncertain. Several studies show that total and LDL cholesterol concentrations might increase slightly more in patients given efavirenz compared with those given integrase inhibitors; however, HDL cholesterol also rises to a greater extent with efavirenz and the total:HDL cholesterol ratio remains unchanged. Investigators of a pilot study suggested that patients given efavirenz-based

Conclusions

Metabolic perturbations in patients with HIV on ART have a substantial role in morbidity and mortality, but our understanding of how (and whether) these disease states develop differentially in the setting of HIV infection is incomplete. Similarly, optimum interventions to prevent and treat comorbid, metabolic disease in patients with HIV are yet to be defined. Further research is needed to fully elucidate the pathophysiology of metabolic disease in this patient population, with particular

Search strategy and selection criteria

We searched PubMed and ClinicalTrials.gov for articles relevant to the pathogenesis and treatment of adipose tissue dysfunction, disorder of glucose insulin homoeostasis, dyslipidaemia, and cardiovascular disease in patients with HIV. Articles published in English between Jan 1, 2011, and Aug 1, 2013, that provided insight into the pathogenesis of these disorders or advanced patient care were reviewed. ClinicalTrials.gov also provided citations for ongoing trials relevant to the treatment of

References (142)

  • PW Hruz

    Molecular mechanisms for insulin resistance in treated HIV-infection

    Best Pract Res Clin Endocrinol Metab

    (2011)
  • IJ Paik et al.

    The prevalence and pathogenesis of diabetes mellitus in treated HIV-infection

    Best Pract Res Clin Endocrinol Metab

    (2011)
  • P Oriot et al.

    Exenatide improves weight loss insulin sensitivity and beta-cell function following administration to a type 2 diabetic HIV patient on antiretroviral therapy

    Ann Endocrinol (Paris)

    (2011)
  • F Magkos et al.

    Leptin replacement improves postprandial glycemia and insulin sensitivity in human immunodeficiency virus-infected lipoatrophic men treated with pioglitazone: a pilot study

    Metabolism

    (2011)
  • PE Sax et al.

    Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks

    Lancet

    (2012)
  • J van Lunzen et al.

    Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial

    Lancet Infect Dis

    (2012)
  • M Torriani et al.

    Deiodinase 2 expression is increased in dorsocervical fat of patients with HIV-associated lipohypertrophy syndrome

    J Clin Endocrinol Metab

    (2012)
  • LA Kosmiski et al.

    Brown fat activity is not apparent in subjects with HIV lipodystrophy and increased resting energy expenditure

    Obesity (Silver Spring)

    (2011)
  • M Torriani et al.

    Increased FDG uptake in association with reduced extremity fat in HIV patients

    Antivir Ther

    (2013)
  • K Sevastianova et al.

    Comparison of dorsocervical with abdominal subcutaneous adipose tissue in patients with and without antiretroviral therapy-associated lipodystrophy

    Diabetes

    (2011)
  • G Garrabou et al.

    Mitochondrial damage in adipose tissue of untreated HIV-infected patients

    AIDS

    (2011)
  • F Vidal et al.

    Adipogenic/lipid, inflammatory, and mitochondrial parameters in subcutaneous adipose tissue of untreated HIV-1-infected long-term nonprogressors: significant alterations despite low viral burden

    J Acquir Immune Defic Syndr

    (2012)
  • ER Feeney et al.

    Zidovudine/lamivudine but not nevirapine in combination with lopinavir/ritonavir decreases subcutaneous adipose tissue mitochondrial DNA

    AIDS

    (2012)
  • GA McComsey et al.

    Changes in fat mitochondrial DNA and function in subjects randomized to abacavir-lamivudine or tenofovir DF-emtricitabine with atazanavir-ritonavir or efavirenz: AIDS Clinical Trials Group study A5224s, substudy of A5202

    J Infect Dis

    (2013)
  • JM Gallego-Escuredo et al.

    Differentially altered molecular signature of visceral adipose tissue in HIV-1-associated lipodystrophy

    J Acquir Immune Defic Syndr

    (2013)
  • KC McGee et al.

    Evidence for a shift to anaerobic metabolism in adipose tissue in efavirenz-containing regimens for HIV with different nucleoside backbones

    Antivir Ther

    (2012)
  • CG Morse et al.

    HIV infection and antiretroviral therapy have divergent effects on mitochondria in adipose tissue

    J Infect Dis

    (2012)
  • JE Lake et al.

    Switching antiretroviral therapy to minimize metabolic complications

    HIV Ther

    (2010)
  • A Martin et al.

    Predictors of limb fat gain in HIV positive patients following a change to tenofovir-emtricitabine or abacavir-lamivudine

    PLoS One

    (2011)
  • R de Waal et al.

    Systematic review of antiretroviral-associated lipodystrophy: lipoatrophy, but not central fat gain, is an antiretroviral adverse drug reaction

    PLoS One

    (2013)
  • GA McComsey et al.

    Mitochondrial function, inflammation, fat and bone in HIV lipoatrophy: randomized study of uridine supplementation or switch to tenofovir

    Antivir Ther

    (2012)
  • E Schlapfer et al.

    Anti-HIV-1 activity of leflunomide: a comparison with mycophenolic acid and hydroxyurea

    AIDS

    (2003)
  • A Mencarelli et al.

    Ritonavir-induced lipoatrophy and dyslipidaemia is reversed by the anti-inflammatory drug leflunomide in a PPAR-gamma-dependent manner

    Antivir Ther

    (2012)
  • SW Read et al.

    The effect of leflunomide on cycling and activation of T-cells in HIV-1-infected participants

    PLoS One

    (2010)
  • J Shuck et al.

    Autologous fat grafting and injectable dermal fillers for human immunodeficiency virus-associated facial lipodystrophy: a comparison of safety, efficacy, and long-term treatment outcomes

    Plast Reconstr Surg

    (2013)
  • JT Nadarajah et al.

    Infectious complications of Bio-Alcamid filler used for HIV-related facial lipoatrophy

    Clin Infect Dis

    (2012)
  • GA McComsey et al.

    Peripheral and central fat changes in subjects randomized to abacavir-lamivudine or tenofovir-emtricitabine with atazanavir-ritonavir or efavirenz: ACTG Study A5224s

    Clin Infect Dis

    (2011)
  • E Capel et al.

    Effects of ritonavir-boosted darunavir, atazanavir and lopinavir on adipose functions and insulin sensitivity in murine and human adipocytes

    Antivir Ther

    (2012)
  • L Gibellini et al.

    The protease inhibitor atazanavir triggers autophagy and mitophagy in human preadipocytes

    AIDS

    (2012)
  • J Diaz-Delfin et al.

    Effects of rilpivirine on human adipocyte differentiation, gene expression, and release of adipokines and cytokines

    Antimicrob Agents Chemother

    (2012)
  • JK Rockstroh et al.

    Long-term treatment with raltegravir or efavirenz combined with tenofovir/emtricitabine for treatment-naive human immunodeficiency virus-1-infected patients: 156-week results from STARTMRK

    Clin Infect Dis

    (2011)
  • J Reynes et al.

    Lopinavir/ritonavir combined with raltegravir or tenofovir/emtricitabine in antiretroviral-naive subjects: 96-week results of the PROGRESS study

    AIDS Res Hum Retroviruses

    (2013)
  • JE Lake et al.

    A randomized trial of raltegravir replacement for protease inhibitor or non-nucleoside reverse transcriptase inhibitor in HIV-infected women with lipohypertrophy

    AIDS Patient Care STDS

    (2012)
  • I Ofotokun et al.

    A switch in therapy to a reverse transcriptase inhibitor sparing combination of lopinavir/ritonavir and raltegravir in virologically suppressed HIV-infected patients: a pilot randomized trial to assess efficacy and safety profile: the KITE study

    AIDS Res Hum Retroviruses

    (2012)
  • ASM Curran et al.

    Body composition changes after switching from protease inhibitors to RAL: SPIRAL LIP substudy

    AIDS

    (2012)
  • P Perez-Matute et al.

    Neutral actions of Raltegravir on adipogenesis, glucose metabolism and lipolysis in 3T3-L1 adipocytes

    Curr HIV Res

    (2011)
  • MJ Glesby et al.

    Recombinant human growth hormone and rosiglitazone for abdominal fat accumulation in HIV-infected patients with insulin resistance: a randomized, double-blind, placebo-controlled, factorial trial

    PLoS One

    (2013)
  • TL Stanley et al.

    Reduction in visceral adiposity is associated with an improved metabolic profile in HIV-infected patients receiving tesamorelin

    Clin Infect Dis

    (2012)
  • P Koutkia et al.

    Metabolic regulation of growth hormone by free fatty acids, somatostatin, and ghrelin in HIV-lipodystrophy

    Am J Physiol Endocrinol Metab

    (2004)
  • S Jain et al.

    Pathophysiology of GHRH-growth hormone-IGF1 axis in HIV/AIDS

    Rev Endocr Metab Disord

    (2013)
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