Clinical review 153: Lipodystrophy in human immunodeficiency virus-infected patients

Human immunodeficiency virus (HIV) infection is a major global health problem. Recently, combination therapy including HIV-1 protease inhibitors (PIs) has dramatically improved the long-term survival of HIV-infected patients. However, such therapy is associated with a lipodystrophy syndrome characterized by selective loss of sc fat from the face and extremities and, in some patients, accumulation of fat around the neck, dorsocervical region, abdomen, and trunk. Lipodystrophy in HIV-infected patients (LDHIV) is associated with insulin resistance and its metabolic complications such as impaired glucose tolerance, diabetes, hypertriglyceridemia and low serum high density lipoprotein cholesterol levels. PIs appear to be the strongest link to LDHIV; however, fat loss has been reported in some patients taking non-PI antiretroviral drugs. Other factors, such as duration of HIV infection, age, and gender, may also contribute to the risk of development of LDHIV. The molecular basis of LDHIV remains unknown. There is no specific therapy for LDHIV. Avoiding weight gain by reducing energy intake and increasing physical activity may be beneficial in reducing fat accumulation as well as improving metabolic complications. Antihyperglycemic drugs may be used to treat diabetes. Management of dyslipidemia may require lipid-lowering drugs; however, the safety and efficacy of such intervention require further studies. Substitution of PIs with other antiretroviral drugs can mitigate dyslipidemia and glucose intolerance, but whether reversal of lipodystrophy occurs remains unknown. Future research is needed to discover the biochemical and molecular markers of lipodystrophy in HIV patients and develop PIs or other antiretroviral agents that are free of metabolic toxicity.     

Dyslipidemia and its Treatment in HIV Infection

HIV-infected patients have metabolic abnormalities that put them at increased risk of cardiovascular disease (CVD), including abnormalities associated with HIV infection itself, antiretroviral treatment, restoration to health, and body composition changes. The 2 major components of dyslipidemia in HIV-infected patients are hypertriglyceridemia and reduction in high-density lipoprotein (HDL) cholesterol (with likely altered function of HDL cholesterol); these abnormalities contribute to increased atherosclerotic risk. Adverse effects of antiretroviral drugs on lipids are not class specific but rather are associated with particular drugs. Thus, practitioners need to be cognizant of the risks of metabolic abnormalities posed by individual drugs. HIV infection increases CVD risk independent of the effects of traditional risk factors. The relative risk of CVD in HIV-infected patients has decreased in recent years with increasing use of lipid-lowering therapy. However, use of lipid-lowering therapy is complicated by numerous potential drug interactions with antiretroviral drugs that practitioners need to consider when prescribing lipid-lowering therapy. This article summarizes a presentation made by Carl Grunfeld, MD, PhD, at the International AIDS Society-USA continuing medical education program in Los Angeles in March 2010. The original presentation is available as a Webcast at www.iasusa.org.     

Approach to the human immunodeficiency virus-infected patient with lipodystrophy

Subcutaneous atrophy and central fat accumulation are common among HIV-infected patients receiving highly active antiretroviral therapy, and may be accompanied by dyslipidemia and insulin resistance. These fat changes, although commonly referred to together as lipodystrophy, are best considered as separate disorders, with distinct pathogeneses and treatment approaches. These morphological and metabolic abnormalities first appeared after introduction of protease inhibitors more than 10 yr ago, but research has demonstrated that their pathogenesis is multifactorial, with contributions from other antiretroviral medications, patient-related factors, and HIV itself. Switching to a less toxic highly active antiretroviral therapy regimen has shown partial effectiveness for the management of fat atrophy and lipid abnormalities. Lifestyle modification or surgical approaches are the treatment of choice for lipohypertrophy, although novel therapies targeting the GH axis show promise. HIV-related dyslipidemia may be difficult to treat, and can be complicated by drug-drug interactions between some lipid-lowering medications and antiretroviral medications. Treatment of diabetes in HIV-infected patients should generally follow established guidelines, but thiazolidinediones, rather than metformin, may be considered first-line treatment in a patient with lipoatrophy, given their potential to increase sc fat. The contribution of body fat changes and metabolic abnormalities to cardiovascular risk and the changing risk profiles of newer antiretroviral regimens are under intense investigation.     

Increased use of lipid-lowering therapy in patients receiving human immunodeficiency virus protease inhibitors

Although human immunodeficiency virus (HIV) protease inhibitors (PIs) improve survival in patients with HIV infection, many patients receiving PIs develop hyperlipidemia, which may increase risk of future coronary events. The purpose of this study was to estimate the changing prevalence of lipid-lowering therapy (LLT) in patients with HIV and to evaluate its association with the use of HIV PIs. This was a cross-sectional study of adults with HIV infection who were registered in the Medicaid of California (MEDI-CAL) administrative claims database. Frequencies of HIV-related and dyslipidemia diagnoses were determined from International Classification of Diseases-9th Edition codes. Use of lipid-lowering and antiretroviral medications was determined by National Drug Codes. Multivariate statistical techniques were used to evaluate trends in use of PIs and lipid-lowering medications from January 1996 to June 2002. The number of HIV-infected patients in MEDI-CAL ranged from 15,764 in 1996 to 13,349 in 2000. The prevalence of LLT use among HIV-infected patients on PIs increased by sixfold (1.7% to 10.6%, p <0.05), and in 2000, exceeded use in the overall MEDI-CAL population (p = 0.09). The increasing rate of LLT in patients taking PIs was greater than in HIV-infected patients not on PIs and in MEDI-CAL (p = 0.002). In multivariate models, increasing age (odds ratio 2.30) and use of PIs (odds ratio 2.08) predicted use of LLT (p <0.001). Thus, in patients taking HIV PIs, use of LLT increased more than sixfold, at a faster rate than in the general population. It has not been proved that use of LLT in HIV-infected patients taking PIs improves survival.     

HIV, metabolic syndrome X, inflammation, oxidative stress, and coronary heart disease risk : role of protease inhibitor exposure

Differences on measures of metabolic syndrome X and coronary heart disease (CHD) risk, as well as potential pathophysiological mediators, inflammation, and oxidative stress, were examined as a function of HIV serostatus and highly active antiretroviral therapy (HAART) regimen with and without protease inhibitors (PIs). Data from 164 men and women, aged 18 to 55 yr, were used to compare 82 HIV+ subjects who were free of hepatitis C virus and were on a stable HAART regimen for >/=6 mo, with 82 seronegative subjects matched on age, sex, body mass index, and ethnicity. For the HIV+ subjects, after controlling for diabetes status and HIV disease progression, PI exposure was associated with greater oxidative stress, triglyceridemia, and lipidemia than it was for non-PI-exposed HIV+ subjects, and the risk of a future myocardial infarction was up to 56% greater in PI-exposed than in non-PI-exposed subjects and 129% greater than in controls. Although it is likely that the greatest proportion of CHD risk in the HIV+ subjects may be accounted for by pathological conditions linked to HIV infection in interaction with mediating processes such as inflammation, central obesity, and dyslipidemia, which was greater than in controls, it appears that PI medications may exacerbate oxidative stress and hypertriglyceridemia to enhance this risk.     

Metabolic syndrome and cardiovascular disease in patients with human immunodeficiency virus

Use of highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus (HIV) infection is associated with the development of cardiovascular risk factors, including dyslipidemia, insulin resistance, fat redistribution, and hypertension. The results of the Data Collection on Adverse Events of Anti-HIV Drugs study showed that HAART therapy is associated with a 26% relative risk increase in the rate of myocardial infarction per year of HAART exposure. A number of studies have shown that insulin resistance often precedes lipodystrophy, suggesting that insulin resistance may be a primary feature of the metabolic syndrome in this population. The rate-limiting step in the uptake of glucose is glucose transport, and the predominant glucose transporter (GLUT) in muscle and fat is GLUT-4. Specific protease inhibitors (PIs) have been associated with decreased GLUT-4-mediated glucose transport and insulin resistance both in vitro and in vivo, whereas newer protease inhibitors may have fewer effects on insulin sensitivity. Data also suggest that endothelial dysfunction, impaired fibrinolysis, and excess inflammation may contribute to increased cardiovascular risk in the population infected with HIV. Moreover, recent data suggest that evidence for coronary atherosclerotic disease can be revealed by means of carotid intimal medial thickness (IMT) assessments in specific groups of HIV patients. Pharmacologic strategies for the prevention and/or treatment of HAART-induced dyslipidemia and abnormal glucose homeostasis include 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), resins, nicotinic acid, fibrates, and insulin-sensitizing agents. However, newer PIs such as atazanavir may result in less insulin resistance and dyslipidemia and, as part of a HAART regimen, use of atazanavir may reduce the metabolic complications associated with HAART.     

HIV, metabolic syndrome X, inflammation, oxidative stress, and coronary heart disease risk

Differences on measures of metabolic syndrome X and coronary heart disease (CHD) risk, as well as potential pathophysiological mediators, inflammation, and oxidative stress, were examined as a function of HIV serostatus and highly active antiretroviral therapy (HAART) regimen with and without protease inhibitors (PIs). Data from 164 men and women, aged 18 to 55 yr, were used to compare 82 HIV⁺ subjects who were free of hepatitis C virus and were on a stable HAART regimen for ≥6 mo, with 82 seronegative subjects matched on age, sex, body mass index, and ethnicity. For the HIV⁺ subjects, after controlling for diabetes status and HIV disease progression, PI exposure was associated with greater oxidative stress, triglyceridemia, and lipidemia than it was for non-PI-exposed HIV⁺ subjects, and the risk of a future myocardial infarction was up to 56% greater in PI-exposed than in non-PI-exposed subjects and 129% greater than in controls. Although it is likely that the greatest proportion of CHD risk in the HIV⁺ subjects may be accounted for by pathological conditions linked to HIV infection in interaction with mediating processes such as inflammation, central obesity, and dyslipidemia, which was greater than in controls, it appears that PI medications may exacerbate oxidative stress and hypertriglyceridemia to enhance this risk.     

Factores de riesgo cardiovascular dependientes del paciente en población con infección por VIH

The pathogenesis of arteriosclerosis in HIV-infected patients is complex. Both patient-related cardiovascular risk factors (CVRF) established for the general population and those related to highly-active antiretroviral therapy (HAART) and HIV infection per se are involved. Some traditional CVRF are more frequent in HIVinfected patients than in the general population. In developed countries, HIV infection is more frequent among men and, due to HAART, their life expectancy has significantly increased. The prevalence of smoking (37-72%) is higher than in the general population, as is that of diabetes mellitus (17%), insulin resistance (17-51%), dyslipidemia (22-49%) and hypertriglyceridemia (34%). The higher prevalence in these patients is probably due to lifestyle and length of exposure to HAART, especially to certain antiretroviral drugs. Although overall cardiovascular risk in patients with HIV remains low, CVRF established for the general population become more important with increasing age. Longitudinal cohort studies indicate the magnitude of the association of these risk factors with cardiovascular disease in patients with HIV infection. In view of all the factors that intervene in HIV infection, specific mathematical models should be designed for this population that would allow individual cardiovascular risk to be calculated in each patient and measures for cardiovascular prevention to be established.     

Diabetes and HIV: Current Understanding and Future Perspectives

Diabetes mellitus is a chronic disease with a higher risk of associated infections. HIV infection severely affects diabetic patients and acts as a significant health concern. Highly active antiretroviral therapy (HAART) has changed HIV from an acute infection to a chronic infection with associated significant metabolic abnormalities such as insulin resistance, impaired glucose tolerance, metabolic syndrome, diabetes, dyslipidemia, obesity, and lipodystrophy. These metabolic disturbances add complexity to the standards of care in HIV infection and further increase the risk for cardiovascular disease and renal complications. The co-association of diabetes and HIV needs to be managed appropriately to prevent mortality and morbidity and improve patient outcome. The current understanding of diabetes and other metabolic abnormalities along with management strategies in HIV infected patients are summarized in this article. The review also focuses on recent challenges in the diagnosis and management of co-existent diabetes and HIV infection.     

Strategies for management and treatment of dyslipidemia in HIV/AIDS

With the improved survival of HIV-infected patients, there are increased concerns about the long-term effects of treatment, including protease inhibitor (PI)-related dyslipidemia. Some 50-70% of patients receiving combination antiretroviral therapy (ART) involving PIs develop lipid abnormalities consisting of elevated levels of total cholesterol, low-density lipoprotein cholesterol and triglycerides that are well-known risk factors for cardiovascular disease. Treatment of HIV dyslipidemia should include lifestyle modifications such as a low-fat diet, increased exercise, reduced alcohol consumption and smoking cessation. In many patients, however, these changes alone will not correct lipid levels. In some patients, changing the PI component of ART to another PI or non-PI and/or lipid-lowering drugs has proven successful. Each approach is associated with advantages and limitations and the need to maintain viral suppression must be balanced with the need to treat abnormal lipid levels.     

Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects

BACKGROUND: Intensive therapy of HIV infection with highly active antiretroviral therapy (HAART) dramatically reduces viral loads and improves immune status. Abnormalities of lipid levels, body fat distribution, and insulin resistance have been commonly reported after starting HAART. Whether the lipid abnormalities result from changes in metabolism after an improvement in HIV status or are partly attributable to the effects of protease inhibitor use is unknown. METHODS: Twenty-one healthy volunteers participated in a 2 week double-blind, placebo-controlled study on the effect of the protease inhibitor ritonavir on total lipids, apolipoproteins, and post-heparin plasma lipase activities. RESULTS: Those taking ritonavir (n = 11) had significantly higher levels of plasma triglyceride, VLDL cholesterol, IDL cholesterol, apolipoprotein B, and lipoprotein (a) compared with placebo (n = 8). HDL cholesterol was lower with therapy as a result of a reduction in HDL3 cholesterol. Post-heparin lipoprotein lipase (LpL) activity did not change but hepatic lipase activity decreased 20% (P < 0.01) in those taking ritonavir-compared with placebo. Although all lipoprotein subfractions became triglyceride enriched, most of the increase in triglyceride was in VLDL and not in IDL particles. CONCLUSION: Treatment with ritonavir in the absence of HIV infection or changes in body composition results in hypertriglyceridemia that is apparently not mediated by impaired LpL activity or the defective removal of remnant lipoproteins, but could be caused by enhanced formation of VLDL. Long-term studies of patients with HIV infection receiving HAART will be necessary to determine the impact of these drugs and associated dyslipidemia on the risk of coronary artery disease.     

The human immunodeficiency virus and the cardiometabolic syndrome in the developing world: an African perspective

The advent of highly active antiretroviral therapy (HAART) has transformed human immunodeficiency virus (HIV)/AIDS into a manageable chronic disorder. Clinical care, however, needs to address the metabolic, anthropometric, and cardiovascular changes associated with HIV infection and HAART. Studies in developing countries suggest an increasing incidence of HIV-associated cardiometabolic syndrome (CMS), especially in urban settings. Predictions indicate that the greatest increase in the prevalence of diabetes will occur in Africa over the next 2 decades due to lifestyle changes. This, coupled with increased access to HAART, may exponentially increase the prevalence of CMS in developing countries, where HIV infection is prevalent. Appropriate evaluation and intervention programs need to be implemented in the developing world, especially sub-Saharan Africa, to curtail HIV-related CMS. This should include routine cardiovascular risk assessments, management of HIV infection with more "metabolically friendly" HAART, and encouragement of lifestyle modifications, particularly smoking cessation, weight management, regular exercise, and adherence to a healthy diet.     

Insulin resistance in HIV-related lipodystrophy

Lipodystrophy (LD) associated with HIV infection is a syndrome of abnormal fat distribution observed in HIV-infected patients treated with various antiretroviral agents. In addition, insulin resistance and dyslipidemia can occur in HIV-infected patients with or without LD. The demonstration of the latter metabolic disorders in normal subjects using protease inhibitors suggests that these agents could play a causative role in their development independently of HIV status. Possible mechanisms whereby protease inhibitors can hinder insulin actions include inhibition of glucose transporter isoform Glut 4, and altered expression of leptin and tumor necrosis factor-α in adipose tissue. The presence of insulin resistance and dyslipidemia can potentially increase the risk of diabetes, cardiovascular disease, and death. However, short-term data in this regard are inconsistent. Treatment of HIV-related LD with metformin may ameliorate insulin resistance, but its impact on fat redistribution requires additional studies. Temporary cessation of antiretroviral therapy does not appear to reverse body fat changes or insulin resistance, but may partially improve the lipid profile. Further investigations are urgently needed to define the mechanisms and cardiovascular consequences of insulin resistance in HIV-related LD, and to find an effective treatment for this complex syndrome.     

Vorzeitige Arteriosklerose bei HIV-infizierten Patienten?

Complex lipodystrophic body changes in association with metabolic abnormalities such as dyslipidemia and insulin resistance have become a common feature in HIV patients on highly active antiretroviral therapy (HAART). If these metabolic changes will lead to an epidemic of cardiovascular events within the next decades, however, remains to be seen. The incidence of myocardial infarctions in HIV-infected patients continues to be low. Current data on changes of the incidence in the HAART era remains somewhat conflicting, probably due to methodological issues. In this review the key studies concerning the incidence of premature arteriosclerosis in HIV-infected patients are discussed.     

Metabolic abnormalities associated with HIV infection and antiretroviral therapy

Although noted early in the HIV epidemic, metabolic abnormalities came to prominence when potent combination antiretroviral therapy was introduced. Complications associated with HIV infection and antiretroviral therapy include cardiovascular disease, lipid disorders, glucose metabolism disorders, adipose tissue disorders, bone metabolism disorders, and lactic acidosis. Metabolic complications have driven the discovery of new agents and classes of antiretrovirals, and have shaped guidelines for the management of HIV infection. However, significant uncertainty remains about pathogenesis and management. Substantial complexity exists in the treatment of these disorders, illustrated by the complex drugdrug interactions between lipid-lowering agents and antiretroviral regimens. Several important new developments include the association of a higher risk of cardiovascular events with the discontinuation of antiretroviral therapy or use of specific drugs like abacavir and didanosine. This article reviews the current understanding of metabolic abnormalities associated with HIV and its treatment.     

Effects of protease inhibitors on hyperglycemia, hyperlipidemia, and lipodystrophy: a 5-year cohort study

BACKGROUND: Although human immunodeficiency virus (HIV)-related morbidity and mortality rates in patients with advanced HIV infection who are treated with combination antiretroviral drugs have declined, significant metabolic adverse effects associated with these regimens have been increasingly recognized. However, since data from patients studied before and after initiation of protease inhibitor (PI) therapy are scant, the true effect of PIs on these metabolic changes remains unknown. OBJECTIVES: To examine temporal trends in serum glucose and lipid levels after initiation of PI therapy, to assess whether changes are independent of virological response and improvement in disease severity, and to determine risk factors associated with the development of hyperglycemia, hyperlipidemia, and lipodystrophy. METHODS: A 5-year historical cohort analysis in a population of 221 HIV-infected patients observed in the Infectious Diseases Clinic of a tertiary care center from October 1, 1993, through July 31, 1998. Clinical and laboratory data were retrieved from medical records and a computerized database. The main outcome measure was the incidence of hyperglycemia, hypercholesterolemia, hypertriglyceridemia, and lipodystrophy. Adjusted incidence rate ratios (IRRs) were estimated by means of Poisson regression. In addition, mixed regression analyses were performed to examine effects of PIs on serum lipid and glucose levels, modeled as continuous outcomes. RESULTS: The cumulative incidence of new-onset hyperglycemia, hypercholesterolemia, hypertriglyceridemia, and lipodystrophy was 5%, 24%, 19%, and 13%, respectively. Most of these events occurred after initiation of PI therapy. Protease inhibitors were independently associated with hyperglycemia (adjusted IRR, 5.0; 95% confidence interval [CI], 1. 3-19.4), hypercholesterolemia (adjusted IRR, 2.8; 95% CI, 1.5-5.2), hypertriglyceridemia (adjusted IRR, 6.1; 95% CI, 3.1-11.7), and lipodystrophy (adjusted IRR, 5.1; 95% CI, 1.9-13.9). Anabolic steroids and psychotropic medications were also associated with lipodystrophy. Inclusion of potential intermediate variables (eg, virological suppression and increase in body weight) did not reduce the magnitude of the association with PIs. The association between hypertriglyceridemia and ritonavir was stronger than for other PIs (Wald test, P=.02). In contrast, the incidence of hyperglycemia, hypercholesterolemia, and lipodystrophy did not vary significantly across different PIs. Longitudinal mixed models confirmed that serum lipid levels were more substantially affected by antiretroviral therapy, particularly PIs, than serum glucose levels. Similarly, controlling for surrogate markers did not abolish the strong association between PIs and increase in serum lipid levels. CONCLUSION: We found an independent association between PI use and hyperglycemia, hyperlipidemia, and lipodystrophy that is not explained by the antiviral and therapeutic effect of PIs.     

Management of dyslipidemia and other cardiovascular risk factors in HIV-infected patients: case-based review

Many HIV-infected patients have dyslipidemia and other cardiovascular risk factors prior to acquiring infection. Both HIV infection itself and antiretroviral therapy can cause or worsen lipid abnormalities. Management of dyslipidemia in the HIV-infected patient requires awareness of the effects of antiretroviral agents on lipid profiles, including potential sex- and race-related effects, and interactions between lipid-modifying agents and antiretroviral agents. This article uses individual case histories to illustrate the decisions encountered in treating HIV infection and dyslipidemia. The article is based on a presentation on management of dyslipidemia and other cardiovascular risk factors in HIV infection made by Judith A. Aberg, MD, at the International AIDS Society-USA Los Angeles CME program in February 2006.