Despite advances in the treatment of human immunodeficiency virus (HIV) and AIDS, the disease continues to be a global problem. As of December 2006, the World Health Organization estimated that 33.3 million persons were living with HIV or AIDS worldwide, including 2.5 million children.1 Effective prevention of mother to child transmission has lowered the incidence of perinatal HIV in the United States, and increasing use of prophylactic medications in developing nations is helping to contain the epidemic in those countries as well.1
Cardiometabolic problems in children with human immunodeficiency virus (HIV) infection have recently begun to emerge as distinct clinical problems that require monitoring and often intervention. The cardiometabolic issues that face HIV-infected children include high rates of unfavorable lipid profiles, insulin resistance, cardiovascular inflammation, and vascular stiffness as well as the phenotypic features of truncal adiposity and facial/extremity wasting. Children differ from adults in that many have been exposed to both HIV and antiretroviral therapies even before birth. The future risk of adverse cardiovascular outcomes is poorly defined yet warrants close tracking because a number of risk factors are present in early childhood. Preventive care and interventions that include surveillance of nutrition and body composition, dietary counseling, exercise programs, and drug therapy should be considered standard care for all HIV-infected children.
Pediatric HIV Infection
Pediatric HIV infection is best classified by route of transmission. Childhood infections are usually the result of transmission of the virus from the mother to the child prenatally or postnatally.2 Infants can be infected in utero, during delivery, or during breastfeeding. A smaller proportion of children become infected through contaminated blood products or sexual abuse. New-onset HIV infection in adolescents is typically acquired horizontally through sexual intercourse or intravenous drug use.2
The natural history of perinatal HIV infection (in the pre-highly active antiretroviral therapy [HAART] era) is different from that of adults.3 Newly infected adults experience a rapid increase in viral load followed by a sharp decline and plateau once the immune response is elicited. Conversely, infected infants sustain high viral loads after acute infection because of the absence of a fully developed immune system. Viral loads typically decline somewhat after the first year of life (Figure 1).
HAART has delayed disease progression and improved mortality in HIV-infected children. In addition to viral suppression, HAART is associated with immune reconstitution.3 Compared with adults, the immune response to HAART in children may be more vigorous because of an active thymus.3 HAART has resulted in overall enhanced health status, slower HIV disease progression, and improved developmental outcomes. However, the efficacy of viral suppression needs to be balanced against the toxicities and adverse effects of HAART. This review will focus on the cardiometabolic factors associated with both HIV infection and its treatment in children.
Pediatric HIV and Nutrition in the Pre-HAART Era. Prior to the advent of HAART, malnutrition was one of the most frequent and devastating complications of pediatric HIV infection that was predictive of both morbidity and mortality.4 There is a well-defined association between nutrition, growth, and immune function in both children and adults (with and without HIV infection).5 While HIV infection can directly impact nutritional status, there is a cyclical effect; malnutrition can intensify the immunologic effects of HIV infection, thus leading to a downward vicious cycle of malnutrition, immune dysfunction, and advancing HIV disease (Figure 2).3,5
Malnutrition in HIV-infected children has a multifactorial etiology6 and is attributed to:
- 1Reduced oral intake, secondary to HIV infection-induced primary cachexia, opportunistic infections of the upper gastrointestinal tract, and medication side effects.
- 2Malabsorption,7 secondary to HIV infection alone, and overt or occult infections of the GI tract.
- 3Altered metabolic state due to the proinflammatory effects of chronic HIV infection.6
Although developed nations now have far fewer HIV-infected children with malnutrition or failure to thrive, it remains prevalent even in the HAART era.6
Pediatric HIV Infection and Nutrition in the HAART Era. HAART refers to a combination of antiretroviral agents, generally including a protease inhibitor (PI) that is highly effective against viral replication. Other classes of drugs include nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). The mechanisms of PI effects have been described elsewhere.8 Current pediatric treatment guidelines include a PI in the recommended combination therapy regimen for any HIV-infected child with clinical symptoms (Centers for Disease Control and Prevention [CDC] class A, B, C); immune suppression (CDC class 2, 3); or HIV RNA levels ≥100,000 copies/mL or a diagnosis in any child younger than 1 year, because of the high viral load during this period.9 Thus, the majority of children infected with HIV in developed countries are given these medications.
Despite the success of this therapy, problematic adverse effects pose a challenge for managing treatment. Similarities between host cell proteins and HIV-1 protease may be responsible for PIs interacting with proteins responsible for lipid metabolism. In addition, NRTIs are associated with mitochondrial DNA toxicity in adipocytes. The aforementioned interactions, as well as HIV itself, are linked to metabolic and cardiovascular abnormalities in HIV-infected patients. Altered body composition, lipid abnormalities, and abnormal glucose metabolism - all factors leading to increased risk of global cardiovascular disease - are manifestations of drug and HIV effects.
Growth and Body Composition
Changes in body fat were first reported in 1997 among HIV-infected adults on HAART.8 Fat redistribution varies phenotypically from peripheral wasting of fat (lipoatrophy) in the face, extremities, and buttocks to fat accumulation (lipohypertrophy) in the abdominal and dorsocervical spine regions (buffalo hump). The manifestation of these and other metabolic features, whether independently or concomitantly, defines one component of the lipodystrophy syndrome. Compared with adults, lipodystrophy in children is more difficult to assess because of growth and puberty.10 Lipodystrophic changes in children can be subtle and less severe than in adults and are often associated with puberty.
HAART, especially with PI therapy, positively affects weight, weight-for-height, and muscle mass in HIV-infected children. A longitudinal study of 67 HIV-infected children tracked in the pre-HAART and post-HAART eras showed these changes were independent of the concurrent decrease in HIV viral load and improved CD4 T-lymphocyte counts.11 The immediate treatment effects were most apparent with weight and muscle mass, and there was a trend toward increased height. Other studies have substantiated the positive growth effects with HAART.3
Cross-sectional studies of HIV-infected children on HAART estimate the prevalence of lipodystrophy to be up to 29%.12 In 94 HIV-infected children on PI therapy for 4 years, 10% displayed some aspect of lipodystrophy within 3 years of starting therapy.13 Simultaneous features of lipoatrophy and lipohypertrophy are more prevalent in older children, supporting the association with puberty. Vigano and colleagues14 longitudinally tracked and compared body composition in HIV-infected children and healthy controls using dual energy x-ray absorptiometry. The HIV-infected children showed significant peripheral fat loss and increased central adiposity over time. The European Lipodystrophy Cohort also found fat redistribution in 26% of HIV-positive children, yet with clinically inapparent lipodystrophy.15Figure 3 demonstrates the typical anthropometric changes associated with the introduction of HAART.
In addition to the increased cardiovascular risk associated with lipodystrophy, the adverse psychological consequences in HIV-infected children can be significant and include reduced adherence to HAART, low self-esteem, depression, and problematic emotional sexual development. These issues are heightened in adolescents who are already prone to these normal developmental phases.
The change in body composition is only one factor that can lead to or represent increased cardiometabolic risk in HIV-infected children. Several studies in HIV-infected children report dyslipidemia, elevated C-peptide levels, and abnormal glucose measurements.16 These findings suggest that lipodystrophy is only one component of a greater, more global, metabolic syndrome in HIV-infected children.
Prior to the introduction of antiretrovirals, elevated triglyceride and low-density lipoprotein (LDL) cholesterol levels were reported and associated with HIV infection in adults. These changes point to the effect of chronic immune activation alone on lipid metabolism. One mechanism that has been suggested includes the effect of proinflammatory cytokines (as a response to the chronic viral infection) on lipid pathways (such as lipoprotein lipase activity). After the initiation of PI therapy, several investigators in the United States and abroad17,18 reported a 20% to 50% rise in lipid levels of HIV-infected children. In one study,19 lipid levels increased but subsequently stabilized after the initiation of PI therapy. In another study, however, cholesterol levels rose 6 months after initiation of PI-based therapy and continued to rise through the second year.20 Other factors associated with hyperlipidemia include successful viral suppression, improved CD4 T-lymphocyte counts, and demographic factors.21 The impact of PIs on lipid levels, independent of HIV infection, is effectively described in HIV infection-seronegative volunteers who developed dyslipidemia following PI treatment.22
Mechanistically, PI therapy may have direct influences on lipid levels by inhibiting an LDL cholesterol receptor-related protein that blocks the uptake of lipoproteins and their subsequent metabolism8 or increased apolipoprotein B metabolism.23 Other theories include stimulation of very low-density lipoprotein cholesterol synthesis by PIs, adipogenesis,24 or lowering the expression of insulin receptors on adipocytes, thus increasing release of free fatty acids into the circulation with the potential for inducing hepatic production of lipoproteins.25
Abnormal glucose homeostasis was documented in HIV-infected adults with lipodystrophy well before it was reported in children. However, insulin resistance is of particular concern in both HIV-infected children and adolescents who naturally experience a relative insulin resistance in puberty. Some studies report no difference in fasting insulin and glucose levels in children treated with PIs compared with children treated with other drugs.26 However, insulin levels become elevated across both groups after initiating HAART. Bitnun and colleagues27 surveyed several pediatric HIV cohorts and found insulin resistance with the full metabolic syndrome increasingly prevalent. These symptoms increased in severity with gradual increases in age. Verkauskiene and coworkers28 found significantly higher fasting insulin levels in HIV-infected children with some aspect of lipodystrophy than those without.
The etiology of insulin resistance is multifactorial and has been linked with both PI and NRTI use singly and in combination; the exact mechanisms have not been well defined. A study by Beregszàszi and colleagues29 demonstrated that insulin resistance occurs at the level of the adipose tissue and that children with lipodystrophy have more pronounced insulin resistance than those without, suggesting that metabolic changes occur as a result of the central adiposity. A possible mechanism by which HAART causes insulin resistance is direct inhibition of the transport function of the GLUT4 glucose transporter, which is responsible for insulin-stimulated glucose uptake into muscle and fat.30 Other potential causes of insulin resistance include mitochondrial DNA mutations or depletions associated with NRTI therapy. Although there are limited data in adults,31 striking similarities have been noted between rare mitochondrial disorders; multiple symmetrical lipomatosis (MSL), for example, is a condition that is phenotypically very similar to HAART-associated lipodystrophy.32 The mitochondrial DNA mutations known in MSL lead to impaired function of cytochrome c oxidase and a subsequent decrease in fat turnover.
Inflammatory cytokines have been linked to insulin resistance and diminished adiponectin levels, which positively affects insulin signaling and glucose homeostasis. Adipose tissue is a major determinant of insulin sensitivity, and changes associated with lipodystrophy can alter the secretion of adiponectin. Kim and coworkers33 report patients with PI-induced lipodystrophy had increased levels of circulating inflammatory cytokines. Among 18 children with lipohypertrophy, increased fasting insulin/glucose ratios were associated with decreased adiponectin even after adjustment for pubertal stage, age, percent body fat, and serum lipids.28 A separate study of children on PI-based treatment observed reduced insulin sensitivity and impaired β-cell response.34 Although there are fewer studies in children compared with adults, the elevated risk of diabetes mellitus in HIV-infected children on HAART is becoming increasingly clear.
Cardiovascular Risk in HIV-Infected Children. Only a few short years after pediatric HIV was described, Lipshultz and colleagues35 reported significant cardiovascular abnormalities in perinatally HIV-infected children. In the pre-HAART era, approximately 10% to 25% of HIV-infected children presented with cardiovascular symptoms including abnormal left ventricular fractional shortening and left ventricular hypertrophy.36 Mean cardiac weight of HIV-infected children was up to 184% higher than in healthy controls, with 10% of afflicted children requiring medication to avoid heart failure. Furthermore, Shearer and coworkers37 reported that a decreased CD4 T-lymphocyte count, wasting, encephalopathy, and rapid HIV progression were predictive of a cardiac event. Others reported fetal cardiovascular anomalies in infants born to HIV-infected mothers38 and higher incidences of atrial and ventricular septal defects.39 Thus, in addition to metabolic factors contributing to cardiovascular risk, HIV-infected children may have intrinsic myocardial and anatomic abnormalities.
Considering the extant evidence as presented in the prior sections, it is obvious that HIV-infected children have many critical risk factors for the development of global cardiovascular disease. However, different from adults, children are exposed to these risk factors earlier in life (many since birth and in utero), may not be exposed to other adverse lifestyle risks that may potentiate the cardiovascular risk, and may not have lived long enough to develop the outcomes of interest (ie, myocardial infarction or cerebrovascular events [stroke]). Thus, the prevalence or risk of adverse cardiovascular outcomes in children has yet to be determined.
Chronic HIV infection places children in a perpetual proinflammatory state, which can initiate the atherosclerotic process through inflammatory mediators such as tumor necrosis factor α (TNF-α) and interleukin-1 β (IL-1β).40 Elevated circulating inflammatory markers in HIV infection can induce oxidative stress, collagenase synthesis, and overall activation of the vascular endothelium leading to the atherosclerotic plaque.
Vascular endothelial dysfunction results in increased vessel wall stiffness and decreased endothelium-dependent dilation. This phenomenon may occur as a result of chronic inflammation and injury in the endothelium and, in HIV infection specifically, may result from oxidative stress due to HAART or direct cytopathic effect of the virus.41 In addition, dyslipidemia, insulin resistance, and chronic inflammation due to ongoing immune activation in HIV-infected individuals also contribute to endothelial damage. Johnson and colleagues42 reported an increase in proinflammatory cytokines (eg, TNF-α) in the subcutaneous adipose tissue and increased circulating IL-6 and insulin levels of HIV-infected individuals with lipodystrophy. Other researchers also found that HIV-infected patients had significantly higher plasma levels of TNF-α and IL-6 than uninfected controls and this correlated with viral load and von Willebrand factor (produced by the vascular endothelium in response to activation or injury).43 Furthermore, Wolf and coworkers44 found that not only were levels of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and von Willebrand factor higher in untreated patients with HIV infection but the levels decreased significantly after treatment with a regimen containing either one PI or one NNRTI. Cell adhesion proteins such as the selectins may be elevated as well.40
Atherosclerotic cardiovascular risk can be defined by several methods, including carotid intimamedia thickness (CIMT), brachial artery reactivity, and proinflammatory mediators. Children are being evaluated by these methods with increasing frequency. A study of a British cohort of HIV-infected children found elevated inflammatory markers, with lower flow-mediated vasodilatation (increased arterial stiffness) and greater CIMT that increased with age.45 These changes were particularly evident in PI-treated children and are associated with the proinflammatory phenotype of infected children, adding to their potential cardiovascular risk.
Interventions and Treatment.
Monitoring. All HIV-infected children and adolescents should be closely monitored at regular intervals for nutritional, metabolic, and cardiac problems (Table I). Any abnormalities should prompt further evaluation or treatment. Furthermore, lifestyle can mitigate cardiometabolic risks associated with HIV infection and HAART. Growing children should be advised of the additional cardiovascular risks of cigarette smoking and recreational drug use. Discouraging these behaviors in HIV-infected children should be a priority.
|Category||Frequency||Measures||Triggers and Additional Considerations|
|Anthropometry||6 months||Height, weight, BMI, skinfolds (tricep, bicep, suprailiac, subscapular), waist and hip circumference||• Weight Z score ≤−2 or ≥2|
|• Height Z score <−2|
|• BMI Z score <−2 or >2 at risk for overweight or overweight|
|Diet||6 months||24-hour dietary recall, 3-day food record, or food frequency questionnaire||• See Table II|
|Body composition||Annual||Bioelectric impedance analysis; dual energy x-ray absorptiometry|
|Lipids||3–6 months||Lipid blood panels||• AHA guidelines54|
|Glucose/insulin||3–6 months||Baseline fasting glucose and fasting insulin with repeat assessments for comparison||• Glucose >100 mg/L|
|• Insulin >2.5 (Tanner I)|
|• Insulin >4 (Tanner II–V)|
|Blood pressure||3 months||If first value is abnormal, would perform additional 2 measures, separated by 5-minute intervals||• Monitor readings above acceptable range55|
|• If pressure is abnormal, repeat in 1 month; consider intervention|
|Abbreviations: AHA, American Heart Association; BMD, bone mineral density; BMI, body mass index; HIV, human immunodeficiency virus.|
Diet and Exercise. Diet modifications can have a positive effect on HIV-infected children with metabolic dysfunction46,47 (Table II). As children become healthier from effective antiretroviral therapy, their diet may become more like that of a “normal” child than that of one with chronic illness. Increased dietary sugars and low intakes of calcium and vitamin D are a few notable concerns in their diet.48 Balanced diets rich in fiber, antioxidants, and micronutrient supplementation help sustain healthy weight and mitigate nutrient deficiencies in this population. Dietary fat should be monitored and intakes >30% of total calories should be modified.
|Nutrient||Recommended Intake||Additional Comments|
|Total calories (energy)||Based on child's growth pattern, usual intake, diet history, and exercise pattern.||If intakes of fat, along with carbohydrate and protein, are inadequate to meet energy needs, the child will be in negative energy balance. Intakes greater than recommended may result in increased cardiometabolic risk and obesity.|
|Overall nutritional adequacy should be achieved by eating a wide variety of foods.|
|Carbohydrate||About 55% of total calories. No more than 10% of carbohydrates should be from sucrose or other refined carbohydrates.||Should derive predominantly from foods rich in complex carbohydrates including grains (especially whole grains), fruits, and vegetables.|
|Fibers||A reasonable intake is 0.5 g/kg/d to a maximum of 35 g daily.||Consider increased viscous soluble fiber (10–25 g/d); dietary sources: oatmeal, legumes, and some fruits and vegetables with pectin.|
|Fat||Total fat no more than 30% of total calories and no less than 20% of total calories.||• Provide anticipatory guidance regarding the importance of a low-fat, low-saturated fat, low-cholesterol diet for all otherwise healthy HIV-infected patients older than 2 years and their families.|
|Saturated fatty acids <10% of total calories (<7% for therapeutic approach).|
|Trans fatty acids as low as possible (limit processed foods, hard fats, and hard margarine as a practical way to limit intake of saturated and trans fatty acids).||• No restriction of fat or cholesterol is recommended for children aged <2 years when rapid growth and development require high energy intakes.|
|Cholesterol <300 mg/d (<200 mg/d for therapeutic approach).||• There are indications that variations of the ratio of n-6 to n-3 modulate allergy, inflammation, clotting, and vascular responses.|
|Polyunsaturated fatty acids (PUFA), up to 10%.|
|• n-3 PUFA: 1%–2%; n-6 PUFA: 4%–13%|
|• n-6:n-3 ratio = 5:1 to 10:1|
|Monounsaturated fatty acid 10%–15%.|
|Protein||About 15% to 20% of total calories. DRI, estimated average intake based on age and body weight.||The variation in requirements is based on the variation in both maintenance needs and the rate of protein deposition (protein for growth).|
|Calcium||Based on DRI for age (1997).||The largest source of dietary calcium for most persons is milk and other dairy products. Knowledge of dietary calcium sources is a first step toward increasing the intake of calcium-rich foods.|
|Currently, evidence is inadequate to alter the dietary recommendations for children living with a chronic illness (eg, HIV) or those taking medications that alter bone metabolism. However, an effort should be made to achieve at least the recommended intake levels. The provision of adequate vitamin D also may be important for children with chronic illnesses.|
|Plant stanols/sterols||2 g/d. Plant sterols safely and effectively reduce serum cholesterol concentrations by inhibiting cholesterol absorption.||Dietary consumption of plant stanols/sterols can be obtained from commercially available products containing plant sterols/stanols (eg, margarine, juices).|
|Vitamin D||Based on DRI for age (1997). The Committee on Nutrition of the AAP recommends a supplement of 200 IU/d for children and adolescents who do not get regular sunlight exposure, do not ingest at least 500 mL/d of vitamin D-fortified milk, or do not take a daily multivitamin supplement containing at least 200 IU of vitamin D.||Dietary sources include fortified foods (eg, milk and breakfast cereals).|
|Antioxidant and micronutrient supplements||Multivitamin use at DRI levels can be an easy and inexpensive adjunctive therapy to decrease the side effects of HAART therapy and to improve clinical outcomes in HIV-infected children.||Intervention studies on single antioxidant vitamins (A, C, E, and β-carotene) have been few and have shown mixed beneficial effects on decreasing oxidative stress.|
|Abbreviations: AAP, American Academy of Pediatrics46; DRI, dietary reference intake47; HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus.|
Combined with diet, exercise can improve health status in HIV-infected children. Robinson and colleagues49 describe a reduction in triglyceride levels, decreased central adiposity, and improved insulin sensitivity in HIV-infected adults who exercise. In another study, reduction in visceral adiposity, decrease in body mass index, and improved strength were found.50 There is growing evidence that exercise contributes to a more competent immune system while providing therapeutic effects to the patient. The effects of exercise on children's metabolic parameters are emerging51 (Table III).
|Infant||No specific requirements||Physical activity encourages motor development|
|Toddler||1.5 hours||• 30 minutes planned|
|• 60 minutes unstructured|
|Preschooler||2 hours||• 60 minutes planned|
|• 60 minutes unstructured|
|School-aged child||1 hour or more||Divide into 15-minute segments|
|Abbreviation: AHA, American Heart Association.|
Pharmacotherapy. HIV-infected children found to have identifiable metabolic and cardiac risks should first undergo a complete assessment of their antiretroviral regimen. Certain drugs are known to carry more adverse effects, and often a switch to another medication of the same class or a different class can minimize them. For example, in the first pediatric “switch” study, researchers replaced a PI with an NNRTI and found a significant reduction in lipid levels.52 Other investigators have also found that NNRTIs carry less metabolic risk than other classes of medications.21 Modification of antiretroviral therapy should only be considered, however, when other methods of reducing cardiovascular risk have failed and a change in therapy can be made without compromising viral suppression.
Health care providers should be aware that medications that control metabolic disorders might potentially interact with antiretrovirals. In addition, adverse effects and high pill burden may affect adherence. Table IV presents indications and treatments for cardiometabolic disorders in children53; however, it should be noted that many of the recommendations are based on the adult literature and few of these medications are approved by the US Food and Drug Administration for children.
|Diabetes mellitus||Biguanides (metformin)||• Effective first-line therapy|
|• Approved for use in children|
|• Adverse effects include abdominal pain, nausea, vomiting, and increased risk of lactic acidosis|
|Sulfonylureas (acetohexamide, tolazamide, glyburide, glimepiride)||• Used in concert with first-line therapies|
|• Not currently approved in children (clinical trials in process)|
|• Adverse effects include weight gain, hypoglycemia, nausea, vomiting, and skin rashes|
|Other medications (meglitinides, thiazolidinediones, α-glucosidase inhibitors)||• Not approved in children|
|• Useful in concert with monotherapy|
|• Various side effects including flatulence, weight gain, fluid retention, and short duration of action|
|Insulin||• Recommended only after other methods fail|
|• 0.5–1.0 U/kg body weight per day|
|• Dose adjustments are necessary until diabetes is controlled|
|• Must be referred to pediatric diabetes specialist|
|Dyslipidemia||HMG-CoA reductase inhibitors (statins)||• Adverse interaction with protease inhibitors|
|• Increased risk of hepatoxicity|
|• Preferably used in older children (≥13 y)|
|Bile acid-binding resins (cholesterolymine)||• Only drug approved for children <8 y|
|• Effective for lowering total cholesterol|
|• Increased risk of hypertriglyceridemia|
|Other medications (niacin, fibrates)||• Not approved in children|
|• Most effective as combination therapy|
|Dietary supplements||• Fiber, omega-3 fatty acids, and sterol/stanol margarines|
|Abbreviations: HIV, human immunodeficiency virus; HMG-CoA, hydroxymethyl glutaryl coenzyme A.|
Cardiometabolic problems are a growing yet poorly defined concern for HIV-infected children on HAART. Although it is clear that HIV-infected children are at risk for early cardiovascular complications, the long-term follow-up in children has been insufficient to detect the magnitude of these risks. Thus, it is important to effectively manage cardiometabolic risks through a multidisciplinary approach with particular focus on close nutritional monitoring and early indicators and treatment of metabolic dysfunction. Until additional treatment options are developed, effectively managing HAART remains a burgeoning priority in maintaining the health and quality of life in HIV-infected children.