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Antimicrobials In Perspective

Metabolic complications of antiretroviral therapy in children

LEONARD, ETHAN G. MD; MCCOMSEY, GRACE A. MD

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The Pediatric Infectious Disease Journal: January 2003 - Volume 22 - Issue 1 - p 77-84
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Abstract

INTRODUCTION

The implementation of potent antiretroviral drugs in combination regimens has profoundly decreased mortality and disease progression in HIV-infected patients. 1 Concomitantly morbidity from the long term effects of antiretroviral therapy has grown in importance. Among all these complications, lipodystrophy syndrome, mitochondrial toxicity and more recently osteopenia are the most concerning side effects of prolonged antiretroviral therapy. The adult medical literature contains many studies and reports about these complications. This review discusses each of these abnormalities separately in an attempt to summarize the current understanding of their pathogenesis and management with a focus on HIV-infected children.

LIPODYSTROPHY

Although recognized since 1996, HIV-associated lipodystrophy syndrome remains controversial in its definition and mysterious in its etiology. A variety of terms describe this syndrome in terms of its clinical manifestations or its postulated etiologies: “the fat redistribution syndrome,” “truncal obesity syndrome,” “buffalo hump,” “symmetric lipomatosis,” “protease paunch” and “Crix belly.”2 Recently lipodystrophy syndrome has been reported in HIV-infected children. 3, 4 Estimates of its prevalence among HIV-infected adults range from 2 to 84%5 and from 1 to 43%6 of HIV-infected children, likely reflecting the lack of standardized definitions for the features of this syndrome. The lipodystrophy syndrome involves body fat maldistribution as well as the metabolic alterations of hyperlipidemia and insulin resistance. Affected individuals demonstrate differing combinations and severity of these derangements. Each of these derangements is discussed separately.

FAT MALDISTRIBUTION

Despite the confusing nomenclature the morphologic changes of lipodystrophy syndrome have been consistently described. In decreasing order of frequency, patients present with peripheral loss of adipose tissue (lipoatrophy), central gain in adiposity (lipohypertrophy) or both features (mixed syndrome). Various means of assessing these changes have been reported. Patients often are the first to identify the symptoms by noting changes in their facial features or tightness of clothing. 7, 8 Various objective techniques to assess the changes in body fat content and distribution have been utilized including bioelectrical impedance, 9 anthropometric measurements, 5, 10 dual energy X-ray absorptiometry (DEXA), 5, 11 and abdominal computed tomography or magnetic resonance imaging (MRI). 12, 13 Bioelectrical impedance provides useful information about lean body mass and total body fat but not regional fat distribution. Caliper measurements assess only subcutaneous fat. DEXA provides information about regional fat distribution, except for the face. Only computed tomography or MRI scanning discriminates between subcutaneous fat stores and visceral fat. Patients with lipodystrophy often have significant central obesity, but their subcutaneous abdominal fat is significantly lacking whereas visceral stores are markedly increased. Increased visceral fat has clearly been associated with increased risk of coronary artery disease as well as insulin resistance. 14, 15 These body habitus changes are not only esthetically distressing to patients but also predispose them to future cardiovascular diseases and type II diabetes mellitus. These changes can lead to decreased quality of life, sexual difficulties and poor adherence to antiretroviral therapy. 16, 17

The body changes of lipodystrophy are difficult to examine in HIV-infected children because of the normal, dynamic alterations in body composition that occur during childhood and adolescence. Both DEXA 18, 19 and abdominal MRI 12, 20 have been validated to assess fat distribution in children. The entire spectrum of morphologic derangements reported in adults has also been described in pediatric HIV-infected patients. 4 One study demonstrated increased visceral to total fat ratios in HIV-infected children without overt signs of lipodystrophy when they were compared with age-, pubertal stage- and body mass index (BMI)-matched controls. 6 The long term consequences of these morphologic changes in children have not been determined. Adolescents with central adiposity are at increased risk for future cardiovascular disease. 21 Some physicians have expressed concern about the impact that fat maldistribution might have on compliance with therapy in adolescents given their heightened sensitivity to body image. 22 Prospective, longitudinal, control-matched studies are needed to assess the long term effects of fat maldistribution on children.

DYSLIPIDEMIAS

Derangements in lipid metabolism have been commonly reported in HIV-infected adults as part of lipodystrophy syndrome or as isolated abnormalities. The reported abnormalities include elevated total cholesterol, low density lipoprotein cholesterol (LDL), serum triglycerides (TG) and decreased high density lipoprotein cholesterol (HDL). Even before the availability of antiretrovirals, low HDL and elevated TG had been associated with HIV infection. 23 With the advent of protease inhibitor (PI) therapy, dyslipidemias became more prevalent and more pronounced; patients demonstrated significant increases in LDL and even more pronounced elevations of TG. 24 PIs have undergone the greatest scrutiny for their role in HIV-associated dyslipidemia. Several studies show an increased likelihood of dyslipidemia in patients who receive PI therapy, although a true incidence has been difficult to determine. 2, 5, 25, 26 The best supporting evidence for a direct effect of PIs on lipid metabolism comes from a study of HIV-seronegative volunteers who developed significant dyslipidemia after short course treatment with ritonavir. 27 In one of the larger cohort studies, 49% of 581 HIV-infected adults had dyslipidemia as determined by fasting serum lipids. 5 Thirty-three percent of patients had cholesterol >5.5 mM; 12% had HDL <0.9 mM, 25% had TG >2.2 mM and 16% had elevations in cholesterol and TG. Today no study could be ethically performed to examine the longitudinal prevalence of dyslipidemia in a therapeutically undertreated or naive population. Regardless of the true prevalence of dyslipidemia, its medical significance is not in question. Dyslipidemia in HIV-infected adults has led to premature coronary artery disease 25 and pancreatitis. 28

Derangements in lipid metabolism have been reported in children and adolescents infected with HIV, but the literature is sparse relative to dyslipidemia in adult patients. In a cross-sectional pediatric study, 39 patients were evaluated for body change and metabolic abnormalities. 10 Hypercholesterolemia was noted in 18% of this cohort and hypertriglyceridemia in 13%. Cholesterol and TG values in children are defined as values greater than the 95th percentile for age and sex. 29 As in adult patients the frequency of dyslipidemia in these children was greater if fat maldistribution was present; however, the small sample size precluded the findings from reaching statistical significance. PI therapy has the greatest association with dyslipidemia in HIV-infected adults and children. 30, 31

Although longitudinal data for the consequences of dyslipidemia are lacking in the pediatric population, the likely consequence would be premature atherosclerotic disease at rates similar to children heterozygous for familial hypercholesterolemia. 32 Treatment of lipid derangements in HIV-infected adults has been difficult. Many clinicians, including those in the Adult AIDS Clinical Trial Group Cardiovascular Disease Committee, follow the National Cholesterol Education Program guidelines as to when to initiate lipid lowering therapy. 22, 33 The standard lipid lowering agents, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or “statins” must be used cautiously because several of them are metabolized by the P-450 enzyme CYP3YA and therefore can affect serum concentrations of antiretrovirals, leading to myalgias, myopathy and rhabdomyolysis. 34, 35 Guidelines for starting lipid lowering agents in pediatric patients are less clear. The National Cholesterol Education Program threshold for initiation of therapy in children is high. Switching among PIs or to PI-sparing regimens ameliorates lipid abnormalities in HIV-infected adults, 36–39 but few data exist about the efficacy of this strategy in children. To date a single PI switch study in children has been reported. 40 In this study substitution of efavirenz, a nonnucleoside reverse transcriptase inhibitor, for PIs resulted in significant improvement in fasting cholesterol and TG values.

INSULIN RESISTANCE

Insulin resistance and frank diabetes occur in some HIV-infected adults. In 1997 the United States Food and Drug Administration issued a report about the association between PI therapy and diabetes mellitus in 83 patients. 41 The lack of a standardized definition of insulin resistance has led to inconsistencies in the reporting of its prevalence. The diagnostic standard for insulin resistance is the euglycemic clamp, a complex procedure that is not feasible in most clinical settings. Several less optimal diagnostic strategies have been used including the measurement of fasting glucose, fasting insulin, C-peptide, oral glucose tolerance tests and the derivation of various indices generated from these values. 5, 9 As for dyslipidemia PI use has been the most frequently associated variable with derangements in glucose metabolism; however, these derangements do occur in PI-naive adults. Walli et al. 42 reported that ∼61% of PI-treated subjects have some degree of insulin resistance. In the previously cited French cohort study, 5 20% of the 581 patients had derangements in glucose metabolism. In the PI-treated patients the point prevalence for any derangement was 25%, significantly higher than in the non-PI-treated patients (P = 0.01); however, 17% of the patients treated with nucleoside reverse transcriptase inhibitors (NRTI) also had derangements in glucose metabolism. That study is one of the few attempting to correlate metabolic derangements of lipid and glucose metabolism with fat maldistribution. Sixty-three percent of their patients with body shape changes had at least one metabolic derangement compared with 48% of patients without such changes (P = 0.001). This difference remained significant (P = 0.012) when adjusted for PI therapy. Although there are case reports of insulin-resistant diabetes mellitus developing in such patients, the long term consequences of lower grade insulin resistance are unknown.

Hyperglycemia and insulin resistance have also been reported in HIV-infected children. In the 39-patient pediatric cohort, all patients had a normal oral glucose tolerance test and normal fasting blood glucose. However, in patients with body changes, fasting insulin values were more than double those of normal appearing patients. 10 These children also demonstrated a degree of insulin resistance as measured by fasting insulin-to-glucose ratios. Both observations trended toward significance (P = 0.07) even in this small study group. These trends are particularly disturbing in the context of the well-described decreased insulin sensitivity that occurs naturally during puberty. 43 Three of the adolescents in this cohort with body habitus changes had overt insulin resistance. Information is needed to assess the progression of chronic, low level insulin resistance in children.

Two hypoglycemic agents, metformin and rosiglitazone, have been investigated in HIV-infected adults with lipodystrophy-associated insulin resistance. Although preliminary data indicate that both agents improve insulin resistance, neither agent had significant effects on fat maldistribution. 44, 45 In studies of HIV-infected adults, insulin resistance has shown significant improvement when the PI of a virologically successful regimen was switched to either a nonnucleoside reverse transcriptase inhibitor or abacavir, a potent NRTI. 37 Pediatric data are lacking.

MITOCHONDRIAL TOXICITY

Lactic acidemia with related hepatic steatosis has been reported in HIV-infected patients since the early 1990s, 46, 47 but recent clusters of reports have increased physicians’ awareness about the potentially fatal syndrome. Fortunately severe lactic acidemia is rare. Lactic acidemia typically presents as acute onset of nausea, vomiting, abdominal pain, severe fatigue, malaise, tachycardia, dyspnea on exertion, rapid weight loss, frequently with hepatic steatosis and, rarely, hepatic failure. 48–50 Observational studies suggest an incidence of 1.3 to 1.7 cases per 1000 person years of NRTI exposure. 51–53 Several researchers have described a milder, clinical form of mitochondrial toxicity termed symptomatic hyperlactatemia. Its incidence has been reported to be as high as 26 cases per 1000 person-years among NRTI-treated subjects. 54 Lactic acidosis and hyperlactatemia are induced by NRTI therapy, probably by inhibition of mitochondrial DNA. Ultrastructural and functional defects in mitochondria have been demonstrated in NRTI-treated patients with lactic acidosis or symptomatic hyperlactatemia. 55–58

Clinicians rely on the measurements of venous lactate levels as a marker for mitochondrial toxicity. Several cohort studies of NRTI-treated patients reported a prevalence of asymptomatic hyperlactatemia of as much as 36%. 56, 59, 60 In our cohort when strict criteria for venous lactate were adopted, only 4% of heavily NRTI-treated subjects had elevated lactate. 61 There is no evidence to suggest that asymptomatic hyperlactatemia is a marker of future lactic acidosis; therefore routine lactate testing on asymptomatic subjects need not be performed.

Management of the symptomatic forms of mitochondrial toxicity is under investigation. Normalization of serum lactate with revision to a non-stavudine or non-NRTI-containing regimen has been reported. 56, 59, 62 Numerous trials are under way to explore the potential for prevention of mitochondrial toxicity with antioxidants, vitamin B complex vitamins, carnitine and other cofactors of mitochondrial metabolism.

Hyperlactatemia does occur in the pediatric population. There are several concerning reports about HIV-exposed but uninfected infants who developed hyperlactatemia from in utero exposure to NRTIs. One prospective study examined serial lactate values in 25 infants born to NRTI-treated mothers; 92% of infants had elevated lactate, 63 and 35% had lactate >5 mmol/l. As in the adult cohorts the majority of these infants were asymptomatic. There was no correlation with duration of in utero exposure to NRTI or other classes of antiretrovirals. Lactate values were normal in the few mothers who were tested before delivery. The hyperlactatemia resolved in all infants by 6 months. Severe mitochondrial dysfunction is infrequent. The central nervous system seems to be particularly vulnerable. Blanche et al. 64 reported eight cases of hyperlactatemia with neurologic and developmental sequelae from perinatally NRTI-exposed, noninfected children. Another unique aspect of lactic acidemia in children is its potential effect on linear growth. Longitudinal studies are necessary to determine the effects of chronic, “asymptomatic” hyperlactatemia in children. Despite the disturbing reports of mitochondrial dysfunction in NRTI-exposed infants, this risk of treating infection in children and pregnant women is still outweighed by the successes in preventing vertical transmission.

DECREASED BONE MINERAL DENSITY

Derangements in metabolism of bone represent another subtle yet potentially deleterious complication of HAART therapy. At any time an individual’s bone mass, measured as bone mineral density (BMD), represents the dynamic balance between bone accretion and resorption. Basic determinants of BMD include age, health, weight and sex hormones. Other determinants of BMD include level of physical activity, alcohol consumption, cigarette smoking and corticosteroid therapy. In men and women bone mass increases during childhood and adolescence, peaks in young adult life and declines at a rate of ∼0.5 to 1% per year. 65, 66

BMD is most commonly measured by DEXA. 67 This technology involves the same instrument described earlier in its applications for measuring lean and fat mass to measure BMD at common sites: lumbar spine, hip and forearm. The machine is calibrated differently for bone vs. soft tissue density; therefore results of bone density determined from a soft tissue DEXA may not be accurate. A few terms and concepts must be introduced in order to interpret the literature about BMD. BMD is typically measured as grams/cm2 of tissue. This number is used to generate a t score. The t score represents the BMD expressed as a standard deviation from the average value for healthy same sex adults age 20 to 40 years. A score of 1.5 in a man indicates that the individual’s BMD is 1.5 sd above the average value for men in the young adult population. Although this scoring system corrects for differences between genders, it is not as helpful for comparing BMD in patients outside of the young adult range or in those of different ethnic backgrounds. A z score represents a t-score corrected for age and ethnicity. An individual z score represents the patient’s BMD expressed as sd relative to the mean BMD of individuals of the same gender, age and ethnic background. The World Health Organization defines osteopenia as a t score of more than −2.5 and less than −1 and osteoporosis as a t score of ≤−2.5. 68 The clinical significance of the t score is its predictive value in fracture risk. Patients meeting the above definitions of osteopenia, osteoporosis and osteoporosis with an existing fracture have a 2-fold, 5-fold and 20-fold increased risk respectively of fracture compared with patients with normal BMD. 69–71

Although BMD serves as a surrogate for the balance between bone formation and resorption, it does not provide the clinician with a sense of the metabolic trend in a patient. The most accurate predictor of bony metabolic activity is histomorphometric study of bone biopsy; however, the invasiveness of the procedure make it impractical. 72 Certain serum and urinary biochemical markers can be used to determine metabolic activity. 73 Serum bone-specific alkaline phosphatase (BALP), N-terminal propeptide of type I procollagen and osteocalcin reflect bone formation, whereas urinary concentrations of deoxypyridinoline and N-terminal telopeptide of type I collagen (NTx) reflect bone resorption. These markers can be interpreted in the context of the patient’s hormonal milieu (vitamin D, parathyroid hormone) and mineral balance (serum and urinary levels of calcium and phosphorus) to characterize the net metabolic state.

The prevalence and etiology of decreased BMD in HIV-infected patients are not completely known. Historically the recognition of decreased BMD in HIV-infected patients correlates with the introduction of HAART therapy. Paton et al. 74 described a longitudinal cohort of HIV-infected male patients with normal BMD before the HAART era. Other studies demonstrate statistically significant differences between HIV-infected retroviral naive patients and patients receiving HAART, but no significant differences between retroviral naive patients and the general population. The reported prevalence of decreased BMD in HIV-infected individuals ranges from as low as 21 75 to as high as 67.5%. 76 These studies report a rate of osteoporosis in their patients of 3 to 21%. Most HIV-infected patients with decreased BMD are asymptomatic. Pathologic fractures in these patients are limited to a few case reports in the literature. 77, 78

Some studies have shown a significant correlation between PI therapy and decreased BMD, 66 but others found no independent link between PI therapy and decreased BMD. 75, 79, 80 There is no consensus agreement about the correlation between the morphologic changes of lipodystrophy and decreased BMD. The studies are all cross-sectional with numerous confounding variables. In a 221-person cohort, multivariate analysis study from Australia, Carr et al. 75 reported that only lower weight before antiretroviral therapy and elevated serum lactate were independently linked with decrease BMD. For every 1-mmol/l increase in lactate, they report an odds ratio (OR) of 2.39 for developing osteopenia or osteoporosis (P = 0.002). As previously discussed many investigators believe hyperlactatemia to result from NRTI interference with mitochondrial function. In support of this hypothesis, osteoporosis has been described as the only clinical manifestation of mitochondrial disease in HIV-uninfected male individuals, some of whom had asymptomatic hyperlactatemia. 81, 82

Several treatment strategies have been used to reverse osteopenia. One large multicenter study reported no beneficial impact on BMD from PI withdrawal. 83 Longitudinal studies assessing the impact of NRTI substitution have not yet been performed. Limited data exist on the use of pharmacologic agents in this setting, including the use of gonadotropins, bisphosphonates, calcium and vitamin D therapy. In a moderately sized placebo-controlled study, Fairfield et al. 80 demonstrated significant improvement in spinal and hip BMD in eugonadal HIV-infected patients treated with testosterone for 12 weeks. Bisphosphonate therapy may enhance the gastrointestinal side effects caused by HAART. 67 Because most patients with decreased BMD are asymptomatic and the long term consequence of this condition is unclear, screening should not be considered in routine clinical practice. On the other hand we believe that HIV-infected subjects with known risk factors for accelerated bone mineral loss such as older female patients, patients with hypogonadism, patients with wasting syndrome, patients receiving long term glucocorticoid therapy or patients with a history of nontraumatic fractures merit evaluation. No clear guidelines exist as to when to initiate therapy or with what modality in HIV-infected patients. We suggest consultation with an experienced endocrinologist with interest in the metabolic derangements associated with HIV infection/HAART.

Decreased BMD and uncoupling of bony accretion and resorption have been reported in HIV-infected children; data, however, are limited. The study of bony metabolism in pediatrics is complicated by the higher and variable degree of turnover in children and adolescents related to age, gender and pubertal stage. 84–86 Decreased BMD in children seems to be the result of HAART rather than HIV infection. Mora et al. 85 in one of the larger pediatric studies report no difference between healthy controls and antiretroviral naive HIV-infected patients in BMD, BALP, serum N-terminal propeptide of type I procollagen or urinary NTx levels. HAART-treated children had lower spinal BMD (P = 0.004), lower total body BMD (P < 0.0001), higher BALP (P = 0.0007) and higher NTx urinary concentrations (P < 0.0001) than healthy children. That study found a correlation between morphologic changes of lipodystrophy and decreased BMD, but the numbers of patients with lipodystrophy were quite small. We measured BMD by lumbar DEXA in 22 vertically infected children; the mean z score was –2.04. 87 Twelve of the children had osteoporosis, and 4 had osteopenia. Longitudinal studies in children are needed because the effects of HAART on BMD are potentially most devastating to the pediatric population because their cumulative drug exposure is greater than that of adult patients. The potential for long term complications of decreased BMD is particularly concerning given that the majority of bone formation occurs by young adulthood.

GROWTH RETARDATION

Growth retardation associated with HIV infection is unique to the pediatric population. Growth retardation predates the introduction of HAART therapy. 88–90 Unlike children with lipodystrophy, children naive to HAART demonstrated decreased fat-free mass, muscle wasting and decreased linear growth. 91–93 In a large infant cohort, Bobat et al. 92 reported evidence of decreased length for age, “stunting” and decreased weight for age (malnourishment) by 3 months of age. Specific dissipation of muscle mass has been reported by age 2 years. 94 Although inadequately antiretroviral-treated children appear to be starving, an increase in their caloric and protein intake results only in weight gain without improvements in muscle mass or linear growth. 95, 96 In one of the earliest studies of the effects of HAART therapy on growth in children, Verweel et al. 93 followed a cohort of children through 96 weeks of therapy. Approximately one half of the children in this cohort had received NRTI monotherapy in the 48 weeks before initiation of HAART, and the other half were antiretroviral-naive. Both groups had a decrease in z score for height during this period; the naive group, however, had a significantly larger decrease than the NRTI group. In both groups the z score for height improved during the 96-week trial, but only the baseline naive group’s improvement reached statistical significance. The difference in z score for weight was not statistically different for the two groups at baseline. Again the naive group at baseline demonstrated a significant increase in z score for weight at 96 weeks. Effective therapy in this population correlated with improved height velocity and weight gain. Virologic nonresponders did not show improved growth with therapy. In 1999 a group from Children’s Hospital in Los Angeles, CA, published a small trial about the safe and effective use of the anabolic steroid oxandrolone for 3 months in HIV-infected children with decreased lean body mass. 97 This steroid was chosen because of its minimal effects on virilization and bone age. Children had increased weight, muscle mass and sustained height velocity. Oxandrolone must be studied in a much larger trial to assess sustained efficacy and safety.

Growth retardation in children is distinct among the phenomena discussed in this article in that it clearly stems from the disease itself rather than an adverse effect from therapy. HAART in children, associated with many of the morphologic and metabolic derangements in adults, actually corrects growth failure in infected children. Caution should be exercised in interpreting these findings with tremendous optimism; the long term effects of HAART therapy on longitudinal growth have not been studied. Hyperlactatemia and osteopenia may ultimately limit growth. Longitudinal, large cohorts must be followed to determine the true long term consequences of these metabolic derangements on adult height and weight.

CONCLUSIONS

The short and moderate term prognosis for infants and children with HIV infection has greatly improved since the introduction of HAART. Children are living with better viral control, higher CD4+ counts and fewer opportunistic infections. This population, however, is vulnerable to the adverse effects of therapy because of their status as growing organisms and of their likely longer term exposure to HAART. The complete spectrum of metabolic complications in adults with lipodystrophy has been reported in children: fat maldistribution; hyperglycemia; insulin resistance; hyperlipidemia; lactic acidosis; and decreased BMD. Many of these features have been clearly associated with antiretroviral therapy. Growth retardation secondary to infection and the neurologic consequences of mitochondrial toxicity appear to be unique to the pediatric population. An important goal in treating HIV infection is to design drugs with fewer side effects or to better manage those of the current drugs.

GAM received grant support and research funding from GlaxoSmithKline, Bristol Myers Squibb, Agouron Pharmaceuticals and Merck. She is an Advisory Board Member and consultant for GlaxoSmithKline and Bristol Myers Squibb.

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Keywords:

Lipodystrophy; dyslipidemia; insulin resistance; hyperlactatemia; mitochondrial toxicity; osteopenia

© 2003 Lippincott Williams & Wilkins, Inc.