Metabolic complications of HIV therapy in children

Introduction The implementation of potent antiretroviral therapy (ART) in combination regimens has profoundly decreased mortality and disease progression in patients infected with HIV [1]. Concomitantly, morbidity from the long-term effects of ART has grown in importance. Among all these complications, lipodystrophy, dyslipidemia, insulin resistance, and osteopenia are the most concerning side effects of prolonged ART. The medical literature contains numerous studies in adults related to these complications; however, the pediatric literature is relatively sparse. Consequently, comprehensive reviews of metabolic derangements associated with highly active antiretroviral therapy (HAART) in children are rare [2]. The virological successes of HAART certainly promise a longer lifespan for HIV-infected children, but the long-term metabolic consequences of this therapy are of serious concern. This review summarizes the epidemiology, clinical presentation, and management of lipodystrophy, dyslipidemia, insulin resistance, hyperlactatemia, and decreased bone mineral density (BMD) in HIV-infected children. In addition to describing the available pediatric data, our aim is to summarize and put in perspective for pediatricians the reported data on these complications from studies of HIV-infected adults. Each of the aforementioned morphological and metabolic phenomena of HAART-associated lipodystrophy syndrome is discussed separately, with attention to the epidemiology, clinical presentation, pathophysiology, and management of these disorders in HIV-infected children. Lipodystrophy syndrome and cardiovascular disease Soon after reports of morphological and metabolic abnormalities in HIV-infected adults, lipodystrophy syndrome became increasingly recognized in HIV-infected children [3–14]. Estimates of the prevalence of lipodystrophy range from 2 to 84% in HIV-infected adults [15] and from 1 to 43% in HIV-infected children [7]. The lipodystrophy syndrome encompasses changes in fat distribution typically manifesting as lipoatrophy with or without central adiposity, and it is frequently associated with alterations in lipid regulation and glucose homeostasis. Although affected individuals demonstrate differing patterns and severity of fat maldistribution, lipoatrophy is more specific to HIV infection and constitutes a key component of the lipodystrophy syndrome [16]. Regardless of the phenotypical presentation of these fat abnormalities, objective measurements are usually needed to establish the diagnosis unless they are severe enough to be visually obvious to patients and physicians. Various objective techniques to assess body fat content and distribution have been utilized. These are summarized in Table 1 and include bioelectrical impedance [17], anthropometric measurements, [10, 15], dual energy X-ray absorptiometry (DEXA) [15], and abdominal computed tomography or magnetic resonance imaging (MRI) [18,19]. Bioelectrical impedance provides useful information about lean body mass and total body fat but not about regional fat distribution. Anthropometric measurements assess only subcutaneous fat and require significant standardization in order to obtain reproducible measurements. DEXA scanning provides information about regional fat distribution, except for the face. Only computed tomography or MRI discriminates between subcutaneous fat stores and visceral fat.Table 1: Available modalities for assessing fat maldistribution.Patients with lipodystrophy often have significant central obesity; however, their subcutaneous abdominal fat is significantly lacking and visceral stores are markedly increased. Increased visceral fat has independently been associated with increased risk of cardiovascular disease as well as contributing to other known risk factors, including insulin resistance and lipid disorders, in patients without HIV infection [20–26]. The Framingham Offspring Study [25,27–30] has shown an increased 10-year coronary heart disease risk for HIV-infected adults with and without lipodystrophy, compared with healthy control subjects. The impact of fat maldistribution and its association with insulin resistance and dyslipidemia on HIV- infected adults is of obvious concern. Although Bozzette et al. [31] have published a large retrospective study showing no increase in cardiovascular or cerebrovascular hospitalizations in HIV-infected patients treated at Veterans Affairs hospitals between 1993 and 2001, several other studies have reported increased cardiovascular diseases in this population. Among these, the Data Collection on Adverse Events of Anti-HIV Drugs, a large prospective observational study, showed that exposure to combination ART was independently associated with a 26% relative increase in the rate of myocardial infarction per year of exposure during the first 4 to 6 years of use [32,33]. Dyslipidemia and insulin resistance, known metabolic associations with lipodystrophy, were also associated with increased risk of myocardial infarction in these patients. Similarly, Mary-Krause and co-workers [34] reported an increased rate of myocardial infarction in HIV-infected adults specifically related to duration of protease inhibitor (PI) therapy. The independent contribution of the fat abnormalities alone in these patients remains unclear and is currently under study. The overall impact of fat maldistribution on the care of HIV-infected patients has been very noteworthy, with a potential disincentive to therapy [35], low self-esteem, depression, and sexual difficulty [36]. These issues are especially problematic in adolescent patients, who are generally quite sensitive to body image, vulnerable to depression, and prone to non-compliance [37]. The determination of the etiology of fat maldistribution is further complicated by the phenotypical variability: lipohypertrophy, lipoatrophy, and mixed syndromes. Recent studies have proposed that lipoatrophy and lipohypertrophy should be considered as frequently comorbid, but distinct, entities when considered in HIV-infected patients. Lipoatrophy has been recognized as the more specific feature of fat abnormalities in HIV [16,38,39]. Multiple etiologies are hypothesized, with some evidence supporting each of these potential causes of fat changes. Table 2 summarizes the possible causes of lipoatrophy. Initially, PI therapy was implicated as the most likely cause of fat maldistribution [40], but more recent studies have shifted the focus to nucleoside reverse transcriptase inhibitors (NRTI) as primarily responsible for these fat abnormalities, particularly the lipoatrophy component [17,41,42].Table 2: Possible mechanisms of lipoatrophy and summary of available dataLipoatrophy is uncommon in patients who are treated with NRTI-sparing regimens [43,44]. Several clinical trials have demonstrated that an individual's risk to develop lipoatrophy depends on the choice of NRTI and have identified stavudine as having the greatest risk [17,41,42,45–49]. Further evidence for the culpability of NRTI, but not PI, therapy in lipoatrophy comes from the numerous therapy-switch studies. The replacement of a PI with either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or abacavir in a virologically successful regimen did not lead to improvement of the fat abnormalities despite improvements in metabolic derangements in both adult and pediatric studies [50–53]. In contrast, therapy-switch studies to NRTI-sparing regimens [54] and changing certain NRTI (e.g. replacing stavudine with abacavir) did lead to an improvement of lipoatrophy [52,55,56]. Although the NRTI have a major role in the pathogenesis of lipoatrophy, other host factors also contribute. Older age, male gender, and low body fat prior to the initiation of ART are independent risk factors for lipoatrophy [57–59]. 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 [60,61] and MRI [18,62] have been validated to assess fat distribution in children. The entire spectrum of morphological derangements reported in adults has also been described in pediatric HIV-infected patients [3,5–7,10,13,37]. One study demonstrated increased ratios of visceral to total fat in HIV-infected children without overt signs of fat maldistribution when they were compared with age-, and body mass [7]. in adults, central and insulin resistance are also to be risk factors in children for the of cardiovascular disease This increased risk is concerning because dyslipidemia to a insulin resistance are associated with fat maldistribution in HIV-infected pediatric patients. the that the risk of cardiovascular disease is related to the duration of HAART therapy in adults and that fat maldistribution in children is to the exposure to HAART that HIV-infected children treated with HAART be at risk for cardiovascular morbidity and In this data are and the first of children their from these therapy-switch for fat maldistribution in HIV-infected adults. an association between and lipoatrophy et al. a of in HIV-infected adults. significant was reported in but not in other anthropometric measurements. study showed a potential increase in fat with the use of in lipodystrophy but this not be in trials data for this are not available in children. In adults, visceral has been associated with et al. that therapy with visceral without insulin resistance in a of HIV-infected adults without glucose however, several patients did develop insulin resistance in the regimen et al. have reported that HIV-infected with of abdominal when with and These a possible role for in this but studies are on the of decreased central the potential of increased insulin The role and of in HIV-infected children with fat maldistribution is not in lipid have been reported in HIV-infected adults as of a lipodystrophy syndrome or as the of low of density and been associated with HIV infection the of PI dyslipidemia became more and more patients demonstrated in low density and more of PI have the greatest for their role in Several studies an increased of dyslipidemia in patients who PI the depends on the of PI The supporting evidence for a of PI on lipid comes from studies of who dyslipidemia after a of with a PI In of the adult of HIV-infected patients dyslipidemia, as by and in both and in lipid have been reported in children and infected with but the literature is relatively compared with that published on adult patients. Several studies have shown in total in HIV-infected children, with a prevalence from to In the published of lipid in HIV-infected children, et al. HIV-infected children between the of 4 and total the of the and as by in adults, PI therapy the greatest association with dyslipidemia in the pediatric has been a range in the reported prevalence of dyslipidemia, from of children on a PI to of children treated with regimens PI is to that prevalence not and reported a risk of having a total the for gender, and for children and a increase in risk for for PI to a The most data for the contribution of PI therapy to dyslipidemia in children from a study of in children by et al. In this study, of in children 6 to to significant in their total from to et al. published the of a retrospective review of lipid in children and after the addition of PI therapy to a regimen NRTI children were treated with and with Although both showed significant in their total after PI the the the but not the also significant in their These have been the most PI in HIV-infected children are the Although data for the consequences of dyslipidemia are lacking in the pediatric the be the of et al. that HIV-infected children treated with HAART have in their to in patients for have a risk for In the Study were on most of from and for data about cardiovascular risk factors were The and coronary were for the of or body mass and of total and significantly with the of in the coronary and the Although the of these was their demonstrated is a concerning for a with HIV-infected children with and other risk factors of The independent contribution of PI therapy to risk is et al. and et al. have that increased of the a for in HIV-infected adults was associated with cardiovascular risk factors and not with ART. HIV-infected children with dyslipidemia likely be at risk for disease because of their in total and as is discussed their potential increased insulin resistance, and The risk likely not be known this first of children have been of lipid disorders in HIV-infected adults has are no published data the of HIV- infected children with The of the has the for the and of dyslipidemia in HIV-infected patients This improvements in and as the first The inhibitors be because several of are by the of PI, to and data about use in pediatric patients and these studies children with In became the first of this of to be for pediatric in with long-term data in this The of in children only years and the after of of or with a of coronary disease or in the of other risk factors and that significantly These however, lead to further in in patients a PI with these is their potential with the of including antiretroviral has the potential of virological as and and are not by but with to cause and The these for patients with These are by a of that are by the most PI in pediatric HIV-infected patients, and they be only in dyslipidemia for dyslipidemia in HIV-infected adults is to from a PI or to a that have been shown to the lipid abnormalities data, however, about the of these in children. and have published the only pediatric PI therapy study. children were from a regimen to the to in significant improvements in total and virological no data to therapy in HIV-infected children, the of HAART regimens or PI that not lipid be in the of resistance the and in of an association between PI therapy and it has increasingly recognized that insulin resistance and should be to the of potential long-term complications of HIV therapy. The of a of insulin resistance has to in the of its The for insulin resistance is the a that is not in most clinical the of HIV studies have including the of glucose and the of from these for dyslipidemia, PI use has been the most frequently associated with disorders in glucose however, these occur in adults et al. reported that of have some of insulin In the study [15], of the patients disorders in glucose In the patients, the prevalence for was significantly in the patients however, of the patients treated with a NRTI also disorders in glucose This study is of the first to metabolic disorders of lipid and glucose with fat their patients with body at metabolic compared with of patients without changes This significant when for PI therapy. Although are reports of in patients, the long-term consequences of insulin resistance are however, it is to an increased risk for cardiovascular disease The of insulin resistance in patients is not and is likely PI therapy has the most but studies have shown with NRTI studies have an independent contribution of increased fat in HIV-infected patients to the of insulin resistance Several PI have effects on insulin resistance, of glucose by the et al. the on insulin resistance of the for 6 of or to a of healthy the they showed in to did not insulin glucose or the clinical studies be to the long-term clinical of this and insulin resistance have also been reported in HIV-infected children In a pediatric of patients, et al. reported that all patients glucose and glucose insulin in patients with body changes were more in patients of The children with body changes also demonstrated a of insulin resistance, as by Both in this study These are particularly in the of the decreased insulin that during the in glucose reported in HIV-infected adults, insulin resistance in HIV-infected children is not associated with PI therapy are several reports of an association between fat maldistribution in HIV-infected children and insulin resistance, but the of and of these In the published to on glucose in HIV-infected children, et al. reported that only of with insulin The that the alterations in glucose were not in children because of insulin and a to have increased ratios of subcutaneous to visceral The clinical in PI with to glucose in children compared with adults is however, the as to to the of disorders in glucose in children. The and the have insulin resistance in children as a major cardiovascular risk and therapy are data about the management of insulin resistance in HIV-infected patients for In children with insulin resistance, as for with dyslipidemia, the is and control data are concerning the impact of these in HIV-infected patients. et al. the insulin under the after an glucose in a study of HIV-infected adults with fat they reported a significant with the fat and an association with that were independent of PI no large study the impact of on insulin resistance in HIV-infected adults has been In a study, was shown to lipid and fat maldistribution in HIV-infected adults, but it no on derangements in glucose Several studies have demonstrated a of on glucose in HIV-infected adults but has been reported in adult patients with The is in the for the of children years with The insulin resistance and as of to increase glucose have been shown to have in adult patients with In HIV-infected a has been shown to insulin is not for pediatric to a regimen in HIV-infected adults has been shown to insulin resistance are currently no to in adults with metabolic for a PI in no significant changes in or insulin during the study The literature is on the role of therapy in pediatric patients and more studies are disease bone mineral density in of bone are generally in HIV-infected children but have serious In and bone mass during childhood and in adult and at a rate of per year The reported prevalence of decreased in HIV-infected adults has been of adult patients with osteopenia and of with HIV-infected patients with decreased are in these patients are increasingly reported bone is particularly in infected children because of ART be and because of the risk of a bone Several studies have shown a prevalence of decreased in HIV-infected children. to the in adults, the contribution of combination ART to the of decreased in pediatric patients is not This from the of the of available pediatric the of children in these and the that the of these children have been on combination therapy at the of bone In this the first reported study of bone of HIV-infected adults and after initiation of ART that osteopenia was more in these HIV-infected at compared with prevalence in the the initiation of and of the choice of decreased and The was a in of both the and when compared with This was in both it was significantly in the This study as well as that HIV be responsible for at some of these effects on HIV or by of Although the pathogenesis of the bone abnormalities remains it is considered to be HIV and ART as well as other factors known to bone Several of these factors are to HIV-infected children, include severe of the and as and been shown to lead to a more in compared with stavudine in addition to and the of ART on bone has been shown only for This be because DEXA measurements of are not as of large studies in HIV-infected subjects. studies a role for other as is usually by DEXA and is typically as per of and are the most reported The the as a from the for healthy adults to Table the of and In children who have not the bone is as a for a for and In to adults, for pediatric osteopenia and and the of in have not been for children In despite the that most studies of in HIV-infected children use it is to in that measurements of by DEXA be in children, and that age, bone and of are all of DEXA measurements mineral density and for assessing bone rate and bone of the The of this it difficult to to children, it has been in a studies of healthy children In several and of bone and are available the study of bone in is complicated by the and of in children and related to age, gender, and to that described in HIV-infected adults the increased rate of bone be the of decreased studies have changes in bone density of HIV-infected children. and by DEXA in infected children The was to of the children and osteopenia a of and did not of changes in and et al. reported in HIV-infected children who were progression of a of was was a to a of in children study changes of in HIV-infected children all of were ART at the of the bone with a duration of of ART exposure at the first measurements. The measurements were compared with of an healthy control a of the of was to that of the control that of the was The between bone and lipodystrophy is also the metabolic of HIV-infected children and osteopenia in and clinical lipodystrophy, as by central fat fat in to data reported from studies of HIV-infected adults no association was between osteopenia and either lipodystrophy or et al. reported that total but not was significantly in HIV-infected children with lipodystrophy in however, lipodystrophy was not The management of decreased in HIV-infected is not well DEXA is not for HIV-infected adults and children, it should be considered in with several risk factors associated with bone data on management of are available from studies of HIV-infected adults. studies the of and a on and that affected trials of of in HIV-infected with osteopenia or and in studies are a recent study of showed the effects of were for a data on the use of in children and no data are available on its use in HIV-infected children. about the impact of these on the bone in children The effects of and have been in children with of changes in were after the study is and assess no other studies are available in HIV-infected children. or is serious that in HIV-infected adults and children. of were in the HIV and were reported in individuals the of from to increased from to In this study and low duration of HIV and use of not were to be associated with In study, was in of HIV-infected adults who MRI to association was with use of and and not with ART. have been reports of in HIV-infected children. The first of in this were reported by a the reported on and a study of these to examine the association of and ART These were identified from a large prospective of HIV-infected and children. The study reported a increase in the prevalence rate and a increase in the rate of of the in children with HIV compared with the pediatric to the adult ART was not an independent of in this study. of the were the of PI therapy. This that factors other PI are responsible for this has been shown in several adult studies 1 the on of with of of the with children to antiretroviral potential for from in ART exposure has been by studies. In a of in exposure to with in abnormalities have been reported in and in and not Although studies have that be in to NRTI in In the the central to be particularly et al. reported of with and in children. also reported that children in a of children to ART evidence of with of abnormalities, and in often associated with MRI significant The at presentation of was NRTI exposure of of in the first and Although major abnormalities in were reported in of the children and a in only no was The rate for was in these children, compared with for pediatric diseases in the The a retrospective review of prior to the of years from large prospective in the more children between and to HIV-infected with and without ART were to be with are several of but who have from in exposure to et al. a study that children who were from and a first of The was in children from HIV-infected in children of to during and of the children severe that exposure to NRTI increased the risk of after for other prospective study in to of and in the adult the of these were was no with duration of in exposure to NRTI or other of antiretroviral were in the who were The in all by 6 In contrast, et al. to significant or in children to NRTI therapy with a duration of In this study, at in healthy and in 6 both This study the that the of at this is by as the to use a and of at the of the reports of in this risk is by the successes in in HIV-infected children with related has been reported in HIV-infected patients the but recent of reports have increased about the severe is typically as of abdominal severe on and frequently with with studies of HIV-infected adults an of of NRTI exposure Several have described a clinical of hyperlactatemia, with an reported to be as as adults and are by NRTI by of and in have been demonstrated in adults with or on the measurements of as a for several studies of adult patients reported a prevalence of of as as In our when for were only of with despite a of exposure to NRTI therapy study showed the of of as a of or on is not Data on in HIV-infected children are has been to in of HIV-infected children et al. from HIV-infected children, of were ART. 2 was in but in were these with et al. a prospective observational study of measurements during a in HIV-infected children, most of were were identified with hyperlactatemia, of their was these children of in In this study, only a at the of ART was a significant risk for to the from studies of HIV-infected adults, is associated with with NRTI in children, but its clinical remains as in HIV-infected adults, is no currently to of in HIV-infected children, of the or of therapy. of the of is under but include of ART. In the of or severe of all ART is from hyperlactatemia, of an NRTI-sparing regimen remains the from recent studies a potential for NRTI that have as or are to the potential for of with and The long-term for and children with HIV infection has the of are with virological of more and This however, is vulnerable to the long-term effects of therapy because of their as and their likely exposure to The spectrum of metabolic complications in adults with lipodystrophy has been reported in fat maldistribution, insulin resistance, dyslipidemia, hyperlactatemia, and of these have been associated with ART. is that of to be to the pediatric population. in HIV infection in children is to develop with side effects and to metabolic disorders in HIV-infected children prior to and after initiation of therapy. this severe complications of ART in infected pediatric be and from and as an and for and