Cardiometabolic Complications in youth with perinatally acquired HIV in the era of antiretroviral therapy

Abstract

Purpose of Review:

Antiretroviral therapy (ART) scale-up has dramatically reduced rates of pediatric HIV mortality and morbidity. Children living with perinatally acquired HIV (PHIV) are now expected to live through adolescence and well into adulthood, such that adolescents now represent the largest growing population living with HIV. This review aims to discuss the prevalence and mechanisms for cardiometabolic co-morbidities in the setting of newer ART regimens and the research gaps that remain.

Recent Findings:

Data highlight the continued risks of subclinical cardiometabolic complications in PHIV in the setting of newer ART. Novel techniques in imaging and omics may help identify early cardiometabolic abnormalities in this young population and potentially identify early changes in the mechanistic pathways related to these changes.

Summary:

Further studies to determine risk and management strategies of the cardiometabolic effects in PHIV adolescents, beyond ART, are warranted. Focus should be on prevention of these complications in youth to avoid new epidemic of diabetes and cardiovascular disease when these youth become aging adults.

INTRODUCTION

The World Health Organization (WHO) estimates that over two million children have been infected with HIV, most via perinatal transmission[1]. The majority of individuals who acquired HIV through perinatal transmission are now also heading into adolescence (defined as those people between 10 and 19 years of age[2]) and/or adulthood[3, 4]. Wide access to antiretroviral therapy (ART) has transformed HIV from a fatal condition into a chronic disease leading to increases non-AIDS events such as cardiovascular disease (CVD) and metabolic complications. These conditions are becoming major causes of mortality and morbidity in adults living with HIV[5, 6]. The available knowledge about CVD and metabolic disease in the setting of contemporary ART is from adult studies, however recent findings suggest that children, despite ART, continue to be susceptible to subclinical cardiovascular and metabolic complications at an early age. In addition, findings in children suggest that there are unique differences in HIV and ART exposure (in-utero) and treatment during periods of critical development that may exacerbate co-morbidities in this population compared to adults.

Cardiovascular complications (Table 1)

Table 1:

Summary of recent reports of cardiovascular complication in pediatric HIV

Author and Year	Country	Population	Age Range (years)	Design	Parameters used	Findings
CONDUCTION AND FUNCTIONAL ABNORMALITIES
Namuyonga et al, 2016[13]	Uganda	285 PHIV children	1-18	Cross Sectional	• EKG • TT Echocardiogram	• Cardiac abnormalities detected in 14% children • Most common abnormalities: T-wave changes, pericardial disease
Lipshultz et al, 2017[11]	USA	74 HIV+ on ART compared to 140 HIV+ not on ART (conducted from 1990-1997)	3-16	Longitudinal	Serial TT Echocardiograms	• ART + children had more normal LV function and structure than pre-ART children • Cardiac function in ART+ children declined with increased follow up
Wilkinson et al, 2018[12]	USA	Adolescent Master Protocol (AMP) study in the Pediatric HIV/AIDS Cohort Study (PHACS) 246 PHIV Youth 156 HEU	7-16	Cross Sectional	• TT Echocardiogram • Serum TNT	• PHIV had higher biomarker levels associated with lower LV mass and structure
Majonga et al, 2018[14]	Zimbabwe	201 PHIV	6-16	Cross Sectional	TT Echocardiogram	• Abnormalities detected in 42% children • Most common abnormalities: LV diastolic dysfunction, LVH
Majonga et al, 2020[15]	Zimbabwe	197 PHIV	6-16	Longitudinal	TT Echocardiogram at baseline and 18 months later	• RV dilatation persisted at follow up in 92% of participants and LV dysfunction in 88% • 6% of Cardiac abnormalities present at baseline reverted to normal • Overall increase in mean z scores for LV, LA, RV and LV diameters
McCrary et al, 2020[16]	Kenya	643 PHIV	0-26	Cross sectional	TT Echocardiogram Myocardial Performance Index	• PHIV with cardiac dysfunction were older, viremic with exposure to AZT and higher systemic inflammation • MPI was associated with serum inflammatory marker IL6.
VASCULAR DISEASE
Abd-Elmoniem et al, 2014[33]	USA	35 HIV+ and 11 healthy controls	15-29	Cross Sectional	RCA vessel wall thickness measured by MRI	• Increase in vessel wall thickness in HIV+ • Epicardial fat not increased in HIV+ • Smoking and exposure to D4T associated with vessel thickness
Gleason et al, 2016[29]	Ethiopia	231 PHIV	6-17	Cross sectional	PWV , IMT and FMD	• Children on EFV and LPV/r has increased PWV and IMT compared to those on NVP
Hanna et al, 2016[30]	USA	5 cohorts from NHLBI HIV-CVD Collaborative 58 HIV+ and 221 HIV− controls in pediatric study	6-29	Cross sectional	IMT	• Higher IMT in HIV+ than HIV− in 6-29 age group • Increase in IMT in HIV+ compared to HIV-was strengthened when limited to PHIV
Eckard et al, 2017[28]	USA	101 HIV and 86 healthy controls	8-25	Cross sectional	PWV and IMT	• No difference in PWV between the groups
Dirajlal-Fargo et al, 2020[31]	Uganda	101 PHIV and 96 HIV−	10-18	Cross sectional	IMT and PWV	• Higher IMT in PHIV • IMT independently associated with marker of intestinal permeability in PHIV
Majonga et al, 2020[32]	Zimbabwe	117 PHIV and 75 HIV−	6-16	Cross sectional	IMT	• No difference in IMT between groups
ENDOTHELIAL DYSFUNCTION
Dirajlal-Fargo et al, 2017[39]	USA	71 HIV+ and 48 HIV-controls	8-30	Cross Sectional	EndoPAT	• Endothelial dysfunction in PHIV compared to behaviorally infected group and control group
Mahtab et al, 2020[38]	South Africa	431 PHIV and 93 HIV− youth			EndoPAT	• PHIV had higher rates of endothelial dysfunction • PI use associated with endothelial dysfunction

Abbreviations: D4t: stavudine; EFV: efavirenz, FMD: Flow mediated dilation; HEU: HIV-exposed uninfected; IMT: intima media thickness; LA: left atrium; LPV/r: ritonavir boosted lopinavir; LV: left ventricle; LVH: left ventricular hypertrophy; MRI: magnetic resonance imaging; MPI: myocardial performance index; NVP: nevirapine; PHIV: perinatally acquired HIV; PI: protease inhibitors; PWV: pulse wave velocity; RA: right atrium; RCA: right coronary artery; RV: right ventricle; TT : transthoracic

Cardiomyopathy

Cardiomyopathy was one of the leading causes of death in children in the pre-ART era, typically manifested as severe dilated cardiomyopathy and has since decreased in the setting of ART[7]. Exposure to Nucleoside reverse transcriptase inhibitors (NRTIs, in particular thymidine NRTIs) has been associated with mitochondrial toxicity which can lead to cardiomyopathy. While incidence of cardiomyopathy among PHIV children has decreased since the mid-1990s, reports have suggested a higher incidence in children previously exposed to zalcitabine (ddC), and continued or new exposure to zidovudine (AZT) was associated with a higher rate of cardiomyopathy[8].

Adult HIV studies suggest a shift in the pathophysiology of HIV-associated cardiomyopathy which has become more multifactorial including viral associated mechanisms, ART toxicity, inflammation, ectopic adiposity, and nutritional causes[9]. In addition, ART has been increasingly associated from a phenotype of left ventricular systolic dysfunction to left ventricular diastolic dysfunction in adults. Results from the Characterization of Heart Function on Atiretroviral Therapy (CHART) study in adults, a multicentral cross-sectional case-control study of treated and virally suppressed HIV+ adults is the first comprehensive study of virally suppressed HIV+ adults treated with contemporary ART[10]. When comparing participants with and without diastolic dysfunction, with normal ejection fraction and no valvular disease, there was no difference in active ART including NRTI, NNRTI , protease inhibitor,or integrase strand transfer inhibitor (INSTI) use, however prior history of NRTIs was higher in participants with dysfunction. Although commonly adults living with HIV are experiencing comorbidities including hypertension, obesity, and metabolic syndrome likely associated with inflammation and contributing to cardiac dysfunction, the CHART study findings highlight that prior exposure to toxic drugs associated with mitochondrial dysfunction may continue to contribute to myocardial fibrosis and dysfunction well into adulthood.

Conduction and Functional Cardiac Abnormalities

An 11 year follow up of children on HIV (n=74, ages 3-16 years), compared to children followed in the pre-ART era (n=140), clearly demonstrates improvement in cardiac structure and function on ART[11] supporting that symptomatic cardiac disease are now rare compared to the pre-ART era. Overtime, however, children on ART in this study had a consistent decrease in contractility. Studies of children on ART have reported cardiac conduction and functional abnormalities using EKG and echocardiography.

Children with HIV enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS), a prospective cohort study at 14 US research sites, had higher left ventricular mass, volume and lower function as well as higher biomarkers of inflammation and myocardial injury (high-sensitivity cardiac troponin) compared to HIV-exposed uninfected children (HEUs)[12]. Studies in sub-Saharan Africa, where the vast majority of children with PHIV reside, have also found echocardiographic abnormalities. In a study in Uganda, the prevalence of cardiac abnormalities in 285 children living with HIV on ART, most of whom virally suppressed, was 14%, with the most common detected abnormality being T-wave changes and pericardial disease[13]. On the other hand, a study in Zimbabwe, 83 (42%) of children aged 6-16 years had an echocardiographic abnormality, 78% were virally suppressed (VL< 400 copies/mL) and the most common finding was LV diastolic dysfunction (23% of participants)[14]. This cohort was followed for 18 months, only a minority of cardiac abnormality were transient (6%), and there was an overall increase in mean z scores for LV, left atrium, right septum and LV posterior wall diameters over 18 months, however, the majority of participants remained asymptomatic[15]. In addition, no HIV-related factors (CD4 count, viral load, duration on ART, age at ART initiation or type of ART) were associated with incidences of cardiac abnormalities. Differences in techniques and cohorts likely explain the wide prevalence estimates of cardiac abnormalities in children and adolescents on ART in these studies.

A recent large cross sectional cohort study in young Kenyans (n=653, mean age of 14 years), used newer ultrasound-based imaging techniques which have increased sensitivity to detect myocardial dysfunction using strain technology and myocardial performance index (MPI)[16]. In this study, 28% met criteria for early cardiac dysfunction. Myocardial dysfunction was associated with markers of systemic inflammation, HIV-RNA level and history of AZT exposure. Using proteomics profiling, in a substudy of this cohort, proteins associated with cardiac remodeling, inflammation, and metabolism were higher in those with an abnormal MPI index[17]. This suggests that similar pathways as in adults with HIV-related CVD may be dysregulated in children and adolescents with subclinical cardiac dysfunction. These findings highlight that children on contemporary less toxic ART continue to have a wide spectrum of subclinical cardiac abnormalities.

Subclinical Vascular Disease

Increasingly, data in non-HIV adult and pediatric populations have shown that surrogate markers of subclinical vascular diseases, such as carotid intima-medial thickness (IMT), a structural measure, and pulse wave velocity (PWV), a functional measure, are predictive of important clinical outcomes, such as myocardial infarction and strokes[18–20]. There are reports on IMT between PHIV and HIV-children in higher resource settings[21–26] and only three cross sectional studies have measured arterial stiffness with PWV in pediatric HIV[27–29]. There are conflicting results in these reports with some studies highlighting evidence of subclinical vascular disease in PHIV and others showing no difference between the groups. This is again likely due to sample size, the participants and HIV-children varied widely in age, ART use, viremia and varying anatomic sites used to measure IMT and PWV. A recent pooled analysis of >2000 HIV-infected and uninfected individuals in the US found that children and youth living with HIV had greater IMT thickness even after controlling for demographics and CVD risk factors[30]; moreover, HIV infection itself appeared to be the main risk factor for increased carotid artery thickening in this population. Amongst these studies, only a few recent studies have assessed IMT and PWV in African children[29, 31, 32]. Ethiopian children 6-17 years of age on efavirenz and LPV/r had increased PWV and IMT compared to those on nevirapine, however there was no uninfected control group for comparison. In Ugandan children 10-18 years of age (n=197), with PHIV children being mostly virally suppressed (86% with VL < 50 copies/mL), we reported no difference in arterial stiffness as measured by PWV but found that PHIV in Uganda have slightly thicker IMT compared to age- and sex-matched uninfected adolescents. Similar to our findings, reported differences in IMT in children with HIV in prior studies had ranged from 0.02-0.15 mm. We also found no differences in IMT or PWV between sexes or by ART regimen.

Direct evaluation of the coronary vessel using novel MRI techniques in a small cohort of mostly PHIV young adults (86 PHIV%, mean age 22 years old) compared to uninfected controls demonstrated a significant increase in coronary vessel wall thickness without associated increases in coronary plaque or stenosis, as measured by CT scan, in HIV+ compared to controls. In addition, smoking and history of stavudine use were associated with coronary wall thickness[33]. This suggests that similarly to cardiac function, newer and more sensitivity techniques may demonstrate that children and adolescents with HIV on lifelong ART have high rates of early vascular disease with the potential to develop into cardiovascular disease events early in life.

Endothelial Dysfunction

Changes in the endothelium are one of the earliest alterations of the vessel wall which occur prior to atherosclerosis[34]. Forearm flow-mediated vasodilation (FMD) has classically been used to assess peripheral endothelial dysfunction[35] and is predictive of long term cardiovascular events[36]. Its results, however, can vary during measurement and FMD has poor reproducibility[37]. Recently, we and others have conducted studies in children and young adults with HIV[38–40] using Peripheral Arterial Tonometry (endoPAT) which measures vascular function in an automatic and non-invasive manner. These studies have highlighted evidence of endothelial dysfunction in perinatally acquired HIV compared to uninfected controls[38, 39] that does not appear to be associated with immune status or current ART type used (specifically protease inhibitor vs others).

Metabolic Complications

Alteration in adipose tissue and potential mechanisms (Table 2)

Table 2:

Body Composition studies in pediatric and young adults in the setting of newer ART

Author and Year	Country	Population	Age Range (years)	Design	Parameters used	Findings
INTEGRASE INHIBITORS
Dirajlal-Fargo et al, 2020[59]	USA	51 HIV+	0-24	Retrospective study of children Pre and post INSTI-initiation	BMI	• Higher rates of BMI-for-age z score increase after EVG and DTG initiation compared to pre-INSTI.
Taramasso et al, 2020[95]	Italy	66 HIV+	18-26	Retrospective case-control study, switch to INSTI vs non-INSTI switch	BMI	• PHIV switched to INSTI-based regimen did not experience an excessive weight gain compared to those who did not switch to INSTI
Thivalapill et al, 2020[96]	Eswatini	605 PHIV	12-19	Retrospective observational cohort pre and post DTG	BMI	• adolescents receiving TDF/3TC/DTG had a BMI greater than those receiving ABC/3TC/DTG • After switching to DTG, odds of becoming overweight or obese increased by 1% everyday
Giacomet et al, 2021[60]	Italy	13 HIV+	12-19	Switch from a PI- or NNRTI-based regimens to ABC/3TC/DTG-longitudinal	BMI and DXA	• BMI, triponderal and total % body fat did not change post DTG. • Trunk fat and trunk/body fat ratio increased after 12 months post switch.
Turkova, 2021[61]	Multi-center ODYSSEY trial (Europe, Asia and sub-Saharan Africa)	707 PHIV	3-18	Randomized non-inferiority trial evaluated DTG +2NRTIs vs standard of care (NNRTI or PI-based ART)	BMI	• Slight but significant increase in BMI compared to standard of care.
Yeoh, et al 2021[97]	Australia	8 HIV	13-15	Retrospective cohort study of children switched to a regimen containing DTG	BMI	• Increase in BMI z score 12 months post switch with stabilization in subsequent months
TENOFOVIR ALAFENAMIDE
Yeoh, et al 2021[97]	Australia	9 HIV	9-14	Retrospective cohort study of children switched to a regimen containing TAF	BMI	• Increase in BMI z score 12 months post switch with stabilization in subsequent months

Abbreviations: 3TC: lamivudine; ABC: abacavir; BMI: body mass index; DTG: dolutegravir; DXA: dual energy x-ray absorptiometry; EVG:elvitegravir; INSTI: Integrase strand transfer inhibitor; NRTI: nucleotide reverse transcriptase inhibitor; NNRTI:non-nucleoside reverse transcriptase inhibitors; TAF: tenofovir alafenamide; TDF: tenofovir disoproxil fumarate

Lipoatrophy and lipodystrophy, caused by thymidine analogue NRTIs and d-drugs like ddI and ddC, were historically common early in the HIV epidemic[41, 42]. Reassuringly, low prevalence of mild lipodystrophy have been reported on newer ART regimen, even those including AZT[43, 44], however, children previously treated with stavudine still have a greater risk for lipoatrophy[43]. Obesity is increased in people living with HIV[45, 46] and continued abnormalities in fat distribution remain an issue despite contemporary ART [47]. The few studies that have quantified body mass composition in youth with HIV with standardized imaging have also suggested increased fat and specifically trunk fat, compared to uninfected youth[48–51]. In PHACS[49], HIV-infected children who had ever used stavudine, didanosine or zidovudine had a lower percentage of extremity fat, and higher percentage of trunk fat and in a longitudinal study from children in South Africa and the Netherlands[52], history of stavudine was also associated with lower subcutaneous fat. These findings suggest that, similarly to adult studies, previous exposure to thymidine NRTIs, may result in ongoing adiposity alteration in a cumulative, time-dependent manner.

Despite having similar total body fat percentage, alterations in regional fat distribution as measured by dual-energy x-ray absorptiometry (DXA) are detectable in perinatally infected youth compared to HIV-youth, with greater trunk fat and decreased leg fat and differences that appear to accelerate over time[53]. The little data that exist on the longitudinal changes in body composition in YLHIV also suggest that young PHIV females demonstrate greater gains in trunk fat and total percent body fat over a 7 year period compared to uninfected controls[50].

INSTI use has become more widespread for pediatric and adolescent ART. The most promising and affordable INSTI, DTG, has recently moved to the position of preferred first line drug regimen on the World Health Organization HIV treatment guidelines for adults and older children[1] and has just been approved for use in young infants[54]. Recent data from large cohort studies suggest that adults living with HIV on an INSTI-based regimen, have significant weight gain and metabolic complications [55–58]. There are only a few reports on the effect of dolutegravir (DTG) or other INSTIs on anthropometric changes in children. In a retrospective analysis of a longitudinal observational cohort known as the DC Cohort, among 117 youth with HIV (57% PHIV) we have shown an increase in the rate of BMI-z score post-INSTI initiation predominantly in those perinatally infected[59]. In an observational longitudinal study in Italy, 12 participants transitioning to a DTG-based regimen, changes in body composition, as measured by DXA scan were detected, including a significant increase in trunk fat, but not changes in BMI, total body or limbs fat[60]. Data on randomized trials in children on INSTI are very limited; recent findings presented from the multicenter ODYSSEY trial, an open label randomized trial where children were randomized to DTG, suggest a slight but significant increase in weight, height and BMI(1kg, 0.7cm, 0.3kg/m² respectively) at week 96 compared to standard of care (PI or NNRTI based ART)[61].

Although overall changes in body weight can have significant effects on cardiometabolic complications, the location of fat accumulation is important. Trunk/visceral fat is known to be associated with cardiovascular disease risk (CVD) in adults[62, 63] raising concern that with survival extending into adulthood, these findings suggest that alterations in regional fat are likely to continue to be significant and may contribute to cardiometabolic complications.

The mechanisms for alteration of body composition in children and adolescents with PHIV are unclear and likely multifactorial. Specifically ART, viremia, mitochondrial dysfunction, alteration of intestinal integrity and the resultant translocation of microbial products from the intestinal lumen may all play a role[62, 64–66]. Mitochondrial function and substrate utilization are perturbed in PHIV when compared to HIV-exposed uninfected youth, additionally, HIV modified the relationship between BMI and complex I suggesting that despite having a lower BMI, PHIV may be unable to utilize substrates efficiently[67]. Even in the era of non-thymidine NRTI-containing regimens, HIV+ adults randomized to regimens containing either abacavir or tenofovir demonstrate a significant decrease in fat mitochondrial DNA[68]. In addition, in subjects receiving TDF, abnormalities in oxidative phosphorylation enzymes were correlated with larger total and visceral adiposity, raising concern for children and adolescents on life-long ART who already had mitochondrial injury due to prior toxic drugs.

Alteration of intestinal integrity and the resultant translocation of microbial products from the intestinal lumen may also play a role in ectopic fat accumulation[62, 64]. In obesity and diabetes, translocation of bacterial products has been shown to promote systemic and adipose tissue inflammation and lead to expansion of visceral adipose tissue and insulin resistance[69]. We have previously shown in a randomized clinical trial of ART initiation in adults, that intestinal fatty acid binding protein (IFAB-P), a marker of intestinal barrier dysfunction, independently predicted increases in total and visceral abdominal fat at 96 weeks after ART[64]. In cross sectional studies, we have also shown evidence of disturbances in intestinal integrity and translocation in children despite viral suppression[70, 71], supporting the fact that ART does not fully restore the gut barrier even in younger populations. In PHACS, we also investigated the role of gut dysfunction on body composition as measured by DXA in youth with HIV (n=261). We found that markers of intestinal integrity and microbial translocation were associated with percent body fat at baseline and 2 years later, even after adjusting for demographic confounders, and ART exposure[72]. We hypothesize that gut dysbiosis, and alteration in intestinal barrier could lead to expansion of visceral fat, and contribute to upregulation of cytokines produced by inflamed adipose tissue.

Insulin Resistance

Insulin resistance is the decreased ability of insulin to stimulate the use of glucose driving increased production of insulin. Several recent pediatric studies both in US and sub-Saharan Africa have measured insulin resistance using the homeostatic assessment of insulin resistance (HOMA-IR)[65, 73–84]. Overall, these studies highlight that despite low or normal BMI and viral suppression on ART, PHIV have derangements in glucose metabolism. Some studies indicated higher prevalence of insulin resistance[83, 84] compared to uninfected children (exposed or unexposed to HIV) while others did not[76, 77], which may be due to a different HOMA-IR cut off value to define insulin resistance. HOMA-IR in PHIV has been independently associated with anthropometric measures[73, 76, 77, 84]. Although prior use of Abacavir was associated with HOMA-IR in South-African adolescents[76], Ugandan children from the Children with HIV in Africa-Pharmacokinetics and Adherence/Acceptability of Simple Antiretroviral Regimens (CHAPAS-3) trial randomized to zidovudine (AZT), stavudine (D4T) or abacavir (ABC) based regimens, HOMA-IR significantly increased in all groups at 48 weeks, however there was no difference between the groups[83].

Despite these controversial results, these findings raise the concern that PHIV adolescents, who will require decades of therapy, may develop persistent elevated levels of insulin which may lead to a high incidence of diabetes overtime. In addition, a rise in insulin resistance during puberty has been noted[85, 86] and may be potentiated in PHIV[87].

Dyslipidemia

The prevalence of dyslipidemia has ranged widely in HIV+ children and adolescents depending on the definition. Newer ART appear to present more favorable lipid profiles, specifically studies in children transitioning to newer protease inhibitors (ATV/r or DRV/r) report reductions in total cholesterol and or triglycerides [88, 89]. Similarly, findings from the ODYSSEY trial have found a significant decline in total cholesterol and triglycerides over 96 weeks in the DTG arm compared to PI or NNRTI-based regimen[61].

Dyslipidemia is traditionally assessed with high abundance-lipids. These basic lipid panels provide insufficient characterization and insight as to the fundamental metabolic perturbations in HIV infection, and their relationship to both inflammation and CVD risk[90]. New methods have been developed that allow for a finer characterization of these elements. ‘Lipidomics’ is a branch of metabolomics that applies to studying lipid metabolism on a broad scale Lipidomics in HIV is still in its infancy. Altered lipid classes have been associated with HIV infection in adults[91]. In a small sub-cohort of 20 HIV+ youth and 20 HIV− in Uganda, we measured concentrations of serum lipids and fatty acid compositions by direct infusion-tandem mass spectrometry[92]. A total of 13 lipid classes constituting 850 different lipid species were identified. The lipidome of PHIV was significantly different from HIV−. Main differences were observed in increased concentrations of cholesterol esters (CE), ceramides (CER), phosphatidylcholines (PC), sphingomyelins (SM) and lactosylceramides (LCER) containing saturated fatty acids (SaFA) in PHIV compared to HIV−. Specifically, lipid species known to be associated with CVD, were increased in HIV, including ceramides. When comparing serum fatty acids concentrations in PHIV to those in HIV+ adults on ART[93], or adults with inflammatory conditions such as nonalcoholic fatty liver disease[94], we find that levels of SaFA are nearly two fold higher in PHIV, suggesting that this population likely has a unique lipidomic signature.

It is important to note however that the majority of lipid studies in PHIV or in adults living with HIV were conducted without assessment of nutritional factors that can substantially affect lipid levels and composition.

Conclusions

Our understanding of the trajectory of cardiometabolic complications in children and adolescents with HIV is sorely lacking. PHIV on ART with viral suppression still show evidence of subclinical cardiac and metabolic disease. The exposure of HIV and ART in utero, the decades of ART therapy, the lasting effects of older toxic ART with mitochondrial toxicity and the long term sub-optimal adherence known to occur with prolonged ART use, heighten concern that sequelae of HIV and ART in children and adolescents may be more frequent and potentially more devastating than in adults. Better understanding of the CVD and metabolic risks and their effects on other organ dysfunction in PHIV is crucial, as it is often easier to limit or even reverse arterial and metabolic injury at an early stage.

As youth worldwide are aging towards adulthood, this special population deserves special consideration and longitudinal studies of prevalence, incidence and pathogenesis are needed and should include resource-limited settings where most of the pediatric HIV population currently reside. Similarly a better understanding of the contribution of nutritional factors, both macro and micronutrients, to these cardiometabolic abnormalities is urgently needed. We need to work together across specialties, to gain a clear understanding of the long term cardiometabolic risk in youth with HIV and the mechanisms behind these comorbidities, in order to guide future preventive and therapeutic interventions.