Immense strides have been made in the reduction of mother-to-child transmission of HIV such that current rates of transmission are now <2%, and the overwhelming majority of HIV-exposed infants/children worldwide are uninfected, giving rise to an increasing population of HIV-exposed uninfected (HEU) children and a decreasing population of HIV-infected children.1 Another growing population is obese children and youth, particularly in high-income countries. Since 1970, rates of obesity in the United States have nearly tripled in children aged 2–19 years,2 raising concern for poor future cardiometabolic outcomes in these children and youth.
Despite the progress in eliminating mother-to-child transmission of HIV, long-term monitoring of HEU children into adolescence and adulthood remains important, given the potential for long-term effects from in utero HIV/antiretroviral (ARV) exposure in these children.3–5 Metabolic disturbances from in utero HIV/ARV exposure have been reported in HEU infants and young children.6–10 These include mitochondrial toxicity,9–11 lipid disturbances,12 alterations in insulin sensitivity,8 and dysregulated intermediary metabolism.7,8,13,14 Because many of these metabolic effects are intertwined and may be influenced by both fetal metabolic programming15 and postnatal environmental factors during the life course of an individual,16 robust studies with rigorous control for confounders have been necessary to disentangle the in utero HIV/ARV effects from other factors. HIV and antiretroviral therapy (ART) are known to be associated with metabolic complications in children living with HIV,17–19 but whether in utero HIV/ARV exposure has the potential to be associated with long-term metabolic complications among uninfected children as well remains unclear. Few published studies exist on metabolic outcomes in HEU youth with an appropriate comparison group of HIV-unexposed youth. The objective of our study was to assess whether obese HEU youth have a higher prevalence of cardiometabolic risk factors such as hypertension, dyslipidemia, and insulin resistance compared with a matched group of obese HIV-unexposed youth in the general US pediatric population.
SUBJECTS AND METHODS
HEU children enrolled in the Surveillance Monitoring of ART Toxicities (SMARTT) protocol of the Pediatric HIV/AIDS Cohort Study (PHACS) network constituted the study population, whereas selected children who participated in the 2005, 2007, 2009, or 2011 National Health and Nutrition Examination Survey (NHANES) study constituted the comparison control population.
SMARTT is a large prospective cohort study of HEU children born to pregnant women living with HIV designed to assess the safety of antenatal ART exposure on childhood and long-term outcomes. Enrollment has been ongoing since 2007 at 22 clinical sites in the United States, including Puerto Rico. Children in the Dynamic SMARTT cohort were enrolled within 1 week of birth, and those in the Static SMARTT cohort were enrolled at age <12 years with early life data collected through other coenrolled studies.20 Children had height, weight,21 and blood pressure (BP) measurements performed yearly beginning at age 1 year and then every other year after age 5 years. Body mass index (BMI) was calculated as kg/m2. Z-scores for weight (WTZ), height (HTZ), and BMI (BMIZ) were calculated from CDC 2000 Growth Charts.22 At age ≥3 years, children who met a predetermined metabolic outcome trigger of obesity (BMIZ >95th percentile) underwent fasting laboratory testing for lipid subfractions [total cholesterol (TC), triglycerides (TGs), low-density lipoprotein cholesterol (LDL), and high-density lipoprotein cholesterol (HDL)] and insulin resistance [Homeostatic Model of Assessment–Insulin Resistance (HOMA-IR)]. Information on potential confounders including age, sex, race/ethnicity, and anthropometrics was collected. In utero ARV exposures were also collected and summarized. If more than 1 ART regimen was used during pregnancy, the most potent ART was chosen. ART was classified in the following manner from most potent to least potent: ART consisting of ≥3 classes of ARVs, integrase strand transfer inhibitor-based ART, protease inhibitor (PI)-based ART, nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART, nucleoside reverse transcriptase inhibitor (NRTI)-based ART consisting of ≥3 NRTIs, noncombination ART, or no ART. If the lipid or BP measurement was more than 6 months from the date of the BMI measurement meeting the >95th percentile criteria, they were excluded from the analysis.
National Health and Nutrition Examination Survey
NHANES is a study designed to assess the health and nutrition of children and adults among the general population in the United States using a combination of survey and physical examination methods.21 Children participating in the NHANES study were aged 6–18 years, and for this analysis, participated in NHANES between 2005 and 2012. Those aged ≥8 years had their BP measured. In addition, those aged ≥6 years had nonfasting lipid subfractions measured (TC and HDL), whereas only those aged ≥12 years had fasting measurements of LDL, TG, and HOMA-IR. Weight and height were measured, and Z-scores were calculated as described above for the SMARTT participants. Because only obese SMARTT children (BMI >95th percentile) had lipid and insulin resistance testing, only NHANES children with a BMI >95th percentile were selected for inclusion (Fig. 1).
Primary outcomes for this analysis included systolic and diastolic BP, insulin resistance as measured using the HOMA-IR,23 and the following fasting lipid subfractions: TC, LDL, HDL, and TG. Hypertension was defined as a systolic or diastolic BP ≥90th percentile according to age, sex, and height standards,24 insulin resistance as a HOMA-IR >4.0,25 hypercholesterolemia as TC >200 mg/dL, high LDL as LDL >130 mg/dL, low HDL as HDL <35 mg/dL, and hypertriglyceridemia as TG >150 mg/dL.26 Secondary analyses were conducted using the continuous measures corresponding to each primary outcome, with HOMA-IR log transformed to more closely approximate a normal distribution and BP Z-scores calculated using US standards.24
For all analyses, nonpregnant SMARTT and NHANES participants aged 6–18 years were selected for inclusion. Because available NHANES data on different metabolic outcomes were limited to particular age groups, analyses were restricted to older cohorts in both SMARTT and NHANES for outcomes requiring a fasting blood specimen (LDL, TG, and HOMA-IR). Therefore, 3 analytic subgroups were created for analyzing different outcomes with the following ages: (1) systolic and diastolic BP outcomes, age ≥8 years; (2) TC and HDL outcomes, age ≥6 years; and (3) TG, LDL, and HOMA-IR outcomes, age ≥12 years. For the first 2 subgroups above, the NHANES cohort was randomly sampled and individually matched by age (<10 vs. ≥10 years for females, <12 vs. ≥12 years for males), sex, and race/ethnicity (non-Hispanic black vs. not Non-Hispanic black) with up to 3 NHANES youth matched to each SMARTT HEU participant. For the third analytic subgroup, the NHANES cohort was randomly sampled, and up to 3 youth were individually matched to each HEU youth on sex and race/ethnicity only.
Baseline characteristics were compared between SMARTT HEU and NHANES children using the Fisher exact test or a t-test with unequal variances, as appropriate. For the primary dichotomous outcomes (eg, hypertension, insulin resistance, and hypercholesterolemia), modified Poisson regression models with a robust error variance were fit to estimate the prevalence ratio (PR) and 95% confidence intervals (95% CIs) of having each outcome as a function of cohort, adjusted for potential confounders of age (years), sex, race/ethnicity (non-Hispanic black vs. not non-Hispanic nlack), and BMIZ. For the underlying continuous measures, generalized estimating equation linear regression models were fit to obtain robust variances, specifying the distribution as normal and the identity link to estimate mean differences of continuous outcomes comparing the 2 cohorts (SMARTT HEU vs. NHANES), unadjusted and adjusted for the same potential confounders. The generalized estimating equation approach was used because of potential non-normality of our outcome measures. Although subjects were already matched on age category, race, and sex, the above variables were added to the models to account for any residual confounding. Additional models adjusting for income were fit because of the inability to match on income, as there were too few non-Hispanic blacks in NHANES who were at the same income level as SMARTT participants. Statistical analyses were performed using SAS 9.4 (SAS Institute, Cary, NC), and 2-sided P values less than 0.05 were considered statistically significant.
Number of Participants in Each Analytic Subgroup
For the BP analytic sample, 1731 NHANES participants were available to be matched to 304 SMARTT participants by age, sex, and race. For the TC/HDL sample, 1793 NHANES participants were eligible to be matched to 385 SMARTT participants. For the TG/LDL/HOMA-IR sample, 445 NHANES participants were eligible to be matched to 83 SMARTT participants (Fig. 1). After matching up to 3 NHANES youth (depending on availability) for each SMARTT HEU participant on age, sex, and race/ethnicity, 1096 participants (n = 304 from SMARTT, n = 792 from NHANES) were included in the BP outcome analytic subgroup, 1301 participants (n = 385 from SMARTT, n = 916 from NHANES) in the TC/HDL outcomes analytic subgroup, and 271 (n = 83 from SMARTT, n = 188 from NHANES) in the TG/LDL/HOMA-IR outcomes analytic subgroup.
Table 1 shows characteristics of each cohort group by outcome analysis. In the BP outcome analytic subgroup, SMARTT HEU youth had higher median HTZ (0.82 vs. 0.65) and WTZ scores (2.24 vs. 2.15), but similar BMIZ compared with NHANES participants. Fifty-two percent of the HEU youth in this analytic group were exposed to in utero PI-based ART, with a median in utero ART exposure duration of the most potent ART of 21.6 weeks. In the TC/HDL outcome analytic subgroup, HEU youth were younger (median of 9.9 vs. 10.6 years), more often non-Hispanic black (58% vs. 47%), more likely to report an annual household income <$20,000 (64% vs. 30%) and have a higher median HTZ (0.85 vs. 0.68) compared with NHANES participants. Fifty-five percent of the HEU youth were exposed to in utero PI-based ART with a median in utero ART exposure duration of 21.4 weeks. In the TG/LDL/HOMA-IR outcome analytic subgroup, SMARTT HEU youth were younger (median of 14.8 vs. 15.4 years) and more likely to report an annual household income <$20,000 (60% vs. 33%) than those in NHANES. In utero ART exposure for HEU youth in this analytic group consisted primarily of PI-based ART (31%), NNRTI-based ART (15%), and noncombination ART (38%).
Comparison of Blood Pressure Between SMARTT HEU and NHANES Youth
Overall, both median systolic and diastolic BP Z-scores were higher in HEU vs. NHANES participants (0.75 vs. 0.11, P < 0.01 and 0.26 vs. −0.44, P < 0.01, respectively), with HEU participants exhibiting higher rates of systolic and diastolic hypertension (28% vs. 9%, P < 0.01 and 7% vs. 3%, P = 0.02, respectively) (Table 2). These differences persisted even after adjustment for age, BMIZ, sex, and non-Hispanic black race/ethnicity [adjusted mean difference = 0.64 in HEU vs. NHANES youth, P < 0.01 for systolic BP; adjusted PR (aPR) = 3.34, 95% CI: 2.48 to 4.50 for systolic hypertension; adjusted mean difference = 0.72 in HEU vs. NHANES youth, P < 0.01 for diastolic BP; aPR = 2.04, 95% CI: 1.18 to 3.52 for diastolic hypertension] (Table 3). Additional models adjusting for income and the above confounders showed similar results (see Table 1, Supplemental Digital Content, http://links.lww.com/QAI/B298).
Comparison of TC and HDL Between SMARTT HEU and NHANES Youth
Although no differences in HDL were observed between HEU and NHANES youth, median TC was lower (155 vs. 162 mg/dL, P < 0.01). However, no differences were observed in the prevalence of high TC between groups or in any of the other lipid subfractions. This difference in TC persisted even after adjustment for age, BMIZ, sex, and non-Hispanic black race/ethnicity (adjusted mean difference = −5.49, P < 0.01; aPR = 0.67, 95% CI: 0.44 to 1.01) (Table 3). Models additionally adjusting for income showed similar results (see Table 1, Supplemental Digital Content, http://links.lww.com/QAI/B298).
Comparison of TG, LDL, and Insulin Resistance Between SMARTT HEU and NHANES Youth
Overall rates of insulin resistance were high in both HEU and NHANES youth combined (67%), and median HOMA-IR was >4.0 in both groups. Median HOMA-IR was lower in HEU vs. NHANES youth (4.05 vs. 5.47, P < 0.01), with lower rates of insulin resistance among SMARTT participants (51% vs. 74%, P < 0.01) in univariate analyses. No differences in TG or LDL levels were observed between groups. After adjustment for sex and non-Hispanic black race/ethnicity, there remained a significantly lower prevalence of insulin resistance in HEU youth compared with NHANES (aPR = 0.67, 95% CI: 0.54 to 0.85), with a corresponding lower log HOMA-IR (adjusted mean difference = −0.37 in HEU vs. NHANES participants, P < 0.01) (Table 3). Table 1, Supplemental Digital Content, http://links.lww.com/QAI/B298, shows models additionally adjusting for income, which demonstrated similar results.
We found that obese HEU children in the PHACS SMARTT study had higher systolic and diastolic BP, but lower HOMA-IR and TC compared with a general obese pediatric population represented in NHANES. Few studies have evaluated long-term metabolic outcomes in HEU vs. HIV-unexposed uninfected (HUU) children.12,27 Our study is the largest to date to investigate these outcomes in older HEU, increasing the generalizability of our findings.
Overall, 14% of the entire study population met the definition of systolic hypertension, reflecting the obese nature of both cohorts. Our findings regarding BP outcomes in HEU children are similar to a study in Zambia of 111 HEU and 279 HUU children where systolic BP trended toward being significantly higher in HEU vs. HUU children.27 Another smaller US study reported no differences in BP outcomes between HEU and HUU children.28 The increased risk of hypertension in our HEU population will be important to monitor as these HEU youth mature into adulthood since hypertension in childhood is known to predict hypertension in adulthood.29,30 A recent study estimated that adolescents with prehypertension progress to frank hypertension at a rate of approximately 7% per year.30 In addition, hypertension in children is known to be associated with several markers of cardiovascular morbidity including left ventricular hypertrophy31 and subclinical atherosclerosis as measured by carotid intima–media thickness.31–34 Compared with HUU children, HEU children have been shown to have left ventricular dysfunction,35 but the long-term significance of this and its relationship with childhood hypertension remain unclear.
Although SMARTT HEU youth had lower HOMA-IR than NHANES youth, median HOMA-IR in both groups was >4.0, and both had high rates of insulin resistance, likely due to the fact that this was an obese population. The lower HOMA-IR that we observed in SMARTT HEU children compared with NHANES children may be explained by differences in pubertal stage, but data on Tanner staging were not available in the NHANES cohort. In addition, this phenomenon of lower HOMA-IR in HEU children has been described in HEU infants in Africa,8 whereas smaller studies have shown no differences in HOMA-IR between younger HEU and HUU children.12 Similar data of this type have not been published in HEU children older than 10 years. In Cameroon, HEU infants at age 6 weeks had lower HOMA-IR than HUU infants, with HEU infants receiving zidovudine (AZT) infant prophylaxis exhibiting the lowest HOMA-IR values compared with HEU infants receiving nevirapine (NVP) prophylaxis and to HUU infants.8 In addition, mitochondrial DNA content was decreased,11 and mitochondrial fuel utilization was altered, raising the notion that perhaps mechanisms involving mitochondrial toxicity from AZT may be at the center of association of in utero HIV/ARV and postnatal AZT exposure with lower HOMA-IR and altered fuel utilization. The vast majority of the SMARTT HEU cohort received AZT infant prophylaxis after birth for 4–6 weeks as per US guidelines.36 Of note, 87% of the HDL and TC analytic subgroup and 90% of the LDL, TG, and HOMA-IR analytic subgroup were exposed to in utero dideoxy analogue NRTIs such as AZT, didanosine (ddI), stavudine (d4T), and zalcitabine (ddC), which are known to cause mitochondrial toxicity through inhibition of mitochondrial DNA polymerase-ɣ.37 Findings in our present study of older SMARTT HEU children would suggest that perhaps these same observations persist at least through childhood and early adolescence among youth who are obese. Long-term effects of these alterations in glucose and fuel utilization are still unknown.
Although the finding of lower TC levels that we observed in SMARTT HEU compared with NHANES children is contradictory to other studies where HEU children have shown higher12 and no differences,27 our results likely reflect the lower HOMA-IR levels observed in our cohort. Insulin resistance is associated with increased cholesterol synthesis and decreased cholesterol absorption,38,39 and, conversely, insulin sensitivity (lower HOMA-IR) would be associated with lower cholesterol synthesis.
Our study comparison was limited because of the cross-sectional nature and lack of information on pubertal status in the NHANES study. However, the SMARTT HEU cohort was followed longitudinally, and in utero HIV/ARV exposures were well documented to allow prospective evaluation of subsequent outcomes. In addition, although we had information on small-for-gestational-age, pre-term birth, and perinatal HIV exposure in SMARTT, these data were not collected in NHANES; both small-for-gestational-age and pre-term birth may be confounders. There is the possibility in NHANES that a child may have been HEU without our knowledge, although this would likely be rare in this US cohort. We also did not have information on diet, physical activity, and family history of hypertension and cardiometabolic outcomes in the NHANES study. Finally, we could not match on income because there were too few non-Hispanic blacks in NHANES who were at the same income level as SMARTT participants. However, when we adjusted for income in the analysis, results did not change.
In summary, obese HEU youth in the United States may have an increased risk of systolic and diastolic hypertension, but lower risks of insulin resistance and hypercholesterolemia compared with a general obese US pediatric population in NHANES. The long-term significance of these findings remains unclear, but monitoring for cardiovascular morbidity in adulthood may be warranted in HEU children.
The authors thank the children and families for their participation in PHACS and the individuals and institutions involved in the conduct of PHACS. This article is dedicated to the memory of Tracie Miller, MD, who died before its completion.
The following institutions, clinical site investigators, and staff participated in conducting PHACS SMARTT in 2017, in alphabetical order: Ann & Robert H. Lurie Children's Hospital of Chicago: Ellen Chadwick, Margaret Ann Sanders, Kathleen Malee, and Scott Hunter; Baylor College of Medicine: William Shearer, Mary Paul, Norma Cooper, and Lynnette Harris; Bronx Lebanon Hospital Center: Murli Purswani, Emma Stuard, Mahboobullah Mirza Baig, and Alma Villegas; Children's Diagnostic & Treatment Center: Ana Puga, Dia Cooley, Patricia A. Garvie, and James Blood; New York University School of Medicine: William Borkowsky, Sandra Deygoo, and Marsha Vasserman; Rutgers-New Jersey Medical School: Arry Dieudonne, Linda Bettica, and Juliette Johnson; St. Jude Children's Research Hospital: Katherine Knapp, Kim Allison, Megan Wilkins, and Jamie Russell-Bell; San Juan Hospital/Department of Pediatrics: Nicolas Rosario, Lourdes Angeli-Nieves, and Vivian Olivera; SUNY Downstate Medical Center: Stephan Kohlhoff, Ava Dennie, Ady Ben-Israel, and Jean Kaye; Tulane University School of Medicine: Russell Van Dyke, Karen Craig, and Patricia Sirois; University of Alabama, Birmingham: Marilyn Crain, Paige Hickman, and Dan Marullo; University of California, San Diego: Stephen A. Spector, Kim Norris, and Sharon Nichols; University of Colorado, Denver: Elizabeth McFarland, Emily Barr, Christine Kwon, and Carrie Chambers; University of Florida, Center for HIV/AIDS Research, Education and Service: Mobeen Rathore, Kristi Stowers, Saniyyah Mahmoudi, Nizar Maraqa, and Laurie Kirkland; University of Illinois, Chicago: Karen Hayani, Lourdes Richardson, Renee Smith, and Alina Miller; University of Miami: Gwendolyn Scott, Sady Dominguez, Jenniffer Jimenez, and Anai Cuadra; Keck Medicine of the University of Southern California: Toni Frederick, Mariam Davtyan, Guadalupe Morales-Avendano, and Janielle Jackson-Alvarez; and University of Puerto Rico School of Medicine, Medical Science Campus: Zoe M. Rodriguez, Ibet Heyer, and Nydia Scalley Trifilio.
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