Browsing by Author "Jacobson, Denise L."

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    Aggregate risk of cardiovascular disease among adolescents perinatally infected with the human immunodeficiency virus
    (Ovid Technologies Wolters Kluwer -American Heart Association, 2014-03-18) Patel, Kunjal; Wang, Jiajia; Jacobson, Denise L.; Lipshultz, Steven E.; Landy, David C.; Geffner, Mitchell E.; DiMeglio, Linda A.; Seage, George R.; Williams, Paige L.; Van Dyke, Russell B.; Siberry, George K.; Shearer, William T.; Young, Luciana; Scott, Gwendolyn B.; Wilkinson, James D.; Fisher, Stacy D.; Starc, Thomas J.; Miller, Tracie L.; Department of Pediatrics, IU School of Medicine
    BACKGROUND: Perinatally HIV-infected adolescents may be susceptible to aggregate atherosclerotic cardiovascular disease risk, as measured by the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) coronary arteries and abdominal aorta risk scores, as a result of prolonged exposure to HIV and antiretroviral therapy. METHODS AND RESULTS: Coronary arteries and abdominal aorta PDAY scores were calculated for 165 perinatally HIV-infected adolescents, using a weighted combination of modifiable risk factors: dyslipidemia, cigarette smoking, hypertension, obesity, and hyperglycemia. Demographic and HIV-specific predictors of scores ≥1 were identified, and trends in scores over time were assessed. Forty-eight percent and 24% of the perinatally HIV-infected adolescents had coronary arteries and abdominal aorta scores ≥1, representing increased cardiovascular disease risk factor burden. Significant predictors of coronary arteries scores ≥1 included male sex, history of an AIDS-defining condition, longer duration of use of a ritonavir-boosted protease inhibitor, and no prior use of tenofovir. Significant predictors of abdominal aorta scores ≥1 included suppressed viral load, history of an AIDS-defining condition, and longer duration of boosted protease inhibitor use. No significant changes in coronary arteries and abdominal aorta risk scores were observed over the 4-year study period. CONCLUSIONS: A substantial proportion of perinatally HIV-infected youth have high PDAY scores, reflecting increased aggregate atherosclerotic cardiovascular disease risk factor burden. High scores were predicted by HIV disease severity and boosted protease inhibitor use. PDAY scores may be useful in identifying high-risk youth who may benefit from early lifestyle or clinical interventions.
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    Associations of Low Vitamin D and Elevated Parathyroid Hormone Concentrations With Bone Mineral Density in Perinatally HIV-Infected Children
    (Wolters Kluwer, 2017-09-01) Jacobson, Denise L.; Stephensen, Charles B.; Miller, Tracie L.; Patel, Kunjal; Chen, Janet S.; Van Dyke, Russell B.; Mirza, Ayesha; Schuster, Gertrud U.; Hazra, Rohan; Ellis, Angela; Brummel, Sean S.; Geffner, Mitchell E.; Silio, Margarita; Spector, Stephen A.; DiMeglio, Linda A.; Pediatrics, School of Medicine
    BACKGROUND: Perinatally HIV-infected (PHIV) children have, on average, lower bone mineral density (BMD) than perinatally HIV-exposed uninfected (PHEU) and healthy children. Low 25-hydroxy vitamin D [25(OH)D] and elevated parathyroid hormone (PTH) concentrations may lead to suboptimal bone accrual. METHODS: PHIV and PHEU children in the Pediatric HIV/AIDS Cohort Study had total body (TB) and lumbar spine (LS) BMD and bone mineral content (BMC) measured by dual-energy x-ray absorptiometry; BMD z-scores (BMDz) were calculated for age and sex. Low 25(OH)D was defined as ≤20 ng/mL and high PTH as >65 pg/mL. We fit linear regression models to estimate the average adjusted differences in BMD/BMC by 25(OH)D and PTH status and log binomial models to determine adjusted prevalence ratios of low 25(OH)D and high PTH in PHIV relative to PHEU children. RESULTS: PHIV children (n = 412) were older (13.0 vs. 10.8 years) and more often black (76% vs. 64%) than PHEU (n = 207). Among PHIV, children with low 25(OH)D had lower TB-BMDz [SD, -0.38; 95% confidence interval (CI), -0.60 to -0.16] and TB-BMC (SD, -59.1 g; 95% CI, -108.3 to -9.8); high PTH accompanied by low 25(OH)D was associated with lower TB-BMDz. Among PHEU, children with low 25(OH)D had lower TB-BMDz (SD, -0.34; 95% CI, -0.64 to -0.03). Prevalence of low 25(OH)D was similar by HIV status (adjusted prevalence ratio, 1.00; 95% CI, 0.81 to 1.24). High PTH was 3.17 (95% CI, 1.25 to 8.06) times more likely in PHIV children. CONCLUSIONS: PHIV and PHEU children with low 25(OH)D may have lower BMD. Vitamin D supplementation trials during critical periods of bone accrual are needed.
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    Changes in insulin sensitivity over time and associated factors in HIV-infected adolescents
    (Lippincott, Williams & Wilkins, 2018-03-13) Geffner, Mitchell E.; Patel, Kunjal; Jacobson, Denise L.; Wu, Julia; Miller, Tracie L.; Hazra, Rohan; Gerschenson, Mariana; Sharma, Tanvi; Silio, Margarita; Jao, Jennifer; Takemoto, Jody K.; Van Dyke, Russell B.; Dimeglio, Linda A.; Pediatric HIV/AIDS Cohort Study (PHACS); Pediatrics, School of Medicine
    OBJECTIVE: To compare prevalence of insulin resistance between perinatally HIV-infected (PHIV+) and perinatally HIV-exposed, but uninfected adolescents (PHEU), determine incidence of and contributory factors to new and resolved cases of insulin resistance in PHIV+, and evaluate glucose metabolism. DESIGN: Cross-sectional design for comparison of prevalence among PHIV+ and PHEU. Longitudinal design for incidence and resolution of insulin resistance among PHIV+ at risk for these outcomes. METHODS: The source population was adolescents from pediatric HIV clinics in the United States and Puerto Rico participating in the Pediatric HIV/AIDS Cohort Study, an ongoing prospective cohort study designed to evaluate impact of HIV infection and its treatment on multiple domains in preadolescents and adolescents. Insulin resistance was assessed by homeostatic model assessment of insulin resistance. Those with incident insulin resistance underwent 2-h oral glucose tolerance test and HbA1c. Baseline demographic, metabolic, and HIV-specific variables were evaluated for association with incident or resolved insulin resistance. RESULTS: Unadjusted prevalence of insulin resistance in PHIV+ was 27.3 versus 34.1% in PHEU. After adjustment for Tanner stage, age, sex, and race/ethnicity, there was no significant difference between groups. Factors positively associated with developing insulin resistance included female sex, higher BMI z score, and higher waist circumference; those associated with resolving insulin resistance included male sex and lower BMI z score. CONCLUSION: Prevalence of insulin resistance in PHIV+ and PHEU was substantially higher than that reported in HIV-uninfected nonoverweight youth, but similar to that in HIV-uninfected obese youth. Factors associated with incident or resolved insulin resistance among PHIV+ were similar to those reported in HIV-negative obese youth. However, a contributory role of HIV infection and/or its treatment to the incident risk of insulin resistance cannot be excluded.
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    Delay in sexual maturation in perinatally HIV-infected youths is mediated by poor growth
    (Lippincott, Williams & Wilkins, 2017-06-01) Bellavia, Andrea; Williams, Paige L.; DiMeglio, Linda A.; Hazra, Rohan; Abzug, Mark J.; Patel, Kunjal; Jacobson, Denise L.; Van Dyke, Russell B.; Geffner, Mitchell E.; International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) P219/219C Study; Pediatric HIV/AIDS Cohort Study (PHACS); Pediatrics, School of Medicine
    OBJECTIVE: To evaluate the association between HIV infection and sexual maturation, and mediation of this association by HIV effects on growth. DESIGN: Pooled data were analyzed from two longitudinal cohort studies, the International Maternal Pediatric Adolescent AIDS Clinical Trials P219/219C Study (1993-2007) and the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol (2007-2015), including perinatally HIV-infected (PHIV) and HIV-exposed uninfected (PHEU) youths. METHODS: We evaluated age at sexual maturity among 2539 PHIV and PHEU adolescents based on annual physician-assessed pubertal staging measures. Interval-censored regression models were used to evaluate associations of HIV infection with age at maturity. Mediation analyses accounting for height and BMI Z-scores at specific ages were used to estimate direct and indirect effects of HIV infection on age at sexual maturity. RESULTS: Mean ages at sexual maturity for PHIV girls (n = 1032) were 15.5 years for both female breast and pubic hair and 15.9 and 15.8 years for PHIV boys (n = 1054) for genitalia and pubic hair, respectively. PHIV youths matured approximately 6 months later on average than PHEU (n = 221 girls and 232 boys), and this difference persisted after adjustment for race/ethnicity and birth cohort. BMI and height Z-scores mediated the association between HIV infection and later maturation in girls, accounting for up to 74% of the total HIV effect. Only height Z-scores mediated the effect of HIV on male age at maturity, accounting for up to 98% of the HIV effect. CONCLUSION: PHIV youths attain sexual maturity later on average than PHEU youths. Much of this difference may be attributable to deficient growth, suggesting directions for future interventions.
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    Fractures in children and adolescents living with perinatally acquired HIV
    (Elsevier, 2020-10) Jacobson, Denise L.; Yu, Wendy; Hazra, Rohan; Brummel, Sean; Geffner, Mitchell E.; Patel, Kunjal; Borkowsky, William; Wang, Jiajia; Chen, Janet S.; Mirza, Ayesha; DiMeglio, Linda A.; Pediatrics, School of Medicine
    Background: Across numerous settings, bone mineral density for age and sex is lower in children/adolescents living with perinatally-acquired HIV (PHIV) compared to uninfected peers. We assessed incidences of any fracture/any long bone fracture, and osteoporosis prevalence in PHIV and HIV-exposed uninfected (PHEU) participants in the Pediatric HIV/AIDS Cohort Study (PHACS). Methodology: Lifetime history of fracture events from birth up to age 20 years was obtained by chart review and/or interview, including age at fracture, mechanism, and bone(s) fractured. Poisson regression models were fit comparing fracture incidence by HIV status adjusted for age, sex, and race, with effect modification by age (<6, ≥6 yr). Results: PHIV (N = 412) were older (median 17.5 vs 16.7 yr) and more frequently reported black race (72% vs 61%) than PHEU children/adolescents (N = 206). 17% of PHIV and 12% of PHEU ever reported a fracture. Among children <6 yr, the adjusted incidence rate ratio of ≥1 fracture was higher (7.23; 95% CI 0.98, 53.51) in PHIV than PHEU, but similar among children/adolescents ≥6 years (1.20; 95% CI: 0.77, 1.87). Results were similar for long bone fracture. The most common fracture mechanisms were falling to the ground from a standing height (23.6% PHIV vs 8.8% PHEU) and sports injuries (21.3% vs 32.4%), and the most commonly fractured sites were the forearm and small bones of the wrist/hands. None of the children had osteoporosis. Conclusions: Among children/adolescents ≥6 yr of age, fractures were similar by perinatal HIV status. Prospective, targeted collection of fracture history will be necessary to determine rates of fracture as PHIV and PHEU age into adulthood. Summary: Lifetime fracture history was collected in children/adolescents living with perinatally-acquired HIV (PHIV) and HIV-exposed uninfected (PHEU) children from birth up to age 20 years. Fracture incidence was higher in PHIV compared to PHEU among children <6 years old, but not among older children/adolescents.
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    Growth Patterns of Uninfected Children Born to Women Living with Perinatally- Versus Non-Perinatally-Acquired HIV
    (Wolters Kluwer, 2022) Yu, Wendy; Jacobson, Denise L.; Williams, Paige L.; Patel, Kunjal; Geffner, Mitchell E.; Van Dyke, Russell B.; Kacanek, Deborah; DiMeglio, Linda A.; Jao, Jennifer; Pediatric HIV/AIDS Cohort Study (PHACS); Pediatrics, School of Medicine
    Objective: The aim of this study was to compare long-term growth between HIV-exposed uninfected children (CHEU) born to women with perinatally acquired HIV (CHEU-PHIV) and CHEU born to women with nonperinatally acquired HIV (CHEU-NPHIV). Design: A longitudinal analysis of anthropometric measurements from a U.S.-based multisite prospective cohort study enrolling CHEU and their mothers since April 2007. Methods: CHEU were evaluated for growth annually from birth through age 5 and again at age 7 years. Z-scores were calculated using U.S. growth references for weight (WTZ), height (HTZ), and weight-for-length or BMI-for-age (WLZ/BMIZ). Mid-upper arm circumference (MUACZ) and triceps skinfold thickness (TSFZ) Z-scores were obtained from ages 1 and 2, respectively, through age 7 years. Piecewise mixed-effects models, overall and stratified by race and sex, were fit to assess differential growth patterns across age by maternal PHIV status. Results: One thousand four hundred fifty-four singleton infants (286 CHEU-PHIV and 1168 CHEU-NPHIV) were included. CHEU-PHIV had slower growth rates than CHEU-NPHIV for WTZ and WLZ/BMIZ at earlier ages and continued to have lower mean WTZ [-0.27, 95% confidence interval (95% CI): -0.50, -0.04] and WLZ/BMIZ (-0.39, 95% CI: -0.67, -0.11) through age 7. Among non-Black boys, CHEU-PHIV had slightly lower WTZ and WLZ/BMIZ at birth than CHEU-NPHIV and these growth deficits persisted through age 7 years. Conclusion: Compared with CHEU-NPHIV, CHEU-PHIV had diminished growth in early childhood with differences most pronounced among non-Black male children. Further longitudinal follow-up of CHEU-PHIV into young adulthood is needed to understand whether these early effects of maternal PHIV status on growth persist and have other health consequences.
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    Lower Newborn Bone Mineral Content Associated With Maternal Use of Tenofovir Disoproxil Fumarate During Pregnancy
    (Oxford University Press, 2015-09-15) Siberry, George K.; Jacobson, Denise L.; Kalkwarf, Heidi J.; Wu, Julia W.; DiMeglio, Linda A.; Yogev, Ram; Knapp, Katherine M.; Wheeler, Justin J.; Butler, Laurie; Hazra, Rohan; Miller, Tracie L.; Seage III, George R.; Van Dyke, Russell B.; Barr, Emily; Davtyan, Mariam; Mofenson, Lynne M.; Rich, Kenneth C.; Department of Pediatrics, IU School of Medicine
    BACKGROUND: Fetal bone effects of maternal tenofovir use have not been well studied. We sought to compare whole-body bone mineral content (BMC) of newborns exposed vs not exposed to tenofovir in utero. METHODS: We enrolled participants from April 2011 to June 2013 at 14 US clinical sites. Singleton infants of women with human immunodeficiency virus (HIV) infection who took tenofovir in late pregnancy (tenofovir-exposed) or no tenofovir during pregnancy (tenofovir-unexposed) were enrolled during late pregnancy or within 72 hours of birth. Infants born before 36 weeks gestation or with confirmed HIV infection were excluded. Whole-body BMC was measured in the first month of life and compared with that of the tenofovir-exposed and tenofovir-unexposed newborns, unadjusted and adjusted for covariates. RESULTS: Seventy-four tenofovir-exposed and 69 tenofovir-unexposed infants had evaluable BMC measurements. Tenofovir-exposed mothers were more likely to be married (31% vs 22%; P = .04) and to use boosted protease inhibitors (84% vs 62%; P = .004). Tenofovir-exposed newborns did not differ from unexposed newborns on mean gestational age (38.2 vs 38.1 weeks) or mean length (-0.41 vs -0.18) or weight (-0.71 vs -0.48) Z-scores. The mean (standard deviation) BMC of tenofovir-exposed infants was 12% lower than for unexposed infants (56.0 [11.8] vs 63.8 [16.6] g; P = .002). The adjusted mean bone mineral content was 5.3 g lower (95% confidence interval, -9.5, -1.2; P = .013) in the tenofovir-exposed infants. CONCLUSIONS: Maternal tenofovir use is associated with significantly lower neonatal BMC. The duration and clinical significance of this finding should be evaluated in longitudinal studies.
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    Markers of Bone Mineral Metabolism and Cardiac Structure and Function in Perinatally HIV-Infected and HIV-Exposed but Uninfected Children and Adolescents
    (Wolters Kluwer, 2020-06-01) Margossian, Renee; Williams, Paige L.; Yu, Wendy; Jacobson, Denise L.; Geffner, Mitchell E.; DiMeglio, Linda A.; Van Dyke, Russell B.; Spector, Stephen A.; Schuster, Gertrud U.; Stephensen, Charles B.; Miller, Tracie L.; Lipshultz, Steven E.; Study (PHACS) for the Pediatric HIV/AIDS Cohort; Pediatrics, School of Medicine
    Background: Disordered bone mineral metabolism and low vitamin D concentrations are associated with cardiovascular abnormalities; few studies have evaluated this relationship in HIV-infected youth. Setting: Adolescent Master Protocol (AMP) is a Pediatric HIV/AIDS Cohort Study (PHACS) network study conducted across 14 United States sites. Methods: Among perinatally HIV-infected (PHIV) and HIV-exposed uninfected (PHEU) youth enrolled in AMP, we evaluated associations of vitamin D (measured as 25-hydroxyvitamin D [25OHD]), parathyroid hormone (PTH), calcium, phosphate, and fibroblast growth factor-23 (FGF-23) concentrations with echocardiographic measures of left ventricular (LV) structure, function and concentrations of NT-proBNP, a biomarker of cardiac damage. Results: Among 485 participants (305 PHIV, 180 PHEU) with echocardiograms and bone mineralization measures, low 25OHD (< 20 ng/mL) was common among all participants (48% PHIV and 44% PHEU), but elevated PTH (> 65 pg/mL) was identified more often among PHIV than PHEU participants (9% vs 3%, p=0.02). After adjusting for HIV status and demographic covariates, both low 25OHD and elevated PTH were associated with lower mean LV mass z-scores, while elevated PTH was associated with higher mean fractional shortening z-scores. Participants with low 25OHD also had slightly higher mean LV end-systolic wall stress z-scores, but differences were more pronounced in PHEU than in PHIV participants. FGF-23 was inversely related to end-diastolic septal thickness both overall and among PHIV participants. Conclusion: In this cohort of PHIV and PHEU youth, we observed associations of 25OHD, PTH, and FGF-23 with both structural and functional cardiac parameters, supporting links between bone mineral metabolism and cardiac status.