Surveillance Monitoring For ART Toxicities Study Research Articles

A Comparison of Metabolic Outcomes Between Obese HIV-Exposed Uninfected Youth From the PHACS SMARTT Study and HIV-Unexposed Youth From the NHANES Study in the United States.

Metabolic perturbations in HIV-exposed uninfected (HEU) obese youth may differ from those in the general obese pediatric population. Metabolic parameters of obese (body mass index Z-score >95th percentile) HEU youth in the Pediatric HIV/AIDS Cohort Study (PHACS) Surveillance Monitoring of ART Toxicities (SMARTT) study were compared with a matched sample of obese youth from the US National Health and Nutrition Examination Survey (NHANES). We evaluated systolic and diastolic hypertension (blood pressure ≥90th percentile for age, sex, and height), total cholesterol >200 mg/dL, high-density lipoprotein cholesterol <35 mg/dL, low-density lipoprotein cholesterol >130 mg/dL, triglycerides (TGs) >150 mg/dL, and Homeostatic Model Assessment-Insulin Resistance >4.0. Modified Poisson regression models were fit to quantify the prevalence ratio (PR) of each outcome comparing the 2 cohorts, adjusting for confounders. The blood pressure outcome analytic subgroup included 1096 participants (n = 304 HEU), the total cholesterol and high-density lipoprotein cholesterol subgroup 1301 participants (n = 385 HEU), and the low-density lipoprotein cholesterol, TG, and Homeostatic Model Assessment-Insulin Resistance subgroup 271 (n = 83 HEU). After adjustment, obese HEU youth had a higher prevalence of systolic and diastolic hypertension [PR = 3.34, 95% confidence interval (CI): 2.48 to 4.50; PR = 2.04, 95% CI: 1.18 to 3.52, respectively], but lower prevalence of insulin resistance (PR = 0.67, 95% CI: 0.54 to 0.85) and hypercholesterolemia (PR = 0.67, 95% CI: 0.44 to 1.01) compared with obese NHANES youth. In the United States, obese HEU youth seem to have an increased risk of hypertension, but lower risk of insulin resistance and hypercholesterolemia, compared with a general obese pediatric population. Monitoring for cardiovascular morbidity in adulthood may be warranted in HEU children.

The PHACS SMARTT Study: Assessment of the Safety of In Utero Exposure to Antiretroviral Drugs.

The Surveillance Monitoring for ART Toxicities (SMARTT) cohort of the Pediatric HIV/AIDS Cohort Study includes over 3,500 HIV-exposed but uninfected infants and children at 22 sites in the US, including Puerto Rico. The goal of the study is to determine the safety of in utero exposure to antiretrovirals (ARVs) and to estimate the incidence of adverse events. Domains being assessed include metabolic, growth and development, cardiac, neurological, neurodevelopmental (ND), behavior, language, and hearing. SMARTT employs an innovative trigger-based design as an efficient means to identify and evaluate adverse events. Participants who met a predefined clinical or laboratory threshold (trigger) undergo additional evaluations to define their case status. After adjusting for birth cohort and other factors, there was no significant increase in the likelihood of meeting overall case status (case in any domain) with exposure to combination ARVs (cARVs), any ARV class, or any specific ARV. However, several individual ARVs were significantly associated with case status in individual domains, including zidovudine for a metabolic case, first trimester stavudine for a language case, and didanosine plus stavudine for a ND case. We found an increased rate of preterm birth with first trimester exposure to protease inhibitor-based cARV. Although there was no overall increase in congenital anomalies with first trimester cARV, a significant increase was seen with exposure to atazanavir, ritonavir, and didanosine plus stavudine. Tenofovir exposure was associated with significantly lower mean whole-body bone mineral content in the newborn period and a lower length and head circumference at 1 year of age. With ND testing at 1 year of age, specific ARVs (atazanavir, ritonavir-boosted lopinavir, nelfinavir, and tenofovir) were associated with lower performance, although all groups were within the normal range. No ARVs or classes were associated with lower performance between 5 and 13 years of age. Atazanavir and saquinavir exposure were associated with late language emergence at 1 year, but not at 2 years of age. The results of the SMARTT study are generally reassuring, with little evidence for serious adverse events resulting from in utero ARV exposure. However, several findings of concern warrant further evaluation, and new ARVs used in pregnancy need to be evaluated.

Congenital anomalies and in utero antiretroviral exposure in human immunodeficiency virus-exposed uninfected infants.

Most studies examining the association of prenatal antiretroviral (ARV) exposures with congenital anomalies (CAs) in children born to human immunodeficiency virus (HIV)-infected women have been reassuring, but some evidence suggests an increased risk with specific ARV agents. To evaluate the association of in utero ARV exposures with CAs in HIV-exposed uninfected children. Prospective cohort study design. The Pediatric HIV/AIDS Cohort Study's Surveillance Monitoring of ART Toxicities (SMARTT) Study was performed at 22 US medical centers among 2580 HIV-exposed uninfected children enrolled in the SMARTT Study between March 23, 2007, and June 18, 2012. First-trimester exposure to any ARV and to specific ARV medications. The primary end point was a CA based on physician review of infant physical examinations according to the Antiretroviral Pregnancy Registry modification of the Metropolitan Atlanta Congenital Defects Program. Rates of CAs were estimated overall and by birth year. Logistic regression models were used to evaluate the association of CAs with first-trimester ARV exposures, adjusting for demographic and maternal characteristics. Congenital anomalies occurred in 175 of 2580 children, yielding a prevalence of 6.78% (95% CI, 5.85%-7.82%); 242 major CAs were confirmed, including 72 musculoskeletal and 55 cardiovascular CAs. The prevalence of CAs increased significantly among successive birth cohorts (3.8% for children born before 2002 and up to 8.3% for those born 2008-2010). In adjusted models, no association of first-trimester exposures with CAs was found for any ARV, for combination ARV regimens, or for any drug class. No individual ARV in the reverse transcriptase inhibitor drug classes was associated with an increased risk of CAs. Among protease inhibitors, higher odds of CAs were observed for atazanavir sulfate (adjusted odds ratio [aOR], 1.95; 95% CI, 1.24-3.05) and for ritonavir used as a booster (aOR, 1.56; 95% CI, 1.11-2.20). With first-trimester atazanavir exposure, risks were highest for skin (aOR, 5.23) and musculoskeletal (aOR, 2.55) CAs. Few individual ARVs and no drug classes were associated with an increased risk of CAs in HIV-exposed infants after adjustment for calendar year and maternal characteristics. While the overall risk remained low, a relative increase was observed in successive years and with atazanavir exposure. Given the low absolute CA risk, the benefits of recommended ARV therapy use during pregnancy still outweigh such risks, although further studies are warranted.