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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).A longitudinal analysis of anthropometric measurements from a U.S.-based multisite prospective cohort study enrolling CHEU and their mothers since April 2007.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.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.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.

Objectives This study explores the association between combination antiretroviral therapy (cART) and oral health outcomes (dental and periodontal) among perinatally HIV-infected (PHIV) youth. Methods We conducted a cross-sectional study of oral health among PHIV youth participating in the Oral Health substudy of the Pediatric HIV/AIDS Cohort Study (PHACS). Dentists at research sites were trained/calibrated on how to perform a standardized oral mucosal, dental and periodontal examination. They assessed the decayed-missing-filled-surfaces and teeth index (DMFS/T). The number of decayed surfaces and teeth and the number of teeth with gingival bleeding on probing for each participant were derived from the examination. Data for analysis included lifetime measurements of CD4 cell count and viral load, sociodemographic information and current/past history of ART. Results Among 209 PHIV youth, 95% were on ART at the time of enrolment. Among 143 PHIV youth on the same cART for at least 1 year, we found that the mean decayed teeth score of those receiving cART containing an integrase inhibitor was 86% higher than that of those on cART without an integrase inhibitor after adjusting for age, lifetime proportion of unsuppressed viral load and CD4 cell count nadir. Initiating protease inhibitors before age 6 years was associated with a significantly lower DMFT score than participants who initiated at age 6 years and older. Conclusion Our study revealed that PHIV youth who received cART containing an integrase inhibitor had a significantly higher number of untreated active caries than those on cART without an integrase inhibitor. This may warrant closer dental surveillance of those receiving an integrase inhibitor.

Objective To evaluate potential adverse associations of individual antiretroviral medications used in combination antiretroviral therapy regimens on cardiac structure and function in youth with perinatally-acquired HIV infection (PHIV). Design PHIV youth (N = 325) enrolled in a prospective multisite cohort study had a single echocardiogram at age 7-16 years to evaluate cardiac function and structure. Methods We applied several statistical approaches to evaluate associations between use of 18 individual antiretroviral medications with Z-scores for 11 measures of left ventricular function and structure. These included simultaneously evaluating all antiretroviral medications in adjusted linear regression models controlling for the false discovery rate (FDR), applying hierarchical models to estimate individual antiretroviral medication effects as deviations from drug class means, and evaluating latent measures of cardiac function and structure underlying multiple echocardiographic parameters. Results Youth taking combination regimens with a protease inhibitor (69%) had significantly better cardiac function than those on other regimens. After FDR control and adjustment for other antiretroviral medications, no individual antiretroviral medication was significantly associated with any measure of left ventricular function, but zidovudine was associated with higher adjusted mean Z-scores for one measure of left ventricular structure (end-systolic wall stress). Factor analysis identified three latent factors: heart function, heart size, and heart wall stress. Lopinavir was associated with better heart function scores, whereas zidovudine was associated with higher wall stress scores. Zidovudine and nevirapine were associated with higher heart size factor scores. Conclusions Despite cardioprotective effects of combination regimens in PHIV youth, individual antiretroviral medications were associated with altered cardiac structure, which could progress to symptomatic cardiomyopathy in adulthood.

Objective: To identify relationships between insulin resistance (IR) and mitochondrial respiration in perinatally HIV-infected youth. Design: Case–control study. Methods: Mitochondrial respiration was assessed in perinatally HIV-infected youth in Tanner stages 2–5, 25 youth with IR (IR+) and 50 without IR (IR−) who were enrolled in the Pediatric HIV/AIDS Cohort Study. IR was defined as a homeostatic model of assessment for IR value at least 4.0. A novel, high-throughput oximetry method was used to evaluate cellular respiration in peripheral blood mononuclear cells. Unadjusted and adjusted differences in mitochondrial respiration markers between IR+ and IR− were evaluated, as were correlations between mitochondrial respiration markers and biochemical measurements. Results: IR+ and IR− youth were similar on age, sex, and race/ethnicity. Mean age was 16.5 and 15.6 years in IR+ and IR−, respectively. The IR+ group had significantly higher mean BMI and metabolic analytes (fasting glucose, insulin, cholesterol, triglycerides, and venous lactate and pyruvate) compared with the IR−. Mitochondrial respiration markers were, on average, lower in the IR+ compared with IR−, including basal respiration (417.5 vs. 597.5 pmol, P = 0.074), ATP production (11 513 vs. 15 202 pmol, P = 0.078), proton leak (584.6 vs. 790.0 pmol, P = 0.033), maximal respiration (1815 vs. 2399 pmol, P = 0.025), and spare respiration capacity (1162 vs. 2017 pmol, P = 0.032). Nonmitochondrial respiration did not differ by IR status. The results did not change when adjusted for age. Conclusion: HIV-infected youth with IR have lower mitochondrial respiration markers when compared to youth without IR. Disordered mitochondrial respiration may be a potential mechanism for IR in this population.

OBJECTIVE To longitudinally characterize noninvasive markers of liver disease in HIV-infected youth. DESIGN HIV infection, without viral hepatitis coinfection, may contribute to liver disease. Noninvasive markers of liver disease [FIB-4 (Fibrosis-4) and APRI (aspartate aminotransferase-to-platelet ratio index)] have been evaluated in adults with concomitant HIV and hepatitis C, but are less studied in children. METHODS In prospective cohorts of HIV-infected and HIV-uninfected youth, we used linear regression models to compare log-transformed FIB-4 and APRI measures by HIV status based on a single visit at ages 15-20 years. We also longitudinally modeled trends in these measures in HIV-infected youth with two or more visits to compare those with behavioral vs. perinatal HIV infection (PHIV) using mixed effect linear regression, adjusting for age, sex, body mass index, and race/ethnicity. RESULTS Of 1785 participants, 41% were men, 57% black non-Hispanic, and 27% Hispanic. More HIV-infected than uninfected youth had an APRI score more than 0.5 (13 vs. 3%, P

OBJECTIVE To evaluate the safety of in-utero antiretroviral exposure in children born to mothers with HIV, using a trigger-based design. DESIGN The Surveillance Monitoring of ART Toxicities Study is a prospective cohort study conducted at 22 US sites to evaluate safety of in-utero antiretroviral drug exposure in HIV-uninfected children born to HIV-infected mothers. Children meeting predefined clinical or laboratory thresholds have more intensive evaluations to determine whether they meet criteria for adverse events. METHODS Adverse event "cases" were defined for the following domains: growth, hearing, language, neurology, neurodevelopment, metabolic, hematologic/clinical chemistry and blood lactate. We used adjusted log-binomial models to calculate relative risks (RR) of case status overall and within individual domains for various antiretroviral exposures during pregnancy. RESULTS Among 2680 youth enrolled between 2007 and 2012 (48% female, 66% black, 33% Hispanic), 48% met a trigger and 25% were defined as a case in at least one domain. Language (13.2%) and metabolic (11.4%) cases were most common. After adjustment for birth cohort and other factors, there was no association of any antiretroviral regimen, drug class, or individual drug with meeting overall case criteria (case in any domain). Within individual domains, zidovudine (74% exposed) was associated with increased risk of metabolic case [RR = 1.69, 95%confidence interval (CI) 1.08-2.64] and didanosine plus stavudine (

To prevent mother-to-child-transmission of HIV-1, the 2010 WHO guidelines recommended prenatal zidovudine (ZDV) monotherapy (option A). To determine if ZDV monotherapy selects for HIV resistance in antiretroviral-naive women during pregnancy, specimens from 50 individuals were examined using pyrosequencing. ZDV-resistance mutations were detected at delivery in seven women (14%, 95% confidence interval 6.6-26.5%). These data raise the question whether women administered ZDV monotherapy for prevention of mother-to-child-transmission could have higher risk of virologic failure when later started on combination antiretroviral therapy, as has been demonstrated following single-dose nevirapine prophylaxis.

Some perinatally infected children do not regain normal CD4(+) T-cell counts despite suppression of HIV-1 plasma viremia by antiretroviral therapy (ART). The frequency, severity and significance of these discordant treatment responses remain unclear.We examined the persistence of CD4(+) lymphocytopenia despite virologic suppression in 933 children (≥ 5 years of age) in the USA, Latin America and the Caribbean.CD4(+) T-cell trajectories were examined and Kaplan-Meier methods used to estimate median time to CD4(+) T-cell count at least 500 cells/μl.After 1 year of virologic suppression, most (99%) children achieved a CD4(+) T-cell count of at least 200 cells/μl, but CD4(+) T-cell counts remained below 500 cells/μl after 1 and 2 years of virologic suppression in 14 and 8% of children, respectively. Median times to first CD4(+) T-cell count at least 500 cells/μl were 1.29, 0.78 and 0.46 years for children with less than 200, 200-349 and 350-499 cells/μl at the start of virologic suppression. New AIDS-defining events occurred in nine children, including four in the first 6 months of virologic suppression. Other infectious and HIV-related diagnoses occurred more frequently and across a wide range of CD4(+) cell counts.ART improved CD4(+) cell counts in most children, but the time to CD4(+) cell count of at least 500 cells was highly dependent upon baseline immunological status. Some children did not reach a CD4(+) T-cell count of 500 cells/μl despite 2 years of virologic suppression. AIDS-defining events occurred in 1% of the population, including children in whom virologic suppression and improved CD4(+) T-cell counts were achieved.

Prevention of mother to child HIV transmission (MTCT) has been a resounding public health success story. In the past 20 years, the rate of MTCT in the US has been reduced from 26% to under 1% using potent combination antiretroviral (cARV) regimens [1-4]. As the use of cARV regimens in pregnancy has increased, concerns have been raised regarding the potential risk of in utero cARV exposure on long-term outcomes among HIV-exposed but uninfected (HEU) children, including mitochondrial toxicity which has also been associated with cardiomyopathy in HIV-unexposed children [5-12]. Among HIV-infected children, cardiomyopathy was common prior to widespread use of cARV and was associated with high mortality [13]. However, a study of both HEU and HIV-infected children in the National Heart, Lung, and Blood Institute (NHLBI) Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection Study (P2C2) born between 1990-1994 found no association between perinatal exposure to zidovudine (ZDV) monotherapy and abnormalities of left ventricular (LV) structure or function [14]. In another report, compared to the subset of ARV-unexposed HEU children in the P2C2 study, 136 children (96% exposed to cARV in utero) born between 2003-2006 in the NHLBI-funded Cardiovascular Status of Highly Active Antiretroviral Therapy (HAART) in HIV-Exposed Infants and Children cohort study (CHAART I) had significantly lower LV mass, septal wall thickness, and LV diameter, and higher LV contractility at age 2 years [15]. Since these prior studies were limited by their small sample size and/or they were conducted during an earlier era when there were fewer antiretroviral (ARV) options compared to the contemporary era which has more robust combination ARV combination therapy options, we evaluated the relationship between perinatal ARV drug exposure and echocardiographic measurements from the Pediatric HIV/AIDS Cohort Study (PHACS) Surveillance Monitoring for ART Toxicities (SMARTT) study.

OBJECTIVE Previous studies of cardiomyopathy among children perinatally infected with HIV were conducted before the routine use of HAART. Nucleoside analogs [nucleoside reverse transcriptase inhibitors (NRTIs)], the backbone of HAART, have been associated with mitochondrial toxicity, which can lead to cardiomyopathy. We evaluated the association of HAART and specific NRTIs associated with mitochondrial toxicity, on development of cardiomyopathy among perinatally HIV-infected children. DESIGN Three thousand and thirty-five perinatally HIV-infected children enrolled in a US-based multicenter prospective cohort study were followed for cardiomyopathy, defined as a clinical diagnosis or initiation of digoxin, from 1993 to 2007. METHODS Cox models were used to estimate the effects of HAART and NRTIs on cardiomyopathy, identify predictors of cardiomyopathy among HAART users, and estimate the association between development of cardiomyopathy and mortality. RESULTS Ninety-nine cases of cardiomyopathy were identified over follow-up (incidence rate: 5.6 cases per 1000 person-years) at a median age of 9.4 years. HAART was associated with a 50% lower incidence of cardiomyopathy compared with no HAART use (95% confidence interval: 20%, 70%). Zalcitabine (ddC) use, however, was associated with an 80% higher incidence of cardiomyopathy. Among HAART users, older age at HAART initiation, ddC use before HAART initiation, initiating a HAART regimen containing zidovudine (ZDV), and a nadir CD4 percentage less than 15% were independently associated with a higher rate of cardiomyopathy. Cardiomyopathy was associated with a six-fold higher mortality rate. CONCLUSION HAART has dramatically decreased the incidence of cardiomyopathy among perinatally HIV-infected children. However, they remain at increased risk for cardiomyopathy and ongoing ZDV exposure may increase this risk.

Background: There is equivocal evidence of in utero nucleoside reverse transcriptase inhibitor (NRTI) exposure and the occurrence of mitochondrial dysfunction (MD) in HIV-uninfected children born of HIV-infected women. Methods: The primary analysis included 1037 HIV-uninfected children born in 19912002 and enrolled in Pediatric AIDS Clinical Trials Group protocols 219/219C. Possible cases with unexplained signs of MD according to the Enquete Perinatale Francaise criteria were identified through retrospective review. Associations between overall in utero NRTI exposure, and trimester of first in utero NRTI exposure and possible MD were estimated with exact logistic regression. Results: Cases (n = 20) were significantly more likely to be male and to be born in earlier years than non-cases (n = 1017). There was no association between overal I in utero NRTI exposure and MD. In unadjusted models there were higher odds of first in utero exposure in the third trimester to lamivudine (3TC) [odds ratio (OR), 3.76 versus 3TC unexposed; 95% confidence interval (CI), 1.09-11.78] and to zidovudine (ZDV) and 3TC in combination (ZDV/3TC) (OR, 3.29 vs. ZDV/3TC unexposed; 95% CI, 0.96-10.25) among cases than noncases. When adjusted for year of birth the odds of first exposure in the third trimester to 3TC (OR, 10.57; 95% CI, 1.93-75.61) and ZDV/3TC (OR, 9.84; 95% CI, 1.77-71.68) were significantly higher among cases than non-cases. Incomplete data precluded control of possible confounding by maternal viral load and psychoactive drug use. Conclusions: Our study suggests that first exposure to 3TC or ZDV/3TC in the third trimester may be associated with the occurrence of possible MD. Further studies that rigorously assess MD and better control confounding are needed. (C) 2007 Lippincott Williams & Wilkins.