Pharmacokinetics of darunavir and cobicistat in pregnant and postpartum women with HIV.

OBJECTIVE: To evaluate darunavir and cobicistat pharmacokinetics during pregnancy compared with postpartum and in infant washout samples after delivery. DESIGN: Nonrandomized, open-label, parallel-group, multicenter phase-IV prospective study of darunavir and cobicistat pharmacokinetics in pregnant women with HIV and their children in the United States. METHODS: Intensive steady-state 24-h pharmacokinetic profiles were performed after administration of 800 mg of darunavir and 150 mg of cobicistat orally in fixed dose combination once-daily during the second trimester, third trimester, and postpartum. Infant washout samples were collected after birth. Darunavir and cobicistat were measured in plasma by validated HPLC-UV and liquid chromatography with tandem mass spectrometry detection (LC-MS)/MS assays, respectively. A two-tailed Wilcoxon signed-rank test (α = 0.10) was employed for paired within-participant comparisons. RESULTS: A total of 29 pregnant women receiving darunavir and cobicistat once-daily enrolled in the study. Compared with paired postpartum data, darunavir AUC0--24 was 53% lower in the second trimester [n = 12, P = 0.0024, geometric mean of ratio (GMR)=0.47, 90% confidence interval (CI) 0.33 - 0.68] and 56% lower in the third trimester (n = 18, P < 0.0001, GMR = 0.44, 90% CI 0.36 - 0.54), whereas cobicistat AUC0--24 was 50% lower in the second trimester (n = 12, P = 0.0024, GMR = 0.50, 90% CI 0.36-0.69) and 56% lower in the third trimester (n = 18, P < 0.0001, GMR = 0.44, 90% CI 0.35-0.55). Placental transfer of darunavir and cobicistat was limited. CONCLUSION: Standard darunavir/cobicistat dosing during pregnancy results in significantly lower exposure during pregnancy, which may increase the risk of virologic failure and perinatal transmission.

Predictors of Viremia in Postpartum Women on Antiretroviral Therapy.

BACKGROUND: HIV-infected, postpartum women on antiretroviral therapy (ART) have high rates of viremia. We examined predictors of postpartum viremia in the PROMISE study. METHODS: Women with pre-ART CD4 T-cell counts ≥400 cells/mm who started ART during pregnancy were randomized postpartum to continue ART (CTART) or discontinue ART (DCART). Viral load and self-reported adherence were collected every 12 weeks, up to 144 weeks. Women in DCART reinitiated therapy when clinically indicated. Viremia was defined as 2 consecutive viral loads >1000 copies/mL after 24 weeks on ART. Adherence was dichotomized as missing versus not missing ART doses in the past 4 weeks. Predictors of viremia were examined using Cox proportional hazards regression with adherence as a time-varying covariate. RESULTS: Among 802 women in the CTART arm, median age at entry was 27 years and median CD4 T-cell count 696 cells/mm. Of 175 women in CTART with viremia (22%), 141 had resistance data, and 12% had resistance to their current regimen. There was an estimated 0.12 probability of viremia by week 48 and 0.25 by week 144. Predictors of viremia included missed ART doses within the past 4 weeks, younger age, shorter duration of pre-entry ART, and being from the South American/Caribbean region. Of 137 women in DCART who reinitiated therapy, probability of viremia was similar to CTART (0.24 by week 96; 0.27 by week 144). CONCLUSIONS: Rates of postpartum viremia are high and viremia is more likely in younger postpartum women who start ART later in pregnancy. Interventions should target these higher-risk women.

Predicting Viral Failure in Human Immunodeficiency Virus Perinatally Infected Youth With Persistent Low-Level Viremia on Highly Active Antiretroviral Therapy.

BACKGROUND: Less than optimal adherence with antiretroviral therapy occurs commonly among human immunodeficiency virus HIV)-infected youth. In this study, our object was to identify patterns in the prefailure measurement of viral load (VL) that can reliably predict virological failure (VF) in HIV perinatally infected youth on highly active antiretroviral therapy (HAART). METHODS: We conducted a retrospective chart review of HIV-infected youth with low-level viremia (LLV), defined as an HIV VL between the lower limits of detection (20-75 copies/mL) and 1000 copies/mL. All patients were perinatally infected, under 22 years of age, observed for at least 24 months of consecutive follow-up between May 2008 and July 2014, and received their HIV care at the University of Miami Miller School of Medicine. Of the 349 subjects screened, 100 were eligible for analysis. Virological failure was defined as 3 or more consecutive VLs greater than 1000 copies/mL. Multiple logistic regression and receiver operator characteristic curves were used to identify patterns in VL that ultimately resulted in VF. RESULTS: Fifteen of the 100 patients experienced VF. Higher log10 mean VL, positive slope of the VL (log10 copies/mL per day), and fewer clinic visits were associated with a higher probability of VF. Sensitivity and specificity were .87 and .95, respectively. Resistance was not found in 12 of 15 patients with VF. CONCLUSIONS: Patients with LLV that had fewer clinic visits and a trend toward increasing VLs had an increased risk of VF. Noncompliance seems to be a major component of VF. Physicians should emphasize the critical nature of medication adherence.

Longitudinal Changes in Body Composition by Dual-energy Radiograph Absorptiometry Among Perinatally HIV-infected and HIV-uninfected Youth: Increased Risk of Adiposity Among HIV-infected Female Youth.

BACKGROUND: Combination antiretroviral therapy has allowed youth with perinatal HIV infection (PHIV+) to live into adulthood, but many youth may experience metabolic and body composition changes that predispose to greater cardiovascular disease (CVD) risk. This longitudinal study evaluated changes in body composition measured by dual-energy radiograph absorptiometry (DXA) in a cohort of PHIV+ youth compared with HIV- controls over a 7-year period. METHODS: PHIV+ youth and HIV- controls were prospectively enrolled in a single-site study to assess nutrition and CVD risk. Anthropometrics and DXA scans were longitudinally obtained to assess percent body fat and regional fat distribution. Using general linear models, we analyzed differences in body composition and anthropometric measures by sex between PHIV+ youth and controls over time. RESULTS: Two hundred thirty-five participants (156 PHIV+ and 79 HIV- controls) with at least 1 DXA performed since study enrollment were included for analysis. During the study period, 471 DXAs were obtained in the PHIV+ group and 95 in HIV- controls. PHIV+ females demonstrated greater increase in weight and body mass index over time compared with HIV- females, and significant increases in total percent body fat [estimate = 1.212 (95% confidence interval: 0.837-1.587) percent per year; P < 0.001) and percent trunk fat [1.3818 (95% confidence interval: 0.922-1.84); P < 0.001] compared with HIV- females and PHIV+ males. CONCLUSIONS: PHIV+ females demonstrate an unfavorable change in fat redistribution and percent body fat over time that exceeds the pattern seen in PHIV+ males or HIV- females. Providers should have heightened awareness of body composition changes of PHIV+ females that may eventually lead to increased CVD risk.

Birth Weight and Preterm Delivery Outcomes of Perinatally vs Nonperinatally Human Immunodeficiency Virus-Infected Pregnant Women in the United States: Results From the PHACS SMARTT Study and IMPAACT P1025 Protocol.

BACKGROUND: Pregnancy outcomes of perinatally human immunodeficiency virus-infected women (PHIV) are poorly defined. METHODS: We compared preterm delivery and birth weight (BW) outcomes (low BW [LBW], <2500 g), small-for-gestational-age [SGA], and BW z scores [BWZ]) in HIV-exposed uninfected infants of PHIV vs nonperinatally HIV-infected (NPHIV) pregnant women in the Pediatric HIV/AIDS Cohort Study Surveillance Monitoring of ART Toxicities or International Maternal Pediatric Adolescent AIDS Clinical Trials P1025 studies. Mixed effects models and log binomial models were used to assess the association of maternal PHIV status with infant outcomes. Age-stratified analyses were performed. RESULTS: From 1998 to 2013, 2270 HIV-infected pregnant women delivered 2692 newborns (270 born to PHIV and 2422 to NPHIV women). PHIV women were younger, (mean age 21 vs 25 years, P < .01) and more likely to have a pregnancy CD4 count <200 cells/mm3 (19% vs 11%, P = .01). No associations between maternal PHIV status and preterm delivery, SGA, or LBW were observed. After adjustment, BWZ was 0.12 lower in infants of PHIV vs NPHIV women (adjusted mean, -0.45 vs -0.33; P = .04). Among women aged 23-30 years (n = 1770), maternal PHIV was associated with LBW (aRR = 1.74; 95% confidence interval, 1.18, 2.58; P < .01). CONCLUSION: The overall lack of association between maternal PHIV status and preterm delivery or infant BW outcomes is reassuring. The higher rates of LBW observed in PHIV women aged 23-30 years warrants further mechanism-based investigations as this is a rapidly growing and aging population worldwide. CLINICAL TRIALS REGISTRATION: PHACS SMARTT study, NCT01310023. CLINICAL TRIALS REGISTRATION: IMPAACT 1025, NCT00028145.

Associations Between Dietary Intake Before 6 Months of Age and Rapid Weight Gain Among HIV-exposed Uninfected Infants.

INTRODUCTION: HIV-exposed, uninfected (HEU) infants are potentially at risk for cardiovascular disease due to in utero exposures. Feeding practices of the infant could compound this risk. Few studies have, however, evaluated dietary intake of HEU infants. We determined dietary factors associated with rapid weight gain (RWG) among HEU infants from birth to 6 months followed at the University of Miami HIV Screening Program. METHODS: In this cross-sectional analysis, logistic regression was used to determine dietary factors associated with RWG defined as a >0.67 SD change in weight-for-age z score from birth to assessment (0.3-6 months). Other covariates included demographics, birth, maternal and gestational characteristics, and antiretroviral exposures. RESULTS: A total of 86 full-term HEU infants with a mean age of 3.4 months (SD 1.8 months) were included in this analysis. Fifty-five percent of mothers were obese. Overall, 39.5% of infants exhibited RWG. A significant association between consumption of infant cereal and RWG (odds ratio, 3.52; 95% confidence interval, 1.02-12.10) was found after adjusting for birth weight, current age, and energy intake. Those infants who consumed the highest tertile of protein were less likely to gain weight rapidly after adjusting for the same covariates (odds ratio, 0.15; 95% confidence interval, 0.02-0.94). CONCLUSIONS: Overall differences in weight gain during early infancy are at least partly explained by means of infant feeding in young HEU infants in the United States. Dietary counseling for families of HEU should reinforce current feeding practice recommendations of the American Academy of Pediatrics.

Missed Opportunities for Prevention of Mother-to-Child Transmission of Human Immunodeficiency Virus.

OBJECTIVE: To identify missed opportunities for prevention of mother-to-child transmission of human immunodeficiency virus (HIV). METHODS: Data regarding HIV-infected children born between 2002 and 2009 to HIV-infected women enrolled in the U.S. International Maternal Pediatric Adolescent AIDS Clinical Trials prospective cohort study (protocol P1025) were reviewed. The characteristics of the HIV-infected infants and their mothers and the mothers' clinical management are described. RESULTS: Twelve cases of mother-to-child transmission of HIV occurred among 1,857 liveborn neonates, for a prevalence of 0.65 per 100 live births to HIV-infected women (95% confidence interval 0.33-1.13). Four transmissions occurred in utero, three were peripartum transmissions, and the timing of transmission for five neonates was unable to be determined. None were breastfed. Seven women had plasma viral loads greater than 400 copies/mL near delivery. Six women had less than 11 weeks of antiretroviral therapy during pregnancy; three of these women had premature deliveries. One woman received no antiretroviral therapy during pregnancy because she was diagnosed with HIV postpartum. Six had poor to moderate adherence to antiretroviral therapy. Four of the five mothers with viral loads greater than 1,000 copies/mL delivered preterm neonates. There were five women who delivered by cesarean; four were nonelective cesarean deliveries and only one was an elective cesarean delivery for HIV prevention. CONCLUSION: Despite access to high-level care and follow-up, a small proportion of HIV-infected women transmitted the virus to their neonates. This case series provides insight into factors contributing to HIV perinatal transmission and can inform the development of new strategies for prevention of mother-to-child transmission of HIV. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT00028145.

Complications and Route of Delivery in a Large Cohort Study of HIV-1-Infected Women-IMPAACT P1025.

OBJECTIVE: To investigate complications of cesarean section in a cohort of HIV-infected pregnant women. METHODS: IMPAACT P1025 is a prospective cohort study of HIV-1-infected women and infants, enrolled 2002-2013, at clinical sites in the United States and Puerto Rico. Demographic, medical, and obstetric data were collected and analyzed including cesarean indications. The delivery route was categorized as elective cesarean (ECS) (before labor and <5 minutes before membrane rupture), nonelective cesarean (NECS) (all other cesareans) or vaginal delivery. Logistic regression models evaluated associations between delivery route and maternal intrapartum/postpartum morbidities. Composite morbidity of vaginal delivery was compared with ECS and NECS. RESULTS: This study included 2297 women. Of note, 99% used antiretroviral medication and 89% were on a combination antiretroviral therapy regimen; 84% had a HIV-1 viral load ≤400 copies per milliliter before delivery; 46% (1055) delivered vaginally, 35% (798) by ECS, and 19% (444) by NECS. Although interruption of HIV-1 infection was the second most frequent indication for cesarean after repeat cesarean, it decreased as an indication over time. There were no delivery-related maternal mortalities. Overall, 19% of women had ≥1 complication(s)-primarily wound complications (14%) or other infections (11%). Vaginal delivery had the lowest complication rate (13%), followed by ECS (23%), and highest NECS (28%) with an overall P < 0.001. HIV-1 mother-to-child transmission rates were low and did not differ by delivery mode group. CONCLUSIONS: HIV interruption as cesarean indicator declined during the study. Morbidity was more common in HIV-infected women delivering by NECS than ECS and lowest with vaginal delivery. CLINICAL TRIAL REGISTRATION: Prenatal and Postnatal Studies of Interventions for Prevention of Mother-To-Child Transmission https://clinicaltrials.gov/ct2/show/NCT00028145?term=impaact+1025&rank=2 NCT00028145.

Brief Report: APOL1 Renal Risk Variants Are Associated With Chronic Kidney Disease in Children and Youth With Perinatal HIV Infection.

APOL1 renal risk alleles are associated with chronic kidney disease (CKD) in adults, with the strongest effect being for HIV-associated nephropathy. Their role in youth with perinatal HIV-1 infection (PHIV) has not been studied. In a nested case-control study of 451 PHIV participants in the Pediatric HIV/AIDS Cohort Study, we found a 3.5-fold increased odds of CKD in those carrying high-risk APOL1 genotypes using a recessive model [95% confidence interval (CI): 1.2 to 10.0]. We report an unadjusted incidence of 1.2 CKD cases/100 person-years (95% CI: 0.5 to 2.5) in PHIV youth carrying APOL1 high-risk genotypes, with important implications for sub-Saharan Africa.

Body mass index and waist circumference of HIV-infected youth in a Miami cohort: comparison to local and national cohorts.

OBJECTIVES: Human immunodeficiency virus (HIV)-infected youth are healthier because of effective antiretroviral therapies. We compared anthropometric measurements and prevalence of overweight and obesity between perinatally HIV-infected youth, a local HIV-uninfected comparison group, and 2007 to 2010 National Health and Nutrition Examination Survey (NHANES) data. In addition, we compared only African American HIV-infected youth with NHANES African Americans. METHODS: Height, weight, body mass index (BMI), and waist circumference (WC) of HIV-infected youth, aged 10 to 19 years, were compared among groups. BMI percentiles were categorized as underweight (<5%), normal (5% to <85%), overweight (85% to <95%), and obese (≥ 95%). Clinical correlates were modeled as predictors of BMI and WC. RESULTS: A total of 134 HIV-infected (including 103 African Americans) (mean age 16.5 years), 75 HIV-uninfected (mean age 14.2 years), and 3216 NHANES (including 771 NHANES African Americans) (mean age 15.0 years) youth were included in the analysis. Height and weight z scores of HIV-infected youth were lower than those of HIV-uninfected and NHANES (P ≤ 0.056) youth. BMI, WC, and BMI category were not statistically different between groups. In the HIV-infected African American group, BMI z score was lower (0.49 vs 0.76, P = 0.04) compared with NHANES African Americans. There were no significant predictors of BMI or WC for the HIV-infected group. CONCLUSIONS: HIV-infected children have similar BMIs and WCs as uninfected children both locally and nationally and show similar high rates of obesity and overweight. When compared with a more racially similar African American national sample, HIV-infected children have a lower BMI, suggesting that there may be persistent anthropometric differences in HIV.

Aggregate risk of cardiovascular disease among adolescents perinatally infected with the human immunodeficiency virus.

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.

Infant growth outcomes after maternal tenofovir disoproxil fumarate use during pregnancy.

OBJECTIVE: To determine whether maternal use of tenofovir disoproxil fumarate for treatment of HIV in pregnancy predicts fetal and infant growth. METHODS: The study population included HIV-uninfected live-born singleton infants of mothers enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Group protocol P1025 (born 2002-2011) in the United States and exposed in utero to a combined (triple or more) antiretroviral regimen. Infant weight at birth and 6 months was compared between infants exposed and unexposed to tenofovir in utero using 2-sample t test, χ test, and multivariable linear and logistic regression models, including demographic and maternal characteristics. RESULTS: Among 2025 infants with measured birth weight, there was no difference between those exposed (N = 630, 31%) versus unexposed to tenofovir in mean birth weight (2.75 vs. 2.77 kg, P = 0.64) or mean gestational age- and sex-adjusted birth weight z-score (WASZ) (0.14 vs. 0.14, P = 0.90). Among 1496 infants followed for 6 months, there was no difference in mean weight at 6 months between tenofovir-exposed (N = 457, 31%) and tenofovir-unexposed infants (7.64 vs. 7.59 kg, P = 0.52) or in mean WASZ (0.29 vs. 0.26, P = 0.61). Tenofovir exposure during the second/third trimester, relative to no exposure, significantly predicted underweight (WASZ < 5%) at age 6 months [odds ratio (95% confidence interval): 2.06 (1.01 to 3.95), P = 0.04]. Duration of tenofovir exposure did not predict neonatal or infant growth. CONCLUSIONS: By most measures, in utero exposure to tenofovir did not significantly predict infant birth weight or growth through 6 months of age.

Cardiac effects in perinatally HIV-infected and HIV-exposed but uninfected children and adolescents: a view from the United States of America.

INTRODUCTION: Human immunodeficiency virus (HIV) infection is a primary cause of acquired heart disease, particularly of accelerated atherosclerosis, symptomatic heart failure, and pulmonary arterial hypertension. Cardiac complications often occur in late-stage HIV infections as prolonged viral infection is becoming more relevant as longevity improves. Thus, multi-agent HIV therapies that help sustain life may also increase the risk of cardiovascular events and accelerated atherosclerosis. DISCUSSION: Before highly active antiretroviral therapy (HAART), the two-to-five-year incidence of symptomatic heart failure ranged from 4 to 28% in HIV patients. Patients both before and after HAART also frequently have asymptomatic abnormalities in cardiovascular structure. Echocardiographic measurements indicate left ventricular (LV) systolic dysfunction in 18%, LV hypertrophy in 6.5%, and left atrial dilation in 40% of patients followed on HAART therapy. Diastolic dysfunction is also common in long-term survivors of HIV infection. Accelerated atherosclerosis has been found in HIV-infected young adults and children without traditional coronary risk factors. Infective endocarditis, although rare in children, has high mortality in late-stage AIDS patients with poor nutritional status and severely compromised immune systems. Although lymphomas have been found in HIV-infected children, the incidence is low and cardiac malignancy is rare. Rates of congenital cardiovascular malformations range from 5.6 to 8.9% in cohorts of HIV-uninfected and HIV-infected children with HIV-infected mothers. In non-HIV-infected infants born to HIV-infected mothers, foetal exposure to ART is associated with reduced LV dimension, LV mass, and septal wall thickness and with higher LV fractional shortening and contractility during the first two years of life. CONCLUSIONS: Routine, systematic, and comprehensive cardiac evaluation, including a thorough history and directed laboratory assays, is essential for the care of HIV-infected adults and children as cardiovascular illness has become a part of care for long-term survivors of HIV infection. The history should include traditional risk factors for atherosclerosis, prior opportunistic infections, environmental exposures, and therapeutic and illicit drug use. Laboratory tests should include a lipid profile, fasting glucose, and HIV viral load. Asymptomatic cardiac disease related to HIV can be fatal, and secondary effects of HIV infection often disguise cardiac symptoms, so systematic echocardiographic monitoring is warranted.

Cardiac status of children infected with human immunodeficiency virus who are receiving long-term combination antiretroviral therapy: results from the Adolescent Master Protocol of the Multicenter Pediatric HIV/AIDS Cohort Study.

IMPORTANCE: Prior to contemporary antiretroviral therapies (ARTs), children infected with human immunodeficiency virus (HIV) were more likely to have heart failure. This study suggests that highly active ART (HAART) does not appear to impair heart function. OBJECTIVE: To determine the cardiac effects of prolonged exposure to HAART on HIV-infected children. DESIGN: In the National Institutes of Health-funded Pediatric HIV/AIDS Cohort Study's Adolescent Master Protocol (AMP), we used linear regression models to compare echocardiographic measures. SETTING: A total of 14 US pediatric HIV clinics. PARTICIPANTS: Perinatally HIV-infected children receiving HAART (n = 325), HIV-exposed but uninfected children (n = 189), and HIV-infected (mostly HAART-unexposed) historical pediatric controls from the National Institutes of Health-funded Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection (P2C2-HIV) Study (n = 70). EXPOSURE Long-term HAART. MAIN OUTCOMES AND MEASURES: Echocardiographic measures of left ventricular (LV) function and structure. RESULTS: The 325 AMP HIV-infected children had lower viral loads, higher CD4 counts, and longer durations of ART than did the 70 HIV-infected children from the P2C2-HIV Study (all P < .001). The z scores for LV fractional shortening (a measure of cardiac function) were significantly lower among HIV-infected children from the P2C2-HIV Study than among the AMP HIV-infected group or the 189 AMP HIV-exposed but uninfected controls (P < .05). For HIV-infected children, a lower nadir CD4 percentage and a higher current viral load were associated with significantly lower cardiac function (LV contractility and LV fractional shortening z scores; all P = .001) and an increased LV end-systolic dimension z score (all P < .03). In an interaction analysis by HIV-infected cohort, the HIV-infected children from the P2C2-HIV Study with a longer ART exposure or a lower nadir CD4 percentage had lower mean LV fractional shortening z scores, whereas the mean z scores were relatively constant among AMP HIV-infected children (P < .05 for all interactions). CONCLUSIONS AND RELEVANCE: Long-term HAART appears to be cardioprotective for HIV-infected children and adolescents.

Growth and body composition of uninfected children exposed to human immunodeficiency virus: comparison with a contemporary cohort and United States National Standards.

OBJECTIVE: To compare growth and body composition of uninfected children exposed to HIV with a contemporary HIV-unexposed group and to US references. STUDY DESIGN: Uninfected children exposed to HIV under 2 years were enrolled into a longitudinal observational study and unexposed children under 2 years of age in a cross-sectional evaluation. Weights, lengths, head circumferences, skinfold thicknesses, and arm and thigh circumferences were measured and adjusted for age using Centers for Disease Control and National Health and Nutrition Examination Survey standards. Uninfected children exposed to HIV were compared with an unexposed nearest-neighbor matched comparison group. Uninfected children exposed to HIV were compared by age to Centers for Disease Control standards for growth measures and National Health and Nutrition Examination Survey standards for body composition. RESULTS: One hundred eleven uninfected children exposed to HIV and 82 children not exposed to HIV were evaluated. For the matched comparison for both groups, the mean age was 10 months, 59% were male, and 73% were African American. No statistical differences were found in anthropometric measurements between uninfected children who were or were not exposed to HIV. Uninfected children exposed to HIV were smaller than US standards at birth with mean (SD) weight-for-age and weight-for-length z-scores of -0.39 (1.06); P = .002 and -0.35 (1.04); P = .005, respectively. Over the first 2 years of life, there was a trend toward increasing weight-for-age z-score, length-for-age z-score, and weight-for-length z-score in uninfected children exposed to HIV. Subscapular and triceps skinfolds among uninfected children exposed to HIV were lower than national standards and there was a trend that mid-upper arm circumference decreased over time. CONCLUSIONS: Growth and body composition of uninfected children who were or were not exposed to HIV were similar. Uninfected children exposed to HIV weigh less at birth and show a pattern of slightly accelerated growth in the first 2 years of life. Uninfected children exposed to HIV had less subcutaneous fat and decreasing mid-upper arm circumference over time when compared with US standards.

Physical fitness in children infected with the human immunodeficiency virus: associations with highly active antiretroviral therapy.

Obesity, sedentary lifestyles, and antiretroviral therapies may predispose HIV-infected children to poor physical fitness. Estimated peak oxygen consumption (VO(2) peak), maximal strength and endurance, and flexibility were measured in HIV-infected and uninfected children. Among HIV-infected children, anthropometric and HIV disease-specific factors were evaluated to determine their association with VO(2) peak. Forty-five HIV-infected children (mean age 16.1 years) and 36 uninfected children (mean age 13.5 years) participated in the study. In HIV-infected subjects, median viral load was 980 copies/ml (IQR 200-11,000 copies/ml), CD4% was 28% (IQR 15-35%), and 82% were on highly active antiretroviral therapy (HAART). Compared to uninfected children, after adjusting for age, sex, race, body fat, and siblingship, HIV-infected children had lower VO(2) peak (25.92 vs. 30.90 ml/kg/min, p<0.0001), flexibility (23.71% vs. 46.09%, p=0.0003), and lower-extremity strength-to-weight ratio (0.79 vs. 1.10 kg lifted/kg of body weight, p=0.002). Among the HIV-infected children, a multivariable analysis adjusting for age, sex, race, percent body fat, and viral load showed VO(2) peak was 0.30 ml/kg/min lower per unit increase in percent body fat (p<0.0001) and VO(2) peak (SE) decreased 29.45 (± 1 .62), 28.70 (± 1.87), and 24.09 (± 0.75) ml/kg/min across HAART exposure categories of no exposure, <60, and ≥ 60 months, respectively (p<0.0001). HIV-infected children had, in general, lower measures of fitness compared to uninfected children. Factors negatively associated with VO(2) peak in HIV-infected children include higher body fat and duration of HAART ≥ 60 months. Future studies that elucidate the understanding of these differences and mechanisms of decreased physical fitness should be pursued.

Cardiac biomarkers in HIV-exposed uninfected children.

OBJECTIVES: To evaluate associations of cardiac biomarkers with in-utero antiretroviral drug exposures and cardiac function/structure measured by echocardiograms in HIV-exposed but uninfected (HEU) children. DESIGN AND METHODS: We analyzed the association of three cardiac biomarkers (cardiac troponin T, cTnT; high sensitivity C-reactive protein, hsCRP; and N-terminal pro-brain natriuretic peptide, NT-proBNP) with prenatal antiretroviral drug exposures, maternal-child characteristics, and echocardiographic parameters. RESULTS: Among 338 HEU children (mean age 4.3 years), 51% had at least one elevated cardiac biomarker. Maternal tobacco use was associated with elevated NT-proBNP [adjusted odds ratio (aOR) 2.28, P=0.02]. Maternal alcohol and abacavir use were associated with elevated cTnT levels (aOR 3.56, P=0.01 and aOR 2.33, P=0.04, respectively). Among 94 children with paired echocardiogram-biomarker measurements, cTnT measurements were correlated with increased left-ventricular thickness-to-dimension ratio (r=0.21, P=0.04); and elevated cTnT was associated with higher mean left-ventricular end-diastolic (LVED) posterior wall thickness (P=0.04). hsCRP measurements were negatively correlated with septal thickness (r=-0.22, P=0.03) and elevated hsCRP was associated with lower mean left-ventricular contractility Z-scores (P=0.04). NT-proBNP measurements were correlated with increased LVED dimension (r=0.20, P=0.05) and elevated NT-proBNP was associated with lower mean end-systolic septal thickness (P=0.03). CONCLUSION: Our findings suggest that cardiac biomarkers may help identify HEU children who require further cardiac evaluation including echocardiography. Potential cardiac effects of prenatal abacavir exposure in this population need further investigation.

Tenofovir treatment duration predicts proteinuria in a multiethnic United States Cohort of children and adolescents with perinatal HIV-1 infection.

BACKGROUND: Tenofovir is associated with renal proximal tubule injury. Such toxicity has not been extensively studied in HIV-1-infected children, in whom tenofovir is increasingly used. METHODS: History, urine and blood were collected at regular intervals from 448 children and adolescents with perinatal HIV-1 infection followed in the Pediatric HIV/AIDS Cohort study. Relationships between tenofovir use and proteinuria and chronic kidney disease (CKD) outcomes were examined using multivariable logistic regression models. Proteinuria was defined as at least one urine protein/creatinine ratio (uPCR) ≥ 0.2, and CKD as ≥ 2 sequential uPCR ≥ 0.2 or estimated glomerular filtration rates <60 mL/min/1.73 m with no subsequent resolution, or a clinical diagnosis not contradicted by a normal uPCR. Subjects with ≥ 2 uPCR <0.2, and no abnormal uPCR and eGFR comprised the comparison group. RESULTS: Subjects were 47% male, 72% black, 24% Hispanic, with entry mean age (± standard deviation) of 11.5 ± 2.5 years. Proteinuria prevalence at entry, and annually during 3 years, ranged from 10.3% to 13.7%. The cumulative prevalence of proteinuria was 22% (94/434, 95% confidence interval: 18%-26%) and CKD 4.5% (20/448, 95% confidence interval: 2.7%-6.8%). Duration of tenofovir use was an independent predictor of proteinuria, with >3 years of exposure having the highest risk compared with no exposure (odds ratio: 2.53, 95% confidence interval: 1.23-5.22, overall P = 0.01). Overall, duration of tenofovir use did not significantly predict the presence of CKD. CONCLUSIONS: Rates of proteinuria and CKD were lower than those seen in the pre-highly active antiretroviral therapy era. However, prolonged exposure to tenofovir increases risk of renal injury.

Has highly active antiretroviral therapy increased the time to seroreversion in HIV exposed but uninfected children?

BACKGROUND: Since the introduction of highly active antiretroviral therapy (HAART) for prevention of mother-to-child transmission of human immunodeficiency virus (HIV) in pregnancy in the United States, the time of seroreversion in infants born to HIV-infected mothers has not been documented. The objective of this study was to determine the timing of clearance of HIV antibodies and to identify any associated biological and clinical factors. METHODS: A retrospective analysis of infants who remained uninfected after perinatal HIV exposure was performed. Infant and maternal medical records from January 2000 to December 2007 were reviewed and the time of seroreversion was estimated using methods for censored survival data. RESULTS: In total, 744 infants were included in the study, with prenatal data available for 551 mothers. The median age of seroreversion was 13.9 months, and 14% of infants remained seropositive after 18 months, 4.3% after 21 months, and 1.2% after 24 months. Earlier age of seroreversion was associated with higher immunoglobulin G (IgG) levels at 3-7 months of age (P = .0029) and a higher rate of IgG change over the next 6 months of life (P = .003). Infants born by vaginal delivery were more likely to serorevert at a younger age (P = .0052), and maternal exposure to protease inhibitors was associated with a later age of seroreversion (P = .026). CONCLUSIONS: Clearance of HIV antibodies in uninfected infants was found to occur at a later age than has been previously reported. Fourteen percent of the infants had persistence of HIV antibodies at or beyond 18 months of age.