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OBJECTIVES: To compare distributions of serum cardiac and inflammatory biomarkers between perinatally HIV-infected (PHIV) and perinatally HIV-exposed uninfected (PHEU) children, to evaluate their associations with echocardiographic measures, and among PHIV youth, with antiretroviral therapy (ART) and HIV disease severity measures. DESIGN: Cross-sectional analysis of temporally-paired serum samples for biomarkers and echocardiograms in a prospective cohort study of PHIV and PHEU youth at 14 US pediatric HIV clinics. METHODS: Serum samples were analyzed among 402 youth in the PHACS Adolescent Master Protocol (AMP) for high-sensitivity cardiac troponin-T (hs-cTnT, a cardiomyocyte injury marker), NT-pro-brain natriuretic peptide (NT-proBNP, a myocardial stress marker), and inflammatory markers (high-sensitivity C-reactive protein, interleukin [IL]-1, IL-6, IL-8, IL-10, IL-18, tumor necrosis factor-α[TNF-α], and soluble TNF receptor II [sTNF-RII]). Echocardiograms were centrally measured and parameters converted to Z-scores to account for differences in age and body size. RESULTS: Compared to PHEU (N=156), PHIV youth (N=246) more often had detectable hs-cTnT and higher levels of sTNF-RII and IL-18. Higher inflammatory biomarkers were generally associated with higher left ventricular (LV) wall stress and lower LV function and LV mass in the two groups. Among PHIV youth, the biomarkers were more strongly associated with current rather than historical immunologic and virologic status. CONCLUSIONS: PHEU and PHIV have modest, significant differences in serum levels of specific inflammatory and active myocardial injury biomarkers. Higher biomarker levels were associated with lower LV mass and shifts in LV structure. Further study is warranted on the longitudinal role of cardiac and inflammatory biomarkers for targeting interventions among PHIV and PHEU youth.

The benefits of early combination antiretroviral therapy (cART) in HIV-infected children are well described and include improvement in virologic and immunologic parameters and reductions in mortality, hospital admissions and comorbidities such as HIV encephalopathy and cardiomyopathy [1–6]. The WHO recommends initiation of cART in all HIV-infected children under 5 years of age [1,7]. However, sustaining the benefits of early treatment requires lifelong adherence to cART, which is hampered by dependence on caregivers for cART administration, poor palatability of drugs, pill burden and frequency of administration, drug toxicities and developmental changes, especially during adolescence [8–10]. Globally, excellent virologic suppression rates in children receiving cART have been described with over 80% viral suppression at 36-month follow-up [11,12]. However, 30–40% of children develop virologic failure over time [13]. In children who develop virologic failure, switching to a new cART regimen on the basis of viral drug resistance testing can lead to virologic suppression. Success of this approach relies on overcoming adherence barriers and on the availability of potent drugs to construct a new cART regimen to which the child's virus is susceptible. In resourced settings, highly treatment-experienced children with prior exposure to numerous antiretroviral drugs are presented with the challenges of multiresistant HIV and lack of active drugs [14]. In resource-limited settings, in which financial and structural constraints limit access to new drugs, it is often difficult to access potent new cART regimens for children with virologic failure on first-line therapy. As more children access cART globally, challenges around optimal management of virologic failure are likely to intensify. Treatment options explored by various studies include optimizing therapy with a new CART regimen [15]; continuing with a failing regimen [16]; switching to a simplified, non-cART drug-sparing regimen [17]; and treatment interruption [18]. No studies to date have directly compared immunological and virologic outcomes with these treatment options in children with virologic failure. We used observational data from two large US-based prospective cohorts of perinatally infected children and adolescents (PHIV) to address this question. Among PHIV with virologic failure after at least 6 months of cART, we compared immunological and virologic outcomes 12 months after virologic failure in children managed with the following treatment options: continue with current failing cART; switch to a new cART; switch to a non-cART, drug-sparing regimen and discontinue all ART.

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.

OBJECTIVE To evaluate associations of perinatal HIV infection, HIV disease severity, and combination antiretroviral treatment with age at pubertal onset. DESIGN Analysis of data from two US longitudinal cohort studies (IMPAACT 219C and PHACS AMP), conducted during 2000-2012, including perinatally HIV-infected (PHIV) and HIV-exposed but uninfected (HEU) youth. Tanner stage assessments of pubertal status (breast and pubic hair in girls; genitalia and pubic hair in boys) were conducted annually. METHODS We compared the timing of pubertal onset (Tanner stage ≥2) between PHIV and HEU youth using interval-censored models. For PHIV youth, we evaluated associations of HIV disease severity and combination antiretroviral treatment with age at pubertal onset, adjusting for race/ethnicity and birth cohort. RESULTS The mean age at pubertal onset was significantly later for the 2086 PHIV youth compared to the 453 HEU children (10.3 vs. 9.6, 10.5 vs. 10.0, 11.3 vs. 10.4, and 11.5 vs. 10.7 years according to female breast, female pubic hair, male genitalia, and male pubic hair staging, respectively, all P

To estimate prevalence of low bone mineral density (BMD) in perinatally HIV-infected (HIV+) and HIV-exposed but uninfected (HEU) children, and to determine predictors of BMD in HIV+.Cross-sectional analysis within a 15-site United States and Puerto Rico cohort study.Total body and lumbar spine BMD were measured using dual energy-X-ray absorptiometry. BMD Z-scores accounted for bone age and sex. Multiple linear regression was used to evaluate differences in Z-scores by HIV status and for predictors of BMD in HIV+.350 HIV+ and 160 HEU were enrolled. Mean age was 12.6 and 10.7 years for HIV+ and HEU, respectively. Most (87%) HIV+ were receiving HAART. More HIV+ than HEU had total body and lumbar spine Z-scores less than -2.0 (total body: 7 vs. 1%, P = 0.008; lumbar spine: 4 vs. 1%, P = 0.08). Average differences in Z-scores between HIV+ and HEU were attenuated after height and/or weight adjustment. Among HIV+, total body Z-scores were lower in those with higher CD4% and in those who ever used boosted protease inhibitors or lamivudine. Lumbar spine Z-scores were lower with higher peak viral load and CD4%, more years on HAART, and ever use of indinavir.Rates of low BMD in HIV+ children were greater than expected based on normal population distributions. These differences were partially explained by delays in growth. As most HIV+ children in this study had not entered their pubertal growth spurt, prepubertal factors associated with BMD, magnified or carried forward, may result in sub-optimal peak BMD in adulthood.

The objective was to determine the safety of the zidovudine (ZDV) regimen utilized in the Pediatric AIDS Clinical Trial Group (ACTG) 076 study. ACTG 076 was a randomized double-blind placebo-controlled trial which demonstrated that a ZDV regimen could prevent mother-to-child HIV-1 transmission. Infants were followed through 18 months of age and women were followed through 6 months postpartum. Maternal complications pregnancy outcomes growth and development of the uninfected infants and HIV-1 disease progression in the women were monitored prospectively. Maternal therapy was well tolerated. There was no serious pattern of adverse pregnancy outcomes associated with ZDV use. Amongst the ZDV-exposed infants the only recognized toxicity was anemia within the first 6 weeks of life; the risk for anemia was not associated with premature delivery duration of maternal treatment degree of maternal immunosuppression or maternal anemia. ZDV treatment was not associated with an increased incidence of newborn structural abnormalities. At 18 months of age uninfected infants did not differ in growth parameters or immune function. No childhood neoplasias were reported in either group. In the women at 6 months postpartum there were no differences in clinical immunologic or virologic disease progression. There were no identified problems that would alter current recommendations for the routine use of ZDV for the prevention of mother--child HIV-1 transmission. (authors)