The percentage of PHIV youth with delay in pubertal onset was 4.1% overall, but showed substantial decreases over time (11.2, 3.1, 1.7, and 0.4% for those born before 1990, 1990–1992, 1993–1996, and 1997 or later, respectively; trend test P-value <0.001). In contrast, delay in pubertal onset was rare among HEU youth (2/453, 0.4%).
Association of HIV disease severity with age at pubertal onset
Mean ages at pubertal onset were significantly later for youth with more advanced HIV disease status at the first pubertal assessment (Table 3). For both girls and boys, there was a significant association of low CD4 (as reflected by CD4% <15% and CD4 cell count <200 cells/μl) and high viral load (>10 000 copies/ml) with later pubertal onset, both with and without adjustment for race/ethnicity and birth cohort, with the exception of female pubic hair (Table 3). Associations remained significant for most Tanner measures after further adjustment for BMI and height Z-scores (Supplemental Digital Content 2, http://links.lww.com/QAD/A340). Measures of past HIV disease severity showed stronger associations with timing of pubertal onset in boys than in girls. Boys with CDC class C (prior AIDS-defining condition), low nadir CD4%, or higher peak viral load had significantly later pubertal onset than those with milder classifications. Cumulative viral burden reflected by copy-years viremia was associated with significantly later age at pubertal onset in boys after adjustment for race/ethnicity and birth cohort, but not in girls. No association with peak viral load or CDC class was observed among girls.
Association of combination treatment and antiretroviral drug classes with age at pubertal onset
In unadjusted models, youth on combination treatment with a protease inhibitor at the first pubertal assessment had a significantly earlier mean age at pubertal onset (by 2.7–3.7 months) than did youth not on combination treatment, with the exception of male genitalia (Table 3). In contrast, there was no significant difference in age at onset for those on combination regimens without protease inhibitors as compared to those youth unexposed to combination regimens for any Tanner measure. Associations for combination treatment with protease inhibitor were nonsignificant in females and reversed direction in males when further adjusted for birth cohort. Examination of differences by birth cohort revealed that mean ages at pubertal onset were earlier for those exposed to combination treatment among those born since 1997 for all measures except male genitalia, but later for those exposed to combination treatment among those born prior to 1990 for all four staging measures (Fig. 2); however, statistical tests for interaction were not significant.
Duration of prior combination treatment, overall or with a protease inhibitor, at the time of the first pubertal assessment also showed significant associations with earlier age at pubertal onset based on all four staging measures in unadjusted analyses (Table 3). Mean ages at onset ranged from 0.6 to 1.2 months earlier for each additional year on combination treatment, depending on staging measure. However, after adjustment for race/ethnicity and birth cohort, there was no association of duration of combination treatment (overall or with protease inhibitor) in girls, and the direction of effect reversed for boys. Similar associations were observed for prior years of use of protease inhibitors and NNRTIs (Table 3). Further adjustment for BMI and height Z-scores and for HIV-disease status as reflected by CD4% below 15% had little effect on estimated mean ages of pubertal onset (Supplemental Digital Content 2, http://links.lww.com/QAD/A340).
We confirmed a significant delay in the mean age at pubertal onset for perinatally HIV-exposed children compared to uninfected but PHIV youth, ranging from a 6 to 8-month later mean age at onset in girls and a 10 to 11-month later onset in boys. The later average age at onset corresponded to an increased prevalence of delayed onset for PHIV vs. HEU youth, but clinical delay among youth born after 1997 was rare regardless of HIV status. The PHIV youth in our cohort were more often born in earlier years than the HEU youth, which is notable given the secular trends in timing of pubertal onset [1–5]; however, the later pubertal onset for PHIV youth persisted even after adjustment for race/ethnicity and birth cohort for all measures except pubic hair in girls. PHIV girls and boys with more advanced HIV disease were at greatest risk of delay in pubertal onset, and these associations persisted for most staging measures after adjustment for birth cohort. Boys had stronger associations with past measures of disease severity than did girls, which could be attributable to either poorer initial immunological status or increased sensitivity of hormonal pathways in boys.
Whereas both prior cART with protease inhibitors and longer duration of combination treatment appeared to be protective in restoring earlier timing of pubertal onset, these associations did not persist after adjustment for birth cohort. Descriptively, the mean age at pubertal onset was earlier for those on a combination regimen compared to those not on combination regimens born in 1997 or later, whereas the reverse was generally true for those born earlier. We did not observe a significant benefit of combination regimens in models adjusting for birth cohort, possibly due to confounding by indication resulting from only the sickest HIV-infected children receiving combination treatment in the earlier birth cohorts (33% of those in the pre1990 cohort), whereas combination treatment was widespread among HIV-infected youth in the later birth cohorts (88% among those born 1997 or later). Although there were no statistically significant interaction effects between combination treatment and birth cohort for any of the four staging measures, power for testing interaction may have been limited.
The mean ages at pubertal onset across the four staging measures and by race/ethnicity in our HEU youth from 219C and AMP were generally similar to other studies using NHANES III (1988–1994) data. Among PHIV youth, our estimated mean ages at onset are similar to those reported by Buchacz et al.  of 10.7 years for girls and 11.8 years for boys (their study population was 52% black non-Hispanic, 33% Hispanic), but substantially earlier than mean ages at onset of 12.1–12.9 years among Caucasian HIV-infected children in an Italian study reported by De Martino et al. .
The cause of delayed puberty in adolescents with HIV infection is not well understood. It has been ascribed to the general effects of chronic illness mediated through cytokine-induced inhibition of gonadotropin secretion [26,44,45]. It has also been suggested that HIV infection directly or indirectly affects production or secretion of hormones that regulate or control pubertal initiation and tempo (e.g. leptin produced in adipose tissue) . Delayed pubertal development in HIV-infected children has been attributed in part to reduced adrenal androgen secretion [11,23].
Implications of altered pubertal timing in the general population have received more attention for early maturation, which has been associated with increased incidence of antisocial behaviors and substance use. A general trend of earlier pubertal onset is thus not necessarily desirable, given the potential adverse social and clinical consequences of early puberty noted in the literature . However, whereas youth in many developed countries are attaining pubertal onset earlier than in previous decades, those with perinatally acquired HIV still tend to have later onset than US norms based on NHANES. Later maturation may also be associated with risk for psychosocial problems, including lower self-esteem and depression, and may have implications for reproductive health [15,46]. Thus, the implications of our study findings in perinatally infected youth focus at the other end of the spectrum, in the benefits of reducing the risk for delayed pubertal onset along with associated psychosocial and reproductive consequences. Finally, our study findings may have particular relevance for low-resource settings such as sub-Saharan Africa, where rates of vertical HIV transmission remain relatively high and thus the population of youth with perinatally acquired HIV remains large . Despite wider availability and earlier initiation of antiretroviral treatment in South Africa and other African countries over the past decade, it has been documented that the majority of children still have severe immunodeficiency before starting treatment, increasing the risk of delayed pubertal onset . Similar studies are warranted to evaluate the impact of early antiretroviral treatment initiation on pubertal onset and maturation in low-resource settings.
We recognize several limitations in our analysis. Our cohort of HEU youth was relatively small and included few white non-Hispanic youth and no uninfected youth born before 1990. Like all studies utilizing Tanner staging measures, there is potential for misclassification, particularly for breast staging, which may be confounded by increased body fat deposition [1,40]. Although orchidometers were not used in 219C, they were used in AMP and may provide better accuracy in future evaluations of pubertal progression and sexual maturation. We lacked information on birth weight or other early life exposures because our cohorts were not followed from birth. As an observational study, our analysis was subject to confounding by indication, particularly for evaluating the association of combination treatment with pubertal onset for the earlier birth cohorts; lack of information for most participants on viral load or CD4 prior to combination treatment initiation precluded our ability to evaluate and adjust for such confounding.
Despite these limitations, this is the largest study to date evaluating the timing of pubertal onset, with more than 2000 PHIV youth. We found that pubertal onset occurs significantly later in HIV-infected than in uninfected youth, with the greatest delays among those with more advanced HIV disease. Importantly, combination treatment may result in more normal timing of pubertal onset, as suggested for youth born since 1997 who were receiving protease inhibitor-containing combination regimens. Further evaluation of pubertal onset and sexual maturation in the current era of widespread treatment with combination treatment will be needed to fully understand the impact of antiretroviral treatment on sexual development of youth with HIV infection.
Contributions: P.L.W. and M.E.G. were the primary authors who conceived and designed the study. P.L.W. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. P.L.W. was responsible for conducting all statistical analyses, and led the writing of the manuscript. J.M.O., R.V.D., P.L.W., M.J.A., R.H., and G.R.S. provided leadership and oversight of the IMPAACT 219C study; R.V.D., G.R.S., P.L.W., R.H., D.L.J., K.P., and M.E.G. provided leadership and oversight of the PHACS AMP study. All authors provided input on the study design, interpretation of analyses, and revisions to manuscript. All authors state that they have no conflicts of interest related to this manuscript.
We thank the children and families for their participation in PHACS AMP and PACTG 219C, and the individuals and institutions involved in the conduct of these studies.
The following institutions, clinical site investigators and staff participated in conducting PHACS AMP in 2011 in alphabetical order: Baylor College of Medicine: William Shearer, Mary Paul, Norma Cooper, Lynette Harris; Bronx Lebanon Hospital Center: Murli Purswani, Mahboobullah Baig, Anna Cintron; Children's Diagnostic & Treatment Center: Ana Puga, Sandra Navarro, Doyle Patton, Deyana Leon; Children's Hospital, Boston: Sandra Burchett, Nancy Karthas, Betsy Kammerer; Ann & Robert H. Lurie Children's Hospital of Chicago: Ram Yogev, Margaret Ann Sanders, Kathleen Malee, Scott Hunter; Jacobi Medical Center: Andrew Wiznia, Marlene Burey, Molly Nozyce; St. Christopher's Hospital for Children: Janet Chen, Latreca Ivey, Maria Garcia Bulkley, Mitzie Grant; St. Jude Children's Research Hospital: Katherine Knapp, Kim Allison, Megan Wilkins; San Juan Hospital/Department of Pediatrics: Midnela Acevedo-Flores, Heida Rios, Vivian Olivera; Tulane University Health Sciences Center: Margarita Silio, Medea Jones, Patricia Sirois; University of California, San Diego: Stephen Spector, Kim Norris, Sharon Nichols; University of Colorado Denver Health Sciences Center: Elizabeth McFarland, Emily Barr, Robin McEvoy; University of Medicine and Dentistry of New Jersey: Arry Dieudonne, Linda Bettica, Susan Adubato; University of Miami: Gwendolyn Scott, Patricia Bryan, Elizabeth Willen.
The following institutions participated in PACTG 219/219C, in alphabetical order: Baystate Medical Center; Boston Medical Center; Bronx-Lebanon Hospital Center; Children's Diagnostic and Treatment Center of South Florida; Children's Hospital at Albany Medical Center; Children's Hospital Boston; Children's Hospital of Columbus, Ohio; Children's Hospital of the King's Daughters; Children's Hospital of Los Angeles; Children's Hospital of Michigan; Children's Hospital of Philadelphia; Children's Hospital & Research Center Oakland; Children's Hospital, Washington, DC; Children's Medical Center of Dallas; Children's Memorial Hospital University of Chicago; Columbia University Medical Center; Columbus Medical Center; Connecticut Children's Medical Center; Cook County Hospital; Cornell University; Duke University School of Medicine; Emory University Hospital; Harbor - UCLA Medical Center; Harlem Hospital Center; Howard University Hospital; Incarnation Children's Center; Jacobi Medical Center; Johns Hopkins University Hospital; LA County/University of Southern California Medical Center; Lincoln Medical & Mental Health Center; Long Beach Memorial Medical Center; Medical College of Georgia School of Medicine; Medical College of Virginia; Medical University of South Carolina; Metropolitan Hospital Center; Montefiore Medical Center - Albert Einstein College of Medicine; Mt. Sinai Hospital Medical Center; New York University Medical Center/Bellevue Hospital; North Shore University Hospital; Oregon Health Sciences University; Palm Beach County Health Department; Phoenix Children's Hospital; Ramon Ruiz Arnau University Hospital; Robert Wood Johnson University Hospital; Sacred Heart Children's Hospital/CMS of Florida; San Francisco General Hospital; San Juan City Hospital; Schneider Children's Hospital; Seattle Children's Hospital & Medical Center; St. Christopher's Hospital for Children; St. Josephs Hospital and Medical Center; St. Jude Children's Research Hospital; St. Luke's-Roosevelt Hospital Center; SUNY at Stony Brook School of Medicine; SUNY Downstate Medical Center; SUNY Upstate Medical University; Texas Children's Hospital (Baylor); Tulane University Health Sciences Center; University of Alabama at Birmingham School of Medicine; University of California Los Angeles Medical Center; University of California San Diego; University of California San Francisco Medical Center; University of Cincinnati; University of Colorado at Denver and Health Sciences; University of Florida College of Medicine; University of Florida Health Science Center Jacksonville; University of Illinois at Chicago; University of Maryland Medical Center; University of Massachusetts Memorial Children's Medical School; University of Medicine and Dentistry of New Jersey; University of Miami Miller School of Medicine; University of Mississippi Medical Center; University of North Carolina at Chapel Hill School of Medicine; University of Puerto Rico; University of Rochester Medical Center; University of South Alabama College of Medicine; University of South Florida; Vanderbilt University Medical Center; Washington University, St. Louis Children's Hospital; Yale University School of Medicine.
Conflicts of interest
Funding: Support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (U01 AI068632) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contract N01-3-3345 and HHSN267200800001C). This work was also supported by the Statistical and Data Analysis Center at Harvard School of Public Health, under the National Institute of Allergy and Infectious Diseases cooperative agreement #5 U01 AI41110 with the Pediatric AIDS Clinical Trials Group (PACTG) and #1 U01 AI068616 with the IMPAACT Group. The Pediatric HIV/AIDS Cohort Study (PHACS) was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with co-funding from the National Institute of Allergy and Infectious Diseases, the National Institute on Drug Abuse, the National Institute of Mental Health, the National Institute of Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, the National Institute of Neurological Disorders and Stroke, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard University School of Public Health (U01 HD052102-04) and the Tulane University School of Medicine (U01 HD052104-01). Data management services were provided by Frontier Science and Technology Research Foundation, and regulatory services and logistical support were provided by Westat, Inc. NIH representatives were part of the study team and therefore the sponsor was involved in study design, coordination, data collection, data analysis, data interpretation, and writing of the report. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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