Pubertal Onset in Children With Perinatal HIV Infection in the Era of Combination Antiretroviral Treatment

Paige L. Williams; Mark J. Abzug; Denise L. Jacobson; Jiajia Wang; Russell B. Van Dyke; Rohan Hazra; Kunjal Patel; Linda A. Dimeglio; Elizabeth J. Mcfarland; Margarita Silio; William Borkowsky; George R. Seage III; James M. Oleske; Mitchell E. Geffner


AIDS. 2013;27(12):1959–1970 

In This Article

Abstract and Introduction


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 < 0.001). PHIV youth with HIV-1 RNA viral load above 10 000 copies/ml (vs. ≤10 000 copies/ml) or CD4% below 15% (vs. ≥15%) had significantly later pubertal onset (by 4–13 months). Each additional year of combination antiretroviral treatment was associated with a 0.6–1.2-month earlier mean age at pubertal onset, but this trend did not persist after adjustment for birth cohort.

Conclusion: Pubertal onset occurs significantly later in PHIV than in HEU youth, especially among those with more severe HIV disease. However, in the current era, combination antiretroviral treatment may result in more normal timing of pubertal onset.


Puberty is a complex biological process involving physical and hormonal changes in which the body transitions to sexual maturity. Epidemiological studies have established a trend over the past two decades toward earlier pubertal onset, particularly in girls.[1–5] These changes have occurred against a backdrop of increasing prevalence of childhood obesity in parallel with changing dietary patterns and declining physical activity.[6] In addition, environmental exposures may play a role in trends of earlier pubertal onset.[1,7]

Perinatally HIV-infected (PHIV) youth have historically demonstrated decreased growth[8,9] and delays in pubertal onset, particularly among those with more advanced HIV disease.[10–16] Metabolic and endocrine abnormalities in PHIV youth may also play a role in deficient growth and delayed pubertal onset.[17–24] Combination antiretroviral treatment (cART) has been associated with improvement in growth[25–28] which could reduce the risk for pubertal delay. However, few studies have addressed the effect of combination treatment on pubertal onset. Buchacz et al. observed significantly earlier pubertal onset among boys with prior protease inhibitor use, but no clear association with protease inhibitor use among girls.[14] This study was conducted prior to 2000, at a time when mono-agent or dual-agent therapy as a standard of care was transitioning to more effective combination regimens, including the use of protease inhibitors. Two recent studies observed later pubertal onset among HIV-infected youth with lower CD4+ cells, but neither addressed the association with antiretroviral regimens.[16,29]

We used data collected from two US-based longitudinal cohort studies, the International Maternal Pediatric and Adolescent Clinical Trials (IMPAACT) 219/219C study (219C) and the Adolescent Master Protocol (AMP) study of the Pediatric HIV/AIDS Cohort Study (PHACS) network, to compare the timing of pubertal onset among PHIV children to that of perinatally HIV-exposed but uninfected (HEU) children. In addition, we evaluated the association of HIV disease severity and antiretroviral treatment with pubertal onset in children with perinatal HIV infection.