See “Body Mass Index and Waist Circumference of HIV-Infected Youth in a Miami Cohort: Comparison to Local and National Cohorts” by Miller et al on page 449.
For the past 20 years, we have been steadily reducing the number of infants acquiring human immunodeficiency virus (HIV) each year in this country; in 2009 there were <10,000 HIV-infected children <13 years of age in the United States who acquired the infection perinatally (1). It took much longer, but we are finally making great strides in prevention globally. Nevertheless, in 2012, approximately 260,000 infants worldwide acquired HIV and 3.3 million children <13 years old live with the disease (2). The number of HIV-infected adolescents who are long-term survivors of perinatally acquired infection is actually increasing (1), as mortality decreases and HIV becomes a chronic disease for children given access to effective combination antiretroviral (ARV) treatment.
Before effective ARV medication, children with HIV often experienced marked stunting and/or wasting. As ARV “cocktails” became available for children in the late 1990s, clinical improvement in growth and development was often dramatic. Despite improvements, normalization of growth and body composition has remained elusive for HIV-positive children (3,4). The report in this issue of the Journal of Pediatric Gastroenterology and Nutrition by Miller et al (5) newly examines this question, comparing weight, height, body mass index (BMI), and waist circumference (WC) in HIV-infected youth 10 to 19 years of age in the United States to both matched controls locally and from the National Health and Nutrition Examination Survey (NHANES). The study population varied widely in degree of viral and immune suppression, as well as length and type of treatment. Local controls were approximately 2 years younger on average and had a slightly different race–ethnicity composition. Hence, z scores for height-, weight-, and BMI-for-age were adjusted for race and biologic relatedness, and WC was additionally adjusted for age and sex because WC z scores are not available. Height-for-age z score (H-A-Z) was significantly lower (−0.51) in the infected youth and weight-for-age z score (W-A-Z) was similarly different (−0.41), even though not statistically significant. Comparison of the infected cohort with NHANES controls revealed an even greater difference of 0.67 H-A-Z and 0.86 W-A-Z, both lower in the infected children and both highly significant; BMI-for-age z score (BMI-A-Z) was not different. A third comparison was made limited to the African American subset of the study group and NHANES, whereby there was a similar difference in H-A-Z as with the previous NHANES comparison, with an even larger difference in W-A-Z (1.08), resulting in a significantly lower BMI-A-Z (0.27) in the infected youth. Adjusted WC was not different in any of the comparisons.
The authors conclude that the similar WC and BMI between the study population and the multiethnic NHANES sample suggest comparable rates of “adiposity,” despite lower weight and height in the HIV-infected study population. Regardless of similar adiposity in the group as a whole, the African American youth in the study had a lower BMI-A-Z than their counterparts from NHANES. Hence, in this subset more prone to overweight and obesity, body composition may be affected in addition to weight and height. An unfortunate limitation to the study is that the authors could not control for pubertal development given a lack of Tanner stage data in the comparison group and in NHANES. HIV infection is associated with delayed onset of puberty (6); pubertal delay and concomitant delay in skeletal maturity could certainly contribute to the statural differences detected.
The finding that these HIV-positive youth without significant immunosuppression (median CD4 cell count >535 cells per cubic millimeter) and with low viral load (median 760 copies per milliliter) have lesser height-for-age than uninfected counterparts is consistent with multiple previous reports. Treatment improves—but does not normalize—growth. The “news” here is that this is true despite long-term treatment, because these children were perinatally infected and had a median of >9 years on highly active ARV therapy. Even early initiation of therapy has not been shown to normalize growth—it is associated with more rapid, but not more complete, growth recovery (7).
We note that there may be more “news” in the Miller et al study upon which the authors did not comment. The fact that WC is preserved in the HIV-infected youth, despite lesser height, suggests the mean waist-to-height ratio would be greater in infected children compared with controls, although it was not a reported measure. Furthermore, in the comparison of HIV-infected African American youth with their NHANES counterparts, the BMI-for-age z score was lower, but adjusted WC was not different, similarly suggesting greater central adiposity in the infected youth.
Waist-to-height ratio has been reported to better predict cardiovascular risk factors in diverse populations than BMI. For example, waist-to-height ratio better predicts hypertension in Mexican children (8) and is more closely associated with severity of cardiovascular disease in adults (9).
We note several themes with growth in HIV-infected children. The first is that despite vast treatment advances, these perinatally infected youth still have substantially impaired growth and likely increased central adiposity. Although the latter was incompletely examined in the study by Miller et al, the contribution to cardiovascular risk profile in these children with lifelong infection is concerning and needs delineation. The second theme is growth hormone (GH) dysregulation. Although the etiology of impaired growth in childhood HIV infection is incompletely understood (and surely multifactorial in many cases), GH resistance as evidenced by blunted insulin-like growth factor 1 and insulin-like growth factor–binding protein-3 responses to exogenous GH appears to contribute (10). Mechanistically, elevated insulin-like growth factor–binding protein-1 occurs in catabolic states and renders insulin-like growth factor 1 unavailable to binding sites, contributing to GH insensitivity. Moreover, there is evidence of treatment-associated decreases in GH resistance (11). Furthermore, GH changes, specifically decreased secretion, are also implicated in increased visceral fat and dyslipidemias in patients with HIV and there is a corresponding decrease in visceral adiposity upon treatment with GH or a GH-releasing hormone analogue (12). Perhaps the altered growth and body composition are more related than first appears. The final theme is how little we understand about the complex interactions among the virus, the immune system, ARV medications, and the endocrine system, which manifest as impaired growth—the hallmark of chronic disease—in the millions of affected children.
We commend the authors for contributing to this growing, although still incomplete, body of work and for their commitment to examining anthropometric differences among particular ethnic groups. Further longitudinal studies assessing growth disturbances and altered body composition in HIV-infected children are clearly indicated—particularly in light of mounting evidence of relations to cardiovascular risk.
1. National Center for HIV/AIDS, Viral Hepatitis, STI and TB Prevention. Division of HIV/AIDS Prevention. Center for Disease Control and Prevention. HIV among pregnant women, infants and children in the United States. http://www.cdc.gov/hiv/pdf/risk_WIC.pdf
. Published December 2012. Accessed May 17, 2014.
2. Joint United Nations Programme on HIV/AIDS (UNAIDS). Global report. UNAIDS report on the global AIDS epidemic. http:/www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2013/gr2013/UNAIDS_Global_Report_2013_en.pdf
. Published 2013. Accessed May 17, 2014.
3. Aldrovandi GM, Lindsey JC, Jacobson DL, et al. Morphologic and metabolic abnormalities in vertically HIV-infected children and youth. AIDS
4. Nachman SA, Lindsey JC, Moye J, et al. Growth of human immunodeficiency virus-infected children receiving highly active antiretroviral therapy. Pediatr Infect Dis J
5. Arbeitman LE, O’Brien RC, Somarriba G, et al. Body mass index and waist circumference of HIV-infected youth in a Miami cohort: comparison to local and national cohorts. J Pediatr Gastroenterol Nutr
6. Williams PL, Abzug MJ, Jacobson DL, et al. Pubertal onset in children with perinatal HIV infection in the era of combination antiretroviral treatment. AIDS
7. Shiau S, Arpadi S, Strehlau R, et al. Initiation of antiretroviral therapy before 6 months of age is associated with faster growth recovery in South African children perinatally infected with human immunodeficiency virus. J Pediatr
8. Villalpando S, Rangel-Baltazar E. Waist-to-height ratio as a predictor of blood pressure in Mexican children. Follow-up study. Rev Invest Clin
9. Sabah KM, Chowdhury AW, Khan HI, et al. Body mass index and waist/height ratio for prediction of severity of coronary artery disease. BMC Res Notes
10. Rondanelli M, Caselli D, Arico M, et al. Insulin-like growth factor I (IGF-I) and IGF-binding protein 3 response to growth hormone is impaired in HIV-infected children. AIDS Res Hum Retroviruses
11. Van Rossum AM, Gaakeer MI, Verweel S, et al. Endocrinologic and immunologic factors associated with recovery of growth in children with human immunodeficiency virus type 1 infection treated with protease inhibitors. Pediatr Infect Dis J
12. Stanley TL, Grinspoon SK. GH/GHRH axis in HIV lipodystrophy. Pituitary