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Session 126 - Complications of ART in exposed and infected HIV children
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Wednesday, February 28, 2007
Carl J. Fichtenbaum, M.D. University of Cincinnati College of Medicine
There were a few reports on metabolic issues in children including one in this session. Araneta and colleagues correlated adiponectin and leptin (two adipocyte hormones) with age. In this study, levels correlated best with age as opposed to type of antiretroviral therapy. Not surprisingly, the use of certain agents like d4T, known to cause adipocyte dysfunction, were correlated with lower levels of adiponectin. This was true for 3TC as well. Leptin levels were unaffected by antiretrovirals. These findings are similar to those observed in adults with HIV. Thus, when studying children, one must control for age and pubertal stage when measuring these metabolically important proteins. These findings have little impact on clinical care but may help shed light on the changes observed with HIV infection and antiretroviral usage. In a second abstract by Cote and colleagues (Abstract 714), the authors suggest that mitochondrial damage persists in antiretroviral-exposed HIV uninfected infants for at least 6 weeks or more. These findings may have some impact on growth and development though this is unknown. The real issue is balancing the benefit of prevention of HIV transmission from mother to child versus the potential consequences of mitochondrial damage from short-term exposure to growing infants. Currently, there are no known long-term consequences thus, we need to collect more data to reassure ourselves that use of antiretrovirals during pregnancy and for 6 weeks after birth do not have serious long-lasting effects.
713
Adiponectin, Leptin, and Antiretroviral Use in HIV-infected Children and Adolescents
Maria Rosario Araneta*1, T Ciaraldi1, R Henry1, and S Spector1
1Univ of California, San Diego, US
Background: Adiponectin and leptin are adipose-derived proteins with important roles in energy and glucose metabolism. Low adiponectin and high leptin concentrations are associated with obesity and HIV lipodystrophy. Although hypoadiponectinemia has been associated with use of some protease inhibitors (PI) and nucleoside reverse transcriptase inhibitors (NRTI), including ritonavir (RTV) and stavudine (d4T) among HIV-infected adults, no data are available in HIV-infected children and adolescents. Methods: Height, weight, and adiponectin and leptin (by radioimmunassay) were measured in 97 HIV-infected children and adolescents. Measures of glucose, cholesterol, triglycerides, hepatic enzymes, ART use, and Tanner stage were obtained from medical charts. Results: Mean age was 15.0 years (range 3 to 24 years), 34 (35%) were children <13 years of age, 50.5% were male, 52 (54%) were Latino, 22 (23%) were African American, 18 (19%) were Caucasian, and 5 (5%) were Asian. Mean body mass index was 21 kg/m2 (range 14 to 41 kg/m2); 23% were Tanner I and 56% were Tanner stage V; 70% used ART, including lamivudine (3TC) (41%), zidovudine (AZT) (28%), nelfinavir (NFV) (26%), 4dT (22%), efavirenz (EFV) (22%), lopinavir/ritonavir (LPV/r) (16%) and RTV (11%). Mean CD4 percentage was 28%, and 55% had viral loads <400 copies/mL. Mean adiponectin levels were 12.74 µg/mL (SD 6.3). In univariate analysis, adiponectin was inversely associated with body mass index, age, and pubertal status (p <0.001), and was marginally associated with female gender (p = 0.06) and alanine aminotransferase (ALT) (p = 0.056). Adiponectin was significantly lower among 4dT (10.63 vs 13.32 µg/mL, p = 0.049) and 3TC users (11.4 vs 13.7 µg/mL, p = 0.031), after adjusting for body mass index, Tanner stage, and sex, but did not differ by PI nor NNRTI use. Multivariable analysis showed that 4dT (_ coefficient: -4.02, p = 0.019) or 3TC use (_ coefficient: -2.47, p = 0.033) were independently associated with lower adiponectin concentration after adjusting for body mass index, sex, Tanner stage, ALT, and concomitant PI or NNRTI use. The mean leptin concentration was 6.37 ng/mL (SD 6.7). Leptin was associated with female sex, body mass index, age, and Tanner stage (p <0.02) in univariate analysis. However, multivariable regression showed body mass index (_ coefficient 0.87, p <0.0001) and female gender (_ coefficient 6.06, p <0.0001) were the only covariates associated with higher leptin levels. Conclusions: Hypoadiponectinemia was associated with d4T and 3TC use, while leptin concentration was not associated with ART use in this cohort of HIV-infected children and adolescents.
714
Mitochondrial DNA and mtRNA Levels during Perinatal ART Exposure in HIV-uninfected Infants Born to HIV-infected Mothers
Helene Cote*1, J Forbes2, A Bitnun3, J Raboud4, D Money1,2, D Money1,2, E Maan2, C Diong4, R Harrigan5, A Alimenti2, and S Read3
1Univ of British Columbia, Vancouver, Canada; 2BC Children and Women Hlth Ctr, Vancouver, Canada; 3Toronto Hosp for Sick Children, Canada; 4Univ of Toronto, Canada; and 5BC Ctr for Excellence in HIV/AIDS, Vancouver, Canada
Background: Nucleoside (NRTI) -containing ART can cause mitochondrial (mt) toxicity. We investigated blood mtDNA and mtRNA levels in HIV-uninfected ART exposed infants (born to HIV-infected women and exposed to HAART in utero and zidovudine (ZDV) for ~6 weeks after birth), and compared them to non-ART-exposed control infants born to HIV-uninfected women. Methods: A total of 75 ART-exposed and 80 control infants from 2 Canadian sites were studied. Blood was collected longitudinally from ART-exposed infants at 1 to 3 days and an additional 1 to 4 times until ~8 months of age. Control infants, aged 1 day to 8 months, had blood collected once. Blood mtDNA/nuclear DNA (nDNA) ratio was quantified in all samples (n = 316). Mt (cytochrome C oxidase I) mRNA/b-actin mRNA was measured in samples from 1 site (n = 197). Comparisons between ART-exposed and control infants were done on log transformed values, using generalized estimating equations modeling over 4 periods (1 to 3 days, 4 days to 6 weeks, 6 to 16 weeks, >16 weeks). Results: ART-exposed infants experienced neutropenia (28%), anemia (57%), and hyperlactatemia (89%). Although blood mtDNA levels were similar at birth (1 to 3 days, p = 0.06), they increased over time until 6 weeks (p <0.0001) in both groups. During the 4-day to 6-week period, mtDNA became significantly higher in ART-exposed infants than in controls (p = 0.0006) and remained so throughout the study period (6 to 16 weeks, p = 0.008; >16 weeks, p <0.0001). In contrast, mtRNA levels were lower in ART-exposed infants than controls at birth (1 to 3 days, p = 0.04). MtRNA increased in both groups over the 4-day to 6-week period (p = 0.009), but tended to remain lower in ART-exposed infants than in controls (4 days to 6 weeks, p = 0.08; >16 weeks, p = 0.07) except in the 6- to 16-week period (p = 0.99), likely due to low number of controls (n = 8) in that age group. Conclusions: In this observational study, mild laboratory abnormalities suggestive of mitochondrial toxicity were frequent in ART-exposed infants. The significantly greater increase in mtDNA levels during the first 6 weeks of life in the ART-exposed infants and the persistence of this elevation long after ZDV discontinuation, along with the concurrent decrease in mtRNA, suggest that significant changes in blood mitochondrial proliferation and gene expression take place during and after ART exposure. Although the relative influence of in utero vs postnatal ART exposure remains unclear, it is postulated that these changes are a consequence of the toxic effect(s) of the drugs on the cells and their mitochondria.The impact of these alterations on mitochondrial function and integrity, as well as their potential long-term implications, requires further study.
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