There were no participants using statins before study eligibility. Only 21 (5.5%) subjects received glucocorticoids (all but one received systemically), which included hydrocortisone, dexamethasone, budesonide, prednisone, or prednisolone (data not shown). Also, there were few reports on or before eligibility of diagnoses of obesity (2.1%) or lipodystrophy (fat accumulation, 1%; fat loss, 2.9%), and there were no reports of type II diabetes.
The mean (±SD) fasting glucose and insulin levels at baseline were 78.4 (±8.9) mg/dL and 4.2 (±4.3) mU/I, respectively. Mean (±SD) HOMA-IR at baseline was 0.84 (±1.04). The mean (±SD) total, HDL and LDL cholesterol levels, and TG levels at baseline were 162.0 (±35.2), 44.4 (±13.9), 96.1 (±30.2), and 106.9 (±55.3) mg/dL, respectively.
Table 3 summarizes the prevalence and the cumulative incidence of lipid, fasting glucose, and HOMA-IR abnormalities during study follow-up. A total of 58 (18.1%; 95% CI: 14.1% to 22.8%) of 320 children developed hypercholesterolemia after baseline. The cumulative incidence of abnormal HDL and LDL was 19.6% (95% CI: 15.1 to 24.7) and 15.0% (95% CI: 11.3 to 19.5), respectively. A total of 103 children developed hypertriglyceridemia after baseline, corresponding to a cumulative incidence of 44.2% (95% CI: 37.7–50.8). The cumulative incidence of insulin resistance was 3.8% (95% CI: 1.8 to 7.1). Although there were 2 subjects with diabetes at baseline (glucose ≥126 mg/dL), there were no incident cases; per WHO definition (glucose 110–125 mg/dL), there were 2 incident cases of impaired fasting glucose, although there were none at baseline. Applying the CDC definition for impaired glucose instead (glucose 100–125 mg/dL), there were 2 cases at baseline and 6 incident cases. Among incident cases with a subsequent laboratory measure available, the persistence of dyslipidemia at a subsequent laboratory measure was as follows: 61.1% for hypercholesterolemia, 46.7% for abnormal HDL, 52.4% for abnormal LDL, and 57.5% for hypertriglyceridemia (data not shown).
Table 4 shows the results of the Cox proportional hazards regression models examining ART use, adjusted for age, gender, country, and HIV RNA. The model for abnormal HDL is also adjusted for CD4 percent.
ART regimen was not associated with the development of hypercholesterolemia; the P-values for the comparisons of PI-containing and non–PI-containing regimens with no ART were 0.46 and 0.52, respectively. The risk of developing an abnormal total cholesterol was significantly lower among those with HIV RNA ≥400 copies per milliliter than those with RNA below this cutpoint [hazard ratio (HR) = 0.4, 95% CI: 0.2 to 0.9; P = 0.0178)]. The risk of experiencing an abnormal total cholesterol level was not associated with subject's age, gender, or country of origin (P > 0.07).
Abnormal HDL Cholesterol
The risk of developing abnormal HDL cholesterol was not associated with type of ART regimen, age, gender, country, or HIV RNA (P > 0.1). However, the risk of developing an abnormal HDL cholesterol was significantly higher among those with CD4 percent ≤25% compared with those with CD4 percent above 25% (HR = 2.5, 95% CI: 1.2 to 5.0; P = 0.0128).
Abnormal LDL Cholesterol
Type of ART regimen received was not associated with risk of abnormal LDL cholesterol level (P > 0.5). Subjects with HIV RNA ≥400 copies per milliliter had a reduced risk of experiencing an abnormal LDL cholesterol compared with those with HIV RNA below this cutpoint (HR = 0.4, 95% CI: 0.2 to 1.0; P = 0.0376). There was no association between the risk of developing abnormal LDL cholesterol and subject's age, gender, or country (P > 0.3).
Children on a PI-containing regimen were nearly 4 times as likely to experience an abnormal TG measure as those receiving no ART (HR = 3.6, 95% CI: 1.3 to 10.5; P = 0.0167). Those receiving a non–PI-containing regimen were at increased risk of experiencing an abnormal triglyceride measure compared with those receiving no ART, but this difference was not significant (HR = 1.5, 95% CI: 0.5 to 4.5; P = 0.51). The risk of hypertriglyceridemia was significantly lower among males than females (HR = 0.5, 95% CI: 0.3 to 0.8; P = 0.0029) and also among those enrolled in Brazil compared with Mexico or Peru (HR = 0.3, 95% CI: 0.2 to 0.5; P < 0.0001). Risk of hypertriglyceridemia was not associated with age (P = 0.22) or HIV RNA (P = 0.21).
In the present study, the cumulative incidence of lipid abnormalities ranged from a low of 15.0% for abnormal LDL cholesterol to a high of 44.2% for triglyceride abnormalities. The incidence of glucose and HOMA-IR abnormalities was quite small in the study population (<4%). The type of ART regimen received was associated only with the risk of developing a triglyceride abnormality in multivariable modeling. The results indicate that the risk of developing a triglyceride abnormality among those receiving a PI-containing regimen was over 3 times that of those receiving no ART. Subjects with detectable viral load were at lower risk of experiencing an abnormal total or LDL cholesterol, possibly due to less exposure to antiretroviral treatment.
Children in our study were generally in good health, with most having normal body mass index, height and weight, and an immunological profile where the majority presented with high CD4 levels, in accordance with high levels of self-reported ART adherence. With a mean duration of ART exposure of 4.6 years and approximately 56% receiving a PI-containing regimen, our study found a prevalence of dyslipidemia at baseline similar to what has been published and consistent with the preliminary report on baseline data from the NISDI cohort.4 The cumulative incidence results support the need for further investigation into the cause of these rather high rates of lipid abnormalities. In a clinical trial in South Africa, Strehlau et al,19 found that initiation of PI-based regimens resulted in significant increases in total cholesterol, LDL and HDL cholesterol and decreases in the total cholesterol:HDL ratio and TG. To our knowledge, the largest longitudinal study that examined the association of PIs and other ART with lipid levels in HIV-infected children was the study of Tassiopoulos et al. In contrast to our findings, this study, which focused only on hypercholesterolemia because fasting was not required, concluded that PI-based (boosted and nonboosted) regimens and use of NNRTIs were significant risk factors for hypercholesterolemia.9
Our results indicate that, although complications of glucose metabolism are uncommon, they do exist in HIV-infected children as shown in other studies.1,20 In addition to the 5.3% of the children, we observed with abnormal HOMA-IR at baseline, 3.8% developed abnormal HOMA-IR during the course of study follow-up. This suggests that the proportion of children with insulin resistance is likely to continue to increase, as ART can interact with the physiologic insulin resistance induced by puberty itself.20 The glucose outcomes did not include sufficient numbers of events (abnormalities) to support proportional hazards regression modeling.
A potential limitation of our analysis is that we did not evaluate factors such as maternal dyslipidemia or family history of heart disease, but this is not likely to have had a major influence on our findings, as some authors indicate that these factors are unlikely to be associated with ART use.9,19 We recognize that our study is a secondary analysis of infrequent measures, with imprecise determination of the onset of abnormalities. Nevertheless, the cohort study was conducted using standardized data collection instruments and fasting measurements, with a relatively large sample size. Another limitation is the self-reported adherence measure used for this study, as another analysis of NISDI study data showed that it “demonstrated some association with viral load, but may not be adequate for reliably identifying nonadherence.”21 This measure is likely over-estimating adherence, which may explain why only 34.2% of the subjects had undetectable viral load despite high rates of adherence. Additionally, although it would have been of interest to investigate the influence of receipt of individual ARVs on the study outcomes, the numbers were not sufficient to support such analyses.
Secondary to HIV infection itself, the explanation for the association between PIs and abnormal lipid levels remains unclear, with some hypotheses considering their potential to increase lipid synthesis by liver enzymes or by inhibition of proteins involved in lipid metabolism and adipocyte differentiation.9 The mechanism involved in glucose homeostasis alteration, especially insulin resistance, is also still under investigation, but seems to be related to the direct inhibition of the GLUT4 (insulin-responsive facilitative glucose transporter isoform 4) attributed to the use of highly active anti-retroviral therapy, including PIs and nucleoside reverse transcriptase inhibitors.5,22
Although we found some evidence of an association of ART including PIs with dyslipidemia, we agree with other authors that, despite the potential adverse consequences of treatment of HIV-infected children with PIs, the benefits outweigh the toxicities, and that there is the need for ongoing metabolic monitoring of treated children.3,7,9,19 According to the UNAIDS 2014 Global Report, there were 783,000 children in June 2014 receiving antiretroviral treatment, an increase of 3% in comparison with that in 2013.23 Based on current WHO guidelines that all HIV-infected children should be treated with cART, the number of children starting presumably lifelong cART at young ages will increase worldwide.24 Those children will possibly experience drug-related adverse events and toxicities that are increasingly recognized and represent one of the most common reasons for treatment discontinuation or switch.25 Metabolic complications of long-term ART exposure remain an on-going problem for perinatally HIV-infected children, potentially affecting their overall quality of life and influencing treatment adherence.1 Further complicating the issue, it is difficult to separate the impact of HIV infection from ART on serum lipid concentrations. Finally, because clinical events are not expected until adulthood, longitudinal analyses, or at least tracking of perinatally HIV-infected youth into adulthood, will be important.
Additional studies are necessary to determine whether these metabolic abnormalities are associated with an increased risk of cardiovascular disease and how this scenario can be managed in children and adolescents.9 Associations between ART use in HIV-infected children and adolescents and glucose metabolism disturbances should continue to be investigated in future studies.
Principal investigators, co-principal investigators, study coordinators, data management center representatives, and NICHD staff include: Brazil: Belo Horizonte: Jorge A. Pinto, Flávia F. Faleiro, Marcelle M. Maia (Universidade Federal de Minas Gerais); Caxias do Sul: Rosa Dea Sperhacke, Nicole Golin, Sílvia Mariani Costamilan (Universidade de Caxias do Sul/Serviço Municipal de Infectologia); Nova Iguacu: Jose Pilotto, Luis Felipe Moreira, Ivete Gomes (Hospital Geral Nova de Iguacu—HIV Family Care Clinic); Porto Alegre: Rosa Dea Sperhacke, Breno Riegel Santos, Rita de Cassia Alves Lira (Universidade de Caxias do Sul/Hospital Conceição); Rosa Dea Sperhacke, Mario Ferreira Peixoto, Elizabete Teles (Universidade de Caxias do Sul/Hospital Fêmina); Rosa Dea Sperhacke, Marcelo Goldani, Carmem Lúcia Oliveira da Silva, Margery Bohrer Zanetello (Universidade de Caxias do Sul/Hospital de Clínicas de Porto Alegre); Regis Kreitchmann, Marcelo Comerlato Scotta, Debora Fernandes Coelho (Irmandade da Santa Casa de Misericordia de Porto Alegre); Ribeirão Preto: Marisa M. Mussi-Pinhata, Maria Célia Cervi, Márcia L. Isaac, Fernanda Tomé Sturzbecher, Bento V. Moura Negrini (Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo); Rio de Janeiro: Ricardo Hugo S. Oliveira, Maria C. Chermont Sapia (Instituto de Puericultura e Pediatria Martagão Gesteira); Esau Custodio Joao, Maria Leticia Cruz, Leon Claude Sidi, Maria Isabel Gouvêa, Mariza Curto Saavedra, Clarisse Bressan, Fernanda Cavalcanti A. Jundi (Hospital dos Servidores do Estado); São Paulo: Regina Celia de Menezes Succi, Daisy Maria Machado (Escola Paulista de Medicina- Universidade Federal de São Paulo); Marinella Della Negra, Wladimir Queiroz, Yu Ching Lian (Instituto de Infectologia Emilio Ribas); Mexico: Mexico City: Noris Pavía-Ruz, Dulce Morales-Pérez, Karla Ojeda-Diezbarroso (Hospital Infantil de México Federico Gómez); Peru: Lima: Jorge O. Alarcón Villaverde (Instituto de Medicina Tropical “Daniel Alcides Carrión”- Sección de Epidemiologia, UNMSM), María Castillo Díaz (Instituto Nacional de Salud del Niño), Mary Felissa Reyes Vega (Instituto de Medicina Tropical “Daniel Alcides Carrión”—Sección de Epidemiologia, UNMSM); Data Management and Statistical Center: Yolanda Bertucci, Laura Freimanis Hance, René Gonin, D. Robert Harris, Roslyn Hennessey, Margot Krauss, Sue Li, Karen Megazzini, Orlando Ortega, James Korelitz, Sharon Sothern de Sanchez, Sonia K. Stoszek, Qilu Yu (Westat, Rockville, MD) NICHD: Rohan Hazra, Lynne M. Mofenson, George K. Siberry (Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD).
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Keywords:Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
children; HIV infection; protease inhibitors; dyslipidemia; glucose abnormalities