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Lipodystrophy, lipid profile changes, and low serum retinol and carotenoid levels in children and adolescents with acquired immunodeficiency syndrome
Nutrition 26 (2010) 612–616
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Nutrition journal homepage: www.nutritionjrnl.com
Applied nutritional investigation
Lipodystrophy, lipid profile changes, and low serum retinol and carotenoid levels in children and adolescents with acquired immunodeficiency syndrome Taˆnia Regina Beraldo Battistini M.Sc. a, Roseli Oselka Saccardo Sarni M.D., Ph.D. a, b, *, Fabı´ola Isabel Suano de Souza M.D., M.Sc. a, b, Tassiana Sacchi Pitta M.D. a, Ana Paula Fernandes M.D. a, Sonia Hix Ph.D. a, Fernando Luiz Affonso Fonseca Ph.D. a, Priscila Chemiotti Tardini M.D. a, Valter Pinho dos Santos M.D., Ph.D. a, Fa´bio Ancona Lopez M.D., Ph.D. b a b
˜o Paulo, Brazil Department of Pediatrics, ABC School of Medicine, Sa ˜o Paulo, Sa ˜o Paulo, Brazil Department of Pediatrics, Federal University of Sa
a r t i c l e i n f o
a b s t r a c t
Article history: Received 20 January 2009 Accepted 26 June 2009
Objective: To assess serum retinol and levels of carotenoids in children and adolescents with acquired immunodeficiency syndrome (AIDS) and to correlate low serum retinol and carotenoid levels with the presence of lipodystrophy, lipid profile changes, lipid peroxidation, and insulin resistance. Methods: A cross-sectional, controlled observational study was carried out with 30 children and adolescents with AIDS (mean age 9.1 y) receiving antiretroviral therapy (median length of treatment 28.4 mo), including 30 uninfected healthy controls matched for age and gender. Clinical and laboratory assessments were performed to determine nutritional status, presence of lipodystrophy, serum concentrations of retinol, b-carotene, lycopene, lipid profile (high-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triacylglycerols), lipid peroxidation (thiobarbituric acid-reactive substances), glycemia, and serum insulin (homeostasis model assessment for insulin resistance, cutoff point >3). Statistical analysis was done with chi-square test and Student’s t test. Results: Lipodystrophy was observed in 53.3% of patients with AIDS, and dyslipidemia was detected in 60% and 23% of subjects with human immunodeficiency virus and control subjects, respectively (P ¼ 0.004). A higher prevalence of retinol deficiency (60% versus 26.7%, P ¼ 0.009) and b-carotene deficiency (23.3% versus 3.3%, P ¼ 0.026) was found in the group with human immunodeficiency virus than in the control group. No correlation was found for low retinol and b-carotene levels, changes in lipid and glucose metabolism, or lipodystrophy in children and adolescents with AIDS. Conclusion: Despite the high frequency of dyslipidemia, lipodystrophy, and retinol and b-carotene deficiencies, it was not possible to demonstrate a correlation of these findings with lipid peroxidation and insulin resistance. More studies are needed to investigate the causes of retinol and b-carotene deficiencies in this population and the clinical consequences of these findings. Ó 2010 Elsevier Inc. All rights reserved.
Keywords: Human immunodeficiency virus Vitamin A b-Carotene Retinol Children Antiretroviral therapy
Introduction An estimated 2.5 million children are infected with the human immunodeficiency virus (HIV) worldwide [1]. The use of highly active antiretroviral therapy, including protease inhibitors, has allowed significant suppression of viral replication, This project was partly supported by Fundaça˜o de Amparo a` Pesquisa de Sa˜o Paulo (FAPESP). * Corresponding author. Tel./fax: þ55-11-5571-9589. E-mail address: [email protected] (R. O. Saccardo Sarni). 0899-9007/$ – see front matter Ó 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2009.06.024
lowering morbidity and mortality and improving the quality of life of patients with acquired immunodeficiency syndrome (AIDS) [1]. These drugs, however, have been linked to the development of metabolic abnormalities called collectively lipodystrophic syndrome of HIV characterized by increased plasma atherogenic lipoprotein levels, insulin resistance, type 2 diabetes, and body fat redistribution in adults and children [2,3], which can potentially increase cardiovascular risk [4]. Antiretroviral therapy may also cause mitochondrial toxicity, which leads to an increased production of oxygen reactive species resulting in exacerbation of oxidative stress, previously
T. R. Beraldo Battistini et al. / Nutrition 26 (2010) 612–616
described in HIV infection and often related to compromised antioxidant defenses observed in patients with retinol and carotenoid deficiencies [5]. These deficiencies may be caused by viral infection, periods of greater nutritional requirements, poor intake or absorption, excessive urinary losses, or diarrhea as a side effect of medications [6–8]. Retinol and carotenoid deficiencies are a common occurrence in HIV-infected subjects and are associated with worse clinical and immunologic courses and higher mortality [9]. However, the benefits of supplementation with retinol and b-carotene are conflicting, with some studies demonstrating improvement [10,11] and others worse outcomes [12] or absence of effect [13]. Another point to be considered is that there seems to be a synergistic effect of retinol/carotenoid deficiency, HIV infection, and antiretroviral therapy in the exacerbation of oxidative stress. The latter is a mechanism involved in HIV-related morbidities such as dyslipidemia [14], cardiovascular diseases [15], and type 2 diabetes [16]. Therefore, the aim of this study was to assess serum retinol and carotenoid levels in children and adolescents with AIDS and to evaluate the correlation of low serum retinol and levels of carotenoids with the presence of lipodystrophy, lipid profile changes, lipid peroxidation, and insulin resistance. Materials and methods Study design A cross-sectional, controlled observational study was carried out with 30 children and adolescents with AIDS 4 to 14 y of age of both genders who were using antiretroviral therapy and regularly treated at the Reference Center in Treatment of AIDS in Santo Andre´ and Sa˜o Bernardo, Brazil, from 2004 to 2006. The study was approved by the research ethics committees of the ABC Medical School and Sa˜o Paulo Federal University. The protocol for treatment of HIV infection adopted was that proposed by the Centers for Disease Control and Prevention (CDC), 1998 [17]. Exclusion criteria included children and adolescents who had received vitamin supplements, immunomodulating drugs, corticosteroids, or growth hormone or had been hospitalized or developed serious illnesses within the 3 mo before the beginning of the study. Children with other chronic diseases were also excluded. A total of 38 patients with AIDS met inclusion criteria; however, seven guardians did not give their consent or were absent at the three meetings held at the beginning of the study and one adolescent was later diagnosed with chronic pulmonary disease. The control group consisted of 30 healthy children and adolescents, matched for gender and age (maximum 12-mo age difference), drawn from a public school in the outskirts of Santo Andre´, Brazil. General data A standard questionnaire was applied to the AIDS group to determine the type of transmission, age at diagnosis, current use of antiretroviral therapy, viral load, and CD4þ cell count (maximum interval of 3 mo before or after the beginning of the study) and if the mother had prophylaxis during pregnancy and breast-fed the infants. The data were used to classify HIV infection according to the 1994 CDC guidelines [18]. Socioeconomic assessment The criteria included the following indicators: purchasing power of families, level of schooling of the head of the family, housing conditions of the family, and the neighborhood [19,20]. Anthropometry and pubertal development Anthropometric measurements (weight, height) and classification of nutritional status were performed according to the World Health Organization (1995) [21]. The children and adolescents in the study were classified as malnourished or stunted when a z score of body mass index or height for age, respectively, was <2 [22]. Pubertal development was rated using stages according to Marshall and Tanner [23].
613
Definition of lipodystrophy Clinical lipodystrophy was diagnosed when examination, performed by two independent physicians, revealed lipoatrophy, lipohypertrophy, or a mixed form (lipoatrophy and lipohypertrophy) [24].
Laboratory assessment A 10-mL sample of venous blood was collected in a dimly lit room after 12-h fasting to assess for following items. Serum retinol, b-carotene, and lycopene samples were stored in tubes containing sodium heparin with photoprotection. Analyses were carried out using high-performance liquid chromatography [25]. The retinol cutoff point was <1.05 mmol/L. b-Carotene and lycopene cutoffs considered age, as proposed by Ford et al. [26]. Lipid profile was measured using kits from Bio Express Plus and Bayer (Siemens Healthcare Diagnostics, Deerfield IL, USA), which employ the colorimetric enzymatic method. For triacylglycerols, high-density lipoprotein cholesterol, and low-density lipoprotein (LDL) cholesterol, cutoffs recommended by the National Cholesterol Education Program were adopted [27]. Thiobarbituric acid-reactive substances were measured by spectrophotometer using a Micronal model B 582 device (Micronal S/A, Sa˜o Paulo, Brazil) at a 532-nm wave amplitude [28]. The cutoff adopted was any value above the 90th percentile of the study population (>5.0 nmol/L). Serum insulin was determined using IMMULITE 1000 and kits from DPC MedLab, which employ the chemoluminescence method. Serum glucose was determined using Bio Express Plus and kits from Bayer, which employ the colorimetric-enzymatic method. Insulin and glucose serum levels were used in calculating the homeostasis model assessment for insulin resistance, which defines resistance to insulin as values >3.0 [29].
Statistical analysis Anthropometric indices were calculated using Epi Info 3.3.2 [30]. Data analysis was performed using SPSS 13.0 [31]. The Shapiro-Wilks test was used to verify the normal distribution of data. Frequency tables were used to describe categorical and bivariate variables, and the chi-square test was employed to assess differences in percentages of inadequacy of the biochemical parameters in the AIDS and control groups. The inadequacy of retinol levels was adjusted to the nutritional status (obesity). Parametric variables were analyzed using Student’s paired and unpaired tests. P < 0.05 was accepted as statistically significant.
Results Thirty children and adolescents with AIDS were evaluated (14 male, 46.7%), with a mean age of 9.1 2.5 y. Statistical analysis showed that the AIDS and control groups were homogenous in terms of socioeconomic level (P ¼ 0.246) and pubertal development (P ¼ 0.123; Table 1). Nutritional assessment of the study group showed four (13.3%), four (13.3%), and one (3.3%) subjects with z scores of body mass index <2 (malnutrition), height for age <2 (stunting), and body mass index and height for age <2, respectively (Table 1). Route of transmission, prophylaxis during pregnancy, breastfeeding, and clinical and laboratory data are presented in Table 2. Median time on antiretroviral therapy use was 28.4 mo (minimum and maximum 7.0 and 85.2 mo). Twenty-four of the 30 patients (80%) were using three drugs in association, whereas nine (30%) were using one protease inhibitor (Table 2). Clinical lipodystrophy was observed in 16 patients (53.3%) in the AIDS group, four of whom (13.3%) presented a mixed form and 12 (40%) lipohypertrophy (Table 2). A statistically significant higher frequency of low serum retinol (60% versus 26.7%, P ¼ 0.009) and b-carotene (23.3% versus 3.3%, P ¼ 0.026) was found in the AIDS group compared with the control group. For retinol, this difference remained
614
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Table 1 Characteristics of the studied population AIDS (n ¼ 30) Male:female Age (y)* Pubertal developmenty B1 or G1 B2 or G2 B3 or G3 B4 or G4 ZBMI <2y ZH <2y ZBMI and ZH <2y
Table 3 Inadequacy of variables studied between AIDS and control groups Controls (n ¼ 30)
P
14:16 9.1 2.5 (4.0–14.0)
13:17 10.3 1.9 (4.9–13.7)
22 6 1 1 4 4 1
19 (63.3%) 3 (10.0%) 6 (20.0%) 2 (6.7%) 0 0 0
(73.3%) (20.0%) (3.3%) (3.3%) (13.3%) (13.3%) (3.3%)
Variable
0.795 0.058x 0.123z
AIDS, acquired immunodeficiency syndrome; B, breast development; G, testicular development; ZBMI, z score of body mass index; ZH, z score of height for age * Mean SD (range). y Number of subjects (percentage). z Descriptive level of chi-square test. x Descriptive level of Student’s t test.
significant after adjusting for nutritional status (55% versus 26.7%, P ¼ 0.042; Table 3). Eighteen subjects (60%) in the AIDS group and seven (23.3%) in the control group presented abnormal plasma lipid values (P ¼ 0.004). In the AIDS group abnormal LDL cholesterol, high-density lipoprotein cholesterol, and triacylglycerol levels were observed in 20%, 13.3%, and 43.3% of the subjects, respectively. In comparison with the control group, the difference was statistically significant only for LDL cholesterol levels (P ¼ 0.011; Table 3). Children and adolescents with AIDS were stratified according to the presence of low serum retinol and b-carotene levels. There
Table 2 Characteristics of children with acquired immunodeficiency syndrome Variable Vertical transmission* Prophylaxis during pregnancy* Breast-feeding* Age at diagnosis (y)y Classification of HIV infection* A1 A2 A3 B1 B2 B3 Lipodystrophy Absent Lipohypertrophy Mixed CD4þ cell count/mm3y Viral load (103 copies/mm3) Duration of current antiretroviral therapy (mo)y Drugs used* NRTI NNRTI PI Antiretroviral therapy* NRTI þ NRTI NRTI þ NRTI þ NRTI NRTI þ NRTI þ NNRTI NRTI þ NRTI þ PI NRTI þ NNRTI þ PI
30 27 24 4.5
(100%) (90%) (80%) (2.0–12.0)
1 6 1 13 6 3
(3.3%) (20%) (3.3%) (43.3%) (20%) (10%)
14 12 4 749 200 28.4
(46.7%) (40%) (13.3%) (349–1781) (172–533) (7.0–85.2)
30 (100%) 15 (50%) 9 (30%) 6 1 14 8 1
AIDS (n ¼ 30)
Controls (n ¼ 30)
Py
18 8 7 6 4 13 1 1
8 4 1 0 1 7 4 2
0.009 0.196 0.026 0.011 0.176 0.100 0.211 0.500
z
(20%) (3.3%) (46.7%) (27.7%) (3.3%)
HIV, human immunodificiency virus; NNRTI, non-nucleoside reverse transcriptase inhibitors; NRTI, nucleoside analog reverse transcriptase inhibitors; PI, protease inhibitors * Number of subjects (percentage). y Median (maximum–minimum).
Retinol* (n ¼ 60) Lycopene (n ¼ 60) b-Carotene (n ¼ 60) LDL cholesterol (n ¼ 60) HDL cholesterol (n ¼ 60) Triacylglycerols (n ¼ 60) TBARS (n ¼ 55) HOMA-IR (n ¼ 60)
<1.05 mmol/L <0.20 mmol/L <0.10 mmol/L 130 mg/dL 45 mg/dL 130 mg/dL >5.0 nmol/L >3
(60%) (26.7%) (23.3%) (20%) (13.3%) (43.3%) (3.8%) (3.3%)
(26.7%) (13.3%) (3.3%) (0%) (3.3%) (23.3%) (13.7%) (6.7%)
AIDS, acquired immunodeficiency syndrome; HDL, high-density lipoprotein; HOMA-IR, homeostasis model assessment for insulin resistance; LDL, lowdensity lipoprotein; TBARS, thiobarbituric acid-reactive substances * Retinol adjusted for nutritional state (P ¼ 0.042). y Level of significance of chi-square test.
was no statistically significant association between the presence of low serum retinol and b-carotene levels and changes in lipid profile, lipid peroxidation, insulin resistance, or presence of lipodystrophy (Table 4). Discussion In this study, we found dyslipidemia in 60% of children and adolescents with AIDS. A statistically significant difference was found between the AIDS and control groups for LDL cholesterol levels. Our prevalence of hypertriglyceridemia was higher than that found in the pediatric cohort study conducted in Houston (28%) but was lower than in a Mexican study (79.2%) [32,33]. Dyslipidemia in HIV-infected patients results from a combination of causes including the viral infection, antiretroviral therapy and genetic factors. The HIV infection itself is associated with a proatherogenic lipid profile characterized by an increase in triacylglycerols and a small dense LDL cholesterol concentration and a decrease in serum high-density lipoprotein cholesterol concentration [2]. With regard to adverse events in lipid metabolism ascribed to antiretroviral therapy, it is known that some commonly used drugs such as protease inhibitors are associated with high levels of circulating cholesterol and triacylglycerols [33], with ritonavir being the most implicated compared with indinavir, nelfinavir, and atazanavir [34]. A recent cohort study in adults that employed adjusted multifactorial analysis found a link between use of protease inhibitors, lipodystrophy development, and acute myocardial infarction [35]. Clinical lipodystrophy was observed in 53% of the children and adolescents with AIDS studied, against the 25–30% rate observed in other pediatric studies [36,37]. Although the physiopathology of lipodystrophic syndrome associated with antiretroviral therapy has not yet been fully elucidated, several mechanisms have been described: mitochondrial dysfunction; impaired differentiation of preadipocytes leading to apoptosis of adipocytes in some regions; reduction in adipogenesis-related transcription factors; increased expression and secretion of proinflammatory cytokines (tumor necrosis factor-a and interleukin-6) involved in modifying the function of adipocytes and reducing adiponectin; higher leptinemia associated to accumulation of central fat and insulin resistance; and increased levels of visfatin and retinol-binding protein-4 [5,24,38]. We detected significantly lower levels of retinol and bcarotene in the AIDS group compared with the control group.
T. R. Beraldo Battistini et al. / Nutrition 26 (2010) 612–616 Table 4 Correlation among lipodystrophy, lipid profile, insulin resistance, and lipid peroxidation in AIDS-infected children and adolescents, and retinol and carotenoid deficiencies P Retinol <1.05 mmol/L (n ¼ 18)
Variable
LDL cholesterol (n ¼ 6) HDL cholesterol (n ¼ 4) Triacylglycerols (n ¼ 13) TBARS (n ¼ 2) HOMA-IR (n ¼ 1) Lipodystrophy (n ¼ 16)
b-Carotene P* <0.10 mmol/L (n ¼ 7)
130 mg/dL
4 (22.2%)
0.545 1 (14.3%)
0.567
45 mg/dL
3 (16.7%)
0.632 2 (28.6%)
0.225
130 mg/dL
3 (16.7%)
0.392 5 (71.4%)
0.532
>5.0 nmol/L >3
0 (0%) 1 (5.5%)
0.423 0 (0%) 0.600 0 (0%)
0.769 0.767
0.529 3 (42.8%)
0.675
Present
10 (55.5%)
AIDS, acquired immunodeficiency syndrome; HDL, high-density lipoprotein; HOMA-IR, homeostasis model assessment for insulin resistance; LDL, lowdensity lipoprotein; TBARS, thiobarbituric acid-reactive substances * Level of significance of chi-square test.
The levels of these micronutrients may be compromised due to several factors: direct action of the virus, type of antiretroviral therapy, low socioeconomic level, poor intake or absorption, lack of adequate nutritional counseling, or drug side effects affecting appetite [39]. Reduced absorption and high losses may also negatively affect nutritional status in terms of retinol and carotenoids [7]. Furthermore, it is noteworthy that the use of highly active antiretroviral therapy and the resulting marked improvement in the clinical evolution of patients have been correlated with improvement of nutritional status of various micronutrients, although such benefits have not yet been proven for retinol [39]. Vitamin A deficiency, a frequent finding in HIV-infected children, is associated with exacerbation of oxidative stress [40], decrease in CD4þ cells, ad increase in HIV-related morbidities, accelerated disease progression owing to greater activation of nuclear factor-kB, and higher mortality [39,41]. No correlation between low retinol and b-carotene levels and higher occurrence of lipid peroxidation and changes in lipid and glucose metabolism was observed in the AIDS group. We propose a number of hypotheses to explain this finding: the young age of the population studied; the small number of patients included; the limitation in the design of the study (cross sectional); a possible role of other vitamins integrated and synergically involved in antioxidant defense, such as vitamins C and E [42,43]; and the lack of an ideal biochemical marker of oxidative stress related to lipid peroxidation [44]. Although some researchers have advocated the benefits of micronutrient supplementation as a coadjuvant therapy in HIVinfected patients, no consensus has yet been reached in terms of dosage and safety, particularly among the pediatric population. There are also limitations in interpreting the results of the studies available: most studies published to date were not adjusted for inflammation markers and have focused largely on biochemical outcomes (modification of sera/plasma levels) rather than clinical outcomes (disease progression and mortality) [10,11]. Indeed, studies in children and adolescents are particularly scarce and inconclusive, perhaps due to the small samples involved. Conclusions Despite the high frequency of dyslipidemia, lipodystrophy, and retinol and b-carotene deficiencies, it was not possible to demonstrate a correlation of these findings with lipid
615
peroxidation and insulin resistance. More studies are needed to investigate the causes of retinol and b-carotene deficiencies in this population and the clinical consequences of these findings.
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Applied nutritional investigation
Lipodystrophy, lipid profile changes, and low serum retinol and carotenoid levels in children and adolescents with acquired immunodeficiency syndrome Taˆnia Regina Beraldo Battistini M.Sc. a, Roseli Oselka Saccardo Sarni M.D., Ph.D. a, b, *, Fabı´ola Isabel Suano de Souza M.D., M.Sc. a, b, Tassiana Sacchi Pitta M.D. a, Ana Paula Fernandes M.D. a, Sonia Hix Ph.D. a, Fernando Luiz Affonso Fonseca Ph.D. a, Priscila Chemiotti Tardini M.D. a, Valter Pinho dos Santos M.D., Ph.D. a, Fa´bio Ancona Lopez M.D., Ph.D. b a b
˜o Paulo, Brazil Department of Pediatrics, ABC School of Medicine, Sa ˜o Paulo, Sa ˜o Paulo, Brazil Department of Pediatrics, Federal University of Sa
a r t i c l e i n f o
a b s t r a c t
Article history: Received 20 January 2009 Accepted 26 June 2009
Objective: To assess serum retinol and levels of carotenoids in children and adolescents with acquired immunodeficiency syndrome (AIDS) and to correlate low serum retinol and carotenoid levels with the presence of lipodystrophy, lipid profile changes, lipid peroxidation, and insulin resistance. Methods: A cross-sectional, controlled observational study was carried out with 30 children and adolescents with AIDS (mean age 9.1 y) receiving antiretroviral therapy (median length of treatment 28.4 mo), including 30 uninfected healthy controls matched for age and gender. Clinical and laboratory assessments were performed to determine nutritional status, presence of lipodystrophy, serum concentrations of retinol, b-carotene, lycopene, lipid profile (high-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triacylglycerols), lipid peroxidation (thiobarbituric acid-reactive substances), glycemia, and serum insulin (homeostasis model assessment for insulin resistance, cutoff point >3). Statistical analysis was done with chi-square test and Student’s t test. Results: Lipodystrophy was observed in 53.3% of patients with AIDS, and dyslipidemia was detected in 60% and 23% of subjects with human immunodeficiency virus and control subjects, respectively (P ¼ 0.004). A higher prevalence of retinol deficiency (60% versus 26.7%, P ¼ 0.009) and b-carotene deficiency (23.3% versus 3.3%, P ¼ 0.026) was found in the group with human immunodeficiency virus than in the control group. No correlation was found for low retinol and b-carotene levels, changes in lipid and glucose metabolism, or lipodystrophy in children and adolescents with AIDS. Conclusion: Despite the high frequency of dyslipidemia, lipodystrophy, and retinol and b-carotene deficiencies, it was not possible to demonstrate a correlation of these findings with lipid peroxidation and insulin resistance. More studies are needed to investigate the causes of retinol and b-carotene deficiencies in this population and the clinical consequences of these findings. Ó 2010 Elsevier Inc. All rights reserved.
Keywords: Human immunodeficiency virus Vitamin A b-Carotene Retinol Children Antiretroviral therapy
Introduction An estimated 2.5 million children are infected with the human immunodeficiency virus (HIV) worldwide [1]. The use of highly active antiretroviral therapy, including protease inhibitors, has allowed significant suppression of viral replication, This project was partly supported by Fundaça˜o de Amparo a` Pesquisa de Sa˜o Paulo (FAPESP). * Corresponding author. Tel./fax: þ55-11-5571-9589. E-mail address: [email protected] (R. O. Saccardo Sarni). 0899-9007/$ – see front matter Ó 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2009.06.024
lowering morbidity and mortality and improving the quality of life of patients with acquired immunodeficiency syndrome (AIDS) [1]. These drugs, however, have been linked to the development of metabolic abnormalities called collectively lipodystrophic syndrome of HIV characterized by increased plasma atherogenic lipoprotein levels, insulin resistance, type 2 diabetes, and body fat redistribution in adults and children [2,3], which can potentially increase cardiovascular risk [4]. Antiretroviral therapy may also cause mitochondrial toxicity, which leads to an increased production of oxygen reactive species resulting in exacerbation of oxidative stress, previously
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described in HIV infection and often related to compromised antioxidant defenses observed in patients with retinol and carotenoid deficiencies [5]. These deficiencies may be caused by viral infection, periods of greater nutritional requirements, poor intake or absorption, excessive urinary losses, or diarrhea as a side effect of medications [6–8]. Retinol and carotenoid deficiencies are a common occurrence in HIV-infected subjects and are associated with worse clinical and immunologic courses and higher mortality [9]. However, the benefits of supplementation with retinol and b-carotene are conflicting, with some studies demonstrating improvement [10,11] and others worse outcomes [12] or absence of effect [13]. Another point to be considered is that there seems to be a synergistic effect of retinol/carotenoid deficiency, HIV infection, and antiretroviral therapy in the exacerbation of oxidative stress. The latter is a mechanism involved in HIV-related morbidities such as dyslipidemia [14], cardiovascular diseases [15], and type 2 diabetes [16]. Therefore, the aim of this study was to assess serum retinol and carotenoid levels in children and adolescents with AIDS and to evaluate the correlation of low serum retinol and levels of carotenoids with the presence of lipodystrophy, lipid profile changes, lipid peroxidation, and insulin resistance. Materials and methods Study design A cross-sectional, controlled observational study was carried out with 30 children and adolescents with AIDS 4 to 14 y of age of both genders who were using antiretroviral therapy and regularly treated at the Reference Center in Treatment of AIDS in Santo Andre´ and Sa˜o Bernardo, Brazil, from 2004 to 2006. The study was approved by the research ethics committees of the ABC Medical School and Sa˜o Paulo Federal University. The protocol for treatment of HIV infection adopted was that proposed by the Centers for Disease Control and Prevention (CDC), 1998 [17]. Exclusion criteria included children and adolescents who had received vitamin supplements, immunomodulating drugs, corticosteroids, or growth hormone or had been hospitalized or developed serious illnesses within the 3 mo before the beginning of the study. Children with other chronic diseases were also excluded. A total of 38 patients with AIDS met inclusion criteria; however, seven guardians did not give their consent or were absent at the three meetings held at the beginning of the study and one adolescent was later diagnosed with chronic pulmonary disease. The control group consisted of 30 healthy children and adolescents, matched for gender and age (maximum 12-mo age difference), drawn from a public school in the outskirts of Santo Andre´, Brazil. General data A standard questionnaire was applied to the AIDS group to determine the type of transmission, age at diagnosis, current use of antiretroviral therapy, viral load, and CD4þ cell count (maximum interval of 3 mo before or after the beginning of the study) and if the mother had prophylaxis during pregnancy and breast-fed the infants. The data were used to classify HIV infection according to the 1994 CDC guidelines [18]. Socioeconomic assessment The criteria included the following indicators: purchasing power of families, level of schooling of the head of the family, housing conditions of the family, and the neighborhood [19,20]. Anthropometry and pubertal development Anthropometric measurements (weight, height) and classification of nutritional status were performed according to the World Health Organization (1995) [21]. The children and adolescents in the study were classified as malnourished or stunted when a z score of body mass index or height for age, respectively, was <2 [22]. Pubertal development was rated using stages according to Marshall and Tanner [23].
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Definition of lipodystrophy Clinical lipodystrophy was diagnosed when examination, performed by two independent physicians, revealed lipoatrophy, lipohypertrophy, or a mixed form (lipoatrophy and lipohypertrophy) [24].
Laboratory assessment A 10-mL sample of venous blood was collected in a dimly lit room after 12-h fasting to assess for following items. Serum retinol, b-carotene, and lycopene samples were stored in tubes containing sodium heparin with photoprotection. Analyses were carried out using high-performance liquid chromatography [25]. The retinol cutoff point was <1.05 mmol/L. b-Carotene and lycopene cutoffs considered age, as proposed by Ford et al. [26]. Lipid profile was measured using kits from Bio Express Plus and Bayer (Siemens Healthcare Diagnostics, Deerfield IL, USA), which employ the colorimetric enzymatic method. For triacylglycerols, high-density lipoprotein cholesterol, and low-density lipoprotein (LDL) cholesterol, cutoffs recommended by the National Cholesterol Education Program were adopted [27]. Thiobarbituric acid-reactive substances were measured by spectrophotometer using a Micronal model B 582 device (Micronal S/A, Sa˜o Paulo, Brazil) at a 532-nm wave amplitude [28]. The cutoff adopted was any value above the 90th percentile of the study population (>5.0 nmol/L). Serum insulin was determined using IMMULITE 1000 and kits from DPC MedLab, which employ the chemoluminescence method. Serum glucose was determined using Bio Express Plus and kits from Bayer, which employ the colorimetric-enzymatic method. Insulin and glucose serum levels were used in calculating the homeostasis model assessment for insulin resistance, which defines resistance to insulin as values >3.0 [29].
Statistical analysis Anthropometric indices were calculated using Epi Info 3.3.2 [30]. Data analysis was performed using SPSS 13.0 [31]. The Shapiro-Wilks test was used to verify the normal distribution of data. Frequency tables were used to describe categorical and bivariate variables, and the chi-square test was employed to assess differences in percentages of inadequacy of the biochemical parameters in the AIDS and control groups. The inadequacy of retinol levels was adjusted to the nutritional status (obesity). Parametric variables were analyzed using Student’s paired and unpaired tests. P < 0.05 was accepted as statistically significant.
Results Thirty children and adolescents with AIDS were evaluated (14 male, 46.7%), with a mean age of 9.1 2.5 y. Statistical analysis showed that the AIDS and control groups were homogenous in terms of socioeconomic level (P ¼ 0.246) and pubertal development (P ¼ 0.123; Table 1). Nutritional assessment of the study group showed four (13.3%), four (13.3%), and one (3.3%) subjects with z scores of body mass index <2 (malnutrition), height for age <2 (stunting), and body mass index and height for age <2, respectively (Table 1). Route of transmission, prophylaxis during pregnancy, breastfeeding, and clinical and laboratory data are presented in Table 2. Median time on antiretroviral therapy use was 28.4 mo (minimum and maximum 7.0 and 85.2 mo). Twenty-four of the 30 patients (80%) were using three drugs in association, whereas nine (30%) were using one protease inhibitor (Table 2). Clinical lipodystrophy was observed in 16 patients (53.3%) in the AIDS group, four of whom (13.3%) presented a mixed form and 12 (40%) lipohypertrophy (Table 2). A statistically significant higher frequency of low serum retinol (60% versus 26.7%, P ¼ 0.009) and b-carotene (23.3% versus 3.3%, P ¼ 0.026) was found in the AIDS group compared with the control group. For retinol, this difference remained
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Table 1 Characteristics of the studied population AIDS (n ¼ 30) Male:female Age (y)* Pubertal developmenty B1 or G1 B2 or G2 B3 or G3 B4 or G4 ZBMI <2y ZH <2y ZBMI and ZH <2y
Table 3 Inadequacy of variables studied between AIDS and control groups Controls (n ¼ 30)
P
14:16 9.1 2.5 (4.0–14.0)
13:17 10.3 1.9 (4.9–13.7)
22 6 1 1 4 4 1
19 (63.3%) 3 (10.0%) 6 (20.0%) 2 (6.7%) 0 0 0
(73.3%) (20.0%) (3.3%) (3.3%) (13.3%) (13.3%) (3.3%)
Variable
0.795 0.058x 0.123z
AIDS, acquired immunodeficiency syndrome; B, breast development; G, testicular development; ZBMI, z score of body mass index; ZH, z score of height for age * Mean SD (range). y Number of subjects (percentage). z Descriptive level of chi-square test. x Descriptive level of Student’s t test.
significant after adjusting for nutritional status (55% versus 26.7%, P ¼ 0.042; Table 3). Eighteen subjects (60%) in the AIDS group and seven (23.3%) in the control group presented abnormal plasma lipid values (P ¼ 0.004). In the AIDS group abnormal LDL cholesterol, high-density lipoprotein cholesterol, and triacylglycerol levels were observed in 20%, 13.3%, and 43.3% of the subjects, respectively. In comparison with the control group, the difference was statistically significant only for LDL cholesterol levels (P ¼ 0.011; Table 3). Children and adolescents with AIDS were stratified according to the presence of low serum retinol and b-carotene levels. There
Table 2 Characteristics of children with acquired immunodeficiency syndrome Variable Vertical transmission* Prophylaxis during pregnancy* Breast-feeding* Age at diagnosis (y)y Classification of HIV infection* A1 A2 A3 B1 B2 B3 Lipodystrophy Absent Lipohypertrophy Mixed CD4þ cell count/mm3y Viral load (103 copies/mm3) Duration of current antiretroviral therapy (mo)y Drugs used* NRTI NNRTI PI Antiretroviral therapy* NRTI þ NRTI NRTI þ NRTI þ NRTI NRTI þ NRTI þ NNRTI NRTI þ NRTI þ PI NRTI þ NNRTI þ PI
30 27 24 4.5
(100%) (90%) (80%) (2.0–12.0)
1 6 1 13 6 3
(3.3%) (20%) (3.3%) (43.3%) (20%) (10%)
14 12 4 749 200 28.4
(46.7%) (40%) (13.3%) (349–1781) (172–533) (7.0–85.2)
30 (100%) 15 (50%) 9 (30%) 6 1 14 8 1
AIDS (n ¼ 30)
Controls (n ¼ 30)
Py
18 8 7 6 4 13 1 1
8 4 1 0 1 7 4 2
0.009 0.196 0.026 0.011 0.176 0.100 0.211 0.500
z
(20%) (3.3%) (46.7%) (27.7%) (3.3%)
HIV, human immunodificiency virus; NNRTI, non-nucleoside reverse transcriptase inhibitors; NRTI, nucleoside analog reverse transcriptase inhibitors; PI, protease inhibitors * Number of subjects (percentage). y Median (maximum–minimum).
Retinol* (n ¼ 60) Lycopene (n ¼ 60) b-Carotene (n ¼ 60) LDL cholesterol (n ¼ 60) HDL cholesterol (n ¼ 60) Triacylglycerols (n ¼ 60) TBARS (n ¼ 55) HOMA-IR (n ¼ 60)
<1.05 mmol/L <0.20 mmol/L <0.10 mmol/L 130 mg/dL 45 mg/dL 130 mg/dL >5.0 nmol/L >3
(60%) (26.7%) (23.3%) (20%) (13.3%) (43.3%) (3.8%) (3.3%)
(26.7%) (13.3%) (3.3%) (0%) (3.3%) (23.3%) (13.7%) (6.7%)
AIDS, acquired immunodeficiency syndrome; HDL, high-density lipoprotein; HOMA-IR, homeostasis model assessment for insulin resistance; LDL, lowdensity lipoprotein; TBARS, thiobarbituric acid-reactive substances * Retinol adjusted for nutritional state (P ¼ 0.042). y Level of significance of chi-square test.
was no statistically significant association between the presence of low serum retinol and b-carotene levels and changes in lipid profile, lipid peroxidation, insulin resistance, or presence of lipodystrophy (Table 4). Discussion In this study, we found dyslipidemia in 60% of children and adolescents with AIDS. A statistically significant difference was found between the AIDS and control groups for LDL cholesterol levels. Our prevalence of hypertriglyceridemia was higher than that found in the pediatric cohort study conducted in Houston (28%) but was lower than in a Mexican study (79.2%) [32,33]. Dyslipidemia in HIV-infected patients results from a combination of causes including the viral infection, antiretroviral therapy and genetic factors. The HIV infection itself is associated with a proatherogenic lipid profile characterized by an increase in triacylglycerols and a small dense LDL cholesterol concentration and a decrease in serum high-density lipoprotein cholesterol concentration [2]. With regard to adverse events in lipid metabolism ascribed to antiretroviral therapy, it is known that some commonly used drugs such as protease inhibitors are associated with high levels of circulating cholesterol and triacylglycerols [33], with ritonavir being the most implicated compared with indinavir, nelfinavir, and atazanavir [34]. A recent cohort study in adults that employed adjusted multifactorial analysis found a link between use of protease inhibitors, lipodystrophy development, and acute myocardial infarction [35]. Clinical lipodystrophy was observed in 53% of the children and adolescents with AIDS studied, against the 25–30% rate observed in other pediatric studies [36,37]. Although the physiopathology of lipodystrophic syndrome associated with antiretroviral therapy has not yet been fully elucidated, several mechanisms have been described: mitochondrial dysfunction; impaired differentiation of preadipocytes leading to apoptosis of adipocytes in some regions; reduction in adipogenesis-related transcription factors; increased expression and secretion of proinflammatory cytokines (tumor necrosis factor-a and interleukin-6) involved in modifying the function of adipocytes and reducing adiponectin; higher leptinemia associated to accumulation of central fat and insulin resistance; and increased levels of visfatin and retinol-binding protein-4 [5,24,38]. We detected significantly lower levels of retinol and bcarotene in the AIDS group compared with the control group.
T. R. Beraldo Battistini et al. / Nutrition 26 (2010) 612–616 Table 4 Correlation among lipodystrophy, lipid profile, insulin resistance, and lipid peroxidation in AIDS-infected children and adolescents, and retinol and carotenoid deficiencies P Retinol <1.05 mmol/L (n ¼ 18)
Variable
LDL cholesterol (n ¼ 6) HDL cholesterol (n ¼ 4) Triacylglycerols (n ¼ 13) TBARS (n ¼ 2) HOMA-IR (n ¼ 1) Lipodystrophy (n ¼ 16)
b-Carotene P* <0.10 mmol/L (n ¼ 7)
130 mg/dL
4 (22.2%)
0.545 1 (14.3%)
0.567
45 mg/dL
3 (16.7%)
0.632 2 (28.6%)
0.225
130 mg/dL
3 (16.7%)
0.392 5 (71.4%)
0.532
>5.0 nmol/L >3
0 (0%) 1 (5.5%)
0.423 0 (0%) 0.600 0 (0%)
0.769 0.767
0.529 3 (42.8%)
0.675
Present
10 (55.5%)
AIDS, acquired immunodeficiency syndrome; HDL, high-density lipoprotein; HOMA-IR, homeostasis model assessment for insulin resistance; LDL, lowdensity lipoprotein; TBARS, thiobarbituric acid-reactive substances * Level of significance of chi-square test.
The levels of these micronutrients may be compromised due to several factors: direct action of the virus, type of antiretroviral therapy, low socioeconomic level, poor intake or absorption, lack of adequate nutritional counseling, or drug side effects affecting appetite [39]. Reduced absorption and high losses may also negatively affect nutritional status in terms of retinol and carotenoids [7]. Furthermore, it is noteworthy that the use of highly active antiretroviral therapy and the resulting marked improvement in the clinical evolution of patients have been correlated with improvement of nutritional status of various micronutrients, although such benefits have not yet been proven for retinol [39]. Vitamin A deficiency, a frequent finding in HIV-infected children, is associated with exacerbation of oxidative stress [40], decrease in CD4þ cells, ad increase in HIV-related morbidities, accelerated disease progression owing to greater activation of nuclear factor-kB, and higher mortality [39,41]. No correlation between low retinol and b-carotene levels and higher occurrence of lipid peroxidation and changes in lipid and glucose metabolism was observed in the AIDS group. We propose a number of hypotheses to explain this finding: the young age of the population studied; the small number of patients included; the limitation in the design of the study (cross sectional); a possible role of other vitamins integrated and synergically involved in antioxidant defense, such as vitamins C and E [42,43]; and the lack of an ideal biochemical marker of oxidative stress related to lipid peroxidation [44]. Although some researchers have advocated the benefits of micronutrient supplementation as a coadjuvant therapy in HIVinfected patients, no consensus has yet been reached in terms of dosage and safety, particularly among the pediatric population. There are also limitations in interpreting the results of the studies available: most studies published to date were not adjusted for inflammation markers and have focused largely on biochemical outcomes (modification of sera/plasma levels) rather than clinical outcomes (disease progression and mortality) [10,11]. Indeed, studies in children and adolescents are particularly scarce and inconclusive, perhaps due to the small samples involved. Conclusions Despite the high frequency of dyslipidemia, lipodystrophy, and retinol and b-carotene deficiencies, it was not possible to demonstrate a correlation of these findings with lipid
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peroxidation and insulin resistance. More studies are needed to investigate the causes of retinol and b-carotene deficiencies in this population and the clinical consequences of these findings.
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