Lipodystrophy in children and adolescents with acquired immunodeficiency syndrome and its relationship with the antiretroviral therapy employed

Abstracts

OBJETIVO: Avaliar a presença de lipodistrofia clínica em crianças com síndrome da imunodeficiência adquirida e relacioná-la com o esquema antirretroviral utilizado, alterações do perfil lipídico e resistência insulínica. MÉTODOS: Por meio de estudo transversal, foram avaliadas 30 crianças e adolescentes (mediana de idade = 9,1 anos) com síndrome da imunodeficiência adquirida, no período entre 2004 e 2005. As avaliações clínico-laboratoriais incluíram: classificação da infecção pelo HIV, medidas antropométricas (peso e estatura), glicemia e insulina séricas e perfil lipídico (LDL-c, HDL-c, triglicérides). A lipodistrofia foi definida por parâmetros clínicos. O teste do qui-quadrado foi utilizado na análise estatística. RESULTADOS: Todos os pacientes recebiam terapia antirretroviral regularmente (mediana de tempo de uso = 28,4 meses), 80% utilizavam três drogas em associação (terapia fortemente ativa) e 30% usavam inibidores de protease. Lipodistrofia e dislipidemia foram observadas em 53,3 e 60% dos pacientes, respectivamente. Crianças que utilizavam terapia fortemente ativa com inibidor de protease apresentaram maior percentual de lipodistrofia mista, com diferença estatisticamente significante em relação ao grupo com terapia fortemente ativa sem inibidor de protease e ao grupo sem terapia fortemente ativa (44,4 versus 16,7%; p = 0,004). Não se observou diferença estatisticamente significante entre presença de lipodistrofia e gênero, idade (> 10 anos), alterações do perfil lipídico e resistência insulínica. CONCLUSÕES: A elevada prevalência de dislipidemia e lipodistrofia verificada nas crianças com síndrome da imunodeficiência adquirida, mostrando relação com o esquema antirretroviral empregado, pode significar um risco elevado para o desenvolvimento futuro de complicações, especialmente as cardiovasculares.

Síndrome da imunodeficiência adquirida; lipodistrofia; dislipidemias; pediatria; agentes antirretrovirais

ORIGINAL ARTICLE

Lipodystrophy in children and adolescents with acquired immunodeficiency syndrome and its relationship with the antiretroviral therapy employed

Roseli Oselka Saccardo Sarni^I; Fabíola Isabel Suano de Souza^II; Tânia Regina Beraldo Battistini^III; Tassiana Sacchi Pitta^IV; Ana Paula Fernandes^IV; Priscila Chemiotti Tardini^V; Fernando Luis Affonso Fonseca^VI; Valter Pinho dos Santos^VII; Fábio Ancona Lopez^VIII

^IDoutora, Medicina, Universidade Federal de São Paulo – Escola Paulista de Medicina (UNIFESP-EPM), São Paulo, SP, Brazil. Professora assistente e coordenadora, Serviço de Nutrologia, Departamento de Pediatria, Faculdade de Medicina do ABC (FMABC), Santo André, SP, Brazil. Médica, Disciplina de Alergia, Imunologia e Reumatologia Clínica, UNIFESP-EPM, São Paulo, SP, Brazil.

^II Mestre, Ciências, UNIFESP-EPM, São Paulo, SP, Brazil. Médica colaboradora, Serviço de Nutrologia, Departamento de Pediatria, FMABC, Santo André, SP, Brazil.

^IIIMestre, Ciências, UNIFESP-EPM, São Paulo, SP, Brazil. Nutricionista colaboradora, Serviço de Nutrologia, Departamento de Pediatria, FMABC, Santo André, SP, Brazil.

^IVAcadêmica de Medicina (6º ano), FMABC, Santo André, SP, Brazil.

^VAcadêmica de Medicina (5º ano), FMABC, Santo André, SP, Brazil.

^VIDoutor, Farmácia, Universidade de São Paulo (USP), São Paulo, SP, Brazil. Professor assistente, Curso de Farmácia, FMABC, Santo André, SP, Brazil.

^VIIDoutor, Medicina, UNIFESP-EPM, São Paulo, SP, Brazil. Professor assistente, Departamento de Pediatria, FMABC, Santo André, SP, Brazil.

^VIIIProfessor titular, Disciplina de Nutrologia, Departamento de Pediatria, UNIFESP-EPM, São Paulo, SP, Brazil.

ABSTRACT

OBJECTIVE: To evaluate the presence of clinical lipodystrophy in children with the acquired immunodeficiency syndrome and to relate it to the antiretroviral regimen employed, to changes in lipid profile and to insulin resistance.

METHODS: This was a cross-sectional study that evaluated 30 children and adolescents (median age = 9.1 years) with the acquired immunodeficiency syndrome during 2004 and 2005. The following clinical and laboratory evaluations were performed: classification of HIV infection, anthropometric measurements (weight and height), serum glycemia, serum insulin and lipid profile (LDL-c, HDL-c, triglycerides). Lipodystrophy was diagnosed using clinical parameters. The chi-square test was used for statistical analysis.

RESULTS: All of the patients were taking antiretroviral therapy regularly (median duration of 28.4 months); 80% were on three drugs in combination (highly active therapy) and 30% were on protease inhibitors. Lipodystrophy and dyslipidemia were observed in 53.3 and 60% of the patients, respectively. Children on a highly active therapy regimen with protease inhibitors exhibited a higher percentage of mixed lipodystrophy; the difference between these children and the group on highly active therapy without protease inhibitors and the group not on a highly active therapy was statistically significant (44.4 vs. 16.7%; p = 0.004). There was no statistically significant association between the presence of lipodystrophy and sex, age (> 10 years), changes to the lipid profile or insulin resistance.

CONCLUSIONS: The elevated prevalence of dyslipidemia and lipodystrophy observed among children with acquired immunodeficiency syndrome, which exhibited a relationship with the antiretroviral regimen employed, may represent an increased risk for future complications, in particular cardiovascular problems.

Keywords: Acquired immunodeficiency syndrome, lipodystrophy, dyslipidemias, pediatrics, antiretroviral agents.

Introduction

Advances in the treatment of children with acquired immunodeficiency syndrome (AIDS), including the use of highly active antiretroviral therapy (HAART) have made it possible to achieve significant suppression of viral replication with consequent reductions in morbidity and mortality and improvements in patient quality of life. Currently, HAART is recommended for the initial treatment of HIV infections in children.

¹ However, these drugs have been linked with the development of metabolic abnormalities that in conjunction are known as HIV lipodystrophy syndrome and which are characterized by increased plasma levels of atherogenic lipoproteins, insulin resistance, diabetes and redistribution of body fat in both adults and children.

^2,3

Lipid abnormalities associated with the use of antiretroviral drugs are common and are most strongly related to treatment with ritonavir, efavirenz and d4T.^2,4 Insulin resistance has also been found in 8 to 10% of adult patients with AIDS.⁵ The presence of lipid and glucose metabolism abnormalities may lead to an increased risk for the development of noninfectious chronic diseases, such as atherosclerotic disease, which begins during childhood.⁶

Another adverse event related to the increased cardiovascular risk resulting from the use of antiretroviral therapy is mitochondrial toxicity, which leads to an increase in production of reactive oxygen species, resulting in exacerbation of oxidative stress, especially when accompanied by compromised antioxidant defense.⁷

From 20 to 50% of children with AIDS treated with HAART, including protease inhibitors, develop dyslipidemia(s), the most common of which is elevated total cholesterol and LDL.⁸ In adults with HIV, dyslipidemia is associated with an increased risk of developing cardiovascular diseases. There is no consensus on the treatment for dyslipidemia(s) in children with AIDS. However, it is worthy of note that treatment with statins, especially in high doses, in association with protease inhibitors, increases the risk of myositis/myolysis.⁸

With relation to the lipodystrophy syndrome, studies indicate that the prevalence is 25 to 30% among the pediatric population with AIDS and that the mean time taken for abnormalities to appear after starting HAART is between 7 and 31 months. Clinical diagnosis of lipodystrophy, widely used in practice, underestimates the redistribution of body fat when compared with specific tests for the same purpose, such as dual-energy X-rays (DXA).⁹

There have been few studies evaluating the relationship between redistribution of body fat assessed clinically (lipodystrophy) and lipid and glucose metabolism abnormalities in children with AIDS. It is against this background that this study was carried out with the objective of evaluating the presence of clinical lipodystrophy in children with AIDS and relating it to their antiretroviral regimens, lipid profile abnormalities and insulin resistance.

Methods

This was a cross-sectional study carried out in 2004 and 2005, with 30 children and adolescents with AIDS, of both sexes, aged 4 to 14 years and being seen regularly at the Pediatric Infectology Clinic at the Faculdade de Medicina do ABC (FMABC) in Santo André, SP, Brazil and at the São Bernardo do Campo Referral Center, SP, Brazil. The study was approved by the Research Ethics Committees at the FMABC and the Universidade Federal de São Paulo, and prior written consent was obtained from patients' parents or guardians. The protocol being used to treat HIV infection was that proposed by the Centers for Disease Control and Prevention.

¹⁰

Children and adolescents were excluded if they were on corticosteroids, if they had suffered severe disease or been admitted to hospital during the 3 months prior to starting the study or if they had other chronic diseases such as heart disease, kidney disease, neuropathy, rheumatic diseases, lung disease or liver disease.

At the time that the study was carried out, there were 38 patients with AIDS being treated at the two services named above and who met the inclusion criteria and did not present any of the exclusion criteria; seven parents or guardians either did not give consent or did not attend after three invitations and one adolescent was excluded after chronic lung disease was detected.

A standardized questionnaire was administered to the group of AIDS patients, collecting data on identification, type of transmission, prophylaxis, breastfeeding, age at diagnosis of infection, regimen and duration of antiretroviral therapy at time of enrollment on the study, viral load and CD4 count (taken at a maximum of 3 months before or after the study outset).

Socioeconomic assessments were made using the Brazilian Economic Classification Criteria (Critério de Classificação Econômica Brasil), which is based on family spending power and the head of the family's level of education.11 The patients' living conditions and environment were also taken into account.¹²

Anthropometric measurements (weight, height) and classification of nutritional status were carried out in accordance with World Health Organization recommendations.13 Therefore, malnutrition and/or short stature were defined as a z score < 2 for body mass index and/or height/age.¹⁴

Puberty staging was carried out by a single pediatrician using the criteria proposed by Marshall & Tanner for both sexes (breasts and testicular development).¹⁵

A diagnosis of clinical lipodystrophy was made when two independent examiners detected either lipoatrophy (reduced fat in peripheral areas, such as arms, legs and buttocks, and relatively prominent muscles and veins), lipohypertrophy (accumulation of fat in the abdominal region, dorsal gibbosity, gynecomastia and increased breast size in adolescents/females) or a combination of lipoatrophy and lipohypertrophy.¹⁶

Peripheral venipuncture was used to collect 10 mL of blood from each patient after 12 hours' fasting in order to assay the following:

- Lipid profile, using the BioExpress Plus (Bayer) enzymatic-colorimetric kit. Triglycerides, HDL-c and LDL-c were classified according to the cutoff points proposed by the National Cholesterol Education Program.17

- Serum insulin, with the IMMULITE chemiluminescence insulin kit (DPC MedLab).

- Serum glycemia, using the BioExpress Plus (Bayer) enzymatic-colorimetric kit.

Insulin and glycemia results were used to calculate the homeostasis model assessment (HOMA-IR), with insulin resistance defined as HOMA-IR > 3.0.¹⁸

The Statistical Package for the Social Sciences (SPSS) version 13.0 was used for statistical analysis.19 Anthropometric indicators were calculated using the software program Epi-Info 2000 version 3.3.2.20 frequency tables were used to describe categorical and bivariate variables and the chi-square test was used to evaluate differences between percentages of abnormal test results for categorical variables. The significance cutoff adopted was α < 0.05.

Results

Table 1 contains the general characteristics of the 30 children and adolescents with AIDS enrolled on the study. Fourteen (46.7%) of them were male and the mean age was 9.1 years (±2.5 years). The majority of them were prepubescent (n = 22, 73.3%) and the most common socioeconomic class was C (n = 18, 60%). With relation to nutritional status, four (13.3%) of the children and adolescents with AIDS had a z score of < -2 for weight/height, four (13.3%) for height/age and one (3.3%) for the ratio between weight/height and height/age.

All of the children and adolescents with AIDS contracted the infection by vertical transmission. Twenty-seven (90%) of them did not receive any type of prophylaxis and 24 (84%) were breastfed. The median age of the children and adolescents at diagnosis of AIDS was 4.5 years (minimum-maximum: 2-12 years) and the most frequent diagnosis stage was B1 (n = 13, 43.3%). The median time on the regimen in use at study outset was 28.4 months (minimum-maximum: 7.0-85.2). Twenty-four of the 30 (80%) patients were on three drugs in combination, and nine (30%) were taking at least one protease inhibitor (Table 2). All of the children taking protease inhibitors were also on HAART. Table 2 provides details on the antiretroviral therapies the children and adolescents were on together with presence/absence and type of lipodystrophy.

With relation to the lipid profile, 18 (60%) of the children and adolescents with AIDS exhibited some type of abnormality. Abnormal LDL-c, HDL-c and triglycerides were observed in 20, 13.3 and 43.3% of the children with AIDS, respectively.

Clinical lipodystrophy was observed in 16 (53.3%) of the children with AIDS. Four children (13.3%) exhibited mixed lipodystrophy, and 12 (40.0%) had lipohypertrophy.

Children who were on HAART regimens with protease inhibitors exhibited a greater percentage of mixed lipodystrophy, with the difference between them and the other groups being statistically significant (44.4 vs. 16.7%; p = 0.004) (Figure 1).

There were no statistically significant differences observed in terms of presence of lipodystrophy among the children and adolescents related to sex, age > 10 years, presence of dyslipidemia(s) (LDL-c, HDL-c and triglycerides) or insulin resistance (Table 3).

Discussion

In this study we found dyslipidemia in 60% of a group of children and adolescents infected with HIV. The prevalence of hypertriglyceridemia found in our study (43.3%) was greater than observed in a pediatric cohort study carried out in Houston (28%), but lower than the prevalence observed in a Mexican study (79.2%).

^21,22

In individuals infected by HIV, dyslipidemia is the result of the combination of infection by the virus, the effect of antiretroviral drugs and genetic factors. The HIV infection itself is associated with a proatherogenic lipid profile characterized by increased triglycerides and a concentration of the lower density particles of the LDL fraction of cholesterol and a reduction in HDL C levels.^23,24

When compared with indinavir, nelfinavir and atazanavir, ritonavir is the protease inhibitor most associated with lipid profile abnormalities.²⁵ With relation to non-nucleoside reverse transcriptase, studies suggest that using nevirapine leads to fewer lipid profile abnormalities than efavirenz. Among the nucleoside analog reverse transcriptase inhibitors, more lipid profile abnormalities have been observed in association with d4T than with tenofovir and abacavir.²³

A recent cohort study found that, after adjusted multifactorial analysis, there was a relationship between the use of protease inhibitors, the development of lipodystrophy and acute myocardial infarction in adults.²⁶

Human immunodeficiency virus infections can result in chronic oxidative stress with apoptosis of T-lymphocytes and increases in viral replication rates due to activation of nuclear factor kappa B. Furthermore, mitochondrial toxicity, which is an adverse event observed with antiretroviral drugs, can contribute to exacerbation of oxidative stress. This toxicity may be responsible for the lipodystrophy that is associated with the use of highly active antiretroviral therapy (HAART). Adult patients starting HAART regimens frequently develop increased central adiposity and a reduction in lean mass during the first 24 weeks of treatment and may develop insulin resistance, dyslipidemia and peripheral lipoatrophy after 6 months on the treatment.^27,28

In this study, we observed that children with AIDS who were on HAART with protease inhibitors exhibited a greater frequency of clinical lipodystrophy than those on regimens without protease inhibitors and than controls. Although the mechanisms by which protease inhibitors lead to lipodystrophy syndrome have not been entirely elucidated, some hypotheses have been proposed: mitochondrial damage; compromised pre-adipocyte differentiation, leading to adipocyte apoptosis in certain regions; reductions in transcription factors related to adipogenesis; increased expression and secretion of the proinflammatory cytokines (tumor necrosis factor α and interleukin 6) involved in modifying adipocyte function and reducing adiponectin; increases in leptinemia associated with the accumulation of central fat and insulin resistance; and increased levels of visfatin and retinol binding protein 4.^6,29

We did not observe a relationship between clinical lipodystrophy and lipid and glucose metabolism abnormalities in these children and adolescents with AIDS. In order to explain this finding, we developed some hypotheses: the low age of the study population; limitations due to the study methodology (cross-sectional), which did not allow for evaluation of the development of the parameters studied over time; and limitations of the clinical examination method used to assess body fat redistribution, without supplementary tests such as DXA.⁹

The importance of early identification of lipodystrophy syndrome lies in the fact that it is related to future development of cardiovascular events.^26,30 The redistribution of body fat may also prejudice compliance with treatment, causing depression and low self-esteem, especially among adolescents. Few studies have dealt with prevention and treatment of redistribution of body fat and lipodystrophy syndrome in the pediatric age group.⁹

Bearing in mind the high frequency of dyslipidemia and lipodystrophy found in this study population, indicating a relationship with the antiretroviral regimen employed, it is pertinent to emphasize the importance of multidisciplinary care for children and adolescents with AIDS, including wide-ranging nutritional education and lifestyle changes, in order to minimize the risk of the development of future complications, such as cardiovascular diseases.

References

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Correspondence

Publication Dates

• Publication in this collection
  10 Sept 2009
• Date of issue
  Aug 2009

History

• Accepted
  15 Apr 2009
• Received
  05 Jan 2009