Lipodystrophic syndrome of HIV and associated factors: a study in a university hospital

Lídia Laís Gomes Silva Eryka Maria dos Santos Luciana Caroline Paulino do Nascimento Mikaella Carla de França Cavalcanti Ilma Kruze Grande de Arruda Marcella Campos Lima Luz Poliana Coelho Cabral About the authors

Abstract

The use of antiretroviral drugs has increased the survival of HIV patients, but may have side effects, such as lipodystrophic syndrome. This article aims to identify the frequency of the lipodystrophic syndrome and its associated factors in patients with HIV using antiretroviral therapy. It involved a cross-sectional study with HIV patients, monitored on an outpatient basis. The syndrome was evaluated by the association of two parameters: peripheral weight loss through the lipodystrophy severity scale and central fat accumulation, measured by the hip waist ratio. Poisson regression analysis was performed to identify the associated variables. Of the 104 patients evaluated, 27.9% presented the syndrome. After adjustment, the female sex (PRadjusted = 2.16 CI95% 1.43-3.39), being overweight (PRadjusted = 2.23 CI95% 1.35-2.65) and a longer period of use of antiretrovirals (PRadjusted = 1.64 CI95% 1.16-2.78), remained positively associated with the syndrome. On the other hand, a negative association with CD4 count £ 350 (PRadjusted = 0.39 CI95% 0.10-0.97) was observed The high prevalence of the syndrome and its association with specific groups reinforce the need for adequate follow-up and early identification to intervene in modifiable factors.

Key words
Lipodystrophy; AIDS; Anthropometry; Antiretroviral therapy

Introduction

Treatment for infection by the human immunodeficiency virus (HIV) involves antiretroviral therapy (ART), which inhibits the replication of the virus and is a benchmark in therapy for acquired immunodeficiency syndrome (AIDS), increasing the life expectancy of affected individuals11 Weiss R. Special Anniversary Review: Twenty-five years of human immunodeficiency virus research: successes and challenges. Clin Exp Immunol 2008; 152(2):201-210.. In Brazil, the public healthcare system offers these medications, which has enabled an increasing number of individuals living with HIV HIV) to obtain treatment, as a 53.2% increase in cases was recorded between 2009 and 201422 Brasil. Ministério da Saúde (MS). Boletim Epidemiológico - Aids e DST 2015; 1(1):1-100..

However, the living conditions of these patients is a major concern of the World Health Organization (WHO). Despite the longer survival, the use of ART has numerous side effects, including HIV-associated lipodystrophy. This outcome is associated with greater cardiovascular risk, morbidity and mortality and also alters body esthetics, which can compromise one’s self-esteem, leading to a reduction in adherence to therapy33 Carr A, Samaras K, Burton S, Law M, Freund J, Chisholm DJE, Cooper DA. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS 1998; 12(7):F51-F58.,44 Santos CP, Felipe YX, Braga PE, Ramos D, Lima ROE, Segurado AC. Self-perception of body changes in persons living with HIV/AIDS: prevalence and associated factors. AIDS 2005; 19(Supl. 4):S14-S21..

Lipodystrophy is defined as a combination of the loss of peripheral fat (lipoatrophy) and the accumulation of central fat (lipohypertrophy). It was first denominated a syndrome in 1998 and includes metabolic disorders55 Tien PC, Cole SR, Williams CM, Li, R, Justman JE, Cohen MH, Young M, Rubin N, Augenbraun ME, Grunfeld C. Incidence of Lipoatrophy and Lipohypertrophy in the Women's Interagency HIV Study. J Acquir Immune Defic Syndr 2003; 34(5):461-466.,66 Wohl DA, Mccomsey G, Tebas P, Brown TT, Glesby MJ, Reeds D, Shikuma C, Mulligan K, Dube M, Wininger D, Huang J, Revuelta M, Currier J, Swindells S, Fichtenbaum C, Basar M, Tungsiripat M, Meyer W, Weihe JE, Wanke C. Current Concepts in the Diagnosis and Management of Metabolic Complications of HIV Infection and Its Therapy. Clin Infect Dis 2006; 43(5):645-653..

The prevalence of HIV-associated lipodystrophy ranges from 10 to 80%. This broad range is related to geographic, age, genetic and lifestyle factors as well as the different methods employed for the diagnosis77 Jacobson DL, Knox T, Spiegelman D, Skinner S, Gorbach S, Wanke C. Prevalence of, Evolution of, and Risk Factors for Fat Atrophy and Fat Deposition in a Cohort of HIV-Infected Men and Women. Clin Infect Dis 2005; 40(12):1837-1845.

8 Carr A. Lactic Acidemia in Infection with Human Immunodeficiency Virus. Clin Infect Dis 2003; 36(s2):S96-S100.

9 Heath KV, Hogg RS, Chan KJ, Harris M, Montessori V, O'shaughnessy MV, Montaner JSG. Lipodystrophy-associated morphological, cholesterol and triglyceride abnormalities in a population-based HIV/AIDS treatment database. AIDS 2001; 15(2):231-239.
-1010 Leitz G, Robinson P. The development of lipodystrophy on a protease inhibitor-sparing highly active antiretroviral therapy regimen. AIDS 2000; 14(4):468.. Indeed, there is no consensus on the diagnostic method for HIV-associated lipodystrophy and several methodological approaches have been used1111 Mutimura E, Stewart A, Crowther NJ. Assessment of quality of life in HAART-treated HIV-positive subjects with body fat redistribution in Rwanda. AIDS Res Ther 2007; 4(1):19.

12 Monnerat BZ, Cerutti Junior C, Caniçali SC, Motta TR. Clinical and biochemical evaluation of HIV-related lipodystrophy in an ambulatory population from the Hospital Universitário Cassiano Antonio de Morais, Vitória, ES, Brazil. Braz J Infect Dis 2008; 12(4):364-368.

13 Anjos EMD, Pfrimer K, Machado AA, Cunha SFDC, Salomão RG, Monteiro JP. Nutritional and metabolic status of HIV-positive patients with lipodystrophy during one year of follow-up. Clinics 2011; 66(3):407-410.
-1414 Kroll AF, Sprinz E, Leal SC, Labrêa MDG, Setúbal S. Prevalence of obesity and cardiovascular risk in patients with HIV/AIDS in Porto Alegre, Brazil. Arq Bras Endocrinol Metabol 2012; 56(2):137-141.. The administration of questionnaires that use self-reported information to complement the examination of a health professional could facilitate the early identification of body changes. After this clinical assessment, anthropometry is generally performed to determine the occurrence of changes in the distribution of fat for the subsequent diagnosis of lipodystrophy1515 Joly V, Flandre P, Meiffredy V, Leturque N, Harel M, Aboulker J, Yeni P. Increased risk of lipoatrophy under stavudine in HIV-1-infected patients. AIDS 2002; 16(18):2447-2454.,1616 Milinkovic A, Martinez E. Current perspectives on HIV-associated lipodystrophy syndrome. J Antimicrob Chemother 2005; 56(1):6-9..

Although there is no reliable parameter that reflects changes in fat distribution specific to HIV-associated lipodystrophy, some authors have used the waist-to-hip ratio (WHR)1717 Brasil. Ministério da Saúde (MS). Síndrome Lipodistrófica em HIV. Brasília: MS; 2011., which is correlated with total abdominal fat determined by computed tomography and offers the advantage of not requiring sophisticated equipment1818 Florindo AA, Latorre MRDO, Santos ECM, Borelli A, Rocha MS, Segurado AAC. Validation of methods for estimating HIV/AIDS patients' body fat. Rev Saude Publica 2004; 38(5):643-649..

The pathogenesis of lipodystrophy in individuals living with HIV is multifactorial and has not yet been fully clarified. Although initially related to the type of ART and duration of use, other factors have also been investigated, such as HIV infection itself, genetic factors, lifestyle factors, the severity of markers of the disease, the T-CD4+ lymphocyte count and viral load. These factors can lead to metabolic disorders, such as dyslipidemia, and a change in the metabolism of glucose, resulting in cardiovascular complications1717 Brasil. Ministério da Saúde (MS). Síndrome Lipodistrófica em HIV. Brasília: MS; 2011.,1919 Hengel R, Watts N, Lennox J. Benign symmetric lipomatosis associated with protease inhibitors. Lancet 1997; 350(9091):1596.

20 Carvalho EH, Miranda Filho DDB, Ximenes RADA, Albuquerque MDFPM, Melo HRL, Gelenske T, Medeiros ZDB, Montarroyos EU, Bandeira F. Prevalence of Hyperapolipoprotein B and Associations with Other Cardiovascular Risk Factors Among Human Immunodeficiency Virus-Infected Patients in Pernambuco, Brazil. Met Synd Rel Dis 2010; 8(5):403-410.

21 Gasparotto AS, Sprinz E, Lazzaretti RK, Kuhmmer R, Silveira JM, Basso RP, Pinheiro CA, Silveira MF, Ribeiro JP, Mattevi VS. Genetic polymorphisms in estrogen receptors and sexual dimorphism in fat redistribution in HIV-infected patients on HAART. AIDS 2012; 26(1):19-26.
-2222 Soares LR, Silva DCD, Gonsalez CR, Batista FG, Fonseca LAM, Duarte AJE, Casseb J. Discordance between body mass index and anthropometric measurements among HIV-1-infected patients on antiretroviral therapy and with lipoatrophy/lipohypertrophy syndrome. Rev Inst Med Trop São Paulo 2015; 57(2):105-110..

It is therefore relevant to identify lipodystrophy syndrome and its frequency to enable interventions targeting modifiable associated factors to improve the health management of individuals with HIV in treatment with ART. Thus, the aim of the present study was to identify the frequency of lipodystrophy syndrome and associated factors in individuals living with HIV in treatment with antiretroviral therapy.

Methods

A cross-sectional study was conducted with individuals in outpatient care at the Infectious-Parasitic Diseases Clinic of the hospital of the Universidade Federal de Pernambuco between March and July 2017. The sample was composed of all patients who met the eligibility criteria for the study in this period. Male and female patients ≥ 20 years of age in treatment with ART for at least six months were included. Individuals unable to answer the questionnaires due to dementia or a low level of consciousness, those unable to undergo the anthropometric examination, those with edema and/or ascites and pregnant women were excluded from the study.

A standardized form was used for the collection of socio-demographic, clinical, biochemical, anthropometric and lifestyle data. Interviews and the nutritional assessment were performed in accordance with the availability of the individual and conducted by a nutritionist. The researcher did not at any time intervene or express an opinion that could interfere with the answers or results of the study.

The diagnosis of HIV-associated lipodystrophy was determined by two parameters: peripheral fat loss, evaluated using the Lipodystrophy Severity Scale, and the accumulation of central fat, measured by the WHR. Patients with both these criteria were identified as having lipodystrophy syndrome.

The Lipodystrophy Severity Scale was adapted from Carr et al.2323 Carr A, Samaras K, Burton S, Law M, Freund J, Chisholm D, Cooper DA. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS 1998; 12(7):F51-F58. for the evaluation of the presence/absence of peripheral fat loss (upper and lower limbs). For such, the patients classified the degree of fat loss as none (score: 0), mild (score: 1), moderate (score: 2) or severe (score: 3). Peripheral fat loss was recorded when a patient attributed a score of 1 to 3 in both regions (arms and legs). For the determination of the accumulation of central fat, the WHR was used considering the classification proposed by the Brazilian Health Ministry1717 Brasil. Ministério da Saúde (MS). Síndrome Lipodistrófica em HIV. Brasília: MS; 2011., which establishes a cutoff point of ≥ 1.0 for males and ≥ 0.85 for females.

Sociodemographic variables were classified as follows: sex (female; male); age (20 to 44; ≥ 45 years), schooling (£ nine; > 9 years of study); income (< R$ 1000; ≥ R$ 1000) and ethnicity/skin color (white; non-white).

Nutritional status was defined using the body mass index (BMI). Weight and height were determined using the methods recommended by Lohman et al.2424 Lohman TG, Martorell R, Roche AF. Anthropometric standardization reference manual. Human Kinetics Books. Champaign: Ill; 1988.. The BMI was then calculated and classified using the recommendations of the WHO2525 World Health Organization (WHO). Obesity. Preventing and Managing the Global Epidemic. Report of a WHO Consultation on Obesity. Geneva: WHO; 1997., with ≥ 25 kg/m² considered indicative of excess weight.

The following clinical and laboratory variables were considered: CD4+ count, viral load, lipid profile, fasting glucose, time since diagnosis, class of ART and duration of treatment with ART. The CD4+ count was categorized as > 350 or £ 350 cells/mm33 Carr A, Samaras K, Burton S, Law M, Freund J, Chisholm DJE, Cooper DA. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS 1998; 12(7):F51-F58.; viral load was categorized as > 40 or £ 40 copies/ml; lipid profile was determined based on the 5th Brazilian Guidelines for Dyslipidemia and the Prevention of Atherosclerosis2626 Xavier HT, Izar MC, Faria Neto JR, Assad MH, Rocha VZ, Sposito AC, Fonseca FA, dos Santos JE, Santos RD, Bertolami MC, Faludi AA, Martinez TLR, Diament J, Guimarães A, Forti NA, Moriguchi E, Chagas ACP, Coelho OR, Ramires JAF. V Diretriz Brasileira de Dislipidemias e Prevenção da Aterosclerose. Arq Bras Cardiol 2013; 101(4 Supl. 1):1-20.; fasting glucose was considered altered when ≥ 100 mg/dL and unaltered when < 100 mg/dL. Time since diagnosis and duration of treatment with ART were categorized as > 60 months and £ 60 months; class of ART was categorized as two types of nucleoside analog reverse-transcriptase inhibitor (NARTI) combined with a non-nucleoside reverse-transcriptase inhibitor (NNRTI) or two types of NARTI combined with a protease inhibitor.

Regarding lifestyle variables, alcohol use was categorized as absent/present regardless of the quantity and quality of the beverages; smoking was categorized as smoker, ex-smoker and non-smoker; and physical activity was investigated using the short version of the International Physical Activity Questionnaire (IPAQ), with the classification of the individual as sedentary, insufficiently active, active or very active2727 Finkelstein JL, Gala P, Rochford R, Glesby MJ, Mehta S. HIV/AIDS and lipodystrophy: Implications for clinical management in resource-limited settings. J Int AIDS Soc 2015; 18(1):19033..

This study was conducted in accordance with the ethical norms for research involving human subjects stipulated in Resolution 466/12 of the Brazilian National Board of Health and received approval from the Human Research Ethics Committee of Universidade Federal de Pernambuco.

Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS), version 13.0, and Stata, version 7.0. Poisson regression analysis with robust variance was performed to determine factors associated with HIV-associated lipodystrophy, calculating prevalence ratios (PR) and 95% confidence intervals (CI). All variables with a p-value < 0.20 in the unadjusted bivariate analysis, determined using either the chi-square test with Yates correction or the linear trend chi-square test, were incorporated into the multivariate analysis using the stepwise method. Only variables with a p-value < 0.05 after the adjustments remained in the final model.

Results

Among the 104 individuals living with HIV who participated in the present study, 68.3% were men, mean age was 41.11 ± 11.46 years and 27.9% (n = 29) had HIV-associated lipodystrophy (Table 1). Some missing data occurred for the following variables: income, schooling, ART, viral load, CD4+ count, total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, excess weight and fasting glucose.

Table 1
Associations between lipodystrophy syndrome and sociodemographic and lifestyle variables in HIV+ patients at an outpatient clinic of a university hospital in the city of Recife, Brazil, 2017.

Among the sociodemographic and lifestyle variables, only the female sex had a greater probability of lipodystrophy (PR = 2.31, p = 0.013) in the bivariate analysis (Table 1). Among the clinical variables, patients with a CD4+ count £ 350 had a lower probability of lipodystrophy (PR = 0.26, p = 0.037). In contrast, patients with excess weight had a threefold greater chance of having lipodystrophy (PR = 3.20 p = 0.002) (Table 2). Other variables, such as age ³ 45 years, hypercholesterolemia, time since diagnosis > 60 months and duration of ART > 60 months, had a p-value < 0.20 in the unadjusted bivariate analysis and were therefore incorporated into the multivariate analysis.

Table 2
Associations between lipodystrophy syndrome and clinical and anthropometric variables in HIV+ patients at an outpatient clinic of a university hospital in the city of Recife, Brazil, 2017.

In the multivariate Poisson regression analysis adjusted by the explanatory variables, the female sex (PRadjusted = 2.16, CI95%: 1.43 to 3.39), excess weight (PRadjusted = 2.23, CI95%: 1.35 to 2.65) and longer duration of ART (PRadjusted = 1.64, CI95%: 1.16 to 2.78) remained positively associated with lipodystrophy syndrome. In contrast, a negative association with CD4+ count £ 350 was found (PRadjusted = 0.39, CI95%: 0.10 to 0.97) (Table 3).

Table 3
Poisson regression with crude and adjusted prevalence ratios of factors associated with lipodystrophy syndrome in HIV+ patients at an outpatient clinic of a university hospital in the city of Recife, Brazil, 2017.

Discussion

Themajor studies on metabolic complications of the use of ART have mainly been conducted in high-income countries. However, there has been an increase in studies evaluating the short-term and long-term effects of ART in middle-income and low-income countries2828 Grinspoon S, Carr A. Cardiovascular Risk and Body-Fat Abnormalities in HIV-Infected Adults. N Engl J Med 2005; 352(1):48-62..

Knowledge regarding the health status and the occurrence of complications in individuals living with HIV in the local population enables the identification of patients at risk and the guidance of prevention methods. Several complications, such as lipodystrophy, can predispose these individuals to cardiovascular risk, impacting their quality of life and adherence to treatment2929 International Physical Activity Questionnaire (IPAQ) [Internet]. 2001 [cited 2016 Oct 26]. Available from: http://www.ipaq.ki.se/ipaq.htm
http://www.ipaq.ki.se/ipaq.htm...
.

Thus, the purpose of the present study was to evaluate the occurrence of lipodystrophy syndrome in patients using ART. The prevalence of HIV-associated lipodystrophy (27.9%) was similar to the rate described by Della Justina3030 Della Justina LB. Prevalence of HIV-Associated Lipodystrophy in Brazil: A Systematic Review of the Literature. J AIDS Clin 2014; 5:9. (32.4%) in a Brazilian cross-sectional study, also using a combination of subjective and objective methods for the diagnosis in outpatients in ART. In other Brazilian studies, the prevalence ranged from 32 to 68%, which is similar to the range found in other countries (30 to 62%). This broad range in the prevalence of HIV-associated lipodystrophy may be explained by the lack of consensus in the literature regarding the diagnosis of the syndrome44 Santos CP, Felipe YX, Braga PE, Ramos D, Lima ROE, Segurado AC. Self-perception of body changes in persons living with HIV/AIDS: prevalence and associated factors. AIDS 2005; 19(Supl. 4):S14-S21.,1212 Monnerat BZ, Cerutti Junior C, Caniçali SC, Motta TR. Clinical and biochemical evaluation of HIV-related lipodystrophy in an ambulatory population from the Hospital Universitário Cassiano Antonio de Morais, Vitória, ES, Brazil. Braz J Infect Dis 2008; 12(4):364-368.,3131 Ceccato M, Bonolo P, Souza Neto A, Araújo F, Freitas M. Antiretroviral therapy-associated dyslipidemia in patients from a reference center in Brazil. Braz J Med Biol Res 2011; 44(11):1177-1183.,3232 Tien P, Grunfeld C. What is HIV-associated lipodystrophy? Defining fat distribution changes in HIV infection. Curr Opin Infect Dis 2004; 17(1):27-32..

Women had a 2.16-fold greater probability of having lipodystrophy. This association has also been reported in previous studies1111 Mutimura E, Stewart A, Crowther NJ. Assessment of quality of life in HAART-treated HIV-positive subjects with body fat redistribution in Rwanda. AIDS Res Ther 2007; 4(1):19.,3333 Dutra CDT, Moura AKM, Saraiva DA, Dias RM, Oliveira SHD, Frazão ADGF, Libonati RMF. Fatores de risco para doenças cardiovasculares em pacientes com síndrome lipodistrófica do HIV. G&S 2012; 3(3):558.

34 Sacilotto LB. Composição corporal e componentes da síndrome metabólica nos diferentes subtipos de lipodistrofia associada ao HIV [dissertação]. Botucatu: Universidade Estadual Paulista; 2017
-3535 Menezes CN, Maskew M, Sanne I, Crowther NJ, Raal FJ. A longitudinal study of stavudine-associated toxicities in a large cohort of South African HIV infected subjects. BMC Infect Dis 2011; 11:244, with a probability 2.5-fold greater in the female sex3434 Sacilotto LB. Composição corporal e componentes da síndrome metabólica nos diferentes subtipos de lipodistrofia associada ao HIV [dissertação]. Botucatu: Universidade Estadual Paulista; 2017

35 Menezes CN, Maskew M, Sanne I, Crowther NJ, Raal FJ. A longitudinal study of stavudine-associated toxicities in a large cohort of South African HIV infected subjects. BMC Infect Dis 2011; 11:244

36 van Griensven J, Zachariah R, Mugabo J, Reid T. Weight loss after the first year of stavudine-containing antiretroviral therapy and its association with lipoatrophy, virological failure, adherence and CD4 counts at primary health care level in Kigali, Rwanda. Trans R Soc Trop Med Hyg 2010; 104(12):751-757.
-3737 Silva ICD, Sampaio E, Almeida M, Ney Freire, A, Ramos L, Medeiros JMB. Perfil metabólico, antropométrico e lipodistrofia em pessoas vivendo com hiv/aids em uso de terapia antirretroviral. Nutr Clín Diet Hosp 2016; 36(3):38-44.. Such an association may be attributed to physiological differences between the sexes. There is evidence of polymorphism of the estrogen receptor gene in adipose cells in women, suggesting a genetic predisposition to the development of lipoatrophy and/or the accumulation of body fat2121 Gasparotto AS, Sprinz E, Lazzaretti RK, Kuhmmer R, Silveira JM, Basso RP, Pinheiro CA, Silveira MF, Ribeiro JP, Mattevi VS. Genetic polymorphisms in estrogen receptors and sexual dimorphism in fat redistribution in HIV-infected patients on HAART. AIDS 2012; 26(1):19-26.,3838 Pedersen SB, Bruun JM, Hube F, Kristensen K, Hauner H, Richelsen B. Demonstration of estrogen receptor subtypes a and ß in human adipose tissue: influences of adipose cell differentiation and fat depot localization. Mol Cell Endocrinol 2001; 182(1):27-37.,3939 Nyblade L, Pande R, Mathur S, MacQuarrie K, Kidd R, Banteyerga H, Kidanu A, Kilonzo G, Mbwambo J, Bond V. Disentangling HIV and stigma in Ethiopia, Tanzania and Zambia. Washington: International Center for Research on Women; 2003.. Thus, it is important to pay attention to this group, because women, especially those in underdeveloped countries, are less likely to receive healthcare, education and support during treatment, which exerts a further impact on the metabolic consequences4040 Mutimura E, Stewart A, Crowther NJ. Assessment of quality of life in HAART-treated HIV-positive subjects with body fat redistribution in Rwanda. AIDS Res Ther 2007; 4(1):19.,4141 Finkelstein JL, Gala P, Rochford R, Glesby MJ, Mehta S. HIV/AIDS and lipodystrophy: Implications for clinical management in resource-limited settings. J Int Aids Soc 2015; 18(1):19033..

The level of physical activity was not associated with lipodystrophy in the present study. However, the literature reports a high incidence of sedentarism among individuals with HIV-associated lipodystrophy3030 Della Justina LB. Prevalence of HIV-Associated Lipodystrophy in Brazil: A Systematic Review of the Literature. J AIDS Clin 2014; 5:9.,3434 Sacilotto LB. Composição corporal e componentes da síndrome metabólica nos diferentes subtipos de lipodistrofia associada ao HIV [dissertação]. Botucatu: Universidade Estadual Paulista; 2017,4242 Segatto AFM, Freitas Junior IF, Santos VRD, Alves KCP, Barbosa DA, Portelinha Filho AM, Monteiro HL. Lipodystrophy in HIV/AIDS patients with different levels of physical activity while on antiretroviral therapy. Rev Soc Bras Med Tro 2011; 44(4):420-424., indicating that the practice of physical activity may be a protection factor regarding the occurrence of this syndrome4343 Mutimura E, Stewart A, Crowther NJ, Yarasheski KE, Cade WT. The effects of exercise training on quality of life in HAART-treated HIV-positive Rwandan subjects with body fat redistribution. Qual Life Res 2008; 17(3):377-385.. The practice of physical activity combined with an adequate diet is known to reduce the progression of lipodystrophy and lower its impact on both health and quality of life. In previous studies, individuals living with HIV and lipodystrophy presented improvements in cardiorespiratory and metabolic aspects as well as quality of life after a six-month exercise program compared to those who did not exercise4444 Mutimura E, Crowther NJ, Cade TW, Yarasheski KE, Stewart A. Exercise Training Reduces Central Adiposity and Improves Metabolic Indices in HAART-Treated HIV-Positive Subjects in Rwanda: A Randomized Controlled Trial. AIDS Res Hum Retroviruses 2008; 24(1):15-23.,4545 Collins E, Wagner C, Walmsley S. Psychosocial impact of the lipodystrophy syndrome in HIV infection. AIDS Read 2000; 10(9):546-550..

Regarding clinical variables of HIV infection, patients with a CD4+ count ≤ 350cells/mm³ had a lower chance of developing lipodystrophy in both the crude and adjusted analyses, which is in agreement with data described in the literature. Lichtenstein et al.4646 Lichtenstein KA, Ward DJ, Moorman AC, Delaney KM, Young B, Palella FJ, Rhodes PH, Wood KC, Holmberg SD. Clinical assessment of HIV-associated lipodystrophy in an ambulatory population. AIDS 2001; 15(11):1389-1398. studied a cohort of 1077 patients with a mean age of 41 years (85% men) and Segatto et al.4242 Segatto AFM, Freitas Junior IF, Santos VRD, Alves KCP, Barbosa DA, Portelinha Filho AM, Monteiro HL. Lipodystrophy in HIV/AIDS patients with different levels of physical activity while on antiretroviral therapy. Rev Soc Bras Med Tro 2011; 44(4):420-424. evaluated 42 patients (55% men) and found an association between the higher levels of TCD4+ cells and lipodystrophy among individuals in treatment with ART. Therefore, this therapy tends to improve one’s immune status, with a consequently slower progression of the disease and lower incidence of death, but is associated with the emergence of HIV-associated lipodystrophy3434 Sacilotto LB. Composição corporal e componentes da síndrome metabólica nos diferentes subtipos de lipodistrofia associada ao HIV [dissertação]. Botucatu: Universidade Estadual Paulista; 2017,4242 Segatto AFM, Freitas Junior IF, Santos VRD, Alves KCP, Barbosa DA, Portelinha Filho AM, Monteiro HL. Lipodystrophy in HIV/AIDS patients with different levels of physical activity while on antiretroviral therapy. Rev Soc Bras Med Tro 2011; 44(4):420-424.,4747 Soares FMG, Costa IMC. Treatment of HIV-associated facial lipoatrophy: impact on infection progression assessed by viral load and CD4 count. An Bras Dermatol 2013; 88(4):570-577.

48 Santos MRD, Araújo JVD, Miranda Filho DDB, Ximenes RADA, Santos Júnior BJD. Perfil lípidico dos pacientes HIV positivos em uso da terapia antirretroviral. Rev Bras Multi 2017; 20(1):61.
-4949 Alencastro PR, Barcellos NT, Wolff FH, Ikeda MLR, Schuelter-Trevisol F, Brandão ABM, Fuchs SC. People living with HIV on ART have accurate perception of lipodystrophy signs: a cross-sectional study. BMC Res Notes 2017; 10:1..

In contrast, Silva5050 Silva LFG. Fatores clínicos e laboratoriais da doença pelo HIV na composição corporal, força muscular, nível de atividade física, lipodistrofia e sua repercussão na qualidade de vida [tese]. Belém: Universidade Federal do Pará; 2014. evaluated 219 patients who were not in regular use of antiretrovirals and found an association between a lower CD4+ count and higher BMI as well as higher percentage of body fat. These findings may be the result of the harmful effects of HIV infection itself, probably as a consequence of the activation of macrophages in adipose cells, which could increase both local and systemic inflammation3030 Della Justina LB. Prevalence of HIV-Associated Lipodystrophy in Brazil: A Systematic Review of the Literature. J AIDS Clin 2014; 5:9.,5151 Crowe S, Westhorpe C, Mukhamedova N, Jaworowski A, Sviridov D, Bukrinsky M. The macrophage: the intersection between HIV infection and atherosclerosis. J Leukoc Biol 2009; 87(4):589-598..

A long time in ART was also associated with the development of lipodystrophy. In a cohort of 219 patients, Soares and Costa5252 Soares FMG, Costa IMC. Lipoatrofia facial associada ao HIV/AIDS: do advento ao sconhecimentos atuais. Anais Brasileiros de Dermatologia 2011; 86(5):843-864. also found that men and women with lipodystrophy had been using ART for a longer time (four to seven years). As these medications are made available in Brazil and contribute to improving immune status, we should bear in mind that individuals in treatment with ART can experience an increase in survival as well as the side effects of this therapy (redistribution of body fat and metabolic abnormalities), exposure to the physiological factors inherent to the aging process and external factors, such as a sedentary lifestyle and high calorie intake, which increase cardiovascular risk22 Brasil. Ministério da Saúde (MS). Boletim Epidemiológico - Aids e DST 2015; 1(1):1-100.,1717 Brasil. Ministério da Saúde (MS). Síndrome Lipodistrófica em HIV. Brasília: MS; 2011.,3434 Sacilotto LB. Composição corporal e componentes da síndrome metabólica nos diferentes subtipos de lipodistrofia associada ao HIV [dissertação]. Botucatu: Universidade Estadual Paulista; 2017,5353 Oliveira JF, Silva RX, Silva RMB, Manita OMG, Martelli A, Delbim LR. Benefícios do Exercício Físico como Terapia Alternativa para Indivíduos Portadores de HIV/AIDS. Rev Saúde em Foco 2016; 3(2):3-16.

54 Capeau J. From lipodystrophy and insulin resistance to metabolic syndrome: HIV infection, treatment and aging. Curr Opin HIV AIDS 2007; 2(4):247-252.
-5555 Guimarães MMM, Greco DB, Ribeiro-Olivera Júnior A, Penido MG, Machado LJC. Distribuição da gordura corporal e perfis lipídico e glicêmico de pacientes infectados pelo HIV. Arq Bras Endocrinol Metab 2000; 51(1):42-51..

No association was found between the type of ART and lipodystrophy in the present study. In contrast, the literature reports that lipodystrophy is among the most prevalent and worrisome side effects of some types of ART5656 Martínez E, Mocroft A, García-Viejo MA, Pérez-Cuevas JB, Blanco JL, Mallolas J, Bianchi L, Conget I, Blanch J, Phillips A, Gatell JM. Risk of lipodystrophy in HIV-1-infected patients treated with protease inhibitors: a prospective cohort study. Lancet 2001; 357(9256):592-598.. The development of the syndrome was initially attributed to the use of the protease inhibitors4646 Lichtenstein KA, Ward DJ, Moorman AC, Delaney KM, Young B, Palella FJ, Rhodes PH, Wood KC, Holmberg SD. Clinical assessment of HIV-associated lipodystrophy in an ambulatory population. AIDS 2001; 15(11):1389-1398.,5757 Palmer M, Chersich M, Moultrie H, Kuhn L, Fairlie L, Meyers T. Frequency of stavudine substitution due to toxicity in children receiving antiretroviral treatment in sub-Saharan Africa. AIDS 2013; 27(5):781-785.. However, with the introduction of other classes of antiretrovirals, NARTIs, particularly stavudine and zidovudine, were also found to be associated with the syndrome1717 Brasil. Ministério da Saúde (MS). Síndrome Lipodistrófica em HIV. Brasília: MS; 2011.,5858 Pontes CMM. Distúrbios metabólicos associados a infecção pelo HIV/AIDS: prevalência em pacientes ambulatórios seguidos em hospital de referência do estado do Ceará, Brasil [dissertação]. Fortaleza: Universidade Federal do Ceará; 2010.

59 Han SH, Zhou J, Saghayam S, Vanar S, Phanuphak N, Chen YA, Sirisanthana T, Sungkanuparph S, Lee CK, Pujari S, Li PC, Oka S, Saphonn V, Zhang F, Merati TP, Law MG, Choi JY. Prevalence of and risk factors for lipodystrophy among HIV-infected patients receiving combined antiretroviral treatment in the Asia-Pacific region: results from the TREAT Asia HIV Observational Database (TAHOD). Endocr J 2011; 58(6):475-484.
-6060 Mallal SA, John M, Moore CB, James IR, McKinnon EJ. Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection. AIDS 2000; 14(10):1309-1316..

Excess weight has been found in 35 to 45% of the population with HIV-associated lipodystrophy2222 Soares LR, Silva DCD, Gonsalez CR, Batista FG, Fonseca LAM, Duarte AJE, Casseb J. Discordance between body mass index and anthropometric measurements among HIV-1-infected patients on antiretroviral therapy and with lipoatrophy/lipohypertrophy syndrome. Rev Inst Med Trop São Paulo 2015; 57(2):105-110.,6161 Santos TMP, Silva DB, Franco TM, Santos VR, Mendonça J, Santos Júnior JA, Novais GB, Costa D. Lipodystrophy and the relationship with cardiovascular risk factors and metabolic syndrome in HIV-infected patients. Nutr Clín Diet Hosp 2017; 37(2):12-20.,6262 Oliveira TGB. Lipodistrofia em indivíduos vivendo com HIV/AIDS: fatores de risco para lipoatrofia e acúmulo de gordura corporal e associação com síndrome metabólica. Um estudo de coorte [tese]. Recife: Universidade Federal de Pernambuco; 2014., which is in agreement with the prevalence in the present study (43%; p < 0.002). In a study conducted in the city of Recife (northeastern Brazil) with a sample of 958 patients (61% men), Arruda Junior et al.6363 Arruda Júnior ERD, Lacerda HR, Moura LCRV, Albuquerque MDFPMD, Miranda Filho, DDB, Diniz GTN, Albuquerque VMGD, Amaral JCZ, Monteiro VS, Ximenes RADA. Perfil dos pacientes com hipertensão arterial incluídos em uma coorte com HIV/AIDS em Pernambuco, Brasil. Arq Bras Cardiol 2010; 95(5):640-647. found that HIV-associated lipodystrophy was associated with overweight/obesity (52.7%) and these individuals had been in ART for a longer period (> 24 months). Moreover, overweight/obesity remained associated even after controlling for confounding factors. Mariz et al.6464 Mariz CDA, Albuquerque MDFPMD, Ximenes RADA, Melo HRLD, Bandeira F, Oliveira TGBE, Carvalho EHD, Silva APD, Miranda Filho, DDB. Body mass index in individuals with HIV infection and factors associated with thinness and overweight/obesity. Cad Saude Publica 2011; 27(10):1997-2008. state that the increase in the prevalence of obesity in individuals living with HIV is associated with a significant reduction in the occurrence of opportunistic diseases and the chronicity of HIV as a consequence of the use of ART, which works directly against important steps in the replication of the virus6565 Koethe JR, Heimburger DC, PrayGod G, Filteau S. From Wasting to Obesity: The Contribution of Nutritional Status to Immune Activation in HIV Infection. J Infect Dis 2016; 214(Supl. 2):S75-S82.. Other studies have also demonstrated excess weight in this population as a worrisome finding, since the use of ART combined with excess weight and the accumulation of fat predisposes these patients to the development of metabolic syndrome and cardiovascular disease6666 Tiozzo E, Konefal J, Adwan S, Martinez LA, Villabona J, Lopez J, Cutrono S, Mehdi S, Rodriguez A, Woolger JM, Lewis JE. A cross-sectional assessment of metabolic syndrome in HIV-infected people of low socio-economic status receiving antiretroviral therapy. Diabetol Metab Syndr 2015; 7(1):15..

We found no association between HIV-associated lipodystrophy and dyslipidemia or altered fasting glucose. However, previous studies have reported these associations6767 Rasmussen LD, Mathiesen ER, Kronborg G, Pedersen C, Gerstoft J, Obel N. Risk of Diabetes Mellitus in Persons with and without HIV: A Danish Nationwide Population-Based Cohort Study. PLoS ONE 2012; 7(9):e44575.

68 Tripathi A, Liese AD, Jerrell JM, Zhang J, Rizvi AA, Albrecht H, Duffus WA. Incidence of diabetes mellitus in a population-based cohort of HIV-infected and non-HIV-infected persons: the impact of clinical and therapeutic factors over time. Diabet Med 2014; 31(10):1185-1193.
-6969 Lazzaretti RK, Gasparotto AS, Sassi MGDM, Polanczyk CA, Kuhmmer R, Silveira JM, Basso RP, Pinheiro CAT, Silveira MF, Sprinz E, Mattevi VS. Genetic Markers Associated to Dyslipidemia in HIV-Infected Individuals on HAART. TSWJ 2013; 2013:1-10.. In a cross-sectional study conducted in Thailand with 278 patients infected by HIV, 93% of those with lipodystrophy had at least one metabolic abnormality (dyslipidemia, glucose intolerance or insulin resistance)7070 Puttawong S, Prasithsirikul W, Vadcharavivad S. Prevalence of lipodystrophy in Thai-HIV infected patients. J Med Assoc Thai 2004; 87(6):605. However, other studies with large databanks found no such association when the results were adjusted for traditional risk factors6767 Rasmussen LD, Mathiesen ER, Kronborg G, Pedersen C, Gerstoft J, Obel N. Risk of Diabetes Mellitus in Persons with and without HIV: A Danish Nationwide Population-Based Cohort Study. PLoS ONE 2012; 7(9):e44575.,6868 Tripathi A, Liese AD, Jerrell JM, Zhang J, Rizvi AA, Albrecht H, Duffus WA. Incidence of diabetes mellitus in a population-based cohort of HIV-infected and non-HIV-infected persons: the impact of clinical and therapeutic factors over time. Diabet Med 2014; 31(10):1185-1193.,7171 Polsky S, Floris-Moore M, Schoenbaum E, Klein R, Arnsten J, Howard A. Incident hyperglycaemia among older adults with or at-risk for HIV infection. Antivir Ther 2011; 16(2):181-188.,7272 Galli L, Salpietro S, Pellicciotta G, Galliani A, Piatti P, Hasson H, Guffanti M, Gianotti N, Bigoloni A, Lazzarin A, Castagna A. Risk of type 2 diabetes among HIV-infected and healthy subjects in Italy. Eur J Epidemiol 2012; 27(8):657-665..

The present study has limitations that should be considered, such as the small sample size, the lack of a diagnostic consensus, the absence of data on adherence to ART and the fact that data collection was performed at a single reference center with unique characteristics inherent to the local reality, thereby limiting the external validity of the findings. However, the present results contribute knowledge on the health status of patients at this service, enabling better care and follow-up for the population. These findings can also be used in clinical practice for the comparison and assessment of individuals living with HIV.

The frequency of lipodystrophy syndrome in the present study was similar to rates described in the literature, demonstrating that anomalous body distribution may be identified in individuals living with HIV in treatment with ART. Moreover, an association was found between lipodystrophy syndrome and modifiable risk factors, such as overweight/obesity, revealing that this group is a greater risk of the development of other comorbidities, such as DM and hypertension.

This study proved that it is possible to diagnose HIV-associated lipodystrophy and identify the main associated factors with using simple methods that are applicable to clinical practice. Thus, it is possible to outline prevention and early intervention measures based on the situation of each individual or population. Such measures can contribute to improvements in the health status of these individuals, with a consequent increase in life expectancy and quality of life.

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Publication Dates

  • Publication in this collection
    06 Mar 2020
  • Date of issue
    Mar 2020

History

  • Received
    08 Feb 2018
  • Accepted
    05 July 2018
  • Published
    07 July 2018
ABRASCO - Associação Brasileira de Saúde Coletiva Rio de Janeiro - RJ - Brazil
E-mail: revscol@fiocruz.br