In refitted models including current ART class, current NNRTI use was associated with an increased risk of fat abnormality [adjusted odds ratio (AOR), 1.97; 95% CI: 1.11 to 3.50], lipohypertrophy (AOR, 2.49; 95% CI: 1.08 to 5.78), combined phenotype (AOR, 6.45; 95% CI: 1.62 to 25.71), and LS (AOR, 2.78; 95% CI: 1.20 to 5.45), whereas current PI use was associated with an increased risk of LS (AOR, 2.56; 95% CI: 1.26 to 6.11) and combined phenotype (AOR, 5.41; 95% CI: 1.36 to 24.48).
To explore the association between triple-class therapy and body fat abnormality, new models adjusted for age, ART duration, and site were tested. Triple-class therapy was a significant risk factor for fat abnormality (AOR, 4.68; 95% CI: 1.07 to 20.5), lipohypertrophy (AOR, 3.67; 95% CI: 1.07 to 12.65), lipoatrophy (AOR, 5.13; 95% CI: 1.0 to 22.0), and the combined phenotype (AOR, 4.35; 95% CI: 1.11 to 17.03).
Repeating the model selection procedure with the inclusion of an interaction between age and sex demonstrated a lack of significance for any outcome. Sensitivity analyses were conducted using the outcome of moderate/severe versus no/mild fat abnormality. Similar directions of association were found although not all risk factors reached statistical significance (data not shown).
More than half of this cohort of HIV-infected children and adolescents (56%) presented with LS and 42% with body fat abnormality: 1 in 2 with moderate or severe abnormalities. Among the subjects with fat abnormality, the proportions with lipohypertrophy-only, lipoatrophy-only, and the combined phenotype were roughly equal at approximately one third each. Factors associated with risk of body fat abnormality included white ethnicity, history of symptomatic HIV disease, and use of specific ART.
The prevalence of fat abnormality in this study was substantially higher than the 18%–33% reported in other pediatric studies,8,10–12,31–33 reflecting variations in LS definitions and methodology, and underlying population differences. However, restricting the definition to moderate and severe cases, resulted in a prevalence of 19%. LS development may be a graded progressive process; furthermore, the natural development of adipose tissue in childhood may have a protective effect against LS, which wanes during and after puberty.31 Thus, the comparatively older age of our participants (median age of 12.2 years compared to the mean of 7.5–11.0 years in the cited studies) may also partly explain the greater prevalence we observed.
In our unadjusted analysis, subjects undergoing puberty or with completed puberty had a 2- to 3-fold increased risk of fat abnormality. We excluded Tanner score from our adjusted models as sex and age were included, and we did not want to overadjust for puberty. In separate analyses where Tanner score was included in our stepwise modeling, it remained significantly associated with fat abnormality in the final model, giving credence to the role of puberty in LS (data not shown). In analyses adjusting for ever-use of ART, there was a significant 17% and 13% increased risk of lipoatrophy and of the combined phenotype per year of age. The similar associations with age reported in adults are generally of a smaller magnitude: In the Swiss HIV Cohort, there was an 18% increased risk of fat abnormality per decade increase in age at baseline.34 It is not certain to what extent such changes are the result of “normal” age-associated fat gain unrelated to HIV in adults.34 The pattern of body fat abnormalities here, with the trunk the most and the neck the least common location, is similar to reports from adult studies2,35 but somewhat dissimilar to that reported in children,8 possibly reflecting the older age of our population.
Lipohypertrophy in the trunk reported in a HIV-seronegative individual undergoing postexposure prophylaxis36 together with animal studies37–39 indicate that ART may be central in LS pathogenesis. However, our finding that some ART-naive children develop fat abnormalities is consistent with a multifactorial process, including possible direct action of HIV itself.40 We demonstrated an increased risk of LS and/or the combined lipoatrophy/lipohypertrophy phenotype associated with current and past PI use. PI use has been inconsistently shown to be associated with lipoatrophy in adults,2,41,42 with data from cross-sectional pediatric studies similarly conflicting.8,11,12,32 Postulated mechanisms behind PI use and lipoatrophy include inhibition of proteins involved in lipid metabolism43–45 and insulin dysregulation.44,46
NRTI use has been strongly implicated in the pathogenesis of fat abnormalities, particularly lipoatrophy,41 with potential mechanisms including mitochondrial damage in adipocytes47 and inhibition of adipogenesis.48 Our findings with respect to stavudine are consistent with previous reports8,11,32,34,42,49–53; more than 10% of our subjects were currently receiving stavudine, despite current guidelines.22
One third of our subjects had both lipoatrophy and lipohypertrophy. Increasing age and BMI and past use of some specific drugs (from all 3 classes) were associated with an increased risk of this combined phenotype, whereas current lamivudine and zidovudine use was associated with a significantly reduced risk. In subgroup analysis, this latter association seemed to be driven by males and children older than 11 years (data not shown). The associations of the combined phenotype with age and past drug exposure suggest that its emergence may be progressive and associated with cumulative ART exposure over time.
Current nevirapine use was associated with an increased risk of LS, whereas associations between LS and fat abnormalities were demonstrated with past and/or current use of efavirenz. Although the association of NNRTIs with fat abnormality has not been investigated in child/adolescent studies, our results are consistent with adult studies.54–56 Pediatric reports have described associations between longer treatment duration and increased risk of fat abnormality in body fat abnormality11,24 unlike in our investigation.
Experience of more serious HIV disease was associated with body fat abnormality, lipohypertrophy, and lipoatrophy, in accordance with an earlier multisite European pediatric study.8 Several studies have identified immunosuppression as an independent risk factor for lipoatrophy42,57 and fat abnormality.58 Indeed, results from the prospective HIV Outpatients Study demonstrating association between low CD4 counts and lipoatrophy independent of ART led to the hypothesis that factors associated with more advanced HIV disease predispose individuals to later develop LS.42
Around two thirds of our cohort was of white ethnicity, associated with 3 to 4 times increased risk of lipoatrophy and fat abnormality, consistent with other studies.49,59,62 Underlying genetic differences between ethnic groups may explain these findings, the metabolic syndrome having been shown to occur less frequently in individuals of black compared with white ethnicity in non–HIV-infected populations.63
Several studies have reported a negative impact of body fat changes on self-esteem and psychological profile in HIV-infected adults,64–66 which has been linked to nonadherence to ART.67,68 Little is known about the impact in children or adolescents,69 but this is likely to be an issue for adolescents, given that this is a time when self-image is important. Our study did not collect information on self-reported body image, but the fact that approximately 7% of children and adolescents had severe and potentially stigmatizing fat loss or gain demonstrates the need for further research.
A limitation of our study is its observational nature and the potential for confounding. Some previous studies have relied on self-reported changes potentially leading to over-reporting of body shape changes.65 Our approach, with fat abnormality assessed according to strictly defined criteria using a scale of severity by the child's established clinician, avoids such misclassification but remains a subjective measure. A minority (28%; 50/176) of body fat abnormality cases were based on abnormality in a single body site; only 31 subjects (7% of all participants) were categorized as having fat abnormality on the basis of trunk lipohypertrophy alone (26 mild and 5 moderate). Furthermore, risk factors identified in our main analyses were confirmed by sensitivity analyses investigating moderate/severe fat abnormality (although not necessarily reaching statistical significance). However, given that the clinician would be aware of the ART status of the patient when making the assessment of fat abnormality, the potential for bias cannot be discounted. Our multisite design provided us with a large sample size compared with previous pediatric studies, resulting in a diverse study sample and good generalizability. We addressed potential systemic differences in clinical practice by incorporating a random effect for clinical site within our models. Finally, the analyses presented here are based on recruitment data and thus limited by their cross-sectional nature. We are collecting longitudinal data on our cohort and will be able to address issues including incidence and progression or regression of fat abnormality in the future.
Our study suggests that body fat abnormality occurs in almost half of HIV-infected children and adolescents, with the same complex range of phenotypes as seen in adults. Moreover, associated risk factors in this population are similar to those seen in adults, with both ART-related and demographic/clinical factors identified. In our cohort of HIV-infected children, most will have accumulated at least a decade of exposure to multiple drugs by the time they become adults. This underscores how important it is to monitor and investigate the long-term implications of life-long HIV and ART use.
1. Heath KV, Hogg RS, Chan KJ, et al.. Lipodystrophy-associated morphological cholesterol and triglyceride abnormalities in a population-based HIV/AIDS treatment database. AIDS. 2001;15:231–239.
2. Carr A, Samaras K, Thorsidottir A, et al.. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet. 1999;353:2093–2099.
3. Saves M, Francois R, Capeau J, et al.. Factors related to lipodystrophy and metabolic alterations in patients with human immunodeficiency virus infection receiving highly active antiretroviral therapy. Clin Infect Dis. 2002;34:1396–1405.
4. Chene G, Angelini E, Cotte L, et al.. Role of long-term nucleoside-analogue therapy in lipodystrophy and metabolic disorders in human immunodeficiency virus-infected patients. Clin Infect Dis. 2002;34:649–657.
5. Shlay JC, Visnegarwala F, Bartsch G, et al.. Body composition and metabolic changes in antiretroviral-naive patients randomized to didanosine and stavudine vs. abacavir and lamivudine. J Acquir Immune Defic Syndr. 2005;38:147–155.
6. Pujari SN, Dravid A, Naik E, et al.. Lipodystrophy and dyslipidemia among patients taking first-line World Health Organization-recommended highly active antiretroviral therapy regimens in Western India. J Acquir Immune Defic Syndr. 2005;39:199–202.
7. George JA, Venter WDF, Van Deventer HE, et al.. A longitudinal study of the changes in body fat and metabolic parameters in a South African population of HIV-positive patients receiving an antiretroviral therapeutic regimen containing stavudine. AIDS Res Hum Retroviruses. 2009;25:771–781.
8. European Paediatric Lipodystrophy Group. Antiretroviral therapy fat redistribution and hyperlipidaemia in HIV-infected children in Europe. AIDS. 2004;18:1443–1451.
9. Beregszaszi M, Dollfus C, Levine M, et al.. Longitudinal evaluation and risk factors of lipodystrophy and associated metabolic changes in HIV-infected children. J Acquir Immune Defic Syndr. 2005;40:161–168.
10. Sanchez-Torres AM, Munoz-Muniz R, Madero R, et al.. Prevalence of fat redistribution and metabolic disorders in human immunodeficiency virus-infected children. Eur J Pediatr. 2005;164:271–276.
11. Ene L, Goetghebuer T, Hainaut M, et al.. Prevalence of lipodystrophy in HIV-infected children—a cross-sectional study. Eur J Pediatr. 2007;166:13–21.
12. Amaya RA, Kozinetz CA, McMeans A, et al.. Lipodystrophy syndrome in human immunodeficiency virus-infected children. Pediatr Infect Dis J. 2002;21:405–410.
13. Bitnun A, Sochett E, Babyn P, et al.. Serum lipids, glucose homeostasis and abdominal adipose tissue distribution in protease inhibitor-treated and naive HIV-infected children. AIDS. 2003;17:1319–1327.
14. Parakh A, Prakash-Dubey A, Kumar A, et al.. Lipodystrophy and metabolic complications of highly active antiretroviral therapy. Indian J Pediatr. 2009;76:1017–1021.
15. Resino S, Micheloud D, Lorente R, et al.. Adipokine profiles and lipodystrophy in HIV-infected children during the first 4 years on highly active antiretroviral therapy. HIV Med. 2011;12:54–60.
16. HIV Lipodystrophy Case Definition Study Group. An objective case definition of lipodystrophy in HIV-infected adults: a case-control study. Lancet. 2003;361:726–735.
17. UNAIDS. AIDS epidemic update 2010. AIDS Epidemic Update. Geneva, Switzerland: UNAIDS; 2010:16–62.
18. WHO. Towards Universal Access; Scaling Up Priority HIV/AIDS Interventions in the Health Sector. Geneva, Switzerland: HIV/AIDS Department, World Health Organization; 2009.
19. Gortmaker SL, Hughes M, Cervia J, et al.. Effect of combination therapy including protease inhibitors on mortality among children and adolescents infected with HIV-1. N Engl J Med. 2001;345:1522–1528.
20. Gibb DM, Duong T, Tookey PA, et al.. Decline in mortality, AIDS, and hospital admissions in perinatally HIV-1 infected children in the United Kingdom and Ireland. BMJ. 2003;327:1019–1023.
21. Brahmbhatt H, Kigozi G, Wabwire-Mangen F, et al.. Mortality in HIV-infected and uninfected children of HIV-infected and uninfected mothers in rural Uganda. J Acquir Immune Defic Syndr. 2006;41:504–508.
23. Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. 2009.
24. Italian Multicentre Study. Epidemiology, clinical features, and prognostic factors of paediatric HIV infection. Lancet. 1988;332:8619;1043–1045.
25. Epidemiology of HIV infection in children in Italy. The Italian Register for HIV Infection in Children. Acta Paediatr Suppl. 1994;400:15–18.
26. Tanner JM. Growth At Adolescence: With a General Consideration of the Effects of Hereditary and Enviromental Factors Upon Growth and Maturation From Birth to Maturity. 2nd ed. Oxford: Blackwell Scientific; 1962.
27. Castro G, Ward JW, Slutker L, et al.. 1993 Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep. 1992; Vol. 41.
28. Caldwell MB, Oxtoby MJ, Simonds RJ, et al.. 1994 Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR Recomm Rep. 1994;43:1–10.
29. Schneider E, Whitmore S, Glynn KM, et al.. Revised surveillance case definitions for HIV infection among adults, adolescents and children aged <18 months and for HIV infection and AIDS among children aged 18 months to <13 years—United States, 2008. MMWR Recomm Rep. 2008;57:1–8.
30. Jolliffe CJ, Janssen I. Distribution of lipoproteins by age and gender in adolescents. Circulation. 2006;114:1056–1062.
31. Jaquet D, Levine M, Ortega-Rodriguez E, et al.. Clinical and metabolic presentation of the lipodystrophic syndrome in HIV-infected children. AIDS. 2000;14:2123–2128.
32. Arpadi SM, Cuff PA, Horlick MN, et al.. Lipodystrophy in HIV-infected children is associated with high viral load and low CD4 B-lymphocyte count and CD4 B-lymphocyte percentage at baseline and use of protease inhibitors and stavudine. J Acquir Immune Defic Syndr. 2001;27:30–34.
33. Bockhorst JL, Ksseiry I, Toye M, et al.. Evidence of human immunodeficiency virus-associated lipodystrophy syndrome in children treated with protease inhibitors. Pediatr Infect Dis J. 2003;22:463–465.
34. Young J, Weber R, Rickenbach M, et al.. Lipid profiles for antiretroviral-naive patients starting PI- and NNRTI-based therapy in the Swiss HIV Cohort Study. Antivir Ther. 2005;10:585–591.
35. Thiebaut R, Daucourt V, Mercie P, et al.. Lipodystrophy, metabolic disorders, and human immunodeficiency virus infection: Aquitaine Cohort, France 1999. Clin Infect Dis. 2000;31:1482–1487.
36. Mauss S, Berger F, Carls H, et al.. Rapid development of central adiposity after postexposure prophylaxis with antiretroviral drugs: a proof of principle? AIDS. 2003;17:944–945.
37. Riddle TM, Kuhel DG, Woollet LA, et al.. HIV protease inhibitor induces fatty acid and sterol biosynthesis in liver and adipose tissues due to the accumulation of activated sterol regulatory element-binding proteins in the nucleus. J Biol Chem. 2001;276:37514–37519.
38. Riddle TM, Schildmeyer NM, Phan C, et al.. The HIV protease inhibitor ritonavir increases lipoprotein production and has no effect on lipoprotein clearance in mice. J Lipid Res. 2002;43:1458–1463.
39. Hruz PW, Murata H, Qui H, et al.. Indinavir induces acute and reversible peripheral insulin resistance in rats. Diabetes. 2002;51:937–942.
40. Safrin S, Grunfeld C. Fat distribution and metabolic changes in patients with HIV infection. AIDS. 1999;13:2493–2505.
41. Saint-Marc T, Partisani M, Poizot-Martin I, et al.. Fat distribution evaluated by computed tomography and metabolic abnormalities in patients undergoing antiretroviral therapy: preliminary results of the LIPOCO study. AIDS. 2000;14:37–49.
42. Lichtenstein KA, Ward DJ, Moorman AC, et al.. Clinical assessment of HIV-associated lipodystrophy in an ambulatory population. AIDS. 2001;15:1389–1398.
43. Domingo P, Matias-Guiu X, Pujol RM, et al.. Subcutaneous adipocyte apoptosis in HIV-1 protease inhibitor-associated lipodystrophy. AIDS. 1999;13:2261–2267.
44. Carr A, Samaras K, Chisholm DJ, et al.. Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet. 1998;351:1881–1883.
45. Bastard JP, Caron M, Vidal H, et al.. Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance. Lancet. 2002;359:1026–1031.
46. Martinez E, Gatell J. Metabolic abnormalities and use of HIV-1 protease inhibitors. Lancet. 1998;352:821–822.
47. Nolan D, Hammond E, Martin A, et al.. Mitochondrial DNA depletion and morphologic changes in adipocytes associated with nucleoside reverse transcriptase inhibitor therapy. AIDS. 2003;17:1329–1338.
48. Pace CS, Martin AM, Hammond EL, et al.. Mitochondrial proliferation, DNA depletion and adipocyte differentiation in subcutaneous adipose tissue of HIV-positive HAART recipients. Antivir Ther. 2003;8:323–331.
49. Mallal SA, John M, Moore CB, et al.. Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection. AIDS. 2000;14:1309–1316.
50. Martinez E, Mocroft A, Garcia-Viejo MA, et al.. Risk of lipodystrophy in HIV-1-infected patients treated with protease inhibitors: a prospective cohort study. Lancet. 2001;357:592–598.
51. Galli M, Ridolfo AL, Adorni F, et al.. Body habitus changes and metabolic alterations in protease inhibitor-naive HIV-1-infected patients treated with two nucleoside reverse transcriptase inhibitors. J Acquir Immune Defic Syndr. 2002;29:21–31.
52. Moyle GJ, Sabin CA, Cartledge J, et al.. A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy. AIDS. 2006;20:2043–2050.
53. Martin A, Smith DE, Carr A, et al.. Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir; the MITOX Extension Study. AIDS. 2004;18:1029–1036.
54. Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). Fat distribution in women with HIV infection. J Acquir Immune Defic Syndr. 2006;42:562–571.
55. Shlay JC, Sharma S, Peng G, et al.. The effect of individual antiretroviral drugs on body composition in HIV-infected persons initiating highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2009;51:298–304.
56. Friis-Moller N, Sabin CA, Weber R, et al.. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med. 2003;349:1993–2003.
57. Joly V, Flandre P, Meiffredy V, et al.. Increased risk of lipoatrophy under stavudine in HIV-1-infected patients: results of a substudy from a comparative trial. AIDS. 2002;16:2447–2454.
58. Seminari E, Tinelli C, Minoli L, et al.. Evaluation of the risk factors associated with lipodystrophy development in a cohort of HIV-positive patients. Antivir Ther. 2002;7:175–180.
59. Bogner JR, Vielhauer V, Beckman RA, et al.. Stavudine versus zidovudine and the development of lipodystrophy. J Acquir Immune Defic Syndr. 2001;27:237–244.
60. Mutimura E, Stewart A, Rheeder P, et al.. Metabolic function and the prevalence of lipodystrophy in a population of HIV-infected African subjects receiving highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2007;46:451–455.
61. Ofotokun I, Chuck SK, Hitti JE. Antiretroviral pharmacokinetic profile: a review of sex differences. Gend Med. 2007;4:106.
62. Lichtenstein KA, Delaney KM, Armon C, et al.. Incidence of and risk factors for lipoatrophy (abnormal fat loss) in ambulatory HIV-1-infected patients. J Acquir Immune Defic Syndr. 2003;32:48–56.
63. Park YW, Zhu S, Palaniappan L, et al.. The metabolic syndrome: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988-1994. Arch Intern Med. 2003;163:427–436.
64. Sanches S. Facial lipoatrophy appearances are not deceiving. J Assoc Nurses AIDS Care. 2009;20:169–175.
65. Burgoyne R, Collins E, Wagner C, et al.. The relationship between lipodystrophy-associated body changes and measures of quality of life and mental health for HIV-positive adults. Qual Life Res. 2005;14:981–990.
66. Blanche S, Newell ML, Mayaux MJ, et al.. Morbidity and mortality in European children vertically infected by HIV-1. J Acquir Immune Defic Syndr Hum Retrovirol. 1997;14:442–450.
67. Plankey M, Bacchetti P, Jin C, et al.. Self-perception of body fat changes and HAART adherence in the women's interagency HIV study. AIDS Behav. 2009;13:53–59.
68. Duran S, Saves M, Spire B, et al.. Failure to maintain long-term adherence to highly active antiretroviral therapy: the role of lipodystrophy. AIDS. 2001;15:2441–2444.
69. Dollfus C, Blanche S, Trocme N, et al.. Correction of facial lipoatrophy using autologous fat transplants in HIV-infected adolescents. HIV Med. 2009;10:263–268.