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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Management of Medication Toxicity or Intolerance

Lipodystrophy, Lipohypertrophy, Lipoatrophy

(Last updated: February 12, 2014; last reviewed: February 12, 2014)

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Table 11h. Antiretroviral Therapy-Associated Adverse Effects and Management Recommendations—Lipodystrophy, Lipohypertrophy, Lipoatrophy
Adverse Effects Associated ARVs Onset/Clinical Manifestations Estimated Frequency Risk Factors Prevention/ Monitoring Management
Lipodystrophy (Fat Maldistribution)
General Information

See below for specific associations. Onset
  • Trunk and limb fat initially increase within a few months of start of cART; peripheral fat wasting may not begin to appear for 12 to 24 months after cART initiation.
Highly Variable

Adults
  • 2%–93%
Children
  • 1%–34%, perhaps more common in adolescents than prepubertal children
Genetic predisposition

Puberty

HIV-associated inflammation

Older age

Longer duration of cART

Body habitus
See below See below
Central Lipohypertrophy
or
Lipoaccumulation
Can occur in the absence of cART, but most associated with PIs and EFV; EFV also associated with gynecomastia and breast hypertrophy Presentation
  • Central fat accumulation with increased abdominal girth, which may include dorsocervical fat pad (buffalo hump) and/or gynecomastia in males or breast hypertrophy in females. The appearance of central lipohypertrophy is accentuated in the presence of peripheral fat wasting (lipoatrophy).
Children:
  • Up to 27%
Adults:
  • 6 to 93%
Obesity before initiation of therapy

Sedentary lifestyle
Prevention:
  • Calorically appropriate low-fat diet and exercise.
Monitoring:
  • Measure BMI.
Calorically appropriate low-fat diet and exercise, especially strength training.

Smoking cessation (if applicable) to decrease future CVD risk.

Data are insufficient to allow the Panel to safely recommend use of any of the following modalities in children: recombinant human growth hormone, growth hormone-releasing hormone, metformin, thiazolidinediones, anabolic steroids, or liposuction.
Facial/Peripheral Lipoatrophy Most associated with thymidine analogues NRTI (d4T > ZDV) Presentation
  • Thinning of subcutaneous fat in face, buttocks, and extremities, measured as decrease in trunk/limb fat by DXA or triceps skinfold thickness. Preservation of lean body mass distinguishes lipoatrophy from HIV-associated wasting.
Children:
  • Up to 47% (particularly in patients on d4T- containing regimens)
  • Risk lower (up to 15%) in patients not treated with d4T or ZDV
Adults:
  • 13% to 59% (particularly in patients on d4T-containing regimens)
d4T and ZDV

Underweight before ART
Prevention
  • Avoid use of d4T and ZDV.
Monitoring:
  • Patient self-report and physical exam are the most sensitive methods of monitoring lipoatrophy.
Switch from d4T or ZDV to other NRTIs if possible without loss of virologic control. 

Data are Insufficient to Allow the Panel to Safely Recommend Use of Any of the Following Modalities in Children
  • Injections of poly-L-lactic acid
  • Recombinant human leptin
  • Autologous fat transplantation
  • Thiazolidinediones.
Key to Acronyms: ARV = antiretroviral; BMI = body mass index; cART = combination antiretroviral therapy; CVD = cardiovascular disease; d4T = stavudine; DXA = dual energy x-ray absorptiometry; EFV = efavirenz; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; ZDV = zidovudine

References 

See the archived version of Supplement III, February 23, 2009 Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection, (http://www.aidsinfo.nih.gov) for a more complete discussion and reference list.

General Reviews

  1. Fernandez JR, Redden DT, Pietrobelli A, Allison DB. Waist circumference percentiles in nationally representative samples of African-American, European-American, and Mexican-American children and adolescents. J Pediatr. Oct 2004;145(4):439-444. Available at http://www.ncbi.nlm.nih.gov/pubmed/15480363.
  2. Lee JM, Davis MM, Woolford SJ, Gurney JG. Waist circumference percentile thresholds for identifying adolescents with insulin resistance in clinical practice. PediatrDiabetes. Aug 2009;10(5):336-342. Available at http://www.ncbi.nlm.nih.gov/pubmed/19175894.
  3. Carr A. Treatment strategies for HIV lipodystrophy. Curr Opin HIV AIDS. Jul 2007;2(4):332-338. Available at http://www.ncbi.nlm.nih.gov/pubmed/19372908.
  4. Phillips DR, Hay P. Current perspectives on the management and prevention of antiretroviral-associated lipoatrophy. J Antimicrob Chemother. Nov 2008;62(5):866-871. Available at http://www.ncbi.nlm.nih.gov/pubmed/18703527.
  5. Wohl DA, McComsey G, Tebas P, et al. Current concepts in the diagnosis and management of metabolic complications of HIV infection and its therapy. Clin Infect Dis. Sep 1 2006;43(5):645-653. Available at http://www.ncbi.nlm.nih.gov/pubmed/16886161.
  6. Moyle G, Moutschen M, Martinez E, et al. Epidemiology, assessment, and management of excess abdominal fat in persons with HIV infection. AIDS Reviews. Jan-Mar 2010;12(1):3-14. Available at http://www.ncbi.nlm.nih.gov/pubmed/20216906.
  7. Dzwonek A, Clapson M, Withey S, Bates A, Novelli V. Severe gynecomastia in an African boy with perinatally acquired human immunodeficiency virus infection receiving highly active antiretroviral therapy. Pediatr Infect Dis J. Feb 2006;25(2):183-184. Available at http://www.ncbi.nlm.nih.gov/pubmed/16462304.
  8. Innes S, Cotton MF, Haubrich R, et al. High prevalence of lipoatrophy in pre-pubertal South African children on antiretroviral therapy: a cross-sectional study. BMC Pediatr. 2012;12:183. Available at http://www.ncbi.nlm.nih.gov/pubmed/23176441.
  9. Piloya T, Bakeera-Kitaka S, Kekitiinwa A, Kamya MR. Lipodystrophy among HIV-infected children and adolescents on highly active antiretroviral therapy in Uganda: a cross sectional study. J Int AIDS Soc. 2012;15(2):17427. Available at http://www.ncbi.nlm.nih.gov/pubmed/22814353.
Associated ARVs/Etiology
  1. Chang E, Sekhar R, Patel S, Balasubramanyam A. Dysregulated energy expenditure in HIV-infected patients: a mechanistic review. Clin Infect Dis. Jun 1 2007;44(11):1509-1517. Available at http://www.ncbi.nlm.nih.gov/pubmed/17479951.
  2. Dube MP, Komarow L, Mulligan K, et al. Long-term body fat outcomes in antiretroviral-naive participants randomized to nelfinavir or efavirenz or both plus dual nucleosides. Dual X-ray absorptiometry results from A5005s, a substudy of Adult Clinical Trials Group 384. J Acquir Immune Defic Syndr. Aug 15 2007;45(5):508-514. Available at http://www.ncbi.nlm.nih.gov/pubmed/17589373.
  3. Haubrich RH, Riddler SA, DiRienzo AG, et al. Metabolic outcomes in a randomized trial of nucleoside, nonnucleoside and protease inhibitor-sparing regimens for initial HIV treatment. AIDS. Jun 1 2009;23(9):1109-1118. Available at http://www.ncbi.nlm.nih.gov/pubmed/19417580.
  4. Hulgan T, Tebas P, Canter JA, et al. Hemochromatosis gene polymorphisms, mitochondrial haplogroups, and peripheral lipoatrophy during antiretroviral therapy. J Infect Dis. Mar 15 2008;197(6):858-866. Available at http://www.ncbi.nlm.nih.gov/pubmed/18419350.
  5. McComsey GA, Libutti DE, O'Riordan M, et al. Mitochondrial RNA and DNA alterations in HIV lipoatrophy are linked to antiretroviral therapy and not to HIV infection. Antivir Ther. 2008;13(5):715-722. Available at http://www.ncbi.nlm.nih.gov/pubmed/18771055.
  6. Tien PC, Benson C, Zolopa AR, Sidney S, Osmond D, Grunfeld C. The study of fat redistribution and metabolic change in HIV infection (FRAM): methods, design, and sample characteristics. Am J Epidemiol. May 1 2006;163(9):860-869. Available at http://www.ncbi.nlm.nih.gov/pubmed/16524955.
  7. Van Dyke RB, Wang L, Williams PL, Pediatric ACTGCT. Toxicities associated with dual nucleoside reverse-transcriptase inhibitor regimens in HIV-infected children. J Infect Dis. Dec 1 2008;198(11):1599-1608. Available at http://www.ncbi.nlm.nih.gov/pubmed/19000014.
  8. Mulligan K, Parker RA, Komarow L, et al. Mixed patterns of changes in central and peripheral fat following initiation of antiretroviral therapy in a randomized trial. J Acquir Immune Defic Syndr. Apr 15 2006;41(5):590-597. Available at http://www.ncbi.nlm.nih.gov/pubmed/16652032.
  9. Scherzer R, Shen W, Bacchetti P, et al. Comparison of dual-energy X-ray absorptiometry and magnetic resonance imaging-measured adipose tissue depots in HIV-infected and control subjects. Am J Clin Nutr. Oct 2008;88(4):1088-1096. Available at http://www.ncbi.nlm.nih.gov/pubmed/18842798.
  10. Benn P, Sauret-Jackson V, Cartledge J, et al. Improvements in cheek volume in lipoatrophic individuals switching away from thymidine nucleoside reverse transcriptase inhibitors. HIV Med. Jul 2009;10(6):351-355. Available at http://www.ncbi.nlm.nih.gov/pubmed/19490181.
Management
  1. Wohl DA, Brown TT. Management of morphologic changes associated with antiretroviral use in HIV-infected patients. J Acquir Immune Defic Syndr. Sep 1 2008;49 Suppl 2:S93-S100. Available at http://www.ncbi.nlm.nih.gov/pubmed/18725818.
  2. Carey DL, Baker D, Rogers GD, et al. A randomized, multicenter, open-label study of poly-L-lactic acid for HIV-1 facial lipoatrophy. J Acquir Immune Defic Syndr. Dec 15 2007;46(5):581-589. Available at http://www.ncbi.nlm.nih.gov/pubmed/18193500.
  3. Cavalcanti RB, Raboud J, Shen S, Kain KC, Cheung A, Walmsley S. A randomized, placebo-controlled trial of rosiglitazone for HIV-related lipoatrophy. J Infect Dis. Jun 15 2007;195(12):1754-1761. Available at http://www.ncbi.nlm.nih.gov/pubmed/17492590.
  4. Falutz J, Allas S, Blot K, et al. Metabolic effects of a growth hormone-releasing factor in patients with HIV. N Engl J Med. Dec 6 2007;357(23):2359-2370. Available at http://www.ncbi.nlm.nih.gov/pubmed/18057338.
  5. Gerschenson M, Kim C, Berzins B, et al. Mitochondrial function, morphology and metabolic parameters improve after switching from stavudine to a tenofovir-containing regimen. J Antimicrob Chemother. Jun 2009;63(6):1244-1250. Available at http://www.ncbi.nlm.nih.gov/pubmed/19321503.
  6. Hadigan C. Peroxisome proliferator-activated receptor gamma agonists and the treatment of HIV-associated lipoatrophy: unraveling the molecular mechanism of their shortcomings. J Infect Dis. Dec 15 2008;198(12):1729-1731. Available at http://www.ncbi.nlm.nih.gov/pubmed/18954262.
  7. Lindegaard B, Hansen T, Hvid T, et al. The effect of strength and endurance training on insulin sensitivity and fat distribution in human immunodeficiency virus-infected patients with lipodystrophy. J Clin Endocrinol Metab. Oct 2008;93(10):3860-3869. Available at http://www.ncbi.nlm.nih.gov/pubmed/18628529.
  8. Lo J, You SM, Canavan B, et al. Low-dose physiological growth hormone in patients with HIV and abdominal fat accumulation: a randomized controlled trial. JAMA. Aug 6 2008;300(5):509-519. Available at http://www.ncbi.nlm.nih.gov/pubmed/18677023.
  9. Mulligan K, Khatami H, Schwarz JM, et al. The effects of recombinant human leptin on visceral fat, dyslipidemia, and insulin resistance in patients with human immunodeficiency virus-associated lipoatrophy and hypoleptinemia. J Clin Endocrinol Metab. Apr 2009;94(4):1137-1144. Available at http://www.ncbi.nlm.nih.gov/pubmed/19174500.
  10. Tebas P, Zhang J, Hafner R, et al. Peripheral and visceral fat changes following a treatment switch to a non-thymidine analogue or a nucleoside-sparing regimen in HIV-infected subjects with peripheral lipoatrophy: results of ACTG A5110. J Antimicrob Chemother. May 2009;63(5):998-1005. Available at http://www.ncbi.nlm.nih.gov/pubmed/19299471.
  11. Tebas P, Zhang J, Yarasheski K, et al. Switching to a protease inhibitor-containing, nucleoside-sparing regimen (lopinavir/ritonavir plus efavirenz) increases limb fat but raises serum lipid levels: results of a prospective randomized trial (AIDS clinical trial group 5125s). J Acquir Immune Defic Syndr. Jun 1 2007;45(2):193-200. Available at http://www.ncbi.nlm.nih.gov/pubmed/17527093.
  12. Dollfus C, Blanche S, Trocme N, Funck-Brentano I, Bonnet F, Levan P. Correction of facial lipoatrophy using autologous fat transplants in HIV-infected adolescents. HIV Med. May 2009;10(5):263-268. Available at http://www.ncbi.nlm.nih.gov/pubmed/19178590.
  13. Cofrancesco J, Jr., Freedland E, McComsey G. Treatment options for HIV-associated central fat accumulation. AIDS Patient Care STDS. Jan 2009;23(1):5-18. Available at http://www.ncbi.nlm.nih.gov/pubmed/19055407.
  14. Degris E, Delpierre C, Sommet A, et al. Longitudinal study of body composition of 101 HIV men with lipodystrophy: dual-energy X-ray criteria for lipodystrophy evolution. J Clin Densitom. Apr-Jun 2010;13(2):237-244. Available at http://www.ncbi.nlm.nih.gov/pubmed/20347366.
  15. Falutz J, Mamputu JC, Potvin D, et al. Effects of tesamorelin (TH9507), a growth hormone-releasing factor analog, in human immunodeficiency virus-infected patients with excess abdominal fat: a pooled analysis of two multicenter, double-blind placebo-controlled phase 3 trials with safety extension data. J Clin Endocrinol Metab. Sep 2010;95(9):4291-4304. Available at http://www.ncbi.nlm.nih.gov/pubmed/20554713.
  16. Ferrer E, del Rio L, Martinez E, et al. Impact of switching from lopinavir/ritonavir to atazanavir/ritonavir on body fat redistribution in virologically suppressed HIV-infected adults. AIDS Res Hum Retroviruses. Oct 2011;27(10):1061-1065. Available at http://www.ncbi.nlm.nih.gov/pubmed/21166602.
  17. Negredo E, Miro O, Rodriguez-Santiago B, et al. Improvement of mitochondrial toxicity in patients receiving a nucleoside reverse-transcriptase inhibitor-sparing strategy: results from the Multicenter Study with Nevirapine and Kaletra (MULTINEKA). Clin Infect Dis. Sep 15 2009;49(6):892-900. Available at http://www.ncbi.nlm.nih.gov/pubmed/19663689.
  18. Raboud JM, Diong C, Carr A, et al. A meta-analysis of six placebo-controlled trials of thiazolidinedione therapy for HIV lipoatrophy. HIV Clin Trials. Jan-Feb 2010;11(1):39-50. Available at http://www.ncbi.nlm.nih.gov/pubmed/20400410.
  19. Sheth SH, Larson RJ. The efficacy and safety of insulin-sensitizing drugs in HIV-associated lipodystrophy syndrome: a meta-analysis of randomized trials. BMC Infect Dis. 2010;10:183. Available at http://www.ncbi.nlm.nih.gov/pubmed/20573187.
  20. Tungsiripat M, Bejjani DE, Rizk N, et al. Rosiglitazone improves lipoatrophy in patients receiving thymidine-sparing regimens. AIDS. Jun 1 2010;24(9):1291-1298. Available at http://www.ncbi.nlm.nih.gov/pubmed/20453626.
  21. Spoulou V, Kanaka-Gantenbein C, Bathrellou I, et al. Monitoring of lipodystrophic and metabolic abnormalities in HIV-1 infected children on antiretroviral therapy. Hormones. Apr-Jun 2011;10(2):149-155. Available at http://www.ncbi.nlm.nih.gov/pubmed/21724540.
  22. Minami R, Yamamoto M, Takahama S, Ando H, Miyamura T, Suematsu E. Comparison of the influence of four classes of HIV antiretrovirals on adipogenic differentiation: the minimal effect of raltegravir and atazanavir. J Infect Chemother Apr 2011;17(2):183-188. Available at http://www.ncbi.nlm.nih.gov/pubmed/20706762.

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