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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: March 1, 2016; last reviewed: March 1, 2016)

Table 12h. 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 ART; peripheral fat wasting may not appear for 12 to 24 months after ART initiation.
Varies greatly depending upon measure and comparator group

Highly Variable in Adults:
  • Up to 93%
Children:
  • Up to 34%, perhaps more common in adolescents than prepubertal children
Genetic predisposition

Puberty

HIV-associated inflammation

Older age

Longer duration of ART

Body habitus
See below. See below

Although more typically associated with certain ARVs (e.g., d4T), a regimen review with consideration of changing the regimen should be considered, whenever present
Central Lipohypertrophy
or
Lipoaccumulation
Can occur in the absence of ART, but most associated with PIs and EFV. 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, particularly with EFV. The appearance of central lipohypertrophy is accentuated in the presence of peripheral fat wasting (lipoatrophy).
Adults:
  • Up to 93%
Children:
  • Up to 27%
Obesity before initiation of therapy

Sedentary lifestyle
Prevention:
  • Calorically appropriate low-fat diet and exercise
Monitoring:
  • BMI measurement
  • Body circumference and waist-hip ratio
Calorically appropriate healthy diet low in saturated fats and simple carbohydrates, and exercise, especially strength training

Smoking cessation (if applicable) to decrease future CVD risk

Consider switching from PIs and EFV to an INSTI

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
  • Liposuction
Facial/Peripheral Lipoatrophy Most associated with thymidine analogue NRTIs (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.
Adults:
Up to 59% (particularly in patients on d4T-containing regimens)

Children:
  • Up to 47% (particularly in patients on d4T- containing regimens)
  • Risk lower (up to 15%) in patients not treated with d4T or 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.
Replace d4T (not widely used and recommended only in special circumstances) or ZDV with 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: ART = antiretroviral therapy; ARV = antiretroviral; BMI = body mass index; 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 (https://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. 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. Pediatric diabetes. 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. 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. 2008;62(5):866-871. Available at http://www.ncbi.nlm.nih.gov/pubmed/18703527.
  5. Moyle G, Moutschen M, Martinez E, et al. Epidemiology, assessment, and management of excess abdominal fat in persons with HIV infection. AIDS reviews. 2010;12(1):3-14. Available at http://www.ncbi.nlm.nih.gov/pubmed/20216906.
  6. 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. 2006;25(2):183-184. Available at http://www.ncbi.nlm.nih.gov/pubmed/16462304.
  7. 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.
  8. 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.
  9. Prendergast AJ. Complications of long-term antiretroviral therapy in HIV-infected children. Arch Dis Child. 2013;98(4):245-246. Available at http://www.ncbi.nlm.nih.gov/pubmed/23413313.
  10. Arbeitman LE, O'Brien RC, Somarriba G, et al. Body mass index and waist circumference of HIV-infected youth in a Miami cohort: comparison to local and national cohorts. Journal of Pediatric Gastroenterology and Nutrition. 2014;59(4):449-454. Available at http://www.ncbi.nlm.nih.gov/pubmed/24709829.
  11. Bwakura-Dangarembizi M, Musiime V, Szubert AJ, et al. Prevalence of lipodystrophy and metabolic abnormalities in HIV-infected African children after 3 years on first-line antiretroviral therapy. Pediatr Infect Dis J. 2015;34(2):e23-31. Available at http://www.ncbi.nlm.nih.gov/pubmed/25068287.

Associated ARVs/Etiology

  1. 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. 2007;45(5):508-514. Available at http://www.ncbi.nlm.nih.gov/pubmed/17589373.
  2. 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. 2009;23(9):1109-1118. Available at http://www.ncbi.nlm.nih.gov/pubmed/19417580.
  3. Hulgan T, Tebas P, Canter JA, et al. Hemochromatosis gene polymorphisms, mitochondrial haplogroups, and peripheral lipoatrophy during antiretroviral therapy. J Infect Dis. 2008;197(6):858-866. Available at http://www.ncbi.nlm.nih.gov/pubmed/18419350.
  4. 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.
  5. 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. American journal of epidemiology. 2006;163(9):860-869. Available at http://www.ncbi.nlm.nih.gov/pubmed/16524955.
  6. 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. 2008;198(11):1599-1608. Available at http://www.ncbi.nlm.nih.gov/pubmed/19000014.
  7. 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. 2006;41(5):590-597. Available at http://www.ncbi.nlm.nih.gov/pubmed/16652032.
  8. 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. The American journal of clinical nutrition. 2008;88(4):1088-1096. Available at http://www.ncbi.nlm.nih.gov/pubmed/18842798.
  9. 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. 2009;10(6):351-355. Available at http://www.ncbi.nlm.nih.gov/pubmed/19490181.
  10. Arpadi S, Shiau S, Strehlau R, et al. Metabolic abnormalities and body composition of HIV-infected children on Lopinavir or Nevirapine-based antiretroviral therapy. Arch Dis Child. 2013;98(4):258-264. Available at http://www.ncbi.nlm.nih.gov/pubmed/23220209.
  11. Foca M, Wang L, Ramteke R, et al. Changes in mitochondrial enzyme function as a predictor of lipodystrophy. Presented at: 7th International AIDS Society. 2015. Vancouver, Canada.
  12. Cohen S, Innes S, Geelen SP, et al. Long-term changes of subcutaneous fat mass in HIV-infected children on antiretroviral therapy: a retrospective analysis of longitudinal data from two pediatric HIV-cohorts. PLoS One. 2015;10(7):e0120927. Available at http://www.ncbi.nlm.nih.gov/pubmed/26148119.
  13. Dos Reis LC, de Carvalho Rondo PH, de Sousa Marques HH, Jose Segri N. Anthropometry and body composition of vertically HIV-infected children and adolescents under therapy with and without protease inhibitors. Public Health Nutr. 2015;18(7):1255-1261. Available at http://www.ncbi.nlm.nih.gov/pubmed/25115797.

Management

  1. Wohl DA, Brown TT. Management of morphologic changes associated with antiretroviral use in HIV-infected patients. J Acquir Immune Defic Syndr. 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. 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. 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. 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. 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. 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. The Journal of clinical endocrinology and metabolism. 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. 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. The Journal of clinical endocrinology and metabolism. 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. 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. 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. 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. 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. Journal of clinical densitometry: the official journal of the International Society for Clinical Densitometry. 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. The Journal of clinical endocrinology and metabolism. 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. 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. 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. 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. 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. 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. Journal of infection and chemotherapy: official journal of the Japan Society of Chemotherapy. 2011;17(2):183-188. Available at http://www.ncbi.nlm.nih.gov/pubmed/20706762.

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