d e c e m b e r 2 0 0 9 T H E S O U T H E R N A F R I C A N J O U R N A L O F H I V M E D I C I N E Antiretroviral agents have led to dramatic advance- ments in life expectancy and quality of life for peo- ple living with HIV/AIDS. Despite this progress, lower- income countries are forced to use older, less expensive antiretrovirals such as stavudine, which are associated with a relatively high frequency of late toxic effects. Nevertheless, the older antiretrovirals are likely to re- main the backbone of the national first-line highly ac- tive antiretroviral therapy (HAART) regimen in South Africa for the foreseeable future due to cost con- straints.1,2 One of the more common late toxic effects of older antiretrovirals is lipodystrophy syndrome (LD). LD is an umbrella term referring to peripheral lipo- atrophy (LA), central lipohypertrophy (LH), and dys- lipidaemia associated with insulin resistance.3,4 These may occur alone or in combination. Although LD was initially thought to be a syndrome of fat redistribution resulting in peripheral LA combined with central LH, preliminary data from the FRAM study in adults (Study of Fat Redistribution and Metabolic Change in HIV in- fection)5 indicate that LH and LA are less closely linked than was previously presumed. Other authors have also noted that LH and LA often occur independently of one another.6 In addition, dyslipidaemia associated with HAART may occur in the absence of LA or LH.7 LA results in disfigurement, particularly of the face (Figs 1 - 6), which can lead to stigmatisation and even forced disclosure of HIV status. This disfigurement has a major impact on adherence, particularly in adolescents.3,6,7 In addition, the long-term health consequences of LD in HIV-infected children, who require lifetime antiretrovi- rals, are considerable: the most important consequence arises from dyslipidaemia and insulin resistance, which are known to significantly accelerate lifetime risk for cardiovascular disease in HIV-infected adults with LD.8 It is unclear whether transient drug-induced dyslipi- daemia in childhood increases the lifetime risk of car- diovascular disease in children.9,10 Nonetheless, these negative health outcomes are of concern given that the prevalence of HAART-related LD in resource-lim- ited settings may be as high as 47% after 2 years of therapy.6 The mechanisms of LD have not yet been firmly estab- lished. The mechanism of LA is related to mitochondrial damage, particularly in adipocytes.11 HAART-related ap- optosis of adipocytes and suppression of pre-adipocyte differentiation have been described in protease inhibi- tor (PI)-induced LA.12 A similar mechanism may occur in nucleoside reverse transcriptase inhibitor (NRTI)- induced LD, since it is known that NRTIs such as stavu- dine can damage adipocyte mitochondria11 and cause a reduction in functioning mitochondria in adults.13 Other chronic toxic effects such as lactic acidosis and peripheral neuropathy have also been associated with mitochondrial dysfunction.14,15 It has been suggested LIPODYSTROPHY SYNDROME IN HIV- INFECTED CHILDREN ON HAART c l i n i c a l Steve Innes1, MB BCh, MRCPCH Leon Levin2, MB BCh, FCPaed (SA), DTM&H Mark Cotton1,3, MB ChB, MMed, PhD, FCPaed, DTM&H, DCH (SA) 1KID-CRU (Children’s Infectious Diseases Clinical Research Unit), Tygerberg Children’s Hospital and Stellenbosch University, Tygerberg, W Cape 2Paediatric HIV Programmes, Right To Care, Johannesburg 3Paediatric Infectious Diseases Unit, Department of Paediatrics and Child Health, Tygerberg Children’s Hospital Lipodystrophy syndrome (LD) is common in HIV-infected children, particularly those taking didanosine, stavu- dine or zidovudine. Lipo-atrophy in particular causes major stigmatisation and interferes with adherence. In addition, LD may have significant long-term health consequences, particularly cardiovascular. Since the stigma- tising fat distribution changes of LD are largely permanent, the focus of management remains on early detection and arresting progression. Practical guidelines for surveillance and avoidance of LD in routine clinical practice are presented. The diagnosis of LD is described and therapeutic options are reviewed. The most important thera- peutic intervention is to switch the most likely offending antiretroviral to a non-LD-inducing agent as soon as LD is recognised. Typically, when lipo-atrophy or lipohypertrophy is diagnosed the thymidine nucleoside reverse transcriptase inhibitor (NRTI) is switched to a non-thymidine agent such as abacavir (or tenofovir in adults). Where dyslipidaemia is predominant, a dietician review is helpful, and the clinician may consider switching to a protease inhibitor-sparing regimen or to atazanavir. 76 T H E S O U T H E R N A F R I C A N J O U R N A L O F H I V M E D I C I N E d e c e m b e r 2 0 0 9 that unknown agents released from damaged mito- chondria in adipocytes may directly trigger apoptosis which leads to subcutaneous fat loss. Quantification of mitochondrial DNA in peripheral leucocytes may be an early warning sign of impending LD in patients exposed to antiretrovirals.16,17 Circulating growth hormone (GH) levels are significantly reduced in patients with LA/LH, and this is likely to aggravate the abnormal fat distri- bution.18 HAART-related dyslipidaemia is thought to be mediated by a different, though related, mechanism: PI-induced alterations in adipokines and pro-inflammatory cy- tokines cause an increased production of triglycerides and cholesterol in hepatocytes, while simultaneously inhibiting glucose uptake in peripheral adipocytes.19 The risk of developing LD is strongly related to the dos- age and duration of exposure to antiretroviral agents. The thymidine NRTIs (zidovudine and stavudine) and didanosine have been linked to LA/LH.20,21 In compari- son, abacavir, tenofovir, and lamivudine have minimal or no LA/LH-causing effect.22 Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are considered a less potent cause of LA.7 Although efavirenz has been as- sociated with lipomastia in some children, this usu- ally resolves spontaneously without withdrawal of efa- virenz.23,24 PIs have been linked to dyslipidaemia,25 and less strongly to LA/LH.21,26 Stavudine, in particular, has been found to be a potent cause of LA in children when taken in the standard pae- diatric dose of 1 mg/kg/dose twice daily.3,7,27,28 Owing to the long-term toxicity of this dose, stavudine is now rarely used in the developed world. A review by Hill et al.29 has recently led the World Health Organization (WHO) to recommend a reduction in the standardised dose of stavudine for adults weighing over 60 kg from 40 mg to 30 mg twice daily,30 since it has been shown that a reduced dose results in a markedly lower risk of LD, while maintaining excellent antiviral efficacy.31,32 The recommended dose of stavudine for children, how- ever, has not yet been reduced. Since the dose of stavu- dine is a major risk factor for the development of LD,33 it would be reasonable to expect that the incidence of LD will fall when a lower dose is employed. The cur- rent standard paediatric dose of stavudine (1 mg/kg/ dose twice daily) was extrapolated from the pharma- cokinetic parameters of the adult dose of 40 mg twice daily, using data from a few small but well-controlled paediatric pharmacokinetic studies34-36 which showed that an oral dose of 1 mg/kg/dose twice daily in chil- dren under 12 years results in plasma exposure similar to that of adults taking 40 mg twice daily, and that an oral dose of 0.5 mg/kg/dose twice daily in children results in plasma exposure similar to that of adults tak- ing 20 mg twice daily. Particular mitochondrial DNA sub-groups (haplo- groups) have been associated with a vulnerability to developing LA after exposure to HAART.37 A recent study showed that Caucasian American men on HAART who have the H mitochondrial haplogroup were at significantly increased risk of LA.37 In addition, certain mitochondrial DNA mutations may make an individual more vulnerable to developing LD when exposed to antiretroviral agents. This may occur because varia- tions of mitochondrial DNA in adipocytes may reduce the efficiency of energy production or lead to increased oxygen free-radical production, resulting in a reduced mitochondrial reserve and an increased vulnerability to apoptosis when exposed to mitochondrial toxins such as antiretrovirals. 77 Significance of lipodystrophy syndrome • Lipodystrophy syndrome (LD) is common in HIV- infected children, particularly in those taking didanosine, stavudine or zidovudine. • Lipo-atrophy (LA) (a component of LD) causes major stigmatisation and interferes with adher- ence. • LD may have significant long-term health conse- quences, particularly cardiovascular. • LA is largely permanent, so the focus remains on early detection and arresting progression. What to look out for • Look for a lean, muscular appearance of face and limbs with prominent limb veins due to loss of subcutaneous fat tissue. • Compare the child’s tricep and bicep skin-fold thickness with your own as a rough guide. • Shrinking buttocks with or without an enlarging abdomen may be monitored using a waist-to- hip ratio (WHR). • Children on HAART should have their blood lipids measured routinely every year. What to do Where subcutaneous LA or lipohypertrophy is di- agnosed: • The most likely offending NRTI should be switched to abacavir (or tenofovir in adults). Where dyslipidaemia is predominant: • A dietician review is helpful. • Consider switching to a PI-sparing regimen or to atazanavir. • Look for insulin resistance. • Statins and metformin are only used in extreme cases. RiSK FacTORS d e c e m b e r 2 0 0 9 T H E S O U T H E R N A F R I C A N J O U R N A L O F H I V M E D I C I N E 78 A complex set of diagnostic criteria for the diagnosis of LD has been developed for adults by Carr et al.38 Equi- valent diagnostic criteria for children have not been formally defined. Most clinicians employ a combination of objective anthropometric and biochemical measure- ments and a subjective assessment in order to diagnose LD in children.6,7,33,39,40 Physical signs in children are due to loss of subcutaneous fat in limbs, buttocks and face, with or without accumulation of intra-abdomi- nal visceral fat. Loss of limb fat results in prominent limb veins and a well-defined, muscular appearance of limbs in the presence of a normal or enlarged abdo- men. Reduced skin-fold thickness (SFT) may be subjec- tively assessed by comparing it with one’s own SFT as a rough guide. Loss of buttock fat, with or without enlargement of the abdomen, results in a greatly increased waist-to- hip ratio (WHR). Breast enlargement and buffalo hump may occur after puberty. Other useful anthropometric measurements include mid-upper arm circumference (MUAC) and waist circumference, from which the waist-to-MUAC ratio can be calculated. SFT measure- ments may be used to calculate the torso-to-arm ratio (TAR) as follows: TAR = [subscapular + suprailiac SKF]/ [bicep + tricep SFT]. A TAR z-score of >2.0 has been used as a diagnostic criterion in some studies.39 As HAART-related dyslipidaemia may occur independ- ently of LA/LH,5-7 children on HAART should have their blood lipids measured routinely at least once a year. Facial fat loss is often subtle and difficult to detect unless severe. The facial muscles are not normally no- ticeable because they are covered in fat. Loss of facial fat results in a lean, muscular appearance of the face with deep laugh-lines when smiling. An old photo- graph may be helpful. Figs 1 and 2 show a child with mild LA of the face. Some recovery is seen 4 years after changing from a stavudine-containing regimen (Fig. 3). Fig. 4 shows a child with moderate facial LA. Figs 5 and 6 show a child with severe facial LA. Her LA was already advanced when she was changed from a sta- vudine-containing regimen 4 years previously, and is unlikely to improve. To date there are limited data comparing the sensi- tivity and specificity of anthropometric and biochemi- cal diagnostic criteria against a gold standard such as dual-energy X-ray absorptiometry or magnetic reso- nance imaging to diagnose early LA/LH in HIV-infected children. Studies are underway to define a practical set of diagnostic criteria to detect early LD in children in resource-limited settings. Since at least 30% of pe- ripheral fat must be lost before LA becomes visibly evi- dent,41 it is hoped that some combination of anthropo- metric and biochemical measures will have reasonable sensitivity and specificity to detect LA/LH in children before it causes noticeable disfigurement (S Innes et al. – unpublished data). This will be an important contri- bution to paediatric HIV care in the developing world. Fig. 2. Mild LA of the face, side view. Fig. 1. Mild LA of the face, front view. DiaGnOSiS Fig. 3. The same child as in Fig. 1. Some recovery is seen 4 years after withdrawal of stavudine. T H E S O U T H E R N A F R I C A N J O U R N A L O F H I V M E D I C I N E d e c e m b e r 2 0 0 9 Since the disfiguration caused by LD is largely perma- nent, the focus of management is on early detection and arrest of progression. Once identified, the most likely offending drug is usually withdrawn in an at- tempt to prevent progression, and is replaced by a less LD-inducing antiretroviral. Where dyslipidaemia is identified, diet and lifestyle modification are essential. If severe and persistent (total cholesterol >13 mmol/l or triglycerides >8.5 mmol/l),1 the PI may be switched to a PI-sparing agent or changed to atazanavir/ritona- vir (ATV/r), which has less effect on blood lipids.21 The effect of statins in lowering triglycerides and choles- terol is well established;42 however, statins are only licensed for use in children over 12 years of age. The potential interaction of statins with PIs must be borne in mind. Metformin has been shown to be effective for LD-related insulin resistance in adults43 and for obes- ity-related insulin resistance in HIV-uninfected chil- dren.44 However, metformin is rarely used in LD-related insulin resistance in children. When LA/LH is diagnosed, significant benefit in halting progression has been shown from switching the thymi- dine NRTI to a non-thymidine agent such as abacavir.21 Tenofovir is generally avoided in children because of renal toxicity and osteopenia. However, there may be a place for switching to tenofovir in older children.45 This switch typically arrests progression of LA/LH, and may result in a small degree of reversal if LA is caught early. Various authors have demonstrated that the more ad- vanced the LA, the less likely it is to reverse when the offending drug is removed.46,47 Intradermal injections of a biodegradable filler such as poly-L-lactic acid (Sculptura) can ameliorate the aesthetic effect of fa- cial LA in adults,48 but this treatment is not appropriate for children. In addition, the cost is significant and the effect is not permanent and injections may need to be repeated. Uridine (NucleomaxX) partially reverses the mitochondrial toxicity caused by thymidine NRTIs, and may have a small but beneficial effect on disfiguring LA. Uridine is not currently available in South Africa, and it has no effect on dyslipidaemia.49 Growth hormone-re- leasing hormone analogues (GH-RH) are helpful in the treatment of LA/LH.50 The mechanism probably involves reversing the reduced GH levels that are consistently found in patients with LA/LH. Although the side-ef- fect profile of GH-RH therapy is attractive, the cost is prohibitive. Future treatments may involve adipokines such as leptin, but these remain experimental.21 Research into reducing the paediatric dose of stavu- dine is urgently needed in order to minimise the risk of LD without compromising antiviral efficacy, since the number of at-risk HIV-infected children exposed to long-term stavudine therapy in South Africa is very large. In addition, non-thymidine NRTIs such as abacavir and tenofovir should be more widely avail- able, particularly in the public sector. 79 Fig. 4. Moderate LA of the face, front view. Note the loss of the buccal fat pad, resulting in lean, muscular appearance of the face with deep laugh-lines. Fig. 6. Severe LA of the face, side view. Fig. 5. Severe LA of the face, front view. This patient’s LA was already advanced when she was changed from a stavudine- containing regimen 4 years previously. Her LA is unlikely to improve. ManaGEMEnT cOncluSiOn d e c e m b e r 2 0 0 9 T H E S O U T H E R N A F R I C A N J O U R N A L O F H I V M E D I C I N E Further research is needed to isolate the particular mitochondrial mutations that make a child vulnerable to LD. This may help public sector clinicians to pre- dict which children should avoid thymidine NRTIs and rather be started on a more expensive, less LD-inducing antiretroviral regimen. Finally, since effective treatment of LD is difficult and remains beyond the reach of resource-limited rural communities, early detection is paramount. It is es- sential to define a simple set of diagnostic criteria to identify early LD in children that can be easily imple- mented in resource-limited settings. This will allow the progression of LD to be halted before it causes notice- able disfigurement and stigmatisation. Children should be switched from stavudine (or zidovudine) to abacavir (and adults to tenofovir or abacavir) at the slightest sign of LD. REFERENCES 1. Meyers T, Eley B, Loening W. Khomanani Guidelines for the Management of HIV- infected Children. Johannesburg: National Department of Health, Jacana Media, 2005. 2. Hogan B (National Minister of Health – South Africa). Southern African AIDS Conference, Durban, April 2009. Plenary address, 3 April. http://www.saaids.com/images/stories/4th_SA_AIDS_Conference_ presentations/minister%20of%20health.pdf (accessed 16 November 2009). 3. McComsey GA, Leonard E. Metabolic complications of HIV therapy in children. AIDS 2004; 18: 1753-1768. 4. Aldrovandi GM, Lindsey JC, Jacobson DL, et al., for the Pediatric AIDS Clinical Trials Group P1045 team. Morphologic and metabolic abnormalities in vertically HIV-infected children and youth. AIDS 2009; 23: 661-672. 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. Am J Epidemiol 2006; 163(9): 860-869. 6. Aurpibul L, Puthanakit T, Lee B, Mangklabruks A, Sirisanthana T, Sirisanthana V. Lipodystrophy and metabolic changes in HIV-infected children on non- nucleoside reverse transcriptase inhibitor-based antiretroviral therapy. Antivir Ther 2007; 12(8): 1247-1254. 7. Ene L, Goetghebuer T, Hainaut M, et al. Prevalence of lipodystrophy in HIV- infected children: a cross-sectional study. Eur J Pediatr 2007; 166(1): 13-21. 8. Hadigan C, Meigs JB, Corcoran C, et al. Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy. Clin Infect Dis 2001; 32: 130-139. 9. Berenson GS, Srinivasan SR, Bao W, et al. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. N Engl J Med 1998; 338: 1650-1656. 10. Girardet JP. Dyslipidemia in childhood and cardiovascular risk. Arch Pediatr 2009; 16: 692-693. 11. Walker UA, Bickel M, Lütke Volksbeck SI, et al. Evidence of nucleoside analogue reverse transcriptase inhibitor-associated genetic and structural defects of mitochondria in adipose tissue of HIV-infected patients. J Acquir Immune Defic Syndr 2002; 29(2): 117-121. 12. Dowell P, Flexner C, Kwiterovich PO, Lane MD. Suppression of preadipocyte differentiation and promotion of adipocyte death by HIV protease inhibitors. J Biol Chem 2000; 275: 41325-41332. 13. Cote HC, Brumme ZL, Craib KJ, et al. Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients. N Engl J Med 2002; 346: 811- 820. 14. Hurst M, Noble S. Stavudine: an update of its use in the treatment of HIV infection. Drugs 1999; 58(5): 919-949. 15. Dragovic G, Jevtovic DJ. Nucleoside reverse transcriptase inhibitor usage and the incidence of peripheral neuropathy in HIV/AIDS patients. Antivir Chem Chemother 2003; 14(5): 281-284. 16. Montaner JS, Cote HC, Harris M, et al. Mitochondrial toxicity in the era of HAART: Evaluating venous lactate and peripheral blood mitochondrial DNA in HIV-infected patients taking antiretroviral therapy. J Acquir Immune Defic Syndr 2003; 34: Suppl 1, S85-S90. 17. Petit C, Mathez D, Barthelemy C, Leste-Lasserre T, Naviaux RK, Sonigo P, Leibowitch J. Quantitation of blood lymphocyte mitochondrial DNA for the monitoring of antiretroviral drug-induced mitochondrial DNA depletion. J Acquir Immune Defic Syndr 2003; 33: 461-469. 18. Rietschel P, Hadigan C, Corcoran C, et al. Assessment of growth hormone dynamics in human immunodeficiency virus-related lipodystrophy. J Clin Endocrinol Metab 2001; 86: 504-510. 19. Parker RA, Flint OP, Mulvey R, et al. Endoplasmic reticulum stress links dyslipidemia to inhibition of proteasome activity and glucose transport by HIV protease inhibitors. Mol Pharmacol 2005; 67: 1909-1919. 20. Jones SP, Qazi N, Morelese J, et al. Assessment of adipokine expression and mitochondrial toxicity in HIV patients with lipoatrophy on stavudine- and zidovudine-containing regimens. J Acquir Immune Defic Syndr 2005; 40: 565- 572. 21. Mallewa JE, Wilkins E, Vilar J, et al. HIV-associated lipodystrophy: a review of underlying mechanisms and therapeutic options. J Antimicrob Chemother 2008; 62(4): 648-660. 22. Moyle GJ, Sabin CA, Cartledge J, et al. A randomized comparative trial of tenofovir or abacavir as replacement for a thymidine analogue in persons with lipoatrophy. Acquir Immune Defic Syndr 2006; 20: 2043-2050. 23. Arranz Caso J, de Miguel Prieto J, Casas E, Sanz J. Gynecomastia without LD syndrome in HIV-infected men treated with efavirenz. AIDS 2001; 15: 1447- 1448. 24. Merciéa P, Viallarda JP, Thiébaut R, et al. Efavirenz-associated breast hypertrophy in HIV-infected patients. AIDS 2001; 15(1): 126-129. 25. Behrens G, Dejam A, Schmidt H, et al. Impaired glucose tolerance, beta cell function and lipid metabolism in HIV patients under treatment with protease inhibitors. Acquir Immune Defic Syndr 1999; 13: F63-70. 26. McComsey GA, Walker UA. Role of mitochondria in HIV lipoatrophy: insight into pathogenesis and potential therapies. Mitochondrion 2004; 4: 111-118. 27. Murphy RA, Sunpath H, Kuritzkes DR, Venter F, Gandhi RT. Antiretroviral therapy- associated toxicities in the resource-poor world: The challenge of a limited formulary. J Infect Dis 2007; 196: S449-S456. 28. ter Hofstede HJM, Koopmans PP, Burger DM. Stavudine plasma concentrations and lipoatrophy. J Antimicrob Chemother 2008; 61(4): 933-938. 29. Hill A, Ruxrungtham K, Hanvanich M, et al. Systematic review of clinical trials evaluating low doses of stavudine as part of antiretroviral treatment. Expert Opin Pharmacother 2007; 8(5): 679-688. 30. Addendum to 2006 WHO guidelines on antiretroviral therapy for HIV infection in adults and adolescents. www.who.int/hiv/en/ (accessed 26 August 2008). 31. Sánchez-Conde M, de Mendoza C, Jiménez-Nacher I, et al. Reductions in stavudine dose ameliorate mitochondrial-associated complications without compromising antiviral activity. HIV Clin Trials 2005; 6(4): 197-202. 32. McComsey GA, LoRe V III, O’Riordan M, et al. Effect of reducing the dose of stavudine on body composition, bone density and markers of mitochondrial toxicity in HIV-infected subjects – a randomized, controlled study. Clin Infect Dis 2008; 46(8): 1290-1296. 33. Amaya RA, Kozinetz CA, Mcmeans A, Schwarzwald H, Kline MW. Lipodystrophy syndrome in human immunodeficiency virus-infected children. Pediatr Infect Dis J 2002; 21: 405-410. 34. Kaul S, Kline MW, Church JA, Dunkle LM. Determination of dosing guidelines for stavudine (2’,3’-didehydro-3’-deoxythymidine) in children with human immunodeficiency virus infection. Antimicrob Agents Chemother 2001; 45(3): 758-763. 35. Kline MW, Dunkle LM, Church JA, et al. A phase I/II evaluation of stavudine (d4T) in children with human immunodeficiency virus infection. Pediatrics 1995; 96(2): 247-252. 36. Dudley MN, Graham KK, Kaul S, et al. Pharmacokinetics of stavudine in patients with AIDS or AIDS-related complex. J Infect Dis 1992; 166: 480-485. 37. Hendrickson SL, Kingsley LA, Ruiz-Pesini E, et al. Mitochondrial DNA haplogroups influence lipoatrophy after highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2009; 51(2): 111-116. 38. Carr A, Emery S, Law M, Puls R, Lundgren JD, Powderly WG. An objective case definition of lipodystrophy in HIV-infected adults: a case-control study. Lancet 2003; 361: 726-735. 39. Hartman K, Verweel G, de Groot R, Hartwig NG. Detection of lipoatrophy in human immunodeficiency virus-1-infected children treated with highly active antiretroviral therapy. Pediatr Infect Dis J 2006; 25(5): 427-431. 40. European Paediatric Lipodystrophy Group. Antiretroviral therapy, fat redistribution and hyperlipidaemia in HIV-infected children in Europe. AIDS 2004; 18: 1443- 1451. 41. Podzamczer D, Ferrer E, Martınez E, et al., for the ABCDE Study Team. How much fat loss is needed for lipoatrophy to become clinically evident? AIDS Res Hum Retroviruses 2009; 25(6): 563-567. 42. Calza L, Manfredi R, Chiodo F. Statins and fibrates for the treatment of hyperlipidaemia in HIV-infected patients receiving HAART. AIDS 2003; 17: 851- 859. 43. Hadigan C, Corcoran C, Basgoz N, et al. Metformin in the treatment of HIV lipodystrophy syndrome: a randomized controlled trial. JAMA 2000; 284: 472- 777. 44. Park MH, Kinra S, Ward KJ, White B, Viner RM. Metformin for obesity in children and adolescents: A systematic review. Diabetes Care 2009; 32(9): 1743-1745. 45. Riordan A, Judd A, Boyd K, Cliff D, et al., on behalf of the CHIPS Study. Tenofovir use in human immunodeficiency virus-1-infected children in the United Kingdom and Ireland. Pediatr Infect Dis J 2009; 28: 204-209. 46. McComsey GA, Ward DJ, Hessenthaler SM, et al., for the TARHEEL study team (Trial to Assess the Regression of Hyperlactatemia and to Evaluate the regression of Established Lipodystrophy in HIV-1-positive subjects). Improvement in lipoatrophy associated with highly active antiretroviral therapy in human immunodeficiency virus-infected patients switched from stavudine to abacavir or zidovudine: The results of the TARHEEL study. Clin Infect Dis 2004; 38: 263-270. 47. Fisher M, Moyle G, Shahmanesh M, et al. for the SWEET study group. A randomized comparative trial of continued zidovudine/lamivudine or replacement with tenofovir disoproxil fumarate/emtricitabine in efavirenz-treated HIV-1-infected individuals. J Acquir Immune Defic Syndr 2009; 51: 562-568. 48. Carey DL, Baker D, Rogers GD, et al., for the Facial LipoAtrophy Study in HIV (FLASH). A randomized, multicenter, open-label study of poly-L-lactic acid for HIV-1 facial lipoatrophy. J Acquir Immune Defic Syndr 2007; 46: 581-589. 49. McComsey GA, O’Riordan M, Setzer B, et al. Uridine supplementation in HIV lipoatrophy: pilot trial on safety and effect on mitochondrial indices. Eur J Clin Nutr 2008; 62: 1031-1037. 50. 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: 2359-2370. 80