Highly active antiretroviral therapy (HAART) has dramatically

Transcription

1 HIV Re p o r t s Recovery From Lipodystrophy in HIV infected Children After Substitution of Stavudine With Zidovudine in a n-nucleoside Reverse Transcriptase Inhibitor based Antiretroviral Therapy Linda Aurpibul, MD,* Thanyawee Puthanakit, MD,* Sineenart Taejaroenkul, MSc,* Thira Sirisanthana, MD,* and Virat Sirisanthana, MD* Background: Substitution of stavudine with zidovudine may lead to recovery from lipodystrophy (LD) in HIV-infected children. Methods: We prospectively followed HIV-infected children enrolled in an earlier LD study conducted between 2002 and 2004 at Chiang Mai University Hospital in northern Thailand. In 2006, stavudine was substituted with zidovudine. All children were evaluated by a clinical LD checklist modified from that of the European Pediatric LD study group together with waist/hip measurement at baseline and 24, 48, 72, and 96 weeks after substitution. The waist-to-hip ratios were converted to age- and sex-adjusted z scores based on normal ranges in healthy Thai children. Results: Forty-five lipodystrophic children with 36 episodes of lipohypertrophy and 22 episodes of lipoatrophy were enrolled. By weeks 48 and 96 after substitution, 40% and 47% of lipohypertrophy resolved, whereas 59% and 73% of lipoatrophy resolved, respectively. The rate of resolution of lipoatrophy was higher than that of lipohypertrophy at 48 weeks after substitution and thereafter. Ninety-six weeks after changing to zidovudine therapy, 8 children still had LD (1 with both lipoatrophy and lipohypertrophy, 7 with lipohypertrophy). clinically significant hematologic adverse event was observed. Conclusions: Substitution of stavudine with zidovudine resulted in decreased severity or resolution of LD among HIV-infected children and adolescents. Key Words: lipodystrophy, HIV, children (Pediatr Infect Dis J 2012;31: ) Highly active antiretroviral therapy (HAART) has dramatically reduced the mortality of HIV-infected children worldwide. 1 3 Long-term adverse effects of HAART, including lipodystrophy (LD) and other metabolic disturbances, have been documented and have become important issues in patients who need life-long HAART. 4 7 LD, a change in body shape owing to redistribution of body fat, has been well described in HIV-infected individuals, particularly those treated with protease inhibitors (PIs) or nucleoside Accepted for publication October 26, From the *Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand; and Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. The authors have no funding or conflicts of interest to disclose. Address for correspondence: Virat Sirisanthana, MD, Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand vsirisan@rihes.org. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal s Web site ( Copyright 2012 by Lippincott Williams & Wilkins ISSN: /12/ DOI: /INF.0b013e31823f0e11 reverse transcription inhibitors, especially stavudine (d4t). 6,8 10 The following 3 phenotypes of LD have been described: central fat accumulation (lipohypertrophy), peripheral wasting (lipoatrophy), and a combination of these (combined form). With or without metabolic derangement, the condition can be severely disfiguring and may adversely affect treatment adherence and outcome We previously reported the prevalence of LD and other metabolic changes in 90 HIV-infected Thai children who were taking d4t-containing non-nucleoside reverse transcription inhibitor (NNRTI)-based HAART, namely regimens consisting of d4t, lamivudine (3TC), and either nevirapine (NVP) or efavirenz (EFV). 14 Most HIV-infected children and adults in resource-limited countries are prescribed d4t-containing NNRTI-based HAART regimens. 15 Thus, millions of HIV-infected persons have developed or are at risk for developing d4t-related LD. A prospective follow-up study of HIV-infected children and adolescents with lipoatrophy reported no improvement in lipoatrophy in the majority of cases after substitution of d4t with tenofovir disoproxil fumarate (TDF). 16 Since 2006, the World Health Organization has recommended that d4t be substituted with abacavir (ABC) in cases with lipoatrophy. However, it was also noted that the substitution might not reverse lipoatrophy. 17 Also, high cost of ABC limits its accessibility to patients in resource-limited settings. The previous World Health Organization recommendation in 2009 had highlighted avoiding the disfiguring and potentially life-threatening toxicity of d4t, and suggested changing d4t to zidovudine (ZDV) or TDF after an assessment of the cost and feasibility. 18 Because TDF is approved for use only in patients 12 years of age and weighing 35 kg, ZDV may be the only available alternative agent for substitution in children. In the present communication, we report the outcome of LD in HIV-infected children 24, 48, 72, and 96 weeks after substituting d4t with ZDV in their NNRTI-based HAART regimens. PATIENTS AND METHODS Study Design and Patient Population We prospectively followed 45 HIV-infected children enrolled in an LD study between August 2002 and October 2004 at Chiang Mai University Hospital, Chiang Mai, Thailand. 14 The inclusion criteria for that study were (i) age, 5 to 15 years; (ii) symptomatic HIV infection with severe immunosuppression, defined as a baseline CD4 + T-cell percentage 15%; and (iii) receiving a treatment regimen consisting of either NVP or EFV with 3TC and d4t. They were followed for up to 144 weeks for the presence of LD and other metabolic changes. Between February and September 2006, d4t was substituted with ZDV in all children. Children who had been on NVP-containing regimen received a fixed-dose-combination tablet The Pediatric Infectious Disease Journal Volume 31, Number 4, April 2012

2 The Pediatric Infectious Disease Journal Volume 31, Number 4, April 2012 Lipodystrophy in HIV-infected Children (GPOvirZ250, Thai Government Pharmaceutical Organization, Bangkok, Thailand), containing 250, 150, and 200 mg of ZDV, 3TC, and NVP, respectively. Children who had been on EFV-containing regimen received a fixed-dose-combination tablet (Zilavir, Thai Government Pharmaceutical Organization, Bangkok, Thailand), containing 300 mg of ZDV and 150 mg of 3TC together with EFV (50 mg and 200 mg capsules; Bristol-Myers Squibb). The fixeddose-combination tablets were prescribed according to the child s body weight, delivering a median ZDV dosage of 202 (interquartile range, ) mg/m 2 per dose. In the present study, children were evaluated at 0, 24, 48, 72, and 96 weeks after substitution with ZDV. The study was approved by the research ethics committee of Chiang Mai University. Informed consent was obtained from each child s parent or legal guardian. Assessment Anthropometric Measurements Measurements of the child s weight, height, and waist and hip circumferences were performed at the time of ZDV substitution and at 24, 48, 72, and 96 weeks after the change. Mid-waist circumference was measured at the level of the umbilicus after full exhalation. Hip circumference was measured at the widest lateral hip diameter, across the maximal protuberance of the buttocks, and perpendicular to the cranial-caudal axis of the body. Measurements of waist and hip circumferences were performed twice, and the average value was used. Because these values vary with age, they were converted to age- and sex-adjusted z scores based on normal ranges for 6- to 15-year-old healthy Thai children. 19 Clinical Assessment Clinical assessment was done at every visit at which anthropometric measurements were performed. The same researcher (V.S.) used serial photography and an LD checklist, modified from that of the European Pediatric LD study group. 5 Body sites for lipoatrophy assessment included the cheeks and the muscles and veins of the arms. A clinical rating scale from 0 to 3 was used to assess atrophy as follows: grade 0, absent; grade 1, mild (noticeable on close inspection); grade 2, moderate (readily noticeable); and grade 3, severe (readily noticeable to other observers). Increased abdominal girth was used to assess lipohypertrophy, using a similar clinical rating scale, when there was no measurement of waist and hip circumferences. Definition of LD Lipoatrophy was defined as the presence of at least 1 of the following 4 criteria: (i) atrophy of the cheeks at any grade, (ii) grade 2 or 3 prominent arm muscles, (iii) grade 2 or 3 prominent arm veins, or (iv) grade 1 prominent arm muscles plus grade 1 prominent arm veins. Lipohypertrophy in children 6 to 18 years of age was defined as age- and sex-adjusted waist-to-hip ratio z score of 3.5. This waist-to-hip cutoff (z score 3.5) has been shown to have a good correlation (72% sensitivity and 74% specificity by Receiver operating characteristic curve) with moderate/severe increased abdominal girth as evaluated by expert with the help of serial photographs. 14 Because reference values were not available for healthy Thai children 15 years of age, lipohypertrophy in children 15 years of age was defined as age- and sex-adjusted waist-to-hip ratio z score of 3.5 when compared with the reference values of healthy Thai children 15 years of age. At 72 and 96 weeks after the substitution, if waist and hip circumferences were not measured, lipohypertrophy was defined as the presence of grade 2 or 3 increased abdominal girth. These definitions had been used in our previous study. 14 Recovery from LD was classified as resolution or improvement as defined in Table 1. Laboratory Procedures At each visit, we measured complete blood count, CD4 cell count, and plasma HIV RNA level. CD4 cell counts were assessed with the use of a FACS Count apparatus (Becton-Dickinson). Plasma HIV RNA levels were measured by the Roche Ultrasensitive Amplicor assay, version 1.5 (Roche). All laboratory tests were done at Chiang Mai University Hospital. Hematologic results were graded according to the Division of Acquired Immunodeficiency Syndrome table for grading the severity of adult and pediatric adverse events. 20 Statistical Methods The characteristics of children were presented as frequency, percent, mean standard deviation, and 95% confident interval. 2 test was used to compare the resolution rate at each time point. 2 test and logistic regression analysis were used to evaluate the factors associated with improvement or resolution versus no improvement of lipoatrophy and lipohypertrophy at 48 weeks after substitution. The proportion of cases with abnormal hematologic results, the change in mean values for weight-for-age z scores, and height-for-age z scores at each time point were compared using Fisher exact test and paired t test as appropriate. All analyses were performed using the Statistical Package for Social Science version 17.0 software (SPSS Inc., Chicago, IL). RESULTS In our previous study, 54 of 90 children developed LD 144 weeks after initiating d4t-containing HAART regimen. 14 Of these 54 children, 5 who had virologic failure before February 2006 were switched to a second-line PI-based regimen, whereas 4 children were transferred to hospitals in their districts/provinces before receiving ZDV for at least 48 weeks. Clinical characteristics of the remaining 45 children are shown in Table 2. These 45 children developed 36 episodes of lipohypertrophy and 22 episodes of lipoatrophy (23 cases with lipohypertrophy alone, 9 cases with lipoatrophy alone, and 13 cases with both lipohypertrophy and lipoatrophy). Of the 36 episodes of lipohypertrophy, 6 were excluded (3 were less than 6 years of age at switching, when there was no normal range of waistto-hip ratio value to compare, and 3 cases did not have serial waist and hip measurement). The cumulative number of children with resolution, improvement, and no improvement from LD are shown in Table 3. By week 48 after changing to ZDV, 40% of lipohypertrophy cases and 59% of lipoatrophy cases resolved (Fig., Supplemental TABLE 1. Definition of Resolution and Improvement From LD Among HIV-infected Children Resolution Lipoatrophy Lipohypertrophy Improvement Lipoatrophy Lipohypertrophy LD indicates lipodystrophy. Absence of all lipoatrophy criteria Waist-to-hip ratio z-score 3.5 or absence of lipohypertrophy criteria at 2 consecutive examinations at least 3 mo apart Decrease in severity grading of sunken cheeks and prominent arm muscles and prominent arm veins, but still meet criteria for lipoatrophy Waist-to-hip ratio z-score 3.5 but a decrease of 0.25 compared with previous 24-wk measurement or decrease in severity grading of increased abdominal girth 2012 Lippincott Williams & Wilkins 385

3 Aurpibul et al The Pediatric Infectious Disease Journal Volume 31, Number 4, April 2012 TABLE 2. Clinical Characteristics of 45 HIV-infected Children With Lipodystrophy Characteristics Values (n 45) Male gender, number (%) 16 (36) Regimen, number (%) d4t 3TC NVP 26 (58) d4t 3TC EFV 19 (42) At diagnosis of LD Age (y)* Tanner stage, number (%) I 23 (55) II 8 (19) III 7 (16) IV 4 (10) Duration of HAART (mo)* Type of LD, number (%) Lipoatrophy 9 (20) Lipohypertrophy 23 (51) Combined type 13 (29) BMI* Weight-for-age z score* Height-for-age z score* At substitution of d4t with ZDV Duration of LD (mo)* CD4 cell count (cells/mm 3 )* HIV RNA level (log copies/ml)* *Values are means standard deviation. LD indicates lipodystrophy; HAART, highly active antiretroviral therapy; BMI, body mass index; d4t, stavudine; 3TC, lamivudine; NVP, nevirapine; EFV, efavirenz; ZDV, zidovudine. Digital Content 1, The rate of resolution of lipoatrophy was higher than that of lipohypertrophy at 48 weeks; however, this difference did not reach statistical significance until 96 weeks after substitution (P 0.049). At 96 weeks after changing to ZDV, 8 children still had LD (1 with both lipoatrophy and lipohypertrophy, 7 with lipohypertrophy alone). Of these 8 children, 3 still had grade 3 LD. In 2 of these 3 children, a 12-year-old boy and a 13-year-old girl (Fig., Supplemental Digital Content 2, ZDV was substituted with TDF at the dose of 8.5 and 7.3 mg/kg, respectively. The remaining child was a 15-year-old girl who refused to take TDF because of potential adverse effects on bone mineral density. Her dosage of ZDV was reduced from 223 to 149 mg/m 2 /dose. One year after these changes, all 3 children experienced improvement. There was no association of improvement of lipoatrophy or of lipohypertrophy at 48 weeks with gender or with regimen used (NVP or EFV). There was also no association of improvement with age, Tanner stages, duration of d4t-containing regimen, body mass index z score, duration of lipoatrophy/lipohypertrophy, CD4 cell count ( 500 cell/mm 3 vs. 500 cell/mm 3 ), or proportion of children with suppressed viral load ( 50 copies/ml) at diagnosis of lipoatrophy/lipohypertrophy. When compared with values at the time of ZDV substitution, a statistically significant decrease in mean hemoglobin values was observed up to 72 weeks after the substitution. However, there were no clinical signs or symptoms associated with this change in the laboratory values. There was no hematologic abnormality more severe than grade 1 observed within 48 weeks after the substitution (Table, Supplemental Digital Content 3, Weight-for-age z score of these children at the time of substitution increased from 0.91 (SD, 1.0) to 0.76 (SD, 1.1) at 96 weeks (P 0.02), whereas heightfor-age z score did not change (Table, Supplemental Digital Content 3, TABLE 3. Children Who Had Resolution, Improvement, and Improvement at Each Time Point After Substitution Week 24 Week 48 Week 72 Week 96 Improvement Resolution Improvement Improvement Improvement Resolution Improvement Improvement Type Total Resolution Improvement Resolution Improvement 30 (100) 10 (33) 6 (20) 14 (47) 12 (40) 8 (27) 10 (33) 13 (43) 9 (30) 8 (27) 14 (47) 8 (27) 8 (27) Lipohypertrophy, number (%) Lipoatrophy, 22 (100) 2 (9) 11 (50) 9 (41) 13 (59) 6 (27) 3 (14) 14 (64) 6 (27) 2 (9) 16 (73) 5 (23) 1 (5) number (%) P* *Comparison between percentage of resolution of lipohypertrophy and lipoatrophy Lippincott Williams & Wilkins

4 The Pediatric Infectious Disease Journal Volume 31, Number 4, April 2012 Lipodystrophy in HIV-infected Children DISCUSSION This study demonstrated that substituting d4t with ZDV in an NNRTI-based HAART among HIV-infected children and adolescents resulted in recovery of LD in most cases. The proportion of cases of lipoatrophy with resolution was higher than that for lipohypertrophy at week 48 and thereafter. By 96 weeks, 73% of lipoatrophy cases and 47% of lipohypertrophy cases had resolved. The use of ZDV in this setting was not found to be associated with any clinically significant adverse hematologic effect. Assessment of LD in children is usually more difficult than that in adults because their process of growth is ongoing. Furthermore, there is a lack of normal values of childhood anthropometric parameters. As children grow up, lipoatrophy may be obscured by effects of hormonal and other age-related physiologic changes. The lipoatrophy checklist of the European Pediatric LD study group includes examination of 4 body sites (face, arms, legs, and buttocks), but our modified approach entailed examination of only the face and arms. We did not include buttocks examination because in our previous study, we found that moderate to severe hollowing of buttocks was rare and was always accompanied by moderate or severe grades of arm and/or cheek atrophy. Similarly, we also did not include examination of the legs because our previous study demonstrated that leg findings were always accompanied by arm findings. Serial photographs further aided assessment of lipoatrophy. For lipohypertrophy, age- and sex-adjusted waist-to-hip ratio z scores when compared with the reference values of healthy Thai children was a better means of assessment compared with using increased abdominal girth by inspection because the latter is subject to interobserver variation. Although the waist-tohip ratio is usually used to evaluate increased abdominal girth, it does have some limitations in that decreased hip girth can also increase the waist-to-hip ratio. However, in our previous study, we found that the occurrence of moderate to severe decreased hip girth was rare. 14 Although our previous study found a higher prevalence of LD among females and those with more advanced disease at baseline, 14 in the current study, there was no association of the resolution/improvement of lipoatrophy/lipohypertrophy with any tested factors. We had expected to find more cases with resolution/improvement among those with shorter duration of LD before drug substitution, but we did not. This may be due to the very long period (mean 15.8 months) between the detection of LD and drug substitution in our cohort. Many studies have focused on the potential life-threatening cardiovascular risk associated with metabolic changes. However, LD also affects the child s body image and self esteem, 12,13 and it hinders optimal adherence to HAART. One Spanish study reported that 54% of vertically acquired HIV infected children had LD at the time of their transfer to an adult clinic. 21 There is a concern because it is probably the most vulnerable time for emergence of adherence problems. One French study has reported a significant association between patients subjective perceptions of LD symptoms and failure to maintain adherence to HAART. 11 Studies in adult populations revealed a trend toward improvement of metabolic abnormalities, including LD and abnormal lipid profiles, after changing antiretroviral regimen. One study in Australia showed that substituting ZDV/d4T with ABC resulted in improvement in subcutaneous fat measured by dual-energy x-ray absorptiometry (DXA), but not clinical LD as assessed by physician. 22 Similar findings were reported from another multicenter study in Australia. 23 In one US study, substituting d4t with either ABC or ZDV resulted in improvement of lipoatrophy after 48 weeks as measured by DXA and CT scan and also by body image questionnaires. 24 One study from the United Kingdom reported that HIV-infected adults with clinical LD while receiving a thymidine nucleoside analog (ZDV or d4t) had significantly increased limb fat mass as measured by DXA scan at 48 weeks after substitution with either TDF or ABC. 25 There have been few studies regarding reversibility of LD in HIV-infected children. ne was similar to our study where only d4t was substituted with ZDV. In a US study, HIV-infected children aged between 24 and 160 months were switched from PI-based regimens to EFV after viral suppression. Improvement in lipid profile was observed, although the bioelectric impedance and anthropometric measurements did not change throughout the 48-week study period. 26 One Italian study showed that lipoatrophy did not improve in 24 children and adolescents after substitution of d4t and PI with TDF and EFV, respectively, for 96 weeks. 16 Our study showed improvement in both lipoatrophy and lipohypertrophy. Improvement of lipoatrophy did not reach statistical significance until 48 weeks. This could explain the lack of improvement in the US study that followed the children for only 48 weeks. 26 In our study, recovery from lipohypertrophy was less evident, consistent with other evidence that the causes of lipohypertrophy are multifactorial. 27 ZDV can cause anemia, which usually occurs within 4 to 6 weeks after initiation, and neutropenia, which can be observed 12 to 24 weeks after initiation. 28 We did not observe clinically significant changes in these hematologic parameters after substitution. This confirmed the result of our previous study that included a larger number of children. 29 This may be because of the fact that children in our study were healthy and stable on HAART at the time of substitution. Furthermore, the incidence of ZDV-induced anemia in Asian children may be low, even when ZDV is used as part of a first-line regimen. In one Thai study in which 67% of 81 children received ZDV as a part of an NNRTI-based regimen, no anemia more severe than grade 2 was reported. 30 A report from South India has also documented the prevalence of anemia in only 4.5% of children on ZDV therapy. 31 Another study of a Chinese cohort revealed no anemia that necessitated the changing of drug regimen. 32 We recognize several limitations. The design was observational, and the substitution of ZDV for d4t in individual children was made at varying time points after the initiation of d4tcontaining HAART. The sample was relatively small. Moreover, the measurement method, especially for lipoatrophy, was somewhat subjective. netheless, it should be pointed out that all LD assessment were performed by the same clinician with the help of serial photography and a checklist modified from that of the European Pediatric LD study group. In summary, in the situation where ABC and tenofovir are not available, ZDV is an acceptable and safe alternative substitute agent for d4t in children with LD. ACKNOWLEDGMENTS The authors thank Mrs. Somluck Nimsakul and colleague from Chiang Mai University for their help on anthropometric measurement. The authors also like to thank Mrs. ngyow Wongnum and Miss Rachaneekorn Nadsasarn from Chiang Mai University for the photography work. REFERENCES 1. Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338: 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: Viani RM, Araneta MR, Deville JG, et al. 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