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Department of Paediatrics (A.V., P.M., L.S., S.B., B.d.N., P.B.), L. Sacco Hospital, University of Milan, 20157 Milan, Italy; Laboratory of Paediatric Endocrinology (S.M.), Istituto di Ricovero e Cura a Carattere Scientifico, HS. Raffaele, 20132 Milan, Italy; and Department of Pharmacology (M.M.), Istituto di Ricovero e Cura a Carattere Scientifico, S. Matteo Hospital, 27100 Pavia, Italy
Address all correspondence and requests for reprints to: Dr. Alessandra Viganò, Cattedra di Pediatria, Ospedale L. Sacco, via GB Grassi 74, 20157 Milano, Italy. E-mail: alessandra.vigano{at}unimi.it.
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Abstract |
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Objective: The objective of this study was to assess the efficacy of rhGH treatment on lipodystrophy in HIV-infected adolescents.
Design: The study is a prospective, 24-wk open-label study of rhGH.
Setting: The study was conducted at a referral center for pediatric HIV infection.
Patients and Other Participants: Eight HIV-infected adolescents (ages, 13.7–18.5 yr), with abnormal IAT accumulation (>41 cm2 at L4-magnetic resonance imaging) and 97 healthy controls (HC) (ages, 9.5–19.9 yr) were enrolled.
Intervention: rhGH was given by sc injection at a daily dose of 0.028 mg/kg.
Main Outcome Measures: The main outcome was change in IAT at L4-magnetic resonance imaging. Body composition by dual-energy x-ray absorptiometry, glucose and lipid metabolism, and IGF-I changes were also evaluated.
Results: All patients completed the study period; none of them showed adverse event, and no change in the daily dose of rhGH was required. The treatment was associated with a mean height increase of 2.4 cm. From baseline to wk 24, IAT area decreased significantly by a median of 34.5% (–19.2 to –70%). Fat mass decreased significantly in patients, compared with HC, with a median loss of total, trunk, and arm and leg fat mass of 10.4, 10.9, 12.7, and 5.4%, respectively. Total, arm, and leg lean masses increased significantly, compared with HC. IGF-I increased significantly, but supraphysiological values of mild degree (2–23% over the upper normal limit) were detected in only nine of 24 samples. No significant effects on glucose metabolism, triglyceride, and cholesterol levels were observed.
Conclusions: Our data showed that rhGH 0.028 mg/kg daily for 24 wk in HIV-infected adolescents reduces IAT, trunk, and also limb fat and increases lean mass. Overall, short-term rhGH is well tolerated and is not associated with a worsening of glucose and lipid metabolism.
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Introduction |
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Physiological effects of GH extend beyond the stimulation of linear growth during childhood and adolescence. Normal GH secretion and action promotes growth of lean tissue and limits the formation of fat in the abdominal visceral depot (9). The state of GH insufficiency observed in children or adults with severe GH deficiency and some other similarly affected individuals (e.g. Prader-Willi syndrome) is characterized by a marked decrease in lean body mass accompanied by increased adipose tissue. Controlled studies have revealed consistent reduction in total body fat mass, particularly abdominal visceral fat, during recombinant human GH (rhGH) treatment in both childhood-onset and adult-onset GH deficiency (10, 11, 12). Thus, GH has important effects on fat metabolism in both childhood and adulthood, and GH replacement may lessen health risk associated with increased adiposity.
Recent reports suggested that GH metabolism is abnormal in HIV-infected subjects with fat redistribution. A significant reduction in GH secretion has been detected in men with lipodystrophy and visceral adiposity was the most significant predictor of reduced GH concentration in this population (13). A pattern of impaired synchronous release of GH and IGF-I was observed in HAART-treated HIV-infected adolescents with central adiposity (14). These data suggest an additional rationale for recombinant human GH (rhGH) therapy in HIV-infected individuals with excess accumulation of IAT.
Although no medical therapy is presently approved to reduce excess accumulation of IAT in patients with HIV infection, several studies have assessed the role of rhGH as a lipolytic agent in HIV-infected adults. rhGH therapy, at doses ranging from 3 to 6 mg daily for 12–24 wk, reduced abdominal and dorsocervical fat and improved the lipid profile in HIV-infected adults with abnormal fat accumulation (15, 16, 17).
We describe a prospective open-label study of 0.028 mg/kg daily rhGH therapy for a period of 24 wk as a treatment of visceral fat accumulation in HIV-infected adolescents. The primary objective was to determine the efficacy and safety of rhGH for reduction of IAT measured by magnetic resonance imaging (MRI). The secondary objective included ascertaining the effects of rhGH on other body composition compartments.
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Subjects and Methods |
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This was an open-label study of rhGH (Saizen click.easy; Serono, Italy) at a daily dose of 0.028 mg/kg for 24 wk. The dose of rhGH could be halved or discontinued in response to adverse effects at any time during the study. Patients were instructed to self-administer the appropriate dose of rhGH sc before bedtime and to rotate the site of sc injection daily.
Patients did not follow any special diet or physical activity program, and they were advised to maintain diet and physical activity style unchanged during the study period.
Subjects
Eight (three boys and five girls) Caucasian, vertically HIV-infected adolescents, followed up at the Pediatric Clinic at L. Sacco Hospital, University of Milan, were eligible for the study.
All were identified as cases of excess accumulation of visceral fat, defined as an IAT area, detected by MRI, greater than 41 cm2. This cut-off value was generated from the mean (21 cm2) plus 2 SD (10 cm2) values observed in healthy children and adolescents previously described (4). Subjects were excluded if blood tests within 30 d before entry included elevated fasting blood glucose [>110 mg/dl (6.1 mmol/liter)], impaired glucose tolerance on oral glucose tolerance testing (OGTT) with 2-h postload glucose level between 144 and 199 mg/dl (8.0 and 11.0 mmol/liter), a diagnosis of diabetes mellitus, or liver function results (aspartate aminotransferase and alanine aminotransferase) more than 5 times the upper limit of normal. Other exclusion criteria included history of carpal tunnel syndrome; any disorder associated with moderate to severe edema; history of cancer; or previous or current therapy with testosterone, anabolic hormones, megestrol acetate, or corticosteroids.
As a control group (HC) for dual-energy x-ray absorptiometry (DXA) data, we studied 97 consecutive Caucasian volunteers. All subjects were healthy and appropriately physically active for their age; none was involved in competitive sport activities. Their height and weight measurements were within the third and 97th percentiles for age. Candidates were excluded if they had a history of chronic illness; they had one or more fractures; and they had taken any medication, hormone, vitamin preparation, or calcium supplements regularly. We enrolled 51 boys and 46 girls, with a mean age of 14.5 (3.0) yr, a mean weight of 50.0 (15.0) kg, a mean height of 157.5 (13.9) cm, and a mean body mass index (BMI) of 19.7 (3.0) kg/cm2.
Informed consent was obtained from the parents or legal guardians of each patient and control before participation. The patients’ assent was also obtained when appropriate. The study was approved by the Ethical Committee of the L. Sacco Hospital.
Body composition measurements
All HCs underwent physical examination to obtain anthropometric measures and body imaging study by DXA. The rhGH-treated subjects were assessed for anthropometric measures at baseline and after 4, 12, and 24 wk of rhGH treatment and body imaging studies by DXA and MRI at baseline and wk 24 of rhGH treatment.
Body weight was measured to the nearest 0.1 kg on a balance beam scale (Seca, Hamburg, Germany), and height was measured to the nearest millimeter using a wall-mounted stadiometer (Holtain Ltd., Crosswell, UK). BMI was then calculated as weight per height2 (kilograms per square meter) (19).
Whole-body composition was assessed with a DXA scanner (Lunar DPX-L, Lunar Radiation Corp., Madison, WI), equipped with a specific pediatric software (version 1.5 h). Scans were performed as previously described (20), with subjects in the supine position, the subjects not requiring sedation. The entire body was scanned, beginning at the top of the head. Mean measurement time was 20 min; radiation exposure was less than 1 µSv. Body fat and lean mass were expressed in kilograms. Three-compartment analyses were performed in the arms, trunk, and legs. Daily quality-assurance tests were performed according to the manufacturer’s directions. All scans were performed and analyzed by the same operator (S.M.). The precision of the instrument is 0.7% for fat mass and 0.9% for lean mass in normal-weight subjects of pediatric age.
IAT area was measured by MRI. Patients were imaged on a Gyroscan ACS-NT 1.5 T (Philips Medical Systems, Best, The Netherlands). The slice passing through the umbilicus (at the fourth lumbar vertebra) was used to estimate IAT. A manual trackball with visual control was used to limit adipose tissue areas, and then areas were automatically computed as previously described (21). IAT area was expressed in square centimeters. The same trained operator (P.B.) performed the MRI analysis.
Metabolic measurements
Fasting blood samples were drawn at baseline and after 4, 8, 12, and 24 wk of rhGH treatment for IGF-I and glucose. Fasting samples were drawn at baseline and after 12 and 24 wk of rhGH treatment for glycosylated hemoglobin (HbA1c), triglycerides, total cholesterol, high-density lipoprotein (HDL) cholesterol, TSH, free T4 (FT4), and free T3 (FT3). An OGTT was performed at baseline and after 24 wk of rhGH treatment. Patients were administered 1.75 g/kg (highest dose 75 g) dextrose in 250 ml of water after a 12-h overnight fast, and blood samples were collected at 0, 30, 60, 90, 120, and 180 min for measurement of plasma glucose and insulin levels. Results of the OGTT were analyzed by the trapezoidal method to obtain area under the curve (AUC). Insulin sensitivity was assessed by the homeostasis model assessment index (HOMA) (22), and a value greater than 3.94 was considered elevated (23).
Serum IGF-I has been measured by a fully automated two-site chemiluminescent immunoassay (Nichols Advantage; Nichols Institute Diagnostics, San Clemente, CA). Serum insulin levels have been measured using a chemiluminescence immunometric assay (Immulite 2000; Medical Systems, Genoa, Italy). Serum glucose, total and HDL cholesterol, and triglycerides levels were determined using standard laboratory assays. Low-density lipoprotein (LDL) cholesterol was determined indirectly by the Friedewald calculation. HbA1c levels were calculated by ion-exchange chromatography-based automated HPLC analyzer (ADAMS-8160, Menarini, Florence, Italy). TSH and FT3 and FT4 were measured by electrochemiluminescence immunoassay (Roche Diagnostics GmbH, Mannheim, Germany).
Statistical analysis
Descriptive statistics were calculated for all the variables, and data are expressed as mean (SD) or median (range). All statistical analyses were conducted at the 
= 0.05 level and were two tailed. The statistical software JMP IN (SAS Institute, Inc., Cary, NC) was used for the analyses.
Changes in body composition variables observed in HIV patients during treatment with rhGH were compared with those computed for healthy children, who were studied cross-sectionally. Expected changes of body composition variables were determined by regression analyses within the control group. Briefly, variables were plotted against age, and regression analyses were used to calculate the anticipated changes. A large number of HC subjects were studied to improve precision for the analyses. Paired t tests were used to compare the observed changes in body composition variables with the estimated changes for healthy children.
ANOVA for repeated measures was used to assess the changes over time of metabolic variables.
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Results |
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All eight eligible HIV-infected subjects were enrolled in the study. All patients were pubertal (stage IV-V) according to the Tanner criteria (24), and their median age was 15.7 yr, ranging from 13.7 to 18.5 yr. From baseline to wk 24, weight (mean, SD: 56.0, 11.7 vs. 56.8, 10.8 kg), height (mean, SD: 162.3, 7.6 vs. 164.7, 8.3 cm), and BMI (mean, SD: 21.1, 2.6 vs. 20.8, 2.3 kg/m2) did not change significantly in rhGH-treated subjects. No significant changes concerning diet style and exercise were reported by any patient during the study.
At baseline, all patients had been exposed to HAART (stavudine + lamivudine + one protease inhibitor) for a median of 79.4 (range 64–83) months, and they continued to receive the same antiretroviral therapy during rhGH treatment. Subjects were clinically stable and between baseline and wk 24 mean (± SD), CD4+ counts (706 ± 315 and 786 ± 300 cells/mm3, respectively) and HIV-1 RNA levels (116.1 ± 183.1 and 155.4 ± 193.4 cp/ml, respectively) were not statistically different.
All patients completed the 24-wk study; no changes of the daily dose of 0.028 mg/kg of rhGH were required, and the total daily dose ranged from 1.25 to 2.20 mg. No patient reported to have skipped any rhGH injection throughout the study period. Overall, rhGH was well tolerated, and clinical side effects were not detected in any patients.
Age, anthropometric measurements, and gender distribution of patients and HC subjects were similar at baseline.
Effects on body composition
At baseline and wk 24, the mean (range) IAT areas were 81.9 (50–150) and 46.9 (20–105), respectively (Fig. 1
). Thus, IAT areas decreased by a median of 34.5% (P = 0.01) after 24 wk of rhGH therapy. The change in IAT area ranged from –19.2 to –70%, and a value lower than 41 cm2 was reached in four of eight rhGH-treated subjects.
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. rhGH-treated patients lost a median 10.4% of baseline total fat mass, 10.9% of baseline trunk fat, 12.7% of baseline arm fat, and 5.4% of baseline leg fat. Overall, 59% of total fat loss (0.88 of 1.49 kg) was from the trunk and 41% was from the limbs. Total lean mass increased by a median 8.2%, compared with baseline, whereas we observed median increments from baseline of 6.7% in the trunk, 12.3% in the arms, and 11.4% in the legs.
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). Fat changes were significantly different in total (P = 0.02), trunk (P = 0.038), arm (P = 0.024), and leg (P = 0.029) levels in rhGH-treated subjects as compared with HCs. Thus, in rhGH-treated patients, total fat mass, trunk fat, arm fat, and leg fat showed a mean decrease of –1.49, –0.88, –0.10, and –0.37 kg, respectively, whereas their expected changes in HCs were increases of 0.59, 0.33, 0.04, and 0.20 kg, respectively. Lean mass changes were significantly higher as a total (P = 0.02) at arm (P = 0.02) and leg (P = 0.019) levels in rhGH-treated subject as compared with HCs. Thus, in rhGH-treated subjects, total lean mass and arm and leg lean mass showed a mean increase of 3.20, 0.50, and 1.26 kg, whereas their expected changes in HCs were an increase of 1.57, 0.19, and 0.54 kg, respectively. Effects on metabolism
Data on metabolic parameters are shown in Table 2. During the 24 wk of rhGH treatment, a significant increase on IGF-I was observed (P < 0.0001). An IGF-I value higher than the upper normal limit (mean + 2 SD of age- and sex-related level) was detected in five of eight (62%) patients and nine of 24 (37%) levels measured during rhGH treatment. However, these supraphysiological IGF-I values ranged from 2 to 23% over the upper normal limit (25).
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Mean fasting triglyceride levels did not change significantly during rhGH treatment. At baseline, wk 12, and wk 24, the mean (SD) fasting triglyceride levels were 131 (76.6), 140 (90.7), and 151 (88.9) mg/dl [7.3 (4.2), 7.8 (5.0), and 8.4 (4.9) mmol/liter], respectively. Four of eight subjects showed baseline fasting triglyceride levels higher than 95th degree percentile for age and maintained elevated values throughout the study period (27). No significant effects on total cholesterol and LDL and HDL cholesterol were registered. At baseline, wk 12, and wk 24, the mean (SD) fasting total cholesterol levels were 164 (27.0), 163 (31.7), and 156 (31.0) mg/dl [9.1 (1.5), 9.1 (1.8) and 8.7 (1.7) mmol/liter], respectively. One of eight patients showed baseline fasting total cholesterol level higher than 95th degree percentile for age and maintained elevated values through the study period (27). Normal values of LDL and HDL cholesterol were observed throughout the study.
No significant effects were elicited by treatment on TSH, FT4, and FT3 (data not shown).
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Discussion |
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We documented a median 34.5% reduction of IAT. Half of the patients at the end of the 24-wk trial had normal IAT measurements. We also observed a median 10.4% reduction of total fat mass, more marked at trunk (58% of total fat loss). The median decline in trunk fat was about 0.75 kg, and the relative decline, compared with the expected value in healthy controls, was 1.1 kg. Incidentally, the lean mass of these patients increased by a median of 8.2% during the study. These body composition changes were associated with an overall acceptable increase of IGF-I: supraphysiological IGF-I levels were mild (2–23% above upper normal limit) and were observed in a minority of measures (nine of 24). These facts, together with the lack of clinical side effects and metabolic derangements, provide initial evidence that the use of rhGH may potentially be a beneficial treatment strategy for pediatric lipodystrophy.
Body components undergo considerable modifications during childhood and adolescence. Therefore, simple statistical analyses are not suitable in the study of body composition modification during this period of life. For this reason, the changes in body composition during treatment with rhGH were compared with those expected for a normal population of similar age, calculated using cross-sectional data of a healthy sample population. Ideally, the comparisons should have been performed with longitudinal measurements of healthy individuals. However, prospective DXA measurements were not considered ethical in control subjects, and therefore they could not be performed. Body fat in every district was expected to increase, as calculated from the data of HCs. To the contrary, we observed a reduction of total, trunk, leg, and arm fat masses in rhGH-treated patients. The reduction of trunk fat mass is particularly important because it is a recognized risk factor for hypertension and metabolic diseases even in youth (28). Our patients at baseline showed a mean trunk fat value higher than published normal values (28), and a significant reduction during GH treatment has to be considered a positive outcome. Furthermore, as observed by lumbar MRI, the reduction in trunk fat was associated with IAT reduction, strengthening the positive clinical outcome of the treatment. On an individual basis, all patients at baseline were above the IAT cut-off (41 cm2), and half of the patients reduced IAT values below this limit. On the other hand, we observed some degree of peripheral lipoatrophy: the median decline in limbs fat was about 0.5 kg, and the relative decline, compared with the expected value in healthy controls, was 0.71 kg. This side effect may be due to the lipolytic action of GH treatment but also to the duration of HAART exposure and protease inhibitor and stavudine use, as previously described in HIV-infected children (3, 5). The entity of lean mass increase in HIV was double expected in HCs for total mass and limbs, whereas the increase was present but not significant at trunk. This last finding could be explained by the fact that GH anabolic effect has its target mainly on skeletal muscles, mainly in limbs, whereas viscera are the principal constituent of trunk lean mass (30).
To our knowledge, our study is the first on GH treatment in a pediatric HIV population. Previous studies on the effects of GH conducted in HIV-infected adults showed different body composition changes due to the different GH regimens and the heterogeneity of the study populations (15, 16, 17, 31). As a whole, these studies reported a significant reduction of trunk fat (21–39%) and limb fat (8–26%) associated with a significant increase (5–9%) in lean mass; the decrease in IAT was strongly dependent on GH dose and individual basal IAT amount (15, 16, 17, 31). We chose a GH daily dose of 0.028 mg/kg (the total daily dose ranging from 1.25 to 2.20 mg), according to the recommended GH regimen in GH-deficient adolescents (32). This dosage is lower, compared with most studies in adults (3–6 mg), but higher than those used by Lo et al. (31). Optimizing GH therapy is still a difficult and debated task (33). The end point of treatment is certainly important in this regard, as are pubertal status, gender, and recurrence of unwanted effects. Among the latter, bone age progression and height increase should be considered carefully in non-GH-deficient children. Recent evidence suggests that 2- to 4-yr GH treatment at daily doses of 0.31–0.34 mg/kg influences only modestly the final height of patients with idiopathic short stature (34, 35). Moreover, the most impressive increases of height velocity were noted during the first 6 months of treatment. Similarly, a short-term observational study failed to show any acceleration of bone age during the first year of treatment with GH in prepubertal children with different diseases (36). Our patients increased their height on average by 2.4 cm, suggesting that our population had not completed their growth development, as expected in patients in the late pubertal phase. Longer surveys should be performed to assess the effect of GH treatment on height increase in HIV patients. Nevertheless, the lower dose able to achieve an effective lipolytic action, thus minimizing possible unwanted effects, should be used.
The magnitude of lean mass increase in our study was similar to that reported in studies of adult patients. Fat mass reduction measured by DXA was remarkable in our cohort, albeit of a lower degree, compared with other studies. However, IAT reduction was similar to that obtained in the high-dose GH protocols (15, 16, 17) and higher than in the low-dose GH study (31). The comparison with adult studies suggests that the dose we used obtained a lipolytic effect on both sc and visceral adipose tissue, the latter being predominant. This might be explained by the metabolism of different adipose tissue cells because visceral fat cells are more sensitive to moderate GH doses (37). In addition, the differences observed could also be due to the peculiar hormonal status and overall metabolism of growing individuals during the last phase of pubertal development (18). A recent study (29) performed on adult patients using GHRH showed a reduction of visceral adipose tissue (VAT), a significant reduction in VAT to sc adipose tissue ratio during treatment, and no worsening of peripheral lipoatrophy. Moreover, no appreciable changes in GH secretion were observed during the trial with GHRH. These results may suggest that even low GH doses could be as efficient as the ones used in our study to accomplish VAT reduction without a reduction in sc adipose tissue. Further studies are thus needed to compare diverse dose regimens in HIV-infected children.
We observed an increase of HOMA index and a trend toward increase of fasting glycemia during GH treatment, although not significant, suggesting that a prolonged therapy even at this dose could have an effect on glucose metabolism, owing to the necessity for regular assessments.
IGF-I levels, within or just above the upper normal range for this age, confirmed the overall adequacy of our dose, but we could not avoid episodic supraphysiological values. Due to the small number of patients, we could not evaluate the effect of gender and GH secretion both on the body composition changes as well as on the individual optimal dose of treatment.
The present study provides initial evidence that the use of short-term rhGH therapy in carefully selected HIV-infected adolescents with excess IAT screened for glucose intolerance may be reasonable, effective, and safe. However, additional studies are needed to confirm these results, and they may help to further define the risk/benefit of rhGH therapy in pediatric lipodystrophy. Therefore, clinicians should use extreme care in prescribing GH to HIV-infected adolescents with excess visceral fat.
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Footnotes |
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First Published Online April 19, 2005
Abbreviations: AUC, Area under the curve; BMI, body mass index; DXA, dual-energy x-ray absorptiometry; FT3, free T3; FT4, free T4; HAART, highly active antiretroviral therapy; HbA1c, glycosylated hemoglobin; HC, healthy control; HDL, high-density lipoprotein; HOMA, homeostasis model assessment index; IAT, intraabdominal adipose tissue; LDL, low-density lipoprotein; MRI, magnetic resonance imaging; OGTT, oral glucose tolerance testing; rhGH, recombinant human GH; VAT, visceral adipose tissue.
Received December 10, 2004.
Accepted April 7, 2005.
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