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Division of Endocrinology, Department of Medicine (J.C.L., K.M., M.A.N., J.-M.S., C.G., M.S.), and Department of Radiology (R.A.H), University of California–San Francisco, San Francisco, California 94143; and Department of Nutritional Sciences (J.-M.S.), University of California–Berkeley, Berkeley, California 94720
Address all correspondence and requests for reprints to: Joan C. Lo, M.D., Division of Endocrinology, San Francisco General Hospital, Building 30, Room 3501-K, San Francisco, California 94110. E-mail: jlo{at}itsa ucsf.edu.
Abstract
GH has been proposed as a therapy for patients with HIV-associated
fat accumulation, but the pharmacological doses (6 mg/d) used have been
associated with impaired fasting glucose and hyperglycemia. In
contrast, physiologic doses of GH (
1 mg/d) in HIV-negative men
reduced visceral adiposity and eventually improved insulin sensitivity,
despite initially causing insulin resistance. We conducted an
open-label study to evaluate the effects of a lower pharmacologic dose
of GH (3 mg/d) in eight men with HIV-associated fat accumulation. Oral
glucose tolerance, insulin sensitivity, and body composition were
measured at baseline, and 1 and 6 months. Six patients completed 1
month and 5, 6 months of GH therapy. IGF-I levels increased 4-fold
within 1 month of GH treatment. Over 6 months, GH reduced buffalo hump
size and excess visceral adipose tissue. Total body fat decreased
(17.9 ± 10.9 to 13.5 ± 8.4 kg, P =
0.05), primarily in the trunk region. Lean body mass increased
(62.9 ± 6.4 to 68.3 ± 9.1 kg, P =
0.03). Insulin-mediated glucose disposal, measured by a euglycemic
hyperinsulinemic clamp, declined at month 1 (49.7 ± 27.5 to
25.6 ± 6.6
nmol/kgLBM·min/pmolINSULIN/liter,
P = 0.04); values improved at month 6 (49.2 ±
22.6, P = 0.03, compared with month 1) and did not
differ significantly from baseline. Similarly, the integrated response
to an oral glucose load worsened at month 1 (glucose area under the
curve 20.1 ± 2.3 to 24.6 ± 3.7 mmol·h/liter,
P < 0.01), whereas values improved at month 6
(22.1 ± 1.5, P = 0.02, compared with month 1)
and did not differ significantly from baseline. One patient developed
symptomatic hyperglycemia within 2 wk of GH initiation; baseline oral
glucose tolerance testing revealed preexisting diabetes despite normal
fasting glucose. In conclusion, GH at 3 mg/d resulted in a decrease in
total body fat and an increase in lean body mass in this open-label
trial. While insulin sensitivity and glucose tolerance initially
worsened, they subsequently improved toward baseline. However, the dose
of GH used in this trial was supraphysiologic and led to an increase in
IGF-I levels up to three times the upper normal range. Because there
are known adverse effects of long-term GH excess, the effectiveness of
lower doses of GH should be studied. We also recommend a screening oral
glucose tolerance test be performed to exclude subjects at risk for
GH-induced hyperglycemia.
WITH THE CHANGING epidemiology of HIV disease and the advent of highly active antiretroviral therapy (HAART), there has been a dramatic reduction in HIV-associated morbidity and mortality (1). However, the optimism generated by overall improving health among patients on HAART has been tempered by concerns that these therapies may be associated with adverse metabolic effects, such as insulin resistance and hyperlipidemia, and changes in body composition (2, 3, 4, 5, 6, 7, 8, 9, 10). In the past 4 yr, several syndromes of regional fat accumulation have been reported in patients with HIV infection, including dorsocervical fat pad enlargement ("buffalo hump"), symmetric lipomatosis, and abdominal obesity (7, 8, 11, 12, 13, 14, 15), although not all of these patients were on HAART. In addition, loss of sc fat in the face, buttocks, and/or extremities, either alone or in combination with syndromes of fat accumulation, has been reported (2, 15, 16). The mechanisms underlying the abnormal distribution of fat and their relationship to specific antiretroviral therapies remain unclear. For many patients, these alterations have had a substantial negative impact on quality of life. Concerns have also been raised about the possible cardiovascular risks that these body composition changes, together with associated insulin resistance and dyslipidemia, may convey (17, 18).
Although there are no approved drugs for fat distribution
abnormalities, reports of treatments that have reversed these
abnormalities have led patients and clinicians to use unproven, and in
some cases, potentially deleterious therapies. Included among
treatments that are being used is recombinant human GH, which was
granted accelerated approval in 1996 for the treatment of
HIV-associated wasting (19). Preliminary studies suggest
that GH may have a therapeutic role in HIV-associated fat accumulation,
based on its lipolytic effect on adipose tissue (20, 21, 22, 23).
However, endogenous GH excess (i.e. acromegaly) and GH
administration have been associated with insulin resistance and
carbohydrate intolerance (24, 25, 26, 27, 28). To date, no studies
have systematically evaluated the effect of GH on glucose metabolism in
patients with HIV-associated fat accumulation. On the other hand, in
HIV-negative men with abdominal obesity, treatment with GH at a dose of
9.5 µg/kg·d (1 mg/d) has been shown to reduce total body fat and
visceral abdominal fat mass (29). In these subjects,
despite an initial worsening of insulin sensitivity during the first 6
wk presumably due to GH-induced insulin resistance, insulin sensitivity
improved compared with placebo-treated subjects after 9 months of
therapy. The authors speculated that the eventual improvement in
insulin sensitivity might have been due to the reduction in visceral
adiposity observed with GH treatment. A similar pattern in insulin
action, but without improvement beyond baseline levels, has also been
reported in GH-deficient adults treated with replacement doses of GH
(27). In HIV-positive men with dorsocervical fat pad
enlargement and/or abdominal obesity, treatment with pharmacologic
doses of GH (4–6 mg/d) has been shown to reduce hump size, abdominal
girth, waist-to-hip ratio, and visceral adipose tissue volume
(20, 21, 22, 30). However, in one group of patients who
received a dose of 6 mg/d, mean fasting glucose levels increased
significantly into the impaired fasting glucose range
(21), and frank hyperglycemia has been reported in several
patients (21, 22, 30).
We hypothesized that a lower dose of GH (3 mg/d) would reduce buffalo
hump and abdominal adiposity in HIV- infected patients with fat
accumulation and result in an initial impairment in glucose tolerance
and insulin sensitivity, followed by improvement over time, similar to
the pattern seen in HIV-negative individuals. We selected a
supraphysiologic dose of GH based on prior evidence of relative GH
resistance in HIV-infected patients with the wasting syndrome; in these
patients, administration of a pharmacologic (100 µg/kg·d or 6
mg/d) dose of GH resulted in a significantly lower IGF-I response when
compared with healthy HIV-negative control subjects (31, 32). This report describes the first study of GH therapy in HIV-
infected patients with regional fat accumulation in which insulin
action has been quantified in conjunction with body composition
measurements.
Materials and Methods
Subjects and study protocol
Eight HIV-positive men who had developed an enlarged dorsocervical fat pad and/or abdominal obesity while on antiretroviral therapy were enrolled in the study. Patients with overt diabetes, fasting triglyceride levels of 11.29 mmol/liter or higher, or active malignancy were excluded. The study protocol was approved by the Committee on Human Research of the University of California–San Francisco, and informed consent was obtained from each subject.
Subjects were admitted to the General Clinical Research Center (GCRC) at San Francisco General Hospital for 5 d and placed on a diet with fixed proportions of carbohydrate, fat, protein, and energy content designed to maintain body weight and minimize dietary influences on metabolism (33); the identical diet was given during subsequent inpatient metabolic evaluations. Fasting lipid studies were performed on d 2, an oral glucose tolerance test on d 3, body composition measurements on d 4, and a euglycemic hyperinsulinemic clamp on d 5. After the baseline evaluation, subjects began treatment with recombinant human GH (Serono Laboratories, Inc., Norwell, MA) at a dose of 3 mg/d (30–40 µg/kg·d) by sc injection on an outpatient basis. The same 5-d metabolic assessments were performed at months 1 and 6 while on GH therapy.
Laboratory measurements
Hemoglobin A1C (HbA1C) levels were measured by ion exchange high-performance liquid chromatography and CD4 cell count by flow cytometry in the Clinical Laboratories at San Francisco General Hospital. HIV-1 RNA levels were quantified using the Amplicor HIV-1 Monitor test (detection limit 50 copies/ml; Roche Diagnostics, Branchburg, NJ) in the Virology Core Laboratory of the Gladstone Institute of Virology and Immunology. Fasting triglyceride, total and high-density lipoprotein (HDL) cholesterol levels were measured by enzymatic colorimetric methods using reagents from Sigma Diagnostics (St. Louis, MO). HDL cholesterol was quantified after precipitation of Apo B-containing lipoproteins with phosphotungstic acid and MgCl2. The intra-assay coefficients of variation (CV) for triglyceride and total and HDL cholesterol are 3%, 3%, and 1%, respectively. Low-density lipoprotein (LDL) cholesterol levels were calculated based on the Friedewald equation (34). Direct LDL cholesterol levels were measured using reagents from Equal Diagnostics (Exton, PA) with an intra-assay CV of 1%. In addition, the following measurements were performed in the Core Laboratory of the GCRC at San Francisco General Hospital: whole blood and plasma glucose levels by the glucose oxidase method (YSI 2300 STAT-Plus Glucose/Lactate Analyzer, YSI Inc., Yellow Springs, OH); IGF-I levels by immunoradiometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA) with an intra-assay CV of 4.6%; and serum insulin levels by RIA (Coat-A-Count, Diagnostic Products Corporation, Los Angeles, CA) with an intra-assay CV of 7%, interassay CV of 14.1%, and 40% cross-reactivity with proinsulin.
Body composition
Weight was measured on a calibrated scale each morning after an overnight fast with patients wearing only a hospital gown. Height was measured using a stadiometer. Body mass index was calculated as body weight (kilograms) divided by height (meters) squared. Anthropometric measurements were performed in triplicate, including waist circumference measured at the level of the umbilicus and hip circumference measured at the point of maximal gluteal width when viewed from the side. The dorsocervical fat pad was measured in length and width (along surface contours), and the size was estimated by multiplying length and width. Fat and lean body mass were measured by dual-energy x-ray absorptiometry (Lunar Corp. model DPX, Madison, WI) (35). Manual analyses of fat in the arms, legs, and trunk were performed using skeletal and soft-tissue landmarks, as described previously (11), using software version 3.65 in the extended analysis mode. In our laboratory, the coefficients of variation for repeated regional analyses of trunk, arm, and leg fat are 1.0, 2.7, and 1.4%, respectively. Abdominal adipose tissue was measured by computed tomography (CT) using a helical HiSpeed CT/i Scanner (General Electric Medical Systems, Milwaukee, WI). Patients were examined in the supine position with their arms stretched above their head. A preliminary scout image was obtained of the abdomen and pelvis in supine and lateral projections for anatomic localization. A single 7-mm slice obtained at the level of the L4–L5 intervertebral disc space was used to quantify visceral and sc adipose tissue area (VAT and SAT). The axial image was displayed in a matrix of 512 x 512 pixels, and adipose tissue was identified by density mapping for pixel values between -30 and -190 Hounsfield units (36). A cursor line was traced, bisecting the abdominal musculature anterolaterally and outlining the transversalis fascia posteriorly (including the psoas muscles but excluding the vertebrae), to separate the visceral and sc compartments. All images were analyzed by one investigator (J.C.L.) with a CV less than 1% on repeated analyses.
Glucose tolerance and insulin sensitivity
An oral glucose tolerance test (OGTT) was performed at 0800
h after a 10-h overnight fast and 200 g/d carbohydrate intake or higher
during the previous 3 d. Patients were administered 75 g
dextrose in 250 ml water, and blood samples were collected at 0, 30,
60, 90, 120, and 180 min for measurement of plasma glucose levels. The
area under the curve (AUC) for glucose was calculated by the trapezoid
method and used as an integrated measure of glucose tolerance. The
following glucose tolerance criteria from the World Health Organization
were used for clinical characterization (37): normal
glucose tolerance (2-h glucose <7.8 mmol/liter); impaired glucose
tolerance (2-h glucose 7.8–11.0 mmol/liter); and overt glucose
intolerance or diabetes (2-h glucose 
11.1 mmol/liter). Peripheral
insulin sensitivity was measured by the euglycemic hyperinsulinemic
clamp method (38). After an overnight fast, insulin
(Humulin R; Eli Lilly & Co., Indianapolis, IN) was
administered as a primed continuous iv infusion at a rate of 40
mU/m2 · min for 180 min. During this period,
whole blood glucose levels were measured every 5 min from a retrograde
iv line placed in a hand that was warmed in a heated box at 50-55 C
for arterialized blood sampling. A variable infusion of 20% dextrose
was used to maintain euglycemia with a CV less than 5% during steady
state. Blood samples were collected for post hoc
determination of serum insulin concentration. The M value was
calculated as a measure of peripheral insulin sensitivity according to
De Fronzo and co-workers (38, 39), based on steady-state
glucose infusion rates during the final 60 min of the clamp and lean
body mass (kg) by dual-energy x-ray absorptiometry, and was adjusted
for the steady-state insulin concentration achieved (M/I).
Statistical methods
Data are expressed as mean ± SD. Differences between baseline and 6 months were analyzed by Student’s paired t test for continuous outcomes. For measurements pertaining to glucose metabolism, differences between baseline, 1 month, and 6 months were initially analyzed using ANOVA for repeated measures. If the global comparison was statistically significant, pairwise comparisons were conducted between time points using the Student-Newman-Keuls test for multiple comparisons, based on our a priori hypothesis that GH treatment would result in an initial worsening followed by subsequent improvement in glucose metabolism. A two-sided P value less than 0.05 was considered statistically significant. All analyses were performed using SigmaStat software version 2.0 (SPSS Inc., Chicago, IL).
Results
Baseline characteristics and clinical course
The clinical and biochemical characteristics of the eight men with
HIV-associated fat accumulation are shown in Tables 1
and 2.
Five patients had a buffalo hump, including two with associated lipomas
at the base of the scalp posteriorly; one of these patients also had
abdominal obesity. Three patients had only abdominal obesity. All
patients with a buffalo hump had evidence of an elevated waist to hip
ratio, consistent with our previous finding of increased trunk fat in
HIV-infected men with a buffalo hump (11) and suggestive
of a common underlying phenotype. The median duration of HIV infection
was 12 yr (range, 5–16 yr). All patients had been on a stable
antiretroviral regimen for at least 2 months before enrollment
(patients 2–8 for at least 6 months). Six patients were on combination
therapy that included a protease inhibitor, while patient 7 was
naïve to protease inhibitor therapy. Patient 1 was previously
on a protease inhibitor that had been discontinued 6 months before the
baseline study due to virologic failure. All patients remained on a
stable antiretroviral regimen during the study period, except patient
3, in whom abacavir was substituted for stavudine 1 wk after GH
initiation due to persistent stavudine-associated neuropathy. Patient 5
had been on stable replacement doses of testosterone for 2 yr, and
patient 2 on low-dose nandrolone decanoate for 4 months; both patients
continued these therapies at the same dose throughout the study. None
of the other patients were on anabolic agents in the 12 months before
or during the study. In addition, none of the patients had received
systemic glucocorticoid or megestrol acetate therapy.
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11.1 mmol/liter) were excluded. Two additional patients did not complete the study for reasons unrelated to GH treatment. Patient 1 developed antiretroviral drug-induced hepatitis and was withdrawn from the study before the month 1 assessment (hence, there are no follow-up data from patient 1 presented here). Patient 8 relocated after the month 1 assessment and was discharged from the study. The results reported below pertain to the subjects who completed at least 1 month of GH.
Laboratory data
In the six patients who completed 1 month of GH therapy, a 4-fold
increase in IGF-I levels was observed (21.0 ± 3.3 to 88.7 ±
12.2 nmol/liter, P < 0.001; Fig. 1). IGF-I levels were in the
supraphysiologic range (up to three times the upper limit of normal)
and remained elevated at 6 months, with the exception of patient 3,
whose GH dose had been reduced to 1.5 mg/d. After 6 months of GH
treatment, there was a trend toward reduced total cholesterol
(6.03 ± 1.09 to 5.03 ± 1.18 mmol/liter, P =
0.09) and increased HDL cholesterol (0.72 ± 0.07 to 0.81 ±
0.12 mmol/liter, P = 0.09) levels, with a significant
reduction in the total cholesterol to HDL cholesterol ratio (8.3
± 1.3 to 6.3 ± 1.3, P = 0.04). No significant
changes were seen in direct or calculated LDL cholesterol levels and
triglyceride levels. Importantly, hypertriglyceridemia was not
exacerbated by GH in any patient during the study. There were no
significant changes in CD4 cell counts. HIV viral load remained stable
in all but one patient (viral load <50 copies/ml in patients 3, 5, 6,
and 8 and 1,590–8,218 copies/ml in patient 7). Patient 4 had evidence
of virologic failure by the end of the study (viral load increased from
1,070 to 20,880 copies/ml between baseline and month 6) after having
been stable on his antiretroviral regimen for the three previous
yr.
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Treatment with GH significantly increased lean body mass
(62.9 ± 6.4 to 68.3 ± 9.1 kg, P = 0.03) in
the five patients who completed 6 months of therapy (Table 3). Total fat mass decreased in all
patients (17.9 ± 10.9 to 13.5 ± 8.4 kg, P =
0.05), primarily in the trunk region, including patient 3, whose dose
was reduced to 1.5 mg/d. No significant changes were seen in
appendicular fat or total body weight. There was a trend toward
visceral fat reduction (17166 ± 8065 to 10863 ± 2922
mm2, P = 0.08) for the group as a
whole, an effect that was driven by the substantial (30–60%) decline
in VAT in the three patients with the greatest amounts of visceral
adiposity at baseline (Fig. 2). On the
other hand, the patients with less VAT experienced minimal change after
6 months. There was no reduction in sc abdominal fat, except in patient
7, who had the largest amount of sc fat at baseline (Figs. 2 and 3). By the end of 6 months, patients 4
and 5 experienced 43% and 32% reduction in hump size, respectively.
Patient 6 had a progressively enlarging dorsocervical fat pad at the
time of study enrollment that continued to increase (40%) by month 1
but then decreased 31% in size by month 6.
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Five of the six patients who completed at least 1 month of GH
treatment had normal glucose tolerance at baseline. Patient 6 had
mildly impaired glucose tolerance (2-h glucose 8.8 mmol/liter). In this
group, selected for the absence of overt glucose intolerance (diabetes
by OGTT criteria) at baseline, fasting glucose levels increased
significantly at month 1 (4.8 ± 0.3 to 5.4 ± 0.3
mmol/liter, n = 6, P = 0.02) and tended to remain
elevated at month 6 (5.3 ± 0.3 mmol/liter, n = 5,
P = 0.06) compared with baseline. Fasting insulin
levels increased significantly at month 1 (137 ± 67 pmol/liter to
220 ± 85, P = 0.01), but declined by month 6
(159 ± 76 pmol/liter, P = 0.05, compared with
month 1); values at month 6 did not differ significantly from baseline.
There was a small increase in HbA1C levels at month 6 (5.1 ± 0.3
to 5.6 ± 0.5%, P = 0.02) compared with baseline,
but values remained within the normal range. The glucose AUC increased
at month 1 in all six patients (20.1 ± 2.3 to 24.6 ± 3.7
mmol·h/liter, P < 0.01); values declined by month 6
(22.1 ± 1.5 mmol·h/liter, n = 5, P = 0.02,
compared with month 1) and did not differ significantly from baseline
(Fig. 4). However, a mild persisting impairment in oral glucose
tolerance remained evident at month 6 (2-h glucose 8.2 ± 1.0
vs. 6.9 ± 1.1 mmol/liter at baseline,
P = 0.02). Patient 3 developed overt glucose
intolerance consistent with diabetes (2-h glucose 12.0 mmol/liter) at
month 1 but then improved substantially by month 6 (as previously
noted, his GH dose was reduced secondary to arthralgias). However, even
with the exclusion of patient 3, this pattern in oral glucose tolerance
remained apparent, with initial worsening at month 1 (glucose AUC
20.1 ± 2.5 to 23.4 ± 2.4 mmol·h/liter, n = 5,
P < 0.001) and then improvement at month 6 (22.0
± 1.8, n = 4, P < 0.001, compared with month 1),
although values at month 6 remained higher than baseline
(P = 0.01).
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). In patient 4, who was the most
insulin resistant at baseline, insulin sensitivity did not worsen at
month 1 but rather improved slightly during the course of the study.
Patient 6, who had impaired glucose tolerance at baseline, had a
reduction in insulin sensitivity at month 1 and only minimal
improvement by month 6. When patient 3 (whose dose of GH had been
reduced) was excluded from the analysis, the overall differences in
insulin-mediated glucose disposal did not reach statistical
significance (44.2 ± 26.8 at baseline, 23.9 ± 5.8 at month
1, 45.3 ± 24.1 at month 6, P = 0.11). Discussion
The results of this pilot study suggest that administration of GH at a dose of 3 mg/d reduced total body and trunk fat in patients with HIV-associated fat accumulation. Furthermore, GH treatment reduced buffalo hump size and excess visceral adiposity. These results need to be confirmed in a larger randomized, placebo-controlled study. While changes in appendicular fat were not observed in the small number of patients enrolled, other studies have reported that appendicular fat stores may be reduced with GH treatment (40, 41). Thus, while GH may be an effective therapy for patients with regional fat accumulation, it would not be appropriate for patients whose primary complaint is lipoatrophy.
Consistent with results in HIV-negative individuals, oral glucose tolerance initially worsened after 1 month of GH therapy and then improved toward baseline after 6 months. However, plasma glucose measurements obtained at 6 months were slightly higher than baseline levels and consistent with a mild persisting impairment in glucose tolerance. In the one patient who, in retrospect, had overt glucose intolerance at baseline, GH therapy led to fasting hyperglycemia and symptomatic diabetes within 2 wk of treatment initiation. The effect of GH on insulin-mediated glucose disposal followed a similar pattern with initial worsening and then improvement to baseline values, as evident in the majority of the subjects. It should be noted that this biphasic response occurred in patients selected for the absence of overt glucose intolerance (diabetes by OGTT) at baseline and does not apply to those with abnormal glucose tolerance.
Overall, the initial detrimental effects on glucose metabolism observed after 1 month of GH treatment are consistent with previous observations of GH action attributed to impairment of insulin action in the liver and peripheral tissues (24, 26, 27, 28). In the current study, the specific changes in hepatic glucose regulation and intermediary carbohydrate metabolism remain to be elucidated. The subsequent improvement in glucose metabolism toward baseline values might have been mediated, in part, by the reduction in body fat. However, we were not able to establish a causal relationship between visceral fat reduction and improvement in insulin sensitivity in this small number of patients. It is also possible that other effects of GH, including the action of GH-induced increases in IGF-I levels on glucose transport (42), may have contributed to these findings. Among the patients with normal glucose tolerance, the degree of fasting hyperinsulinemia at baseline did not reliably predict the GH-induced changes in peripheral insulin sensitivity or response to glucose challenge.
In our current study, a 4-fold increase in IGF-I levels (up to three times the upper normal range) was observed with administration of GH at a pharmacologic dose of 3 mg/d. These results are in contrast to previous studies in patients with HIV-associated wasting demonstrating less than a 2-fold increase in IGF-I concentrations following treatment with GH at an approximate dose of 6 mg/d (100 µg/kg·d) (19, 31), indicating that the GH resistance in HIV-infected patients with wasting is not apparent in patients with fat accumulation. Indeed, the dose of GH used in the current study would be expected to result in supraphysiologic IGF-I levels, except in individuals with GH resistance. Our observations underscore the need for further investigation of lower doses in the treatment of affected patients to avoid negative effects of long-term GH excess. Evidence that obesity and excess visceral fat are associated with blunted GH secretion in HIV-negative individuals (43, 44, 45) may provide an additional rationale for low-dose GH therapy in patients with fat accumulation syndromes. Indeed, recent data indicate that visceral adiposity seems to be a strong predictor of reduced GH concentrations in patients with HIV-related lipodystrophy (46), and future studies should assess whether individuals with excess visceral fat might respond best to low-dose GH treatment. Furthermore, a dose-ranging study may be necessary to determine the optimal dose of GH to reduce visceral adiposity, improve insulin sensitivity and minimize complications.
Within our sample of men with HIV-associated fat accumulation, in whom baseline HDL cholesterol concentrations were low and fasting triglyceride levels were elevated in the majority of cases, GH treatment was associated with a more favorable lipoprotein profile. After 6 months of treatment, a significant reduction in the total cholesterol to HDL cholesterol ratio was apparent, as well as a tendency toward decreased total cholesterol and increased HDL cholesterol levels. In addition, hypertriglyceridemia was not exacerbated despite the pharmacologic doses of GH used. Additional studies are needed to confirm these preliminary observations and to determine the potential metabolic pathways involved.
Although one patient experienced virologic failure during the course of study, previous studies have shown no deleterious effect of GH on HIV replication as measured by HIV RNA levels in plasma, immune-complex dissociated p24 antigen levels, and titers of infectious viremia in plasma, particularly in patients with high viral burden (19). Concerns about a potential effect of GH on HIV replication were initially raised when in vitro data showed augmented release of p24 antigen from phytohemagglutinin-activated, HIV- infected mononuclear cells after incubation with GH (47). However, this effect was variable and inhibited by the addition of zidovudine to the culture media. All patients in the current study continued antiretroviral therapy while receiving GH. The fact that one patient experienced virologic failure after maintaining the same antiretroviral regimen for more than 3 yr is not unexpected (48, 49).
In conclusion, treatment with GH at 3 mg/d resulted in a decrease in total body fat and an increase in lean body mass in this open-label trial. The most common side effects seen during the study were arthralgias and edema, probably reflecting the pharmacologic dose of GH used and the resultant supraphysiologic levels of IGF-I. Given the known negative aspects of chronic supraphysiologic GH and IGF-I levels, notably acromegaly with increased morbidity and mortality, long-term exposure to these high doses cannot be recommended at this time as treatment for HIV-infected men with fat accumulation. Rather, future studies should assess the efficacy of lower doses of GH that result in serum IGF-I levels within the normal range. Even with lower doses, we recommend performing an OGTT to exclude individuals with glucose intolerance before GH initiation. Testing may be particularly relevant as a significant proportion of HIV-infected subjects with fat distribution abnormalities have evidence of abnormal glucose tolerance despite normal fasting glucose levels (50, 51). In these individuals, significant hyperglycemia and frank diabetes mellitus can be precipitated by GH therapy. Finally, appropriate caution with monitoring of IGF-I levels, fasting glucose concentrations, and subsequent oral glucose tolerance testing are advised for patients continued on maintenance doses of GH therapy to avoid the long-term adverse consequences associated with hyperglycemia and GH excess.
Acknowledgments
We thank Scott Evans, M.D., Kyle Yu, M.D., and Rafael Ibarra, R.T., for efforts in developing the radiology CT protocol; the GCRC Nursing and Dietary Staff for help in performing the inpatient metabolic studies; Serono Laboratories, Inc. for the provision of GH; and Barbara Chang, Joy Hirai, Natalie Patterson, Carlynn Yee-Hicaiji, and Viva Tai for technical assistance.
Footnotes
This work was supported by the NIH (Grants DK45833 and DK54615) and the Universitywide AIDS Research Program (F98-SF-054). J.C.L. is a recipient of a Clinical Associate Physician Award from the National Center for Research Resources. All studies were conducted in the General Clinical Research Center at San Francisco General Hospital with support by the National Center for Research Resources, NIH (Grant RR00083). This work was presented in part at the 2nd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, Toronto, Canada, September 2000.
1 Present address: University of Medicine and Dentistry of New
Jersey, Newark, New Jersey 07103. 
Abbreviations: AUC, Area under the curve; CT, computed tomography; CV, coefficient(s) of variation; GCRC, General Clinical Research Center; HAART, highly active antiretroviral therapy; HbA1C, hemoglobin A1C; HDL, high-density lipoprotein; LDL, low-density lipoprotein; OGTT, oral glucose tolerance test; SAT, sc adipose tissue; VAT, visceral adipose tissue.
Received December 5, 2000.
Accepted April 6, 2001.
References
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M. K. S. Leow, C. L. Addy, and C. S. Mantzoros Human Immunodeficiency Virus/Highly Active Antiretroviral Therapy-Associated Metabolic Syndrome: Clinical Presentation, Pathophysiology, and Therapeutic Strategies J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 1961 - 1976. [Full Text] [PDF]
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 M J Rennie Claims for the anabolic effects of growth hormone: a case of the Emperor's new clothes? Br. J. Sports Med., April 1, 2003; 37(2): 100 - 105. [Abstract] [Full Text] [PDF]
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D. Chen, A. Misra, and A. Garg Lipodystrophy in Human Immunodeficiency Virus-Infected Patients J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 4845 - 4856. [Abstract] [Full Text] [PDF]
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S. Grinspoon and M. Gelato Editorial: The Rational Use of Growth Hormone in HIV-Infected Patients J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3478 - 3479. [Full Text] [PDF]
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); patient 5 (
); patient 6 (
); patient 7
(
); patient 8 (
). To convert nmol/liter to ng/ml, multiply by
7.649.
