Download Growth Hormone–Releasing Hormone in HIV

PRELIMINARY
COMMUNICATION
Growth Hormone–Releasing Hormone
in HIV-Infected Men With Lipodystrophy
A Randomized Controlled Trial
Polyxeni Koutkia, MD, MA
Bridget Canavan, BA
Jeff Breu, BS
Martin Torriani, MD
John Kissko, MS
Steven Grinspoon, MD
T
HE HUMAN IMMUNODEFIciency virus (HIV) lipodystrophy syndrome is highly prevalent among patients receiving
antiretroviral therapy.1 Although heterogeneous in its presentation, the syndrome is often characterized by excessive truncal and visceral adiposity,
subcutaneous and extremity fat loss,2
and metabolic abnormalities including hypertriglyceridemia, reduced highdensity lipoprotein cholesterol levels,
and insulin resistance, which may increase risk of coronary artery disease.3,4 Cross-sectional studies do not
uniformly show an association between lipodystrophy and antiretroviral therapy,5 but longitudinal cohort
studies suggest that protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) may be associated with loss of peripheral fat.6
Prospective studies of body composition in antiretroviral-naive individuals suggest loss of extremity fat and gain
in truncal fat with institution of highly
active antiretroviral therapy.7 In a randomized study of antiretroviral-naive
individuals initiating antiretroviral
therapy, use of a stavudine-containing
regimen was associated with a greater
Context Reduced growth hormone (GH) concentrations are observed in men with
human immunodeficiency virus (HIV) lipodystrophy.
Objective To investigate the effects of growth hormone–releasing hormone (GHRH),
a GH secretagogue, in treatment of HIV lipodystrophy.
Design, Setting, and Participants Randomized, double-blind, placebocontrolled trial conducted at a research center in the United States between October
2002 and June 2003 and enrolling 31 HIV-infected men aged 18 to 60 years with
evidence of lipodystrophy.
Interventions Participants were assigned to receive GHRH (1 mg subcutaneously
twice daily) or placebo for 12 weeks.
Main Outcome Measures The primary outcome was change in concentrations of
insulin-like growth factor 1 (IGF-1) to detect overall change in GH levels in response
to GHRH. Secondary end points included body composition by dual-energy x-ray absorptiometry and computed tomography, lipodystrophy ratings, and levels of glucose, insulin, and lipids.
Results Mean (SD) IGF-1 concentrations increased significantly in the GHRH group vs
the placebo group (104 [110] ng/mL vs 6 [44] ng/mL, P=.004). Lean body mass significantly increased in the GHRH group vs the placebo group (0.9 [1.3] kg vs −0.3 [1.7]
kg, P=.04), trunk fat significantly decreased (−0.4 [0.7] kg vs 0.2 [0.6] kg, P=.03), and
the ratio of trunk to lower extremity fat improved significantly (−0.22 [0.32] vs 0.14 [0.29],
P=.005). Abdominal visceral fat was reduced (–19.2 [36.6] cm2 vs 2.3 [24.3] cm2, P=.07)
and the ratio of abdominal visceral fat to abdominal subcutaneous fat improved significantly more in the GHRH group (–0.19 [0.28] vs 0.07 [0.27], P=.02). Both physician and
patient rating of lipodystrophy in the arms, legs, and abdomen also improved significantly. Levels of glucose, insulin, and lipids did not change significantly.
Conclusions GHRH was well tolerated and effectively increased levels of IGF-1 in
HIV-infected men with lipodystrophy. Total and regional body composition improved
in response to GHRH, with increased lean mass and reduced truncal and visceral fat.
Use of GHRH may potentially be a beneficial treatment strategy for this population.
www.jama.com
JAMA. 2004;292:210-218
Author Affiliations: Massachusetts General Hospital
Program in Nutritional Metabolism and Neuroendocrine Unit (Drs Koutkia and Grinspoon, Ms Canavan)
and Department of Radiology (Dr Torriani and Mr
Kissko), Harvard Medical School, Boston, Mass; General Clinical Research Center, Massachusetts Institute of Technology, Cambridge (Mr Breu).
Financial Disclosures: Dr Grinspoon has received unrestricted educational grant funding from Serono,
GlaxoSmithKline, Abbott, Boehringer Ingelheim, and
Solvay Pharmaceuticals (all unrelated to the study
herein); research grants from Gilead, Amgen, Serono, and Ortho Pharmaceuticals (all unrelated to the
210 JAMA, July 14, 2004—Vol 292, No. 2 (Reprinted)
study herein); and honoraria/lecture sponsorships from
Alza Pharmaceuticals, Serono, Pharmacia, Merck, Vertex Pharmaceuticals, Biogen Pharmaceuticals, Agouron Pharmaceuticals, GlaxoSmithKline, Bristol-Myers
Squibb, Millenium, Solvay, Praecis Pharmaceuticals,
and Auxillium Pharmaceuticals (all unrelated to the
study herein); has consulted for Bristol-Myers Squibb,
TheraTechnologies, and Solvay (all unrelated to the
study herein); and has received NIH funding.
Corresponding Author: Steven Grinspoon, MD, Program in Nutritional Metabolism, Massachusetts General Hospital, 55 Fruit St, LON 207, Boston, MA 02114
([email protected]).
©2004 American Medical Association. All rights reserved.
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GHRH IN HIV-INFECTED MEN WITH LIPODYSTROPHY
loss of limb fat than was use of other
NRTIs, and use of nelfinavir was associated with greater loss of extremity fat
than an efavirenz-based regimen.8 It is
unknown whether newer, low-dose,
“boosted” PIs are less significantly associated with the development of lipodystrophy. Accumulation of truncal fat
is a significant cardiovascular risk factor in non–HIV-infected patients,9,10 and
preliminary data suggest that the severity of the metabolic abnormalities increases in association with excess visceral adiposity in patients with HIV.11
Men with HIV lipodystrophy have reduced levels of growth hormone (GH)
secretion in association with excess visceral fat,12,13 and this may further contribute to increased cardiovascular risk
in this population.
To date, no effective therapy has been
established to treat the lipodystrophy
syndrome. Use of GH is a potentially appealing strategy to treat the lipodystrophy syndrome because of its known lipolytic actions to reduce visceral fat in
GH-deficient patients14 and because of
the recent data suggesting low GH concentrations in individuals with HIV lipodystrophy.12 However, use of highdose GH may be associated with insulin
resistance and fluid retention, myalgias, and other adverse effects.15-19 Although restoration of normal GH levels may be possible and safe with lowdose GH administration, another
approach is to treat with a natural GH
secretagogue, such as growth hormone–
releasing hormone (GHRH), to restore
a more physiologic pattern of GH than
that achieved with pharmacologic GH
therapy. With GHRH, feedback inhibition of insulin-like growth factor 1
(IGF-1) (a hepatic factor the secretion
of which is stimulated by GH and which
is responsible for many of its actions)
may help to prevent excessive GH secretion and adverse effects.20,21 In contrast, exogenous GH administration is
not significantly affected by feedback inhibition from IGF-1, titration is more difficult, and adverse effects may occur
relating to GH excess. We used
concentration of IGF-1 as the primary
end point of the study to assess the
changes in the GH axis in response to
GHRH. Because GH is pulsatile, use of
IGF-1, an integrated measure of GH secretion, is better suited to assess increases in GH secretion. Prior studies indicate that levels of IGF-1 are lower by
approximately 100 ng/mL in HIVinfected patients with lipodystrophy,13
and the GHRH regimen used in this
study increased IGF-1 to this degree.
METHODS
Patients
From 2002 to 2003 (individuals were
screened from September 10, 2002,
through January 31, 2003), 31 HIVinfected men with HIV-related lipodystrophy were recruited through community advertisements and contact with
physicians in the multidisciplinary HIV
practice at the Massachusetts General
Hospital in Boston. The lipodystrophy
was not congenital and was acquired in
all participants in the context of treatment of HIV disease. Participants were
asked to report when they first noted fat
redistribution, and the mean (SD) duration of self-reported lipodystrophy was
32 (22) months.
Inclusion criteria included: men aged
18 to 60 years previously diagnosed with
HIV infection; stable antiviral regimen
for at least 6 weeks prior to enrollment;
waist-to-hip ratio of 0.90 or greater; and
evidence of at least 1 of the following recent changes: (1) increased abdominal
girth, (2) relative loss of fat in the extremities, and (3) relative loss of fat in
the face. A similar algorithm was previously used to identify patients with HIV
having fat redistribution and decreased
levels of GH.12 Participants were excluded if they had diabetes mellitus (defined as fasting blood glucose ⬎126
mg/dL [7.0 mmol/L]); body mass index less than 20; hemoglobin concentration less than 9 g/dL; or if they had
used GH, GHRH, oral or parenteral glucocorticoids, megesterol acetate, or antidiabetic agents within the 3 months
prior to study initiation.
The protocol was approved by the institutional review board of the Massachusetts General Hospital and written informed consent was obtained from each
©2004 American Medical Association. All rights reserved.
participant prior to testing (ie, at the beginning of the study, before any tests
were performed), in accordance with the
Subcommittee on Human Studies at the
Massachusetts General Hospital.
The primary outcome was change in
levels of IGF-1 to detect overall changes
in levels of GH in response to GHRH.
Secondary end points included body
composition determined by dualenergy x-ray absorptiometry (DXA) and
computed tomography (CT); lipodystrophy ratings; levels of glucose, insulin, lipids, and glycosylated hemoglobin (HbA1c); energy expenditure; caloric
intake; blood pressure; CD4 cell count;
viral load; and GH pulse dynamics.
Clinical Research Protocol
After a 12-hour overnight fast, participants reported to the General Clinical
Research Center (GCRC) at the Massachusetts General Hospital for a
screening visit for measurement of glucose levels and complete blood cell
count. Data regarding past and current use of antiretroviral medications
were provided by the participant during the medical history intake and recorded. Participants had a physical examination that included measurement
of the neck, mid arm, trunk, and waistto-hip ratio. Eligible participants returned to the GCRC for an inpatient
baseline visit, outpatient safety visit at
1 and 6 weeks, and an inpatient endof-study visit at 12 weeks.
During the baseline and end-ofstudy visits the following data were collected after a 12-hour overnight fast: (1)
height and weight; (2) levels of IGF-1,
glucose, HbA1c, insulin, cholesterol,
low-density lipoprotein cholesterol,
high-density lipoprotein cholesterol,
and triglycerides; (3) 75-g oral glucose tolerance test to determine levels
of glucose and insulin; (4) CD4 cell
count and viral load; (5) resting energy expenditure and 4-day food record; (6) whole-body DXA scan; (7)
single-slice abdominal CT scan at L4
and mid thigh; (8) physician and participant rating of lipodystrophy; and (9)
overnight GH sampling, from 7 PM to
7:40 AM every 20 minutes.
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211
GHRH IN HIV-INFECTED MEN WITH LIPODYSTROPHY
After baseline testing was completed, participants were randomly assigned to receive daily subcutaneous injections of Geref (GHRH 1-29; Serono,
Rockland, Mass) (1 mg every 12 hours)
or identical placebo. An investigational
new drug application was filed for the
use of GHRH in this study, but an exemption was granted by the US Food and
Drug Administration. The GHRH dose
was determined from a prior study in elderly persons22 in which a similar dose
of GHRH (1 mg subcutaneously twice
daily) was safely used in elderly men to
restore physiologic GH levels over 14
days.22 Randomization codes were available to the study statistician and the Massachusetts General Hospital pharmacy,
but not to study investigators. Placebo
was manufactured by the Massachusetts General Hospital pharmacy and was
identical to active drug in color, consistency, and packaging. Participants received instruction on self-administration of the study medication by the
nursing staff of the GCRC and study
drug administration was witnessed at the
baseline and 1-week visits to ensure
proper technique. Compliance history
and vial count were performed at each
visit. Compliance was measured by return of used vials and review of medication use at each subsequent visit by the
investigator and nursing staff. Missing
or broken vials were assumed to be unused. Of those men completing the study
(n=29), 2 were unable to continue with
study drug injections; for those 2 men
and for 2 men (1 in each group) who
were lost to follow-up, compliance was
not calculated.
Body Composition Analysis
Whole-body and regional fat was determined by DXA. The technique has
a precision error, in our laboratory, of
1.7% for fat and 2.4% for fat-free mass.
Lower extremity fat, trunk fat, and
trunk-to-extremity ratios were assessed using DXA as in prior studies.23
Single-slice cross-sectional abdominal
CT scanning was also performed to assess the relative distribution of abdominal subcutaneous adipose tissue (SAT),
abdominal visceral adipose tissue
(VAT), and mid-thigh SAT as previously described.24
Laboratory Methods
Levels of IGF-1 were measured by 2-site
radioimmunometric assay (RIA) (Diagnostic Systems Laboratories Inc,
Webster, Tex) (intra-assay coefficient
of variation [CV], 4.93%). Levels of GH
were measured by RIA (Corning Inc,
Nichols Institute, San Juan Capistrano, Calif ) (intra-assay CV, 3.33%;
sensitivity, 0.01 ng/mL). Insulin levels were determined by RIA (Diagnostic Products Corp, Los Angeles, Calif)
(intra-assay CV, 5.2%). Glucose, HbA1c,
and lipid concentrations were measured by standard techniques.25 Concentrations of direct low-density lipoprotein cholesterol were determined by
immunoseparation spectrophotometry (Specialty Laboratories, Santa
Monica, Calif) (intra-assay CV, 3.0%).
The CD4 cell count was performed using standard flow cytometry technology (B-D TruCount; Becton Dickinson, San Jose, Calif), and the HIV viral
load was determined by ultrasensitive
assay (Roche Amplicor HIV-1 Monitor Assay Version 1.0; Roche, Indianapolis, Ind), with a lower limit of detection of 50 copies/mL.
Pulsatility Analysis
Circulating GH levels in humans fluctuate widely due to pulsatile GH secretion by the pituitary gland. As a result,
random measurement of serum GH will
not establish accurate GH secretory patterns. We therefore used standard pulsatility techniques and sampling rates
to determine the pattern of GH pulse
secretion as has been previously established to assess GH pulsatility in response to GHRH administration.26,27 To
assess growth hormone pulsatility we
used Cluster28,29 and specified individual test-cluster sizes for the nadir and
peak width of 2 (2⫻2).30
Lipodystrophy Rating Scales
Physicians and participants independently rated lipodystrophy in the face,
abdomen, arms, and legs at the baseline and final visit using a 4-point rat-
212 JAMA, July 14, 2004—Vol 292, No. 2 (Reprinted)
ing scale (none, mild, moderate, or
severe), and the changes in rating scores
were compared between the groups.
The patient rating scale was adapted
from Lichtenstein et al.31,32 In contrast
to prior studies using this scale, we limited our analysis to the face, arms, legs,
and abdomen to allow assessment of the
relative distribution of fat in the trunk
and extremities in response to GHRH.
Lipodystrophy ratings were performed by a single investigator (P.K.).
At the final visit, participants also
completed a self-administered questionnaire regarding change in overall
appearance over 3 months. Participants were asked if they believed their
overall appearance to be much worse,
somewhat worse, not different, somewhat better, or much better compared
with 3 months previous. All questionnaires were completed at the final visit
prior to unblinding of the study. Participants were not prompted or aided
by the investigators in their answers.
Statistical Methods
The primary end point of the study was
change in levels of IGF-1 between the
groups. The study enrolled 31 men with
a planned 10% dropout rate and was
powered to detect a treatment difference of 105 ng/mL in IGF-1 level at a
2-sided P⬍.05 significance level, based
on prior data showing the standard deviation of IGF-1 level in this population to be 87.0 ng/mL.12 The study was
not powered in advance to detect
changes in other metabolic variables but
achieved statistical significance in many
secondary end points (see “Results” section). Post hoc power analyses showed
that the study was well powered to detect clinically relevant changes into the
abnormal range in levels of glucose (91%
power at P⬍.05) and HbA1c (99% power
at P⬍.05) but may have been underpowered to detect significant changes in
some variables. The t test was used to
compare baseline data. Treatment effect
was determined by comparison of
change from baseline between treatment groups using the t test. For viral
load and CD4 cell count, baseline values and the changes between treat-
©2004 American Medical Association. All rights reserved.
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GHRH IN HIV-INFECTED MEN WITH LIPODYSTROPHY
ment groups were compared with the
Wilcoxon test. Race and overall antiretroviral use were compared using ␹2 likelihood ratios. The Fisher exact test was
used for comparison of individual antiretroviral medications. All available data
are included in the analyses in an intention-to-treat design. Similar results were
obtained excluding the follow-up data
from the 2 participants in the placebo
group who completed the trial on an intention-to-treat basis (Grinspoon et al,
unpublished data, February 2004). Also,
we performed another analysis with the
last observation carried forward for the
2 men who discontinued placebo injections and the results were again similar. Their treatment status was made
available for safety reasons (because of
adverse effects) (see “Results” section).
In terms of missing data, we were unable to obtain follow-up data (and thus
unable to calculate change from baseline) for 2 men, 1 in the treatment group
and 1 in the placebo group. These men
were unwilling or unable to make the
follow-up visits (see “Results” section),
and no interim data were available for
them. We performed an analysis with the
last observation carried forward for these
2 men and the results were nearly identical. P values remained significant for
all the variables that are significant in the
current analysis (Grinspoon et al, unpublished data, February 2004). Thus,
these missing data do not skew the results, even with a conservative approach to impute missing data.
Outlier analysis was performed using the Dixon criterion.33 The randomization code was determined by the
GCRC biostatistician using a permutedblock algorithm. All statistical analyses were performed using SAS JMP Statistical Database Software version 4
(SAS Institute Inc, Cary, NC). Statistical significance was defined as a 2-tailed
␣ value of Pⱕ.05. Results are mean (SD)
unless otherwise indicated.
Growth hormone–releasing hormone is generally well tolerated and adverse effects have been shown to occur in a minority of patients. Adverse
effects known to occur rarely in response to GHRH administration in-
clude brief injection-site reactions,
headache, flushing, dizziness, and urticaria.34 Approximately 60% of patients may develop anti-GHRH antibodies with no effect on response.35
With excess dosing, adverse effects
similar to those observed with highdose GH may occur, including arthralgias and fluid retention.36,37 In children, rare hypothyroidism can occur.35
An independent data and safety monitoring board, consisting of an AIDS expert, statistician, and community advocate, met every 3 months during the
study to review adverse events.
RESULTS
Participant Characteristics
The 12-week treatment phase of the
study took place from October 9, 2002,
through June 15, 2003. Two of the 31
participants were unable to complete the
protocol (FIGURE). One participant, assigned to the placebo group, withdrew
from the study immediately after the
baseline visit because of poor vision and
an inability to learn the injection techniques. A second participant, assigned
to the treatment group, was incarcerated after the baseline visit and unavailable to continue with the study. Two additional participants in the placebo group
discontinued the study medication after the baseline visit because of adverse
events (chest pain and rash) but agreed
to remain in the study (without receiving further doses of study drug) and
return for all subsequent study evaluations.
Clinical and demographic characteristics for the HIV-infected participants are
shown in TABLE 1. Baseline characteristics, including age, weight, racial demographics, and risk factors for HIV infection, did not differ between the treatment
groups (P⬎.05 for all baseline comparisons) (Table 1). The percentages of men
using PI-, NRTI-, and NNRTI-containing regimens did not differ between the
groups (Table 1). At baseline, use of individual drugs among the study participants was: abacavir (16%), abacavir in
combination with lamivudine and zidovudine (Trizivir; GlaxoSmithKline, Research Triangle Park, NC) (10%), am-
©2004 American Medical Association. All rights reserved.
Figure. Flow of Participants Through the
Study
35 Individuals Assessed for Eligibility
4 Excluded (Did Not
Meet Inclusion Criteria)
31 Randomized
16 Assigned to Receive
Placebo
14 Received Placebo
2 Did Not Receive
Placebo as
Assigned
15 Assigned to Receive
GHRH
15 Received GHRH
as Assigned
1 Discontinued
Intervention (Unable to
Perform Injections)
1 Lost to Follow-up
15 Included in Analysis
14 Included in Analysis
GHRH indicates growth hormone–releasing hormone.
prenavir (3%), didanosine (19%),
efavirenz (39%), indinavir (3%), lamivudine (32%), lopinavir in combination with ritonavir (Kaletra; Abbott Laboratories, Abbott Park, Ill) (16%),
nelfinavir (10%), nevirapine (23%), ritonavir (10%), saquinavir (3%), stavudine (39%), tenofovir (23%), zidovudine (6%), and zidovudine in
combination with lamivudine (Combivir; GlaxoSmithKline) (16%). The rate
of stavudine use was not statistically different (20% vs 56% for GHRH vs placebo, P=.07). Also, controlling for stavudine use did not affect the results for
trunk and extremity fat (Grinspoon et al,
unpublished data, May 2004). There
were no significant differences for any of
the baseline antiretroviral drugs except
for nevirapine (40% vs 6% for GHRH vs
placebo, P=.04). However, nevirapine
may not have an effect on body composition.38,39 Moderate to severe fat accumulation in the abdomen was observed
in 94% of the men, moderate to severe
fat loss in the legs or arms in 87%, and
moderate to severe fat loss in the face in
84%, as determined by physician rating
of lipodystrophy at baseline.
Changes in response to GHRH treatment for metabolic and body composition variables are shown in TABLE 2.
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213
GHRH IN HIV-INFECTED MEN WITH LIPODYSTROPHY
Variables did not differ at baseline between treatment groups (P⬎.05 for all
baseline comparisons). Mean (SD) concentrations of IGF-1 increased significantly in the GHRH group compared
with the placebo group in response to
GHRH (104 [110] ng/mL vs 6 [44]
ng/mL for GHRH vs placebo, P=.004).
Lean body mass increased significantly (0.9 [1.3] kg vs −0.3 [1.7] kg,
P=.04), whereas total fat mass did not
change significantly between the groups
(0.0 [1.3] kg vs –0.1 [1.4] kg, P = .80).
By DXA, lower extremity fat increased
in the GHRH group vs the placebo
group (0.2 [0.4] kg vs –0.1 [0.3] kg,
P=.05), whereas trunk fat decreased significantly (−0.4 [0.7] kg vs 0.2 [0.6] kg,
P=.03), with a significant change in the
ratio of trunk fat to lower extremity fat
(−0.22 [0.32] vs 0.14 [0.29], P = .005)
(Table 2).
By CT, abdominal VAT decreased on
average 9% in the GHRH group and increased 1% in the placebo group (−19.2
[36.6] cm2 vs 2.3 [24.3] cm2 for GHRH
vs placebo, P=.07) (Table 2). In con-
trast, abdominal SAT increased 4% in
the GHRH-treated group and decreased 2% in the placebo group, although these changes were not significant. The net overall effect of GHRH on
the ratio of abdominal VAT to abdominal SAT was significant and amounted
to a 12% decrease in the GHRH group
vs a 7% gain in the placebo group
(P=.02) (Table 2). Subcutaneous fat at
the mid thigh decreased less in the
GHRH group vs the placebo group
(−0.1 [5.0] cm 2 vs –3.8 [4.7] cm 2 ,
P = .05).
Levels of fasting glucose, HbA1c, fasting insulin, total cholesterol, and triglycerides, as well as glucose area under the curve, insulin area under the
curve, and lipid profile, did not change
significantly between treatment groups
(Table 2). One person in the GHRH
group developed an asymptomatic fasting glucose level greater than 126 mg/dL
(7.0 mmol/L) at the end-of-study visit
(P=.22). Neither CD4 cell count nor viral load changed significantly between treatment groups (Table 2).
Table 1. Baseline Demographic and Clinical Characteristics of the Study Population
Characteristic
Demographics
Age, mean (SD), y
Race, No. (%)
White
Hispanic
Black
Other
Body mass index, mean (SD)†
Waist-to-hip ratio, mean (SD)
Duration of HIV infection, mean (SD), mo
Mode of HIV infection, No. (%)
Men who have sex with men
Intravenous drug use
Blood transfusion
Unknown
HIV treatment classes
Current PI use, No. (%)
PI exposure, mean (SD), mo
Current NRTI use, No. (%)
NRTI exposure, mean (SD), mo
Current NNRTI use, No. (%)
NNRTI exposure, mean (SD), mo
Placebo
(n = 16)
GHRH
(n = 15)
46.3 (6.2)
45.7 (8.3)
12 (75)
1 (6)
2 (13)
1 (6)
26.8 (3.5)
0.97 (0.05)
114 (55)
10 (67)
1 (7)
2 (13)
2 (13)
25.5 (2.8)
0.97 (0.04)
122 (56)
.28
.95
.71
14 (88)
0
1 (6)
1 (6)
14 (93)
1 (7)
0
0
.58
.22
.24
.24
7 (43.8)
20 (29)
15 (93.8)
39 (33)
9 (56.3)
14 (20)
5 (33.3)
21 (24)
13 (86.7)
36 (24)
10 (66.7)
20 (17)
.55
.91
.50
.77
.55
.37
P Value*
.85
.92
Abbreviations: GHRH, growth hormone−releasing hormone; HIV, human immunodeficiency virus; NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor.
*By t test except for “race” and “antiretroviral use,” determined by ␹2 likelihood ratio.
†Calculated as weight in kilograms divided by the square of height in meters.
214 JAMA, July 14, 2004—Vol 292, No. 2 (Reprinted)
Physician and patient rating of lipodystrophy improved significantly in the
arms, legs, and abdomen in the GHRH
group vs the placebo group (TABLE 3).
Participants were also asked to answer an exit question at the final visit
as to how their overall appearance compared with that 3 months previous. The
percentages of men answering were as
follows: much worse (0% vs 0% for
GHRH vs placebo), somewhat worse
(0% vs 20%), no difference (21% vs
53%), somewhat better (50% vs 27%),
much better (29% vs 0%) (overall
P=.005 by likelihood ratio). Initial lipodystrophy ratings did not correlate
with change in overall appearance as assessed by exit questionnaire.
Pulse dynamics were determined
from every 20-minute frequent sampling. The number of secretion peaks
did not change between the 2 groups,
but the peak height decreased whereas
the valley mean level and nadir increased significantly in the GHRH
group vs the placebo group (TABLE 4).
Compliance with study drug was assessed as described above and was 94%
for the GHRH group and 95% for the
placebo group (P=.86). One person in
each group discontinued antiretroviral
medications. Two men in the GHRH
group changed therapy: 1 switched from
an NRTI/NNRTI regimen to an NRTI/PI
regimen and the second added another
NRTI. Use of PIs, NRTIs, and NNRTIs
were not different between the groups
at the end-of-study visits (end-of-study
PI use: 29% vs 40% for GHRH vs placebo, P= .52; NRTI use: 79% vs 87%,
P=.56; NNRTI use: 64% vs 53%, P=.55).
Use of individual drugs did not change
significantly between groups over the
course of the study (Grinspoon et al, unpublished data, February 2004).
Blood pressure did not increase in the
GHRH group (Table 2), and no participant experienced edema, arthralgias, or
any other symptoms of GH excess. No
participant in the GHRH group dropped
out of the study due to adverse effects.
Three months after completion of the
study, 1 participant in the GHRH group
with a history of anal warts was diagnosed with anal carcinoma. The par-
©2004 American Medical Association. All rights reserved.
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GHRH IN HIV-INFECTED MEN WITH LIPODYSTROPHY
ticipant’s IGF-1 level did not exceed the
normal range during the study. This
event was believed by the data and
safety monitoring board not to be related to GHRH.
The study was powered for the primary end point only. Although many
secondary end points changed signifi-
cantly in response to GHRH, the study
may have been underpowered to detect changes in certain variables, eg, abdominal VAT, which approached statistical significance. Post hoc power
analysis showed that the study was well
powered to detect significant changes
in the primary safety parameters, eg,
levels of glucose and HbA1c (see “Statistical Methods” section).
COMMENT
In this study, we investigated the novel
use of GHRH to restore physiologic GH
levels in HIV-infected men with lipodystrophy. Restoration of physiologic
Table 2. Changes From Baseline in Body Composition and in Metabolic and Safety Parameters*
Mean (SD)
GHRH (n = 14)
Placebo (n = 15)
Reference
Range†
NA
Characteristic
Baseline
Body mass index§
27.3 (2.9)
DXA
Lean mass, kg
NA
67.9 (9.0)
Total fat, kg
NA
17.5 (6.6)
Trunk fat, kg
NA
10.6 (4.4)
Lower extremity fat, kg
NA
3.6 (2.3)
Trunk fat/lower extremity fat ratio
NA
3.26 (1.17)
Computed tomography
NA
163.2 (71.5)
Abdominal VAT, cm2
Abdominal SAT, cm2
NA
184.2 (99.0)
VAT/SAT ratio
NA
1.07 (0.70)
Leg SAT, cm2
NA
41.4 (22.8)
Metabolic parameters
IGF-1, ng/mL
100-494㛳
205 (111)
HbA1c, %
3.8-6.4
4.9 (0.4)
Fasting glucose, mg/dL
70-110
97 (12)
Glucose area under the
NA
18 446 (4246)
curve, (mg/dL) ⫻ min
Fasting insulin, µU/mL¶
⬍15
21.0 (22.2)
Insulin area under the
NA
13 184 (14 971)
curve, (µU/mL) ⫻ min
Lipids, mg/dL
Total cholesterol
120-199
208 (80)
Triglycerides
40-150
257 (201)
LDL-C
50-130
112 (51)
HDL-C
35-85
42 (13)
Resting energy expenditure, kcal#
NA
1754 (311)
kcal/d by 4-day food record#
NA
2238 (651)
Blood pressure, mm Hg
Systolic
NA
120 (14)
Diastolic
NA
75 (11)
Immune function
348-1456
466 (350 to 564)
CD4 cell count, median (IQR),
cells/mm2
Undetectable
1.7 (1.7 to 2.4)
Viral load, median (IQR), log10
copies/mL
Change From
Baseline
−0.18 (0.52)
Baseline
25.5 (2.9)
Change From
Baseline
0.36 (0.81)
P Value for
Change Between
Treatment Groups‡
.04
−0.3 (1.7)
−0.1 (1.4)
0.2 (0.6)
−0.1 (0.3)
0.14 (0.29)
63.1 (7.4)
15.6 (5.5)
9.6 (3.5)
3.3 (1.8)
3.28 (0.99)
0.9 (1.3)
0.0 (1.3)
−0.4 (0.7)
0.2 (0.4)
−0.22 (0.32)
.04
.80
.03
.05
.005
2.3 (24.3)
−4.3 (29.1)
0.07 (0.24)
−3.8 (4.7)
216.5 (90.3)
133.8 (72.1)
1.57 (0.80)
37.5 (21.8)
−19.2 (36.6)
5.4 (16.2)
−0.19 (0.28)
−0.1 (5.0)
.07
.28
.02
.05
6 (44)
0.0 (0.3)
−1 (9)
674 (3737)
228 (113)
5.1 (0.5)
101 (16)
19 227 (3963)
104 (110)
0.1 (0.5)
4 (12)
1405 (3188)
.004
.42
.21
.58
2.5 (12.4)
85 (7913)
17.2 (9.2)
8596 (3978)
2.3 (7.6)
1723 (3511)
.96
.48
−3 (18)
72 (131)
−4 (25)
−3 (8)
171 (245)
74 (535)
177 (47)
251 (221)
97 (35)
35 (11)
1672 (216)
2465 (678)
−1 (21)
40 (220)
−9 (20)
−2 (4)
167 (168)
−190 (665)
.76
.63
.59
.55
.97
.41
−3 (12)
−4 (6)
130 (13)
81 (8)
−1 (15)
−1 (9)
.82
.36
33 (−57 to 119)
291 (183 to 567)
0.0 (0.0 to 0.3)
1.8 (1.7 to 3.2)
−5.5 (−55 to 24)
0.0 (−0.3 to 0.0)
.38
.10
Abbreviations: DXA, dual-energy x-ray absorptiometry; GHRH, growth hormone−releasing hormone; HbA1c, glycosylated hemoglobin; HDL-C, high-density lipoprotein cholesterol;
IGF-1, insulin-like growth factor 1; IQR, interquartile range; LDL-C, low-density lipoprotein cholesterol; NA, not applicable.
SI conversion factors: To convert mg/dL of glucose to mmol/L, multiply by 0.0555; µU/mL of insulin to pmol/L, multiply by 6.945; mg/dL of total cholesterol, LDL-C, and HDL-C to
mmol/L, multiply by 0.0259; and mg/dL of triglycerides to mmol/L, multiply by 0.0113.
*Baseline comparisons are all P⬎.05 by t test (Wilcoxon test for CD4 cell count and viral load).
†Reference ranges for all laboratory parameters except where otherwise indicated are values from the Massachusetts General Hospital chemistry and hematology laboratories.
‡By t test (Wilcoxon test for CD4 cell count and viral load).
§Calculated as weight in kilograms divided by the square of height in meters. Two individuals were lost to follow-up; thus, values for body mass index vary from those given in Table 1.
㛳RIA kit DSL-2800 [package insert]. Webster, Tex: Diagnostic Systems Laboratories.
¶Reference range for insulin is considered the 90th percentile for normal glucose-tolerant patients ages 26-50 years, which is ⬎15.0 µU/mL based on the Framingham Offspring
Data (James B. Meigs, MD, MPH, Massachusetts General Hospital, written communication, June 10, 1999).
#Data on food records are missing for 2 individuals in the GHRH group and 4 in the placebo group at baseline and 8 individuals in each group at the end of the study (these data
are used to calculate kcal/d).
©2004 American Medical Association. All rights reserved.
(Reprinted) JAMA, July 14, 2004—Vol 292, No. 2
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215
GHRH IN HIV-INFECTED MEN WITH LIPODYSTROPHY
may further contribute to increased abdominal adiposity, in a vicious cycle of
adiposity and reduced GH. Among
non–HIV-infected individuals, restoration of more normal GH concentrations results in improved fat distribution and improved metabolic
parameters.40 Our data suggest that interruption of the GH-adiposity cycle by
restoration of more normal GH concentrations can result in an improved
pattern of fat distribution. The study
was approved for men by the institutional review board and the General
Clinical Research Center Scientific Advisory Committee because of the known
effects of sex on the GH axis.42-45 Sev-
GH levels has been investigated in non–
HIV-infected patients with abdominal
obesity,40 but prior studies have only
used administration of pharmacological GH and not previously investigated GHRH in the HIV population.
Body composition improved without
adverse effects on glucose levels or GH
excess, suggesting the potential usefulness of this strategy in the HIV population.
In the HIV population, markedly reduced mean GH secretion and pulse
area are observed in association with increased visceral adiposity.13 Reduced
GH secretion is observed in other populations with abdominal obesity41 and
Table 3. Changes From Baseline in Physician and Participant Assessment of Lipodystrophy*
Mean (SD)*
GHRH (n = 14)
Placebo (n = 15)
Face
Arms
Abdomen
Legs
2.1 (0.6)
1.5 (0.5)
2.3 (0.7)
1.9 (0.8)
Change From
Change From
Baseline
Baseline
Baseline
Physician Assessment
−0.3 (0.5)
2.1 (0.9)
−0.8 (0.8)
−0.1 (0.5)
1.9 (0.8)
−0.6 (0.6)
−0.4 (0.5)
2.6 (0.5)
−1.1 (1.0)
−0.1 (0.5)
2.4 (0.6)
−0.9 (0.9)
Face
Arms‡
Abdomen
Legs‡
2.2 (0.7)
1.5 (0.6)
2.3 (0.7)
1.9 (0.7)
Participant Assessment
−0.3 (0.6)
2.2 (0.9)
−0.7 (0.9)
0.0 (0.8)
2.2 (0.8)
−0.8 (0.8)
−0.4 (0.7)
2.6 (0.5)
−1.1 (0.7)
−0.1 (0.5)
2.6 (0.5)
−1.0 (1.0)
Baseline
P Value for
Change Between
Treatment Groups†
.04
.02
.03
.01
.13
.01
.02
.005
Abbreviation: GHRH, growth hormone−releasing hormone.
*Means compared using the t test. Lipodystrophy was independently graded by physicians and participants at each
site at baseline and end of study using a 4-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe).31,32 Negative
change indicates improvement in lipodystrophy score.
†By t test.
‡P⬍.05 for baseline comparison between treatment groups.
Table 4. Changes From Baseline in Growth Hormone Pulse Dynamics*
Mean (SD)
GHRH (n = 14)
Placebo (n = 15)
P Value for
Change From Change Between
Baseline
Baseline
Treatment Groups†
3.3 (1.2)
0.2 (1.4)
.56
133 (36)
−4 (63)
.83
1.19 (0.57) −0.20 (0.32)
.02
Baseline
Change From
Baseline
3.0 (1.3)
120 (24)
1.59 (1.36)
−0.3 (2.8)
−0.1 (38)
0.33 (0.70)
Area, (ng/mL) ⫻ min 95.2 (94.4)
Valley mean level,
0.27 (0.20)
ng/mL
Nadir, ng/mL
0.22 (0.16)
0.7 (52.3)
−0.03 (0.13)
59.3 (38.2)
0.19 (0.14)
10.0 (92.7)
0.07 (0.12)
.74
.05
−0.02 (0.10)
0.14 (0.12)
0.06 (0.10)
.05
Secretion peaks
Peak width, min
Peak height, ng/mL
Abbreviation: GHRH, growth hormone−releasing hormone.
*All baseline comparisons between groups P⬎.05 by t test.
†By t test.
216 JAMA, July 14, 2004—Vol 292, No. 2 (Reprinted)
enty-one percent of the population was
white, and further studies in women
and minorities will be important.
A number of prior studies have investigated GH administration in HIVinfected patients and shown positive effects on abdominal fat, but all such
studies have used administration of
pharmacological GH. For example,
Wanke et al15 investigated a GH dose
of 6 mg/d in an open-label study and
demonstrated a reduction in abdominal adiposity, but glucose level increased significantly in 1 patient and
complaints of myalgias and stiffness
were common. Engelson et al18 demonstrated an approximate 50% reduction in abdominal VAT after 24 weeks
in response to growth hormone at 6
mg/d in an open-label study, but 3 participants developed diabetes. Lo et al19
used a lower dose of 3 mg/d in an openlabel study of 8 patients, and observed
beneficial effects on trunk fat, but IGF-1
levels increased to 3 times the upper end
of the normal range, and glucose intolerance worsened initially in all patients. Although glucose levels tended
to return to normal, 1 patient developed overt diabetes mellitus and arthralgias necessitating dose reduction, and 2-hour glucose levels as well
as glucose area under the curve remained increased at the end of the study
compared with baseline.19 Kotler et al46
reported on the results of a large,
double-blind, randomized, dosefinding study of GH in individuals with
HIV and with lipodystrophy and
marked visceral obesity, demonstrating significant reductions in visceral fat
in the 4-mg daily group, but not in the
group receiving 4 mg on alternate days.
Significant reductions in trunk fat determined by DXA, ratio of trunk fat to
limb fat, and levels of serum total and
non–high-density lipoprotein cholesterol were observed at both dosages. Insulin resistance tended to worsen initially but then improve toward baseline
with continued therapy.
Endogenous GHRH is a natural secretagogue for GH.47 Prior studies have used
GHRH to restore normal GH levels and
increase levels of IGF-1.22 Once-daily
©2004 American Medical Association. All rights reserved.
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GHRH IN HIV-INFECTED MEN WITH LIPODYSTROPHY
dosing with nightly GHRH is less effective than multiple daily doses of GHRH,48
and we chose twice-daily dosing.
The use of GHRH to restore physiologic GH levels is less often associated with adverse effects than is GH itself
and may reduce abdominal adiposity
without inducing insulin resistance,
fluid retention, or myalgias,35 because
IGF-1 feedback inhibition remains
intact. Corpas et al22 investigated the use
of GHRH (Geref; 1 mg subcutaneously twice per day) in elderly men to
restore levels of IGF-1 and physiologic GH without an increase in glucose levels. No adverse effects were
reported. A longer-term study using
GHRH in children also demonstrated
excellent tolerability and efficacy.35
Our data demonstrate that physiological increases in GH levels after administration of GHRH result in fat redistribution that includes an improved
ratio of abdominal VAT to SAT. Similar changes in fat distribution with sparing of subcutaneous fat have been
shown in response to low-dose GH in
non–HIV-infected GH-deficient patients.14,49 Although further studies will
be necessary to determine the longterm effects of GHRH on body composition, our data suggest that GHRH at
the dose and duration used in this study
is not lipolytic for subcutaneous fat.
In this study, we did not observe adverse effects on levels of glucose and
HbA1c. It is unlikely that we would have
detected clinically significant changes,
even with a much larger population
based on a post hoc power analysis. Individuals with diabetes mellitus were
excluded from this study, and larger increases in glucose levels may be observed in those with higher baseline levels. No significant changes in levels of
cholesterol or triglycerides were observed between treatment groups, but
the study may have been underpowered to detect such changes based on
the variability in responses. GHRH was
well tolerated. Blood pressure did not
differ between groups, and no evidence of edema or GH excess was observed in participants receiving GHRH.
Further studies of longer duration will
be needed to confirm the absence of
clinically significant effects of GHRH on
glucose levels in HIV-infected patients, and those with significant elevations in blood glucose levels should be
excluded from such studies. In addition, individuals with underlying malignancy are not appropriate for treatment with GHRH. Further long-term
studies are needed to determine if
changes in fat distribution from administration of GHRH are associated with
improvement in insulin resistance and
to determine the durability and optimal dosing duration for GHRH.
Immunological parameters remained stable. Growth hormone has
been shown to increase CD4 cell counts
and thymic mass in patients with HIV.50
In addition, GH secretagogues have
been shown to have immunomodulatory effects in both animal51 and human 52 studies. Further studies are
needed to determine the long-term effects of GHRH on immune function in
HIV-infected patients.
Our data suggest a mixed effect on
pulse dynamics, with increased nadir
and valley but decreased peak height in
response to GHRH vs placebo. One potential explanation of our data is a direct stimulatory effect of GHRH to increase the basal GH secretion and nadir,
with feedback inhibition of increased
IGF-1 on peak height.
No established therapy yet exists to
treat patients with HIV and lipodystrophy. The novel strategy investigated in
this study, treatment with GHRH, addresses a physiologic abnormality, eg,
reduced GH levels, to achieve physiological increases in GH levels and significant changes in fat redistribution.
GHRH is not currently approved for
chronic treatment of HIV lipodystrophy and not commercially available, approved, or recommended for any indication in adults. The cost of such a
treatment is unknown. However, an estimate based on the previously published price in children53 would be approximately $1775 per month at 2
mg/d. Twice-daily subcutaneous injections may not be feasible, but other GH
secretagogues dosed orally or by less-
©2004 American Medical Association. All rights reserved.
frequent injections may be developed
and useful to study in the HIV population. Treatment of reduced GH levels might alternatively use low-dose
physiologic GH to reduce visceral fat
and improve ratios of central fat to peripheral fat. Metformin54,55 and rosiglitazone56-58 may improve insulin sensitivity, and rosiglitazone may increase
subcutaneous fat.56,58 It is unknown how
long a patient would need to continue
to receive treatment with GHRH.
The present study provides initial evidence of the principle that restoration
of physiologic GH levels may be beneficial in HIV-infected men with reduced GH levels and suggests the need
for further studies using GHRH, other
secretagogues, or physiologic GH to improve fat distribution in HIV-infected
patients.
Author Contributions: As corresponding author and
principal investigator, Dr Grinspoon had full access to
all of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the data
analyses.
Study concept and design; obtained funding; study
supervision: Grinspoon.
Acquisition of data; drafting of the manuscript:
Koutkia, Canavan, Breu, Torriani, Kissko, Grinspoon.
Analysis and interpretation of data: Koutkia, Canavan,
Torriani, Kissko, Grinspoon.
Critical revision of the manuscript for important intellectual content: Koutkia, Canavan, Breu, Grinspoon.
Statistical expertise: Koutkia, Canavan, Grinspoon.
Administrative, technical, or material support: Canavan, Breu, Torriani, Kissko.
Funding/Support: The NIH provided the funding for
this study (grants R01 DK063639 and M01RR01066). Serono Inc provided study medication only.
Role of the Sponsor: Serono Inc had no role in the
design and conduct of the study; collection, management, analysis, and interpretation of the data; or the
preparation of the manuscript. As per prenegotiated
material transfer agreement, Serono was provided a
final draft prior to submission but did not have final
approval rights.
Acknowledgment: We acknowledge the nursing and
bionutrition staffs of the General Clinical Research Center of the Massachusetts General Hospital and Massachusetts Institute of Technology for their dedicated patient care.
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