| Annals of
Internal Medicine
Recombinant Human Growth Hormone in Patients with HIV-Associated
Wasting
A Randomized, Placebo-Controlled Trial
Annals of Internal Medicine, 1 December 1996. 125:873-882..
Morris Schambelan, MD; Kathleen Mulligan, PhD; Carl Grunfeld, MD,
PhD; Eric S. Daar, MD; Anthony LaMarca, MD; Donald P. Kotler, MD; Jack
Wang, MS; Samuel A. Bozzette, MD, PhD; James B. Breitmeyer, MD, PhD; and
the Serostim Study Group (See Appendix.)
Background: Body wasting, particularly loss of body
cell mass, is an increasingly prevalent acquired immunodeficiency
syndrome (AIDS)-defining condition and is an independent risk factor for
death in patients infected with the human immunodeficiency virus (HIV).
Treatment with growth hormone for 7 days resulted in weight gain and
nitrogen retention, but the long-term effects of this treatment in
patients with HIV-associated wasting are not known.
Objective: To evaluate the long-term effect of
treatment with growth hormone on weight, body composition, functional
performance, and quality of life in patients with HIV-associated
wasting.
Design: Randomized, double-blind,
placebo-controlled, multicenter trial.
Setting: Outpatient university and community-based
patient care facilities.
Patients: 178 HIV-infected patients with a
documented unintentional weight loss of at least 10% or weight less than
90% of the lower limit of ideal body weight.
Intervention: Patients were randomly assigned to
receive either recombinant human growth hormone, 0.1 mg/kg of body
weight per day (average dosage, 6 mg/d) (n = 90) or placebo (n
= 88) for 12 weeks.
Measurements: Weight; body fat, lean body mass, and
bone mineral content (measured by dual-energy x-ray absorptiometry);
total body water (by deuterium oxide dilution); extracellular water (by
sodium bromide dilution); work output (by treadmill exercise); quality
of life; and safety of treatment.
Results: Treatment with growth hormone resulted in a
sustained and statistically significant increase in weight (mean
increase ± SD, 1.6 ± 3.7 kg [P < 0.001]) and lean body
mass (3.0 ± 3.0 kg [P < 0.001]), accompanied by a decrease
in body fat (-1.7 ± 1.7 kg [P < 0.001]). In contrast, in
patients receiving placebo, weight (increase, 0.1 ± 3.1 kg), lean body
mass (decrease, 0.1 ± 2.0 kg), and body fat (decrease, 0.3 ± 2.2 kg)
did not change significantly from baseline. Differences between groups
at week 12 were statistically significant (P = 0.011 for body
weight and P < 0.001 for lean body mass and body fat). A
greater increase in treadmill work output was noted in the group
receiving growth hormone (increase, 99 ± 293 kg · m/min) compared with
the group receiving placebo (increase, 20 ± 233 kg · m/min) (P
= 0.039). Health status (quality of life) scores did not differ between
groups at baseline or after treatment. Days of disability and use of
medical resources were the same for both groups. Treatment was well
tolerated; no significant differences were seen between groups in
clinical events, progression of AIDS, CD4+ or CD8+
cell counts, or viral burden.
Conclusion: Treatment with growth hormone increases body weight, lean
body mass, and treadmill work output and appears to be a safe and
potentially effective therapy in patients with HIV-associated wasting.
|
Ann Intern Med. 1996;125:873-882. Annals of
Internal Medicine is published twice monthly and
copyrighted © 1996 by the American College of Physicians.
For current author affiliations and addresses, see end
of text.
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Body wasting is an increasingly frequent acquired immunodeficiency
syndrome (AIDS)-defining condition (1, 2). Wasting
is associated with impaired functional performance and quality of life (3).
Prospective (4-6) and retrospective (7-9)
studies have shown that loss of weight (4, 7-9)
and body cell mass (5-7) are statistically related
to death in patients with human immunodeficiency virus (HIV) infection.
The effect of weight and body composition on survival was notably
independent of other factors that were thought to influence mortality.
Nutritional supplementation (10, 11) and
appetite stimulation (12, 13) can increase body
weight and body fat in patients with HIV-associated wasting, but these
treatments do not consistently restore lean tissue. The apparent failure
of nutritional therapy to restore lean tissue suggests that, in some
HIV-infected patients, metabolic alterations either promote nitrogen
wasting or at least prevent repletion of lean tissue during periods when
the patients presumably have adequate energy intake. Although increases
in body fat in this setting may not be intrinsically harmful, body fat
content is not correlated with survival (5, 7).
Thus, optimal therapy for patients with HIV-associated wasting should
specifically reverse or forestall loss of lean tissue. Pharmacologic
doses of growth hormone have induced nitrogen retention and increased
protein synthesis and lean body mass in other catabolic states (14-17).
This treatment has also produced weight gain and nitrogen retention in a
short-term study (18) of patients with
HIV-associated wasting. The results of an open-label study (19)
of a small group of patients with HIV-associated wasting suggested that
growth hormone may have a sustained effect on lean body mass. We report
the results of a randomized, multicenter, double-blind,
placebo-controlled study that assessed the effects of growth hormone
therapy on weight, body composition, functional performance, and quality
of life in patients with HIV-associated wasting.
Methods
Patients
Eligible patients were 18 years of age or older and had antibodies to
HIV type 1, documented unintentional weight loss of at least 10% or
weight less than 90% of the lower limit of ideal body weight (20),
a Karnofsky score of 50 or greater, and life expectancy of 4 months or
longer. Patients had to be able to consume at least 75% of maintenance
energy requirement based on concurrent body weight. Patients had to have
been receiving a stable regimen of antiretroviral therapy for at least
30 days before study entry and had to continue to receive antiretroviral
therapy during the study.
Exclusion criteria included pregnancy; severe diarrhea (gretaer than
or equal to 6 stools per day); use of anabolic agents, glucocorticoids,
appetite stimulants, or parenteral or tube feeding; initiation of
therapy for a systemic infection within 30 days of enrollment; an active
malignant condition other than localized Kaposi sarcoma (<10
cutaneous lesions, <2 cm in diameter); recent radiotherapy or
systemic chemotherapy; untreated hypertension; history of diabetes
mellitus, significant cardiovascular disease, chronic edema, or the
carpal tunnel syndrome; fasting glucose level greater than 6.7 mmol/L;
triglyceride level greater than 5.6 mmol/L; amylase level more than 3
times the upper limit of normal; or hemoglobin level less than 85 g/L.
The study was approved by the institutional review board at each
participating center, and signed informed consent was obtained before
patients were enrolled. Baseline measures included results of history
and physical examination; weight; body composition; assessment of
treadmill work output and quality of life; routine hematologic and
biochemical assessments; and measurement of insulin-like growth factor 1
levels, CD4+ and CD8+ lymphocyte counts, and p24
antigen levels. Plasma HIV RNA levels were measured in a subset of
patients from whom appropriate samples were available.
Patients were randomly assigned to receive recombinant human growth
hormone derived from mammalian cells (Serostim, Serono Laboratories,
Norwell, Massachusetts), 0.1 mg/kg of body weight subcutaneously every
evening (average dosage, 6 mg/d), or an equivalent amount of placebo.
This dose of growth hormone caused weight gain and nitrogen retention in
a short-term study of patients with HIV-associated wasting (18).
Patients were randomly assigned according to a computer-generated
randomization list that was balanced across all patients and within
sites. Kits that contained either the active study drug or placebo in
identical vials were given to the study sites. Patients and
investigators were blinded to the content of the vials until the study
was complete. Patients were reevaluated at weeks 1, 2, 6, and 12;
adverse events were recorded and laboratory assessments were done at
these evaluations.
Doses were reduced for patients with fasting triglyceride levels
greater than 7.9 mmol/L, fasting glucose levels greater than 8.9 mmol/L,
moderate hypertension, arthralgia that did not respond to
anti-inflammatory therapy, the carpal tunnel syndrome, edema that did
not respond to diuretics, moderate systemic allergic reaction, or severe
paresthesia. The dose was reduced by 50% and again by 50% if symptoms
did not resolve within 10 days. Patients in whom symptoms persisted at
the lowest dose were withdrawn from the study. Severe events that
required suspension of treatment included fasting triglyceride levels of
16.9 mmol/L or greater, glucose levels of 22.2 mmol/L or greater,
pseudotumor cerebri, congestive heart failure, pancreatitis, marked
hypertension (blood pressure > 200/110 mm Hg), intolerable
paresthesia, or severe systemic allergic reaction. If symptoms resolved
within 5 days, patients could resume therapy at 50% of the dose used at
the time of the event. Treatment was discontinued immediately and not
resumed in patients who developed a new occurrence of cancer (including
Kaposi sarcoma) and in patients who had progression of existing Kaposi
sarcoma (new lesions or >50% growth of existing lesions). Patients
who had acute infections could remain in the study at the discretion of
the investigator.
Outcome Assessments
All measurements were done by investigators and their associates at
each study site; investigators and associates were unaware of assignment
to growth hormone or placebo. At baseline and 6 and 12 weeks, weight and
body composition were measured after overnight fasting and voiding.
Patients wore only a hospital gown. Weights were measured on the same
calibrated scales (certified to have an accuracy to ±0.2 kg and a
coefficient of variation of 0.3%) throughout the study; the average of
three determinations was used. Weight was also recorded at weeks 1 and 2
but not necessarily in the fasting state.
Body fat, lean body mass, and bone mineral content were measured by
dual-energy x-ray absorptiometry (21-23) with
either a Lunar model DPX (Madison, Wisconsin) or Hologics model
QDR-1000W or QDR-2000W (Waltham, Massachusetts). Scanning was done with
the same equipment and software throughout the study.
Total body water was measured by deuterium oxide dilution (24),
and extracellular water was measured by sodium bromide dilution (25).
Plasma samples were collected at baseline and 3 hours after patients
ingested 10 g of deuterium oxide and 5 g of 4 M sodium bromide. Patients
fasted throughout the test period.
For assessment of work output, patients walked on a treadmill at
increasing workloads according to an adaptation of a protocol for
patients with limited exercise capacity (26).
Speed or grade was increased at 3-minute intervals, and exercise was
terminated when patients reached volitional exhaustion or estimated
maximal heart rate (26). Work output was
calculated from body weight and treadmill speed and grade (27).
Changes in overall health status, functioning, disability, and
symptoms were assessed by having patients complete a visual analogue
self-appraisal (on a scale of 1 to 10) of overall quality of life and a
self-administered questionnaire, the HIV-Patient Assessed Report of
Status and Experience (HIV-PARSE) (28). The
HIV-PARSE questionnaire contains modified items and scales from the
Medical Outcomes Study that can be analyzed separately or as an overall
index (29) and that have been shown to reflect
differences in quality-of-life outcomes with HIV therapies (30).
Laboratory Assessments
Routine hematologic and biochemical variables were measured in the
clinical laboratories at each site. Enrichment of deuterium oxide in
plasma was determined by isotope ratio mass spectrometry (24).
Concentration of bromide in plasma was determined by ion chromatography (25).
Levels of plasma insulin-like growth factor 1 were measured by
radioimmunoassay (31). Levels of immune-complex
dissociated p24 antigen were measured in acid-treated sera (32);
a change in p24 antigen levels was defined as an increase or decrease
from baseline of 50% or greater, as long as one sample was 30 pg/mL or
greater. Levels of HIV RNA in plasma were measured by branched-DNA assay
(33, 34).
Statistical Analysis
Sample size was calculated to detect a 2% difference between groups
in weight change at week 12 with at least 80% power for a two-sided test
with 5% type I error, assuming an SD of ±4%. The groups were compared
at baseline using analysis of variance. Analysis of variance was also
used to compare changes in weight and body composition in patients who
had measurement at baseline and week 12 and at least 80% compliance with
the dosing regimen. An intention-to-treat analysis using the Wilcoxon
rank-sum test was done on changes from baseline to the last postbaseline
value measured in each patient, regardless of whether they completed the
study or complied with the dosing regimen. The Wilcoxon rank-sum test
was also used to evaluate the change in work output during treadmill
exercise. We investigated a treatment-by-center interaction for data
that did not have a normal distribution by examining the median values
of change from baseline body weight across all centers. For data that
had a normal distribution, we compensated for a possible
treatment-by-center effect in the analysis of variance model. Because no
evidence suggested an interaction, the analyses were not done separately
for each center.
Health status scores and other continuous data from the HIV-PARSE
survey were analyzed using the Wilcoxon rank-sum test. Pearson
correlation coefficients were calculated between change in work output
during exercise and changes in lean body mass and body fat. Analysis of
covariance was done to determine the predictive value of selected
baseline characteristics on the change in lean body mass.
The groups were compared for rates of adverse events by using the
Fisher exact test. Changes from baseline to end point (week 12 or the
last available measure) for clinical and laboratory values were compared
between groups by using unpaired t-tests. Patients who received
at least one injection of the study drug were included.
Data are presented as the mean ± SD, median, and 95% CIs where
appropriate. All analyses were done using SAS software, version 6.08 (SAS
Institute, Cary, North Carolina).
Results
Patient Characteristics
One hundred seventy-eight patients were enrolled at 12 centers
between July 1992 and December 1993 (Table
1). Ninety patients were randomly assigned to receive growth hormone
and 88 were assigned to receive placebo. Five patients (3 assigned to
receive growth hormone and 2 to receive placebo) failed to meet the
eligibility criteria for documented weight loss but were still included
in the analysis. Weight, body composition, and severity of HIV infection
did not differ significantly between groups. Most patients were in the
advanced stages of HIV infection (average CD4+ lymphocyte
count, <100 cells/mm3). The groups were balanced according
to history of opportunistic infections. Of the 178 patients who were
assigned to a group, 140 (79%) were considered evaluable for efficacy
(69 patients assigned to the growth hormone group and 71 assigned to the
placebo group). The number of days that the drug or placebo was
administered did not differ (73 ± 23 days in the growth hormone group
and 73 ± 25 days in the placebo group). We also found no significant
differences between groups in the frequency or nature of changes in
antiretroviral therapy during the study.
Body Weight
Treatment with growth hormone resulted in a significant and sustained
increase in weight, but no net change was seen in the weight of patients
given placebo (Figure).
Weight change at week 12 was significantly greater in patients who
received growth hormone (1.6 ± 3.7 kg) than in those who received
placebo (0.1 ± 3.1 kg) (P = 0.011). According to the
intention-to-treat analysis, the change in body weight also
significantly differed between groups (growth hormone group: median, 1.8
kg and mean, 1.1 ± 4.0 kg; placebo group: median, 0.0 kg and mean, 0.1
± 2.9 kg [P = 0.009]).
Body Composition
Lean body mass increased significantly in patients receiving growth
hormone and was unchanged in those receiving placebo (Figure).
At week 12, the average increase in lean body mass in the growth hormone
group was nearly twice that in body weight, and the difference between
groups was highly significant (change of 3.0 ± 3.0 kg in the growth
hormone group compared with -0.1 ± 2.0 kg in the placebo group [P
< 0.001]). A similar difference was seen in the intention-to-treat
analysis (growth hormone group: median, 3.0 kg and mean, 2.5 ± 3.4 kg;
placebo group: median, 0.0 kg and mean, 0.1 ± 2.9 kg [P <
0.001]).
Body fat decreased significantly in patients treated with growth
hormone and was unchanged in those given placebo (Figure).
At week 12, the difference between groups was highly significant (change
of -1.7 ± 1.7 kg in the growth hormone group compared with -0.3 ± 2.2
kg in the placebo group [P < 0.001]). A similar
difference was seen in the intention-to-treat analysis (growth hormone
group: median, -1.5 kg and mean, -1.7 ± 1.8 kg; placebo group: median,
-0.1 kg and mean, -0.3 ± 2.1 kg [P < 0.001]). Bone
mineral content was unaffected (data not shown).
Baseline measures of total body water, extracellular water, and
intracellular water did not differ significantly between the two groups.
Significant increases in these fluid compartments occurred in patients
treated with growth hormone (P < 0.001 for total body water
and intracellular water, P = 0.003 for extracellular water) but
not in those given placebo (Table
2). The hydration coefficient (a ratio of total body water to lean
body mass) and the ratios of extracellular water to lean body mass and
extracellular water to intracellular water did not change significantly
in either group and did not differ between groups (Table
2).
Functional Performance and Quality of Life
At baseline, work output and time to volitional exhaustion did not
differ significantly between the two groups (Table
3). The change in work output at termination of exercise was
significantly greater in patients treated with growth hormone (an
increase of 13.2%) than in those given placebo (an increase of 2.5%) (Table
3). Intention-to-treat analysis resulted in a similar difference in
the increase of work output (growth hormone group: median, 63 kg ·
m/min and mean, 67 ± 312 kg · m/min; placebo group: median, 0 kg ·
m/min and mean, 2 ± 229 kg · m/min [P = 0.038]). Because work
output represents the product of speed, grade, and weight and because
growth hormone increased weight, we calculated the proportion of the
increase in work that was attributable to the increase in weight: Only
22% of the increase in work induced by growth hormone was attributable
to the increase in weight. Thus, most of the increase in work output was
attributable to increases in speed or grade. For all evaluable patients,
changes in work output (r = 0.320; P < 0.001) and
time to volitional exhaustion (r = 0.225; P = 0.012)
correlated significantly with change in lean body mass but not with
change in body fat.
Baseline scores on the health status scale were similar in both the
treatment groups (Table
4). At 39 of 100 points, the overall score on the general health
perceptions scale was lower than that reported in other populations of
patients with HIV infection (30). Average scores
on the other scales were similar to those reported in similar
populations (30). In the intention-to-treat
analysis, changes in scale scores were small and similar across scales
and between groups. The average difference between baseline and end
point on the scales that ranged from 0 to 100 was minimal. Days of
disability and use of ambulatory, hospital, and home care services did
not differ between the groups. Slightly more telephone contacts with
health care providers were made by patients receiving growth hormone
than by those receiving placebo (2.3 contacts/wk compared with 1.2
contacts/wk, respectively [P = 0.05]).
Factors Contributing to Treatment Effects
Baseline levels of serum insulin-like growth factor 1 were similar
between groups (178 ± 71 ng/mL in the growth hormone group and 184 ±
83 ng/mL in the placebo group) but increased only in patients who
received growth hormone (increase of 243 ±240 ng/mL [n = 67]
in the growth hormone group compared with decrease of 2 ± 79 ng/mL [n
= 70] in the placebo group at week 12 [P < 0.001]). The
changes in level of insulin-like growth factor 1 and lean body mass were
significantly correlated in patients evaluable at week 12 (r =
0.393; P < 0.001).
When evaluated by analysis of covariance, only baseline CD4+
lymphocyte count and body mass index were significantly related to the
change in lean body mass during treatment (P = 0.012 for
baseline CD4+ lymphocyte count and 0.017 for body mass
index). However, increases in lean body mass were seen at all levels of
CD4+ lymphocyte counts and body mass index. The change in
lean body mass during treatment was not related to baseline measures of
age, Karnofsky score, percentage of ideal body weight, or duration of
HIV infection or the presence of an AIDS-defining diagnosis other than
wasting at baseline.
Safety
A similar number of patients prematurely withdrew from the study in
both groups (Table
5). Two patients in the growth hormone group withdrew because of
adverse events (one for edema and pain and one for arthralgias). Five
patients (one in the growth hormone group and four in the placebo group)
were withdrawn because of new or progressive Kaposi sarcoma; progressive
Kaposi sarcoma was noted at week 12 in another patient treated with
growth hormone. Eight patients (four in each group) had Kaposi sarcoma
at baseline that did not progress during the study.
A new HIV-associated event was reported in 24 patients (10 in the
growth hormone group and 14 in the placebo group); the most frequent
event was Pneumocystis carinii pneumonia (3 in the growth
hormone group and 5 in the placebo group). Five patients (3 in the
growth hormone group and 2 in the placebo group) died as the result of
an infection.
Among commonly reported side effects, only swelling or puffiness,
arthralgia or myalgia, and diarrhea differed significantly between
groups (Table
6). These events were usually mild to moderate in severity and
resolved with treatment. Eighteen patients (15 in the growth hormone
group and 3 in the placebo group) required a reduction in dose. Three
patients who were receiving growth hormone developed the carpal tunnel
syndrome. The syndrome resolved in 2 of the patients after a single dose
reduction and in 1 despite continued treatment. Other commonly reported
symptoms that are typical of advanced HIV infection did not differ
between groups (Table
6).
Baseline laboratory measures did not differ significantly between
groups (Table
7). Increases in glucose, hemoglobin A1C, calcium, and
phosphorus values associated with use of growth hormone were higher than
those associated with use of placebo. These changes, which are a
predictable response to growth hormone therapy, were minimal. In
addition to the laboratory measures shown in Table
7, only serum alanine aminotransferase levels differed significantly
between study groups. This difference appeared to be the result of one
patient in the growth hormone group who developed severe hepatitis A
virus infection.
No significant changes in CD4+ or CD8+
lymphocyte counts or plasma HIV RNA level occurred during the study (Table
7). In addition, mean changes in titers of infectious viremia in
plasma, done in a subgroup of 21 patients at one site, did not
significantly differ between treatment groups (data not shown). No
change in immune-complex dissociated p24 antigen levels was noted in 84%
of patients receiving growth hormone and 86% of patients receiving
placebo (P > 0.2).
Discussion
Treatment with growth hormone resulted in a sustained and significant
increase in weight and lean body mass and a decrease in body fat in a
large group of patients with HIV-associated weight loss. In contrast,
weight and body composition were not altered in patients who received
placebo. The increase in lean body mass and decrease in body fat that
occurred after 3 months of growth hormone therapy in an outpatient
setting are consistent with the short-term effects of growth hormone
therapy on protein and lipid metabolism seen in a small group of
patients who were hospitalized and fed a constant diet in a metabolic
ward (18). Growth hormone therapy is therefore
effective as an anabolic agent even when administered to patients who
consume diets that they select themselves under their usual living
conditions.
In clinically stable patients infected with HIV, decreased body cell
mass is associated with decreased physical function (3).
We found that the increase in lean body mass during treatment with
growth hormone correlated with improvement in functional performance
determined by work output during treadmill exercise. However, these
changes were not reflected by changes in perceived health status or use
of medical resources. A trend toward increased power of skeletal muscle
and increased endurance was noted in a small group of HIV-infected
patients who gained lean body mass when given growth hormone for a
period similar to that of our study (19).
Similarly, strength (35, 36), work output (37),
and lean body mass (35, 36, 38, 39) improved in
studies of growth hormone replacement therapy in growth
hormone-deficient adults.
Current therapies for HIV-associated anorexia or weight loss include
nutritional supplements and therapy with appetite-stimulating drugs such
as megestrol acetate and dronabinol. Of these, dronabinol has failed to
consistently increase weight (40, 41), and the
others have failed to consistently restore lean tissue (11-13).
Because lean tissue and not fat may independently affect survival (5-7)
and function (3) in patients with HIV-associated
wasting, the sustained increase in lean body mass that we found suggests
a potential advantage for growth hormone as anabolic therapy. For
example, although patients with HIV-associated weight loss gained an
average of 3.0 kg while receiving total parenteral nutrition, body fat
increased by 3.9 kg and total body potassium levels (an index of body
cell mass) did not change (11). A similar
disproportionate increase in body fat with minimal or no accrual of lean
tissue occurs when patients with HIV-associated wasting are given an
appetite stimulant. In one recent trial (13),
treatment with megestrol acetate (800 mg/d for 12 weeks) resulted in a
4.5-kg increase in body fat and no change in lean body mass. In another
trial (12), patients gained an average of 3.5 kg
but only 1.1 kg of lean body mass (the remainder, by inference, was
fat). These minimal or negligible changes in lean body mass contrast
with the 3.0-kg increase noted during therapy with growth hormone.
The growth hormone-induced increase in total body water (2.4 L by
dilution analysis) was similar to the value predicted through the
observed increase in lean body mass (3.0 kg by dual-energy x-ray
absorptiometry) and the proportion of lean body mass as total body water
(0.75 L/kg) at baseline (Table
2). Because the ratios of total body water to lean body mass,
extracellular water to lean body mass, and extracellular water to
intracellular water did not change significantly, the expansion in lean
body mass included intracellular and extracellular water in a proportion
similar to that at baseline. Because intracellular water is the most
direct measure of body cell mass (42), the
expansion in intracellular water that we found suggests that growth
hormone increased metabolically active tissue.
Our results provide no evidence of a deleterious effect of growth
hormone on HIV replication as measured by HIV RNA levels in plasma,
immune-complex dissociated p24 antigen levels, and titers of infectious
viremia in plasma. Concern about a potential effect of growth hormone on
HIV replication was prompted by the increase in release of p24 antigen
from phytohemagglutinin-activated, HIV-infected mononuclear cells from
peripheral blood seen in incubation with growth hormone (43).
This effect varied, however, and could be inhibited by adding zidovudine
to the culture media. Despite the absence of evidence that growth
hormone promotes replication of HIV in vivo, concomitant treatment with
approved antiretroviral agents was a requirement for our study and in
ongoing trials of growth hormone in this patient population.
A theoretical concern could also be raised about a possible
tumor-promoting effect of growth hormone use in patients with HIV
infection (44). However, review of the extensive
data obtained on children treated with growth hormone does not support a
relation with either new types of cancer or tumor recurrence (45,
46). No difference was seen in the rate of occurrence or progression
of AIDS-associated neoplasms between the growth hormone and placebo
groups.
Overall, growth hormone was well tolerated. Side effects that may
have been related to growth hormone were mild, did not negatively affect
quality of life, and generally responded to reductions in dose. The
rates of withdrawal and serious adverse events did not differ
significantly between treatment groups. Together with the sustained
increases in body weight and lean body mass and increased functional
performance, these results indicate that growth hormone may be a useful
therapy in patients with HIV-associated wasting. Although the cost of
this therapy has not been established, a 12-week course of treatment
currently approved by the Food and Drug Administration under the
auspices of an expanded access program costs approximately $12 000. An
analysis of the implications of the cost of this and other new therapies
in patients with HIV infection should consider the potential savings
gained from any improvement in quality of life, increase in work days,
and reduction in HIV-associated complications resulting from the
therapy, as future studies might show.
Appendix
The following persons participated in the Serostim Study Group: A.
Hurley and K. Javaly (Bellevue Hospital, New York, New York); E.S. Daar
and J. Pitt (Cedars-Sinai Medical Center, Los Angeles, California); C.
Grunfeld and M. Pang (Department of Veterans Affairs Medical Center, San
Francisco, California); A.E. Heald and K.W. Shipp (Duke University
Medical Center, Durham, North Carolina); D. Pearce and K. Sova (HIV
Research Group, San Diego, California); P. Pate (ID Associates, Dallas,
Texas); S.L. Boswell and T. Flynn (Massachusetts General Hospital,
Boston, Massachusetts); B. Polsky (Memorial Sloan-Kettering Cancer
Center, New York, New York); L. Haverstick and M.M. Rothkopf (Metabolic
Associates, Florham Park, New Jersey); D.L. Bliffen (Metroplex Clinical
Research Center, Dallas, Texas); R. Rosenfeld (Oregon Health Sciences
University, Portland, Oregon); D.P. Kotler, R.N. Pierson Jr., J. Wang,
and G. Winson (St. Luke's-Roosevelt Hospital Center, New York, New
York); K. Mulligan, M. Schambelan, and V. Tai (San Francisco General
Hospital, San Francisco, California); W.M. Bennison, J.B. Breitmeyer,
S.M. Kennedy, T.K. Neu, C.E. Robinson, and R.J. Schwalbert (Serono
Laboratories, Inc., Norwell, Massachusetts); A. LaMarca and D. LaMarca (Therafirst
Medical Center, Ft. Lauderdale, Florida); S.A. Bozzette (University of
California, San Diego, California); D.R. Kuritzkes and M.G. Ray
(University of Colorado Health Services Center, Denver, Colorado); J.W.
Mellors (University of Pittsburgh Medical Center, Pittsburgh,
Pennsylvania); B.E. Balser and J.P. Balser (Veristat, Inc., Holliston,
Massachusetts).
This paper was presented in part in August 1994 at the 10th
International Conference on AIDS, Yokohama, Japan.
From San Francisco General Hospital; Department of Veterans Affairs
Medical Center; and University of California, San Francisco, San
Francisco, California; Cedars-Sinai Medical Center and University of
California, Los Angeles, Los Angeles, California; Therafirst Medical
Center, Fort Lauderdale, Florida; St. Luke's-Roosevelt Medical Center
and Columbia University, New York, New York; Department of Veterans
Affairs Medical Center and University of California, San Diego, San
Diego, California; and Serono Laboratories, Norwell, Massachusetts.
Grant Support: By National Institutes of Health grants
DK45833, DK40990, DK49448, and RR-00083 and by Serono Laboratories.
Requests for Reprints: Morris Schambelan, MD, San Francisco
General Hospital, Building 100, Room 321, 1001 Potrero Avenue, San
Francisco, CA 94110.
Current Author Addresses: Drs. Schambelan and Mulligan: San
Francisco General Hospital, Building 100, Room 321, 1001 Potrero Avenue,
San Francisco, CA 94110.
Dr. Grunfeld: Department of Veterans Affairs Medical Center 111F, 4150
Clement Street, San Francisco, CA 94121.
Dr. Daar: Cedars-Sinai Medical Center, Division of Infectious Diseases,
B217, 8700 Beverly Boulevard, Los Angeles, CA 90048.
Dr. LaMarca: Therafirst Medical Center, 4011 North Federal Highway, Fort
Lauderdale, FL 33308.
Dr. Kotler: G.I. Immunology, St. Luke's-Roosevelt Hospital Center, 1111
Amsterdam Avenue, New York, NY 10025.
Mr. Wang: Body Composition Unit, St. Luke's-Roosevelt Hospital Center,
1111 Amsterdam Avenue, New York, NY 10025.
Dr. Bozzette: San Diego Veterans Affairs Medical Center 111N1, 3350 La
Jolla Village Drive, San Diego, CA 92161.
Dr. Breitmeyer: Serono Laboratories, Inc., 100 Longwater Circle,
Norwell, MA 02061.
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